Clinical trial NCT04819438
Conditions: Healthy Participants
Keywords: Bioequivalence Riluzole Orodispersible film
Sponsor: Cross Research S.A.
Start date: 2021-01-15; Completion date: 2021-03-14
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The objective of the study is to compare the pharmacokinetic profile of riluzole after replicate single dose of the novel orodispersible film test formulation and of the marketed reference Rilutek® tablets and to evaluate their bioequivalence.

Detailed description:
The new formulation riluzole orodispersible film is expected to fill an important medical need, since the medication can be easily administered without water and may improve patient care. Riluzole orodispersible film is easily administered, because the patient or caregiver needs only to place the film on the tongue, where it can immediately dissolve into the saliva and be ingested with intentional swallowing or during the normal reflex of swallowing, thus eliminating the need for swallowing a tablet with liquid or crushing it into soft food.

Zambon S.p.A., Italy, is sponsoring the present bioequivalence study in order to investigate the bioequivalence of the novel unit-dose product versus Rilutek® tablets, commercially available in Europe as 50 mg tablets. The dose strength for the test formulation is 50 mg, matching the 50 mg strength of the reference formulation.

The subjects will receive single oral doses of 50 mg of riluzole, as test orodispersible film and reference film-coated tablets, under fasting conditions, in each of 4 subsequent periods separated by wash-out intervals of at least 7 days between consecutive administrations, according to a 2-treatment, 4-period, replicate cross-over design.

Arms: arm 1: Riluzole orodispersible film (test): The subjects will be treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence Rilutek® (reference): The subjects will be treated with one film-coated tablet containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence. arm 2: Riluzole orodispersible film (test): The subjects will be treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence Rilutek® (reference): The subjects will be treated with one film-coated tablet containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence.
Interventions: intervention 1: Riluzole 50 mg orodispersible film intervention 2: Rilutek® 50 mg riluzole tablets
Intervention descriptions: intervention 1: Before each administration, the subjects will drink 20 mL of still mineral water in order to wet their mouth. Afterwards, using gloves, the investigator or deputy will take the orodispersible film (32.0x22.0 mm) out of the provided pouch and place the product directly on the top surface (dorsal aspect) of the subjects' tongue. intervention 2: One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral water.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
 
Study CRO-PK-20-344 - Sponsor code Z7251J01 
 
Comparative bioavailability study of a new riluzole orodispersible 
film vs. a marketed oral reference (Rilutek® tablets) in healthy 
male and female volunteers 
 
Single centre, single dose, open-label, randomised, 2-sequence, 4-period replicate  
cross-over study 
 
 
 
Test formulation: 
Riluzole 50 mg orodispersible film, Aquestive Therapeutics, USA 
 
 
Reference formulation: Rilutek®, 50 mg riluzole tablets, Sanofi Mature IP, France 
 
 
Sponsor: 
Zambon S.p.A., via Lillo del Duca 10, I-20091 Bresso, Italy 
Phone: +39.02.66.52.42.99 
Fax: 
+39.02.66.52.48.87 
Email: carlo.cattaneo@zambongroup.com 
 
 
Investigator: 
Milko Radicioni, MD - Principal investigator 
CROSS Research S.A., Phase I Unit, Via F.A. Giorgioli 14, CH-
6864 Arzo, Switzerland 
Phone: +41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: clinic@croalliance.com 
 
 
Development phase: 
I 
 
 
Version and date: 
Final version 1.0, 28APR20 
 
 
This study will be conducted in accordance with the current version of Good Clinical Practice (GCP),  
ICH topic E6 (R2) 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 67 pages 
 
 








CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 5 
STUDY SYNOPSIS 
 
Title: Comparative bioavailability study of a new riluzole orodispersible film vs. a marketed oral reference 
(Rilutek® tablets) in healthy male and female volunteers 
 
Protocol number: CRO-PK-20-344 - Sponsor code Z7251J01 
 
Clinical phase: Phase I 
 
Study design: Single centre, single dose, open-label, randomised, 2-sequence, 4-period replicate cross-over 
study 
 
Planned nr. of centres / countries: 1/Switzerland 
 
Investigator and centre: Principal investigator: Milko Radicioni, MD; CROSS Research Phase I Unit, Via 
F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Investigational products:  
TEST (T):  
Riluzole 50 mg orodispersible film, Aquestive Therapeutics, USA 
REFERENCE (R): 
Rilutek®, 50 mg riluzole tablets, Sanofi Mautre IP, France 
 
Dose regimen: The subjects will receive single oral doses of 50 mg of riluzole, as test orodispersible film and 
reference film-coated tablets under fasting conditions, in each of 4 subsequent periods separated by wash-out 
intervals of at least 7 days between consecutive administrations, according to a 2-treatment, 4-period, replicate 
cross-over design.  
 
Objective:  
The objective of the study is to compare the pharmacokinetic profile of riluzole after replicate single dose of the 
novel orodispersible film test formulation and of the marketed reference Rilutek® tablets and to evaluate their 
bioequivalence.  
 
End-points:  
Primary end-point:  
 To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of riluzole after replicate single 
dose administration of test and reference. 
Secondary end-points:  
 To describe the pharmacokinetic profile of riluzole after replicate single dose administration of test and 
reference; 
 to evaluate the test product palatability; 
 to collect safety and tolerability data of test and reference after replicate single dose administration. 
 
Study variables: 
Primary variables:  
 Cmax and AUC0-t of plasma riluzole after replicate single dose administration of test and reference 
formulation. 
Secondary variables:  
 AUC0-∞, t1/2, tmax, AUCextra, λz, of riluzole after replicate single dose administration of test and reference; 
 Palatability scores; 
 Treatment-emergent adverse events, vital signs (blood pressure, heart rate), laboratory parameters, physical 
examination including body weight 
 
Analytics: Riluzole will be determined in plasma samples at Accelera S.r.l., Italy,  using a validated LC-MS/MS 
method with a lower quantification limit of 5 ng/mL 
 
Safety and tolerability assessments: Treatment-emergent adverse events; vital signs (blood pressure, heart 
rate), physical examinations including body weight; laboratory tests  
 
Sample size: When the sample size in each sequence group is 26 (and the total sample size is 52), a replicate 
crossover design will have 80% power to reject both the null hypothesis that the ratio of the test mean to the 
reference mean of Cmax is below 0.800 and the null hypothesis that the ratio of test mean to the reference mean of 
Cmax is above 1.250 ( i.e. that the test and standard are not equivalent, in favour of the alternative hypothesis that  
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 6 
STUDY SYNOPSIS (cont.) 
 
Sample size (continued):  
the means of the two treatments are equivalent) assuming that data will be analysed in the natural log scale using 
t-tests for differences in means and that each t-test will be made at the 5.0% significance level. 
In conclusion, 54 subjects will be enrolled in order to have 52 completed subjects. 
 
Main selection criteria: Inclusion criteria: 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex and Age: men/women, 18-55 years old inclusive 
3. Tobacco: non-smokers for at least 6 months prior to study screening 
4. Body Mass Index: 18.5-29 kg/m2 inclusive 
5. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 
bpm, measured after 5 min at rest in the sitting position 
6. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study 
7. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the 
following reliable methods of contraception: 
a. 
A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with 
spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before 
the screening visit 
b. A male sexual partner who agrees to use a male condom with spermicide 
c. 
A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be 
admitted. 
For all women, pregnancy test result must be negative at screening. 
Exclusion criteria: 
1. Electrocardiogram (ECG) 12-leads: (supine position) clinically significant abnormalities; QTc interval > 
450 msec 
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives 
of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 
4. Cotinine test: positive cotinine test at screening 
5. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; 
history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect 
the outcome of the study 
6. Diseases: clinically significant history or presence of renal, hepatic, gastrointestinal, cardiovascular, 
cerebrovascular, immunological, musculoskeletal, respiratory, skin, haematological, endocrine, psychiatric 
or neurological diseases or surgeries that may interfere with the aim of the study. Gastrointestinal 
pathologies include any clinically significant disorder of the mouth, e.g. impairment of swallowing, lesions, 
ulcerations, deformities, untreated dental caries 
7. Dentures: presence of mouth jewellery, dentures, braces, piercings that may interfere with successful 
completion of the dosing 
8. Medications: medications, including over the counter medications and herbal remedies for 2 weeks before 
study screening; central nervous system depressants, including opioids, benzodiazepines, general 
anaesthetics and anticonvulsants, or CYP inhibitors, including cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and antiretroviral agents, or strong CYP 
inducers, including barbiturates, carbamazepine, glucocorticoids, phenytoin, St John’s wort and rifampin, or 
hormonal oral or transdermal contraceptives for 30 days before study screening; implanted, injected, 
intravaginal or intrauterine hormonal contraceptives for 6 months before study screening 
9. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study. The 3-month interval is calculated as the time between the first calendar day of the month that 
follows the last visit of the previous study and the first day of the present study 
10. Blood donation: blood donations for 3 months before this study 
11. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for 
males, defined according to the USDA Dietary Guidelines 2015], caffeine (>5 cups coffee/tea/day) or 
tobacco use including any tobacco product like e-cigarettes and vaping products 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 7 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria (continued): 
12. Drug test: positive result at the drug test at screening or Day -1 
13. Alcohol test: positive alcohol breath test at Day -1 
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before 
this study; vegetarians and vegans  
15. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, pregnant or lactating 
women 
 
Schedule: 
Day 
Procedures/Assessments 
Notes 
Screening phase 
Screening – visit 1 
From 
Day  
-14 to 
Day -2 
 Explanation to the subject of study aims, procedures and 
possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Laboratory analyses: haematology, blood chemistry, 
cotinine, urinalysis, virology and serum pregnancy test 
(women only) 
 Urine multi-drug kit test 
 Adverse event monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: 
The 
first 
two 
letters of the surname 
followed by the first two 
letters of the first name 
will be used in the Phase 
I Unit source document 
only and will not be 
transferred to the sponsor 
Period 1 
Visit 2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women only) 
 Adverse events and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomisation 
Arrival at the Phase I Unit 
in the evening 
Confinement 
until 
the 
evening of Day 2 
Standardised 
low-fat 
dinner and fasting for at 
least 10 h (overnight) up 
to dosing 
Visit 3 
Day 1 
 Investigational medicinal product administration at 
08:00 ± 1 h 
 Palatability of the test product immediately after 
administration 
 Mouth visual inspections after administration of the test 
investigational medicinal product, at pre-dose and 0.5 
and 1 h post-dose  
 Vital signs measurement at pre-dose and 2 h post-dose 
 Blood sample collection for pharmacokinetic analysis at 
pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8 
and 12 h post-dose. 
 Adverse event monitoring and concomitant medications 
Fasting until about 5 h 
post-dose  
Standardised 
lunch 
at 
about 13:00 
Standardised 
dinner 
at 
about 20:00 (12 h post-
dose)  
Day 2 
 Vital signs measurement at 36 h post-dose 
 Blood sample collection for PK analysis at 24 and 36 h  
post-dose. 
 Adverse event monitoring and concomitant medications 
Standardised breakfast 
and lunch at about 8:00 
and 13:00  
Discharge from the Phase 
I Unit in the evening after 
the 36-h post-dose blood 
sampling and vital signs 
check 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 8 
STUDY SYNOPSIS (cont.) 
 
Schedule (continued): 
 
Day 
Procedures/Assessments 
Notes 
Wash-out 
At least 7 days A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 2 
Visit 4 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 5 
Day 1 
As visit 3. Test or reference investigational medicinal 
product administered according to the randomisation 
list and cross-over design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 3 
Visit 6 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 7 
Day 1 
As visit 3. Test or reference investigational medicinal 
product administered according to the randomisation 
list and cross-over design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 4 
Visit 8 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 9 
Day 1 
As visit 3. Test or reference investigational medicinal 
product administered according to the randomisation 
list and cross-over design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Final phase 
Visit 10 - Final Visit or ETV 
Day 2 of 
period 4 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight and physical 
abnormalities; also vital signs in case of ETV) 
 Laboratory analyses as at screening, with the 
exception of cotinine, virology, urine drug test and 
pregnancy test 
 Adverse events and concomitant medications 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator 
until the normalisation of the concerned clinical 
parameter(s) 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
investigator in case of 
occurrence 
of 
any 
adverse reactions 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 9 
STUDY SYNOPSIS (cont.) 
 
Schedule: 
During each study period, the subjects will be confined from the evening preceding the IMP administration 
(study Day -1) until the evening of Day 2. During confinement, the subjects will not take any food or drinks 
(except water) for about 10 h (i.e. overnight) before each administration and for about 5 h afterwards. On Day -
1 of each study period, a standardised low-fat dinner will be served. Water will be allowed as desired, except for 
one h before and one h after each administration. In order to maintain an adequate hydration, the subjects will 
be encouraged to drink at least 150 mL of still mineral water every 2 h for 5 h post-dose, starting at 1 h post-
dose. On Day 1 of each study period, the subjects will remain fasted until about 5 h post-dose. Standardised 
lunch and dinner will be served at approximately 5 h and 12 h post-dose. On Day 2 of each study period, 
standardised breakfast and lunch will be served at about 8:00 and 13:00, respectively. Coffee, tea or food 
containing xanthines (i.e. coke, chocolate, etc.), smoking, alcohol and grapefruit will be forbidden during 
confinement. In particular, alcohol and grapefruit will be forbidden for 24 h before the first administration until 
the end of the study. 
During confinement, routine ambulant daily activities will be strongly recommended. 
 
Data analysis:  
The data documented in this trial and the measured clinical parameters will be described using classic descriptive 
statistics for quantitative variables and frequencies for qualitative variables. The statistical analysis will be 
performed using SAS® version 9.3 (TS1M1) or higher (the actual versions will be stated in the final report). 
The statistical analysis of pharmacokinetic parameters will be performed using Phoenix WinNonlin® version 6.3 
or higher and SAS® version 9.3 (TS1M1) or higher. Cmax and AUC0-t will be compared using analysis of variance 
(ANOVA) for a 2-sequence, 4-period replicate cross-over design on log-transformed data. Acceptance criterion 
for bioequivalence is that the 90% confidence interval for the test/reference ratio of the AUC0-t geometric means 
is within the 80.00-125.00 range, according to the current EMA guideline for bioequivalence investigations. Due 
to the replicate design of the study, if the within-subject variability of Cmax of plasma riluzole after 
administration of the reference treatment is >30%, bioequivalence range for Cmax will be widened. The extent of 
widening will be determined on the basis of the actual within-subject variability observed in study Cmax.  
 
 
 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 10 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
PERIOD 1, 2, 3, 4 (wash-out≥7 days) 
Final visit/ETV12 
Visit 
V1 
V2, V4, V6, V8 
V3, V5, V7, V9 
V1011/ETV 
 Days -14/-2 
Day -1 
Day 1 
Day 2  
Day 211/ETV 
Informed consent 
x 
 
 
 
 
Demography 
x 
 
 
 
 
Lifestyle 
x 
 
 
 
 
Medical/surgical history  
x 
 
 
 
 
Physical abnormalities 
x 
 
 
 
x 
Previous and concomitant 
treatments 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
Body weight 
x 
 
 
 
x 
Laboratory analysis1 
x 
 
 
 
x 
Cotinine 
x 
 
 
 
 
Virology 
x 
 
 
 
 
Drug screening 
x 
x 
 
 
 
Vital signs 
x 
 
x 2 
x 2 
x13 
Pregnancy test  
x3 
x4 
 
 
 
ECG 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
x5 
 
 
 
Eligibility evaluation 
x 
x5 
 
 
 
Alcohol breath test 
 
x 
 
 
 
Enrolment and randomisation 
 
x5 
 
 
 
Confinement 
 
x 
x 
 
 
Discharge 
 
 
 
x 
 
IMP administration 
 
 
x6 
 
 
Palatability 
 
 
x7 
 
 
Mouth visual inspection  
 
 
x8 
 
 
Blood samplings 9 
 
 
x 
x 
 
Standardised meals 
 
x 
x 
x 
 
AEs monitoring10 
x 
x 
x 
x 
x 
1. 
Haematology, blood chemistry with the exception of cotinine, urinalysis  
2. 
At pre-dose and 2 and 36 h post-dose 
3. 
Women only - serum β-HCG test  
4. 
Women only - urine test  
5. 
Period 1, visit 2 
6. 
At 08:00 ± 1 h under fasting conditions 
7. 
Immediately after each administration of the test product 
8. 
At pre-dose and 0.5 and 1 h post-dose at each administration of the test product 
9. 
At pre-dose (0) and 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h post-dose 
10. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final 
visit/ETV 
11. Final visit on Day 2 of period 4 after the 36-h post-dose blood sampling 
12. Early termination visit (ETV) in case of subject’s premature discontinuation  
13. At the ETV only  
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 11 
TABLE OF CONTENTS 
 
Page 
CLINICAL STUDY PROTOCOL 
1 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
STUDY SCHEDULE 
10 
TABLE OF CONTENTS 
11 
TABLES 
 
13 
FIGURES 
 
13 
LIST OF ABBREVIATIONS 
14 
1 
INTRODUCTION 
16 
1.1 
Amyotrophic Lateral Sclerosis 
16 
1.2 
Riluzole 
16 
1.3 
Riluzole orodispersible film and rationale for the study 
16 
1.4 
Previous pharmacokinetic studies of riluzole orodispersible film 
17 
1.4.1 
Pilot bioavailability Phase I study 
17 
1.4.2 
Pivotal bioequivalence Phase I study 
18 
1.5 
Risks and benefits 
19 
2 
STUDY OBJECTIVES 
21 
2.1 
Primary end-point 
21 
2.2 
Secondary end-points 
21 
3 
CLINICAL SUPPLIES 
22 
3.1 
Treatment 
22 
3.1.1 
Description of products 
22 
3.1.1.1 
Test product 
22 
3.1.1.2 
Reference product 
23 
3.1.2 
Dose regimen 
23 
3.1.3 
Route and method of administration 
23 
3.1.3.1 
Test formulation 
23 
3.1.3.2 
Reference formulation 
24 
3.1.4 
Investigational product distribution 
24 
3.2 
Packaging and labelling 
24 
3.3 
Storage conditions 
25 
3.4 
Drug accountability 
25 
4 
INVESTIGATIONAL PLAN 
26 
4.1 
Overall study design 
26 
4.2 
Discussion of design 
26 
5 
STUDY POPULATION 
27 
5.1 
Target population 
27 
5.2 
Inclusion criteria 
27 
5.3 
Exclusion criteria 
27 
5.3.1 
Not allowed treatments 
28 
6 
STUDY SCHEDULE 
30 
6.1 
Study visits and procedures 
30 
6.2 
Diet and lifestyle 
33 
6.2.1 
Restrictions 
34 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
35 
7.1 
Physical examination 
35 
7.1.1 
Body weight 
35 
7.1.2 
Vital signs 
35 
7.1.3 
ECGs 
35 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 12 
7.1.4 
Mouth visual inspections 
35 
7.1.5 
Palatability 
35 
7.2 
Clinical laboratory assays 
36 
7.3 
Sampling for pharmacokinetic analysis 
37 
7.3.1 
Venous blood sampling 
37 
7.3.2 
Analytics 
38 
7.3.3 
Labelling, storage and transport of samples 
38 
7.3.3.1 
Samples labelling 
38 
7.3.3.2 
Samples storage and transport 
38 
7.4 
Total number of samples and blood withdrawn 
39 
8 
ASSIGNMENT OF STUDY TREATMENT 
40 
8.1 
Randomisation 
40 
8.2 
Treatment allocation 
40 
8.3 
Blinding 
40 
9 
EVALUATION PARAMETERS 
41 
9.1 
Study variables 
41 
9.1.1 
Primary variables 
41 
9.1.2 
Secondary variables 
41 
9.2 
Pharmacokinetic assessments 
41 
9.2.1 
Pharmacokinetic parameters 
41 
9.3 
Safety assessments 
42 
10 
STATISTICAL METHODS 
43 
10.1 
Analysis Sets 
43 
10.1.1 
Definitions 
43 
10.1.2 
Reasons for exclusion from the PK set before bioanalysis 
44 
10.1.3 
Reasons for exclusion from the PK set after bioanalysis 
44 
10.2 
Sample size and power considerations 
44 
10.3 
Demographic, baseline and background characteristics 
45 
10.4 
Drug administration and analysis of film dissolution 
45 
10.5 
Test IMP palatability 
45 
10.6 
Analysis of pharmacokinetic parameters 
46 
10.6.1 
Descriptive pharmacokinetics 
46 
10.6.2 
Statistical comparison of pharmacokinetic parameters 
46 
10.7 
Safety and tolerability evaluation 
47 
11 
DEFINITION AND HANDLING OF AES AND SAES 
49 
11.1 
Applicable SOPs 
49 
11.2 
Definition of Adverse Event (AE) 
49 
11.3 
Definition of Adverse Drug Reaction (ADR) 
49 
11.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
50 
11.5 
Definition of Severity of Adverse Events 
50 
11.6 
Definition of Adverse Event causality 
50 
11.7 
Adverse Events recording 
51 
11.8 
AEs monitoring window 
51 
11.9 
Adverse Events reporting 
51 
11.10 
SAEs reporting 
52 
11.11 
Follow-up for Adverse Events 
52 
11.12 
SUSARs management 
52 
11.13 
Other events qualified for expedited reporting 
53 
11.14 
SAEs: contacts 
54 
11.15 
Pregnancy 
54 
12 
DATA MANAGEMENT PROCEDURES 
55 
12.1 
Data collection – CRFs 
55 
12.2 
Unique subject identifier 
55 
12.3 
Database management 
55 
12.3.1 
Coding dictionaries 
55 


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13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
56 
13.1 
Monitoring 
56 
13.2 
Quality Control and Quality Assurance 
56 
13.3 
Applicable SOPs 
57 
13.4 
Data access 
57 
13.5 
Audits and inspections 
57 
14 
ETHICAL CONSIDERATIONS 
58 
14.1 
Ethics and Good Clinical Practice (GCP) 
58 
14.2 
Informed consent 
58 
14.3 
Insurance policy 
59 
14.4 
Withdrawal of subjects 
59 
14.4.1 
Primary reason for discontinuation 
59 
14.4.2 
Discontinuation procedures 
59 
14.5 
Study termination 
60 
15 
ADMINISTRATIVE PROCEDURES 
61 
15.1 
Material supplied to the clinical centre 
61 
15.2 
Protocol amendments 
61 
15.3 
Study documentation and record keeping 
61 
15.4 
Study subjects’ recruitment 
62 
15.5 
Confidentiality and data protection 
62 
15.6 
Publication policy 
64 
16 
STUDY RESPONSIBLE PERSONS 
65 
16.1 
Sponsor 
65 
16.2 
Institutes performing the study 
65 
16.2.1 
Clinical centre 
65 
16.3 
Drug assay 
65 
16.4 
Centralised clinical laboratory 
66 
16.5 
Packaging and labelling 
66 
16.6 
Co-ordination, data analysis & reporting 
66 
16.7 
Monitoring 
66 
17 
REFERENCES 
67 
 
TABLES 
Page 
 
Table  1.4.1.1 
Mean main pharmacokinetic parameters of plasma riluzole after Treatments A and C and 
the outcome of their statistical comparisons 
17 
Table  1.4.1.2 
Mean main pharmacokinetic parameters of plasma riluzole after Treatments B and C and 
the outcome of their statistical comparisons 
18 
Table  1.4.2.1 
Mean main PK parameters of plasma riluzole after Treatments A and B and the outcome 
of their statistical comparisons 
19 
Table  3.1.1.1 
Quantitative composition of the test IMP 
22 
Table  6.2.1 
Meals’ composition on Day -1 and Day 1 in the four study periods 
33 
Table  7.1.5.1 
Palatability evaluation scores 
36 
Table  7.3.1.1 
Tolerance ranges for the scheduled sampling times 
37 
Table  10.2.1 
Sample size calculation 
44 
Table  10.6.2.1 
Examples of widened bioequivalence acceptance limits of Cmax according to its actual 
CVWR 
47 
 
 
FIGURES 
Page 
 
Figure  1.2.1 
Chemical structure of riluzole 
16 


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Study protocol CRO-PK-20-344 
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LIST OF ABBREVIATIONS 
 
β-HCG 
human chorionic gonadotropin β 
γ-GT 
γ-Glutamyl transpeptidase 
λz 
Terminal elimination rate constant 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOAC 
Attributable-Legible-Contemporaneous-Original-Accurate-Complete 
ALS 
Amyotrophic lateral sclerosis 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUC0-∞ 
Area under the concentration vs. time curve up to infinity 
BLQL 
Below lower quantification limit 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BW 
Body weight 
CA 
Competent authority 
CDISC 
Clinical data interchange standards consortium 
CI 
Confidence interval 
Cmax 
Peak drug concentration 
CMS 
Clinical Medical Service 
CPL 
Clinical Project Leader 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
CVWR 
Coefficient of Variation within-subject 
CYP 
Cytochrome P450 
DBP 
Diastolic Blood Pressure 
DSU 
Drug Safety Unit 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicine Agency 
EPAR 
European Public Assessment Report 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMO 
Glycerol monooleate 
GMP 
Good Manufacturing Practice 
HBs Ag 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibodies 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LQL 
Lower Quantification Limit 


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LSLV 
Last Subject Last Visit 
LSM 
Least square mean 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
N 
Normal 
NA 
Not Applicable 
NC 
Not calculated 
OECD 
Organisation for Economic Co-operation and Development 
OTC 
Over The Counter 
PE 
Point Estimate 
PK 
Pharmacokinetics 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
QTc 
Corrected QT interval 
ROF 
Riluzole oral formulation 
RSI 
Reference safety information 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
THC 
delta-9-tetrahydrocannabinol 
t1/2 
Half-life 
tmax 
Time to achieve Cmax 
USDA 
United States Department of Agriculture 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 


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Riluzole orodispersible film replicate bioavailability 
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Page 16 
1 
INTRODUCTION 
 
1.1 
Amyotrophic Lateral Sclerosis 
 
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterised by 
progressive loss of the motor neurons of the ventral horn of the spinal cord and the cortical 
neurons that provide their afferent input. The disorder is characterised by rapidly progressive 
weakness, muscle atrophy and fasciculation, spasticity, dysarthria, dysphagia and respiratory 
impairment. Sensory function generally is spared, as is cognitive, autonomic and oculomotor 
activity. ALS usually is progressive and fatal with most affected patients dying of respiratory 
failure and pneumonia after 2 to 3 years from the onset of symptoms, although occasional 
individuals have a more indolent course and survive for many years. 
Although the pathogenesis of ALS is not completely elucidated, it is suggested that glutamate 
(the primary excitatory neurotransmitter in the central nervous system) plays a role in cell 
death in the disease. 
 
1.2 
Riluzole 
 
Riluzole (2-amino-6-trifluoromethoxybenzothiazole, C8H5F3N2OS) is an anti-glutamatergic 
agent with neuroprotective properties that has been developed for the treatment of ALS ( 1,  2). 
Its structure is shown below: 
 
Figure  1.2.1 Chemical structure of riluzole 
 
Riluzole is an FDA- and EMA-approved active ingredient. The benzothiazole derivative has 
been shown to exert neuroprotective effects and prolong survival in patients with ALS ( 3), but 
has no effect on the degradation of muscular function.( 4,  5).  
 
1.3 
Riluzole orodispersible film and rationale for the study 
 
Aquestive Therapeutics developed a novel riluzole formulation incorporating the substance 
into a proprietary polymer-based film matrix utilizing PharmFilm® technology ( 6).  
 
Riluzole orodispersible film is expected to fill an important medical need since oral tablet 
administration in ALS patients can be a challenge. Medication that can be easily administered 
without water may improve the quality of life for ALS patients and improve patient care. 
Riluzole orodispersible film is easily administered, because the patient or caregiver needs 
only to place the film on the tongue, where it can immediately dissolve into the saliva and be 
ingested with intentional swallowing or during the normal reflex of swallowing, thus 
eliminating the need for swallowing a tablet with liquid or crushing it into soft food. 


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Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 17 
 
Zambon S.p.A., Italy, is sponsoring the present bioequivalence study in order to investigate 
the bioequivalence of the novel unit-dose product versus Rilutek® tablets, commercially 
available in Europe as 50 mg tablets. The dose strength for the test formulation is 50 mg, 
matching the 50 mg strength of the reference formulation. 
 
1.4 
Previous pharmacokinetic studies of riluzole orodispersible film 
 
1.4.1 
Pilot bioavailability Phase I study 
 
In a previous Phase I, single-centre, open-label, randomised, single-dose, 3-period, 4-arm, 
cross-over pilot study conducted in healthy male and female non-smokers, the organoleptic 
effect of the test formulation administered with or without water in comparison with that of 
crushed Rilutek® 50 mg tablets available in USA administered with 15 mL of apple sauce and 
the bioavailability of plasma riluzole after administration of the test formulation with or 
without water in comparison with that of intact Rilutek® 50 mg tablets administered with 240 
mL of water were investigated in a total of 16 subjects ( 6). Treatment A was riluzole 
orodispersible film 50 mg administered without water and Treatment B with water. Treatment 
C was intact Rilutek® 50 mg tablets administered with water and Treatment D was crushed 
Rilutek® 50 mg tablets administered with apple sauce. 
Blood samples were collected at pre-dose and 0.25, 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 
8, 12, 16, 20, 24, 36, and 48 h post-dose in each study period. 
 
 
Table  1.4.1.1 
Mean main pharmacokinetic parameters of plasma riluzole after Treatments A and C 
and the outcome of their statistical comparisons  
Parameter 
(N/N) 
Geometric Mean  
Arithmetic Mean (CV%) 
Ratio of 
Geometric 
Means 
90% CI 
CVWR% 
Treatment A 
Treatment C 
AUC0-t (ngxh/mL) 
918.200 
807.545 
113.70 
98.89-130.73 
18.43 
(13/12) 
935.591 (25.10) 
908.745 (38.95) 
 
 
 
AUC0-∞ (ngxh/mL) 
955.116 
837.189 
114.09 
99.08-131.36 
18.62 
(13/12) 
971.138 (25.97) 
948.391 (39.90) 
 
 
 
Cmax (ng/mL) 
221.157 
234.384 
94.36 
74.27-119.88 
32.13 
(13/12) 
236.338 (38.44) 
254.237 (48.32) 
 
 
 
tmax (h)a 
0.75 
0.75 
- 
- 
- 
(13/12) 
(0.50-2.50) 
(0.50-2.00) 
 
 
 
AUC0-∞=area under the concentration-time curve from time 0 (dosing) extrapolated to infinity; AUC0-t= area under 
the concentration-time curve from time 0 (dosing) to time of last measurable riluzole; CI=confidence interval; 
Cmax=maximum observed plasma concentration; CVWR%= within-subject variability expressed as percentage; 
tmax=time to maximum concentration. 
a: Presented as median and range. 
Source: Clinical Study Report 1897 
 


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Table  1.4.1.2 
Mean main pharmacokinetic parameters of plasma riluzole after Treatments B and C 
and the outcome of their statistical comparisons  
Parameter 
(N/N) 
Geometric Mean  
Arithmetic Mean (CV%) 
Ratio of 
Geometric 
Means 
90% CI 
CVWR% 
Treatment B 
Treatment C 
AUC0-t (ngxh/mL) 
876.937 
807.545 
108.59 
93.44-126.20 
18.43 
(13/12) 
847.053 (30.16) 
908.745 (38.95) 
 
 
 
AUC0-∞ (ngxh/mL) 
918.048 
837.189 
109.66 
94.21-127.64 
18.62 
(13/12) 
893.901 (31.00) 
948.391 (39.90) 
 
 
 
Cmax (ng/mL) 
206.394 
234.384 
88.06 
68.05-113.95 
32.13 
(13/12) 
180.950 (45.93) 
254.237 (48.32) 
 
 
 
tmax (h)a 
0.75 
0.75 
- 
- 
- 
(10/12) 
(0.50-2.00) 
(0.50-2.00) 
 
 
 
AUC0-∞=area under the concentration-time curve from time 0 (dosing) extrapolated to infinity; AUC0-t= area under 
the concentration-time curve from time 0 (dosing) to time of last measurable riluzole; CI=confidence interval; 
Cmax=maximum observed plasma concentration; CVWR%= within-subject variability expressed as percentage; 
tmax=time to maximum concentration. 
a: Presented as median and range. 
Source: Clinical Study Report 1897 
 
Pharmacokinetic (PK) analyses showed that the extent and the rate of absorption of riluzole 
were approximately 14% higher and approximately 6% lower after Treatment A than after 
Treatment C. After Treatment B (film with water), the extent and the rate of the absorption of 
riluzole were approximately 9% higher and approximately 12% lower than after Treatment C. 
Indeed, while the ratio of geometric means of Cmax was 94.36% between Treatment A and C, 
it was 88.06% between Treatment B and C, thus indicating that the ratio between Treatment A 
and C was nearer the equality than the ration between Treatment B and C, in terms of rate of 
absorption. The ratios of geometric means of AUC0-t and AUC0-∞ (extent of absorption) did 
not vary greatly between the 2 comparisons A vs. C and B vs. C.  
The intra-subject variability (CVWR%) observed in this pilot study namely 18.43%, 18.62% 
and 32.13% for AUC0-t, AUC0-∞ and Cmax, allowed the sample size calculation of the 
following pivotal bioequivalence study (§  1.4.2) and the choice of a single-dose replicate 
design due to the relatively large intra-subject variability observed for Cmax. 
 
1.4.2 
Pivotal bioequivalence Phase I study 
 
In a previous Phase I, single-centre, open-label, 3-treatment, 2-sequence, 5-period, replicate, 
randomised cross-over, comparative bioavailability study with evaluation of food effect in 
healthy male and female non-smokers, primarily the bioavailability of plasma riluzole after 
single dose of the test formulation compared with that of Rilutek® 50 mg tablets available in 
USA and secondarily the safety and tolerability of the test formulation and the effect of food 
on the pharmacokinetics of riluzole were investigated ( 6). 
A total of 32 subjects were enrolled and 30 subjects completed the study. Three (3) treatment 
conditions were studied: the test formulation administered without water under fasting 
conditions (Treatment A); Rilutek® 50 mg tablets available in USA administered with water 
(Treatment B) and the test formulation without water under fed conditions (Treatment C). 


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Study protocol CRO-PK-20-344 
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Riluzole orodispersible film replicate bioavailability 
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Page 19 
Each subject received a total of 3 treatments in 5 periods: Treatment A and Treatment B under 
fasting conditions in Periods 1-4 according to the randomised replicate cross-over design. All 
subjects received Treatment C in Period 5. 
Blood samples were collected at pre-dose and 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 
36, 48, 72, 96, and 120 h post-dose in each study period.  
 
Table  1.4.2.1 
Mean main PK parameters of plasma riluzole after Treatments A and B and the outcome 
of their statistical comparisons  
Parameter 
CVWR 
Geometric LSM 
Ratio 
 
95% upper 
confidence 
bound 
Riluzole 
orodispersible 
film without 
water (A) 
Rilutek 
with 240 mL 
water 
(B) 
90% Geometric CI 
Lower 
Upper 
AUC0-t 
(ngxh/mL) 
12.65 
780.01 
714.48 
109.17% 
105.67% 
112.79% 
- 
AUC0-∞ 
(ngxh/mL) 
12.49 
795.98 
730.02 
109.04% 
105.58% 
112.61% 
- 
Cmax 
(ng/mL) 
32.66 
- 
- 
115.82% 
- 
- 
-0.0123 
AUC0-∞=area under the concentration-time curve from time 0 (dosing) extrapolated to infinity; AUC0-t= area under 
the concentration-time curve from time 0 (dosing) to time of last measurable riluzole; CI=confidence interval; 
Cmax=maximum observed plasma concentration; LSM=least-squares mean; CVWR = within-subject variability for the 
reference product; ratio = point estimate for geometric mean ratio; CI = confidence interval according to the 
reference-scaled bioequivalence approach; source: Clinical Study Report 162020 
 
The ANOVA performed on the primary riluzole PK parameters clearly demonstrated the 
bioequivalence of the novel riluzole orodispersible film to Rilutek® 50 mg tablets available in 
US. CVWR of plasma riluzole AUC0-t and AUC0-∞ was less than 30% and since their 90% 
geometric confidence interval (CI) were respectively 105.67% to 112.79% and 105.58% to 
112.61% both falling within the acceptance range of 80.00% to 125.00%, test and reference 
formulations were bioequivalent in terms of extent of exposure to riluzole. 
Since CVWR of Cmax was higher than 30%, a scaled average bioequivalence approach was 
used according to the FDA guidance on bioequivalence studies. Therefore, also in terms of 
rate of absorption of plasma riluzole, the hypothesis of bioequivalence of test and reference 
formulation was accepted, because the 95% upper confidence bound was ≤0 and the 
geometric mean ratio was within the interval 80.00% to 125.00%.  
 
 
1.5 
Risks and benefits 
 
Riluzole is a known drug which has been used for decades. It is usually well tolerated. 
Adverse events (AEs) reported in the 3 previous single-dose clinical studies in healthy 
volunteers of the same test formulation are: somnolence, nausea, oral hypoaesthesia, oral 
mucosa erythema, dizziness and transiently altered laboratory parameters. Undesired effects 
reported after stable therapy with the reference formulation include malaise, nausea, high 
alanine aminotransferase (ALT) values, headache, abdominal pain, pain, vomiting, dizziness, 
tachycardia, somnolence and circumoral paraesthesia. For details refer to the IB ( 6). 
 


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Blood sampling with cannula insertion may cause minor discomfort. The risks associated with 
blood draws include pain, bleeding and bruising. 
 
No specific benefits for the participants in the current study are foreseen. Their remuneration 
will be paid after study completion. The remuneration covers loss of time and any 
inconvenience caused by the participation in the study. 
 


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Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
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2 
STUDY OBJECTIVES 
 
The objective of the study is to compare the pharmacokinetic profile of riluzole after replicate 
single dose of the novel orodispersible film test formulation and of the marketed reference 
Rilutek® tablets and to evaluate their bioequivalence.  
 
 
2.1 
Primary end-point 
 
 To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of riluzole 
after replicate single dose administration of test and reference. 
 
2.2 
Secondary end-points 
 
 To describe the PK profile of riluzole after replicate single dose administration of test and 
reference; 
 to evaluate the test product palatability; 
 to collect safety and tolerability data of test and reference after replicate single dose 
administration. 
 


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Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 22 
3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
The subjects will receive single oral doses of 50 mg of riluzole, as test orodispersible film and 
reference film-coated tablets under fasting conditions, in each of 4 subsequent periods 
separated by wash-out intervals of at least 7 days between consecutive administrations, 
according to a 2-treatment, 4-period, replicate cross-over design.  
 
3.1.1 
Description of products 
 
The analytical certificates will be supplied with the investigational medicinal products (IMPs) 
and enclosed in the final study report.  
 
3.1.1.1 
Test product 
 
TEST (T) 
 
IMP 
Riluzole 50 mg orodispersible film, Aquestive Therapeutics, USA 
Manufacturer 
(active substance) 
Glenmark Life Sciences, Plot 3109 C GIDC Industrial Estate, 
Ankleshwar, District Bharuch, Gujarat, 393002 India  
(GMP compliant)  
Manufacturer 
(finished product) 
Aquestive Therapeutics, Inc, 6465 Ameriplex Drive, Portage, 
Indiana, 46368, USA  
(GMP compliant)  
QP release: 
Aquestive Therapeutics, Inc, 6560 Melton Road, Portage, Indiana, 
46368, USA  
(GMP compliant)  
Pharmaceutical form: 
Orodispersible film 
Dose 
50 mg  
Administration route: 
Supralingual 
 
The qualiquantitative composition of the test is shown in the table below. 
 
Table  3.1.1.1 
Quantitative composition of the test IMP 
Component 
% Solids (w/w) 
Riluzole 
27.62 
Polacrilex Resin 
35.18 
Polyethylene oxide 
1.05 
Pullulan 
19.24 
Hypromellose, substitution type 2910 
4.08 
Xanthan Gum 
0.31 
Sucralose 
1.57 
Xylitol 
5.49 
Fructose 
1.05 
Glycerin 
2.09 
Glycerol Monooleate, Type 40 (GMO) 
1.67 
Flavor Honey 151a39 
0.46 
Flavor Juicy Lemon 160a04 
0.16 
FD&C Yellow #5 
0.03 
Purified Water 
NA 
Abbreviations: FD&C=Food, Drug, and Cosmetic (Act); NA=not applicable; w/w=weight per weight. 


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Final version 1.0, 28APR20 
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Page 23 
 
3.1.1.2 
Reference product 
 
REFERENCE (R) 
 
IMP 
Rilutek®, 50 mg riluzole tablets 
Marketing 
Authorisation 
Holder 
Sanofi Mautre IP, France 
Pharmaceutical form 
Film-coated tablets 
Dose 
50 mg  
Administration route 
Oral 
 
3.1.2 
Dose regimen 
 
Four single doses of 50 mg of riluzole (2 as test and 2 as reference formulation) will be 
administered to each volunteer in 4 subsequent study periods, separated by wash-out intervals 
of at least 7 days.  
 
3.1.3 
Route and method of administration 
 
Each study dosing was performed in the morning at 08:00 ± 1 h under fasting conditions. The 
test formulation will be administered supralingually and the reference orally.  
 
3.1.3.1 
Test formulation 
 
The study staff will check subjects’ mouth to ensure a clean mouth before study drug 
administration. This will be documented in specific forms. 
 
Before each administration, the subjects will drink 20 mL of still mineral water in order to wet 
their mouth.  
 
Afterwards, using gloves, the investigator or deputy will take the orodispersible film 
(32.0x22.0 mm) out of the provided pouch and place the product directly on the top surface 
(dorsal aspect) of the subjects’ tongue. The subjects will close their mouth in a natural way 
and gently rub the film with the tongue against the roof of the mouth to promote melting and 
disappearance of the film. The subjects will be allowed to swallow saliva but not to chew, 
bite, or swallow the film. After the subjects indicate a complete dissolution of the film 
(confirmed by visual inspection) by raising their hand, they will be allowed to swallow any 
remaining saliva. The study staff will visually inspect the films 1, 2 and 5 min post-dose until 
either complete dissolution is confirmed or until the subject alerts the study staff to 
dissolution of the film. This will be documented in specific forms. If the film is not 
completely dissolved within 5 min, the subjects will be allowed to swallow without water.  
Dosing time is defined as the time the film is placed on the subject’s tongue. The study staff 
will record the actual time of film placement and the actual time of dissolution. If, upon 
inspection, the film is dissolved, the time of mouth check will be recorded as time of 
dissolution.  
In case a subject chews or moves the film before its complete dissolution, this occurrence will 
be noted. During the 5-min observation period, the subjects will inform the study staff in case 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
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Page 24 
the film is accidentally swallowed before its complete dissolution and the staff will record the 
time the film is swallowed.  
 
Dosing, dissolution and accidental swallowing times will be recorded in specific forms and in 
the subject’s CRF.   
 
3.1.3.2 
Reference formulation 
 
One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral 
water. 
 
The investigator or deputy will check and confirm that all subjects take the medication 
appropriately. 
 
Dosing time will be recorded in the specific source documents and in the subject’s CRF.   
 
3.1.4 
Investigational product distribution 
 
The test and reference will be administered by the investigator or by his/her deputy. The IMP 
will be exclusively used for the present clinical study and will only be administered to the 
subjects enrolled in the study.  
 
3.2 
Packaging and labelling 
 
The test primary packaging will be a polyester/foil laminate pouch which is heat sealed. 
 
The formulation labelling will report all the information requested according to the Annex 13 
to the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4;  8) as follows: 
a. 
Name, address and telephone number of the sponsor, contract research organisation or 
investigator (the main contact for information on the product, clinical study and 
emergency unblinding) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor 
if not given elsewhere 
e. 
The study subject identification number/treatment number and the visit/period number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 
i. 
The storage conditions 


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Study protocol CRO-PK-20-344 
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Riluzole orodispersible film replicate bioavailability 
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j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
 
Labels will be in local language (Italian). 
 
3.3 
Storage conditions 
 
The test and the reference will be accurately kept in their pouch until ready to use and stored 
in the Phase I Unit pharmacy between20° and 25° C in a dry locked place, sheltered from 
light.  
 
3.4 
Drug accountability 
 
Test and reference packed in individual subjects’ kits will be provided directly to the 
investigator by STM Pharma PRO Srl., Italy (§  16.5), in excess of the amount necessary for 
the study (at least 25% excess).  
 
The reference will be purchased from the European market. 
 
After receipt of the IMPs, the pharmacist will confirm in writing by signing and dating drug 
accountability forms. 
 
At the end of the study, used, unused and partially used IMPs will either be destroyed on site 
(upon written authorisation) or returned to the sponsor, after final reconciliation of all IMP 
accountability. 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 26 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
Single centre, single dose, open-label, randomised, 2-sequence, 4-period replicate cross-over 
study. 
 
4.2 
Discussion of design 
 
The study was designed in agreement with the EMA guideline “Guidance on the investigation 
of bioequivalence”, CPMP/EWP/QWP/1401/98 Rev. 1 January 2010 ( 9). The well-known 
high variability of riluzole led to the choice of the replicate cross-over design as suggested by 
the current EMA guideline. According to the guideline, an enlargement of the acceptance 
interval for bioequivalence in terms of Cmax is allowed up to 69.84-143.19% in relation to the 
actual intra-subject variability of riluzole Cmax found in this study with the reference 
treatment, by keeping in consideration the favourable safety profile of the test formulation 
previously observed in 3 clinical studies. In detail, a Cmax within-subject variability >30% was 
found in the previous pilot study and =32.66% in the previous bioequivalence study 
performed in USA (§  1.4.2). According to the 2-arm cross-over study design, each 
randomised subject will be allocated to one of 2 sequences of IMP administrations in the 4 
study periods according to a computer generated randomisation list (see §  8.1). Balance 
between the sequences will be made so that subjects have the same chances to be assigned to 
either sequence (either RTRT or TRTR in the 4 consecutive periods). 
 
An open-label design will be used since the primary end-point of the study is based on 
objective measurements of riluzole in plasma and the outcome variables could not be 
influenced by the subjects or investigator being aware of the administered products. The 
bioanalysis will be performed under blinded conditions.  
 
The washout period of 7 days was estimated to be adequate. Based upon a half-life of 12 h 
(Rilutek SmPC reference:  7), it is anticipated that minimal plasma levels would be achieved in 
5 days thus allowing dosing every 7 days. Blood sampling time-points were selected on the 
basis of the known PK profile of riluzole and on the basis of previous Phase I studies of the 
same test formulation administered to healthy volunteers. 
 
The dose for the present study was selected based on EMA Rilutek® European Public 
Assessment Report (EPAR) ( 10), which recommends a dose regimen of 50 mg (one film-
coated tablet) twice a day in the common clinical practice. The dose of 50 mg is the minimal 
unit dose. 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 27 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
Healthy men and women will be enrolled in this study.  
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex and Age: men/women, 18-55 years old inclusive 
3. Tobacco: non-smokers for at least 6 months prior to study screening 
4. Body Mass Index (BMI): 18.5-29 kg/m2 inclusive 
5. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 
50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting position 
6. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study 
7. Contraception and fertility (women only): women of child-bearing potential must be using 
at least one of the following reliable methods of contraception: 
a. A non-hormonal intrauterine device [IUD] or female condom with spermicide 
or contraceptive sponge with spermicide or diaphragm with spermicide or 
cervical cap with spermicide for at least 2 months before the screening visit 
b. A male sexual partner who agrees to use a male condom with spermicide 
c. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at 
least 1 year will be admitted. 
For all women, pregnancy test result must be negative at screening. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. Electrocardiogram (ECG) 12-leads: (supine position) clinically significant abnormalities; 
QTc interval > 450 msec 
2. Physical findings: clinically significant abnormal physical findings which could interfere 
with the objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of 
physical illness 
4. Cotinine: positive cotinine test at screening  


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 28 
5. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or 
formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the investigator considers may affect the outcome of the study 
6. Diseases: clinically significant history or presence of renal, hepatic, gastrointestinal, 
cardiovascular, cerebrovascular, immunological, musculoskeletal,  respiratory, skin, 
haematological, endocrine, psychiatric or neurological diseases or surgeries that may 
interfere with the aim of the study. Gastrointestinal pathologies include any clinically 
significant disorder of the mouth, e.g. impairment of swallowing, lesions, ulcerations, 
deformities, untreated dental caries 
7. Dentures: presence of mouth jewellery, dentures, braces, piercings that may interfere with 
successful completion of the dosing 
8. Medications: medications, including over the counter (OTC) medications and herbal 
remedies for 2 weeks before study screening; central nervous system depressants, 
including opioids, benzodiazepines, general anaesthetics and anticonvulsants, or CYP 
inhibitors, including cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, 
fluconazole, ketoconazole, diltiazem and antiretroviral agents, or strong CYP inducers, 
including barbiturates, carbamazepine, glucocorticoids, phenytoin, St John’s wort and 
rifampin, or hormonal oral or transdermal contraceptives for 30 days before study 
screening; implanted, injected, intravaginal or intrauterine hormonal contraceptives for 6 
months before study screening 
9. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between the 
first calendar day of the month that follows the last visit of the previous study and the first 
day of the present study 
10. Blood donation: blood donations for 3 months before this study 
11. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and 
>2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015 ( 11)], 
caffeine (>5 cups coffee/tea/day) or tobacco use including any tobacco product like e-
cigarettes and vaping products 
12. Drug test: positive result at the drug test at screening or Day -1 
13. Alcohol test: positive alcohol breath test at Day -1 
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in 
the 4 weeks before this study; vegetarians and vegans  
15. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, 
pregnant or lactating women  
 
5.3.1 
Not allowed treatments 
 
No medication, including OTC and herbal remedies, will be allowed for 2 weeks before the 
start of the study and during the whole study duration.  
 
Central nervous system depressants, including opioids, benzodiazepines, general anaesthetics 
and anticonvulsants, or CYP inhibitors, including cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and antiretroviral agents, or 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 29 
strong CYP inducers, including barbiturates, carbamazepine, glucocorticoids, phenytoin, St 
John’s wort and rifampin, or hormonal oral or transdermal contraceptives will be forbidden 
for 30 days before study screening and during the whole study duration. 
 
Implanted, injected, intravaginal or intrauterine hormonal contraceptives will be forbidden for 
6 months before study screening and during the whole study duration.  
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) 
according to the investigator’s opinion.  
 
The intake of any other medication will be reported as a protocol deviation. However, it will 
lead to subject's discontinuation from the study only if the investigator, together with the 
sponsor, considers it could affect the study assessments or outcome 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 30 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
6.1 
Study visits and procedures 
 
Each study subject will undergo 10 visits. 
 
The study protocol foresees 4 periods separated by wash-out intervals of at least 7 days. 
Minimum study duration will be 25 days, screening visit included. A written informed 
consent will be obtained before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the Phase I Unit by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the Phase I Unit by the last subject, i.e. the last visit foreseen by the study protocol, 
independently of the fact that the subject is a completer or a withdrawn subject, and it 
corresponds to the study completion. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening – visit 1: between Day -14 and Day -2 
 Period 1 – visit 2: Day -1 
 
 Interventional phase 
 Period 1 – visit 3: Days 1-2 
 Wash-out interval of at least 7 days 
 Period 2 – visit 4: Day -1 
 Period 2 – visit 5: Days 1-2 
 Wash-out interval of at least 7 days 
 Period 3 – visit 6: Day -1 
 Period 3 – visit 7: Days 1-2 
 Wash-out interval of at least 7 days 
 Period 4 – visit 8: Day -1 
 Period 4 – visit 9: Days 1-2 
 
 Final phase 
 Period 4 – visit 10: Day 2 - Final visit or early termination visit (ETV) in case of early 
discontinuation 
 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 31 
 
 
Day 
Procedures/Assessments 
Notes 
Screening phase 
Screening – visit 1 
From Day -14 to 
Day -2 
 Explanation to the subject of study aims, 
procedures and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, 
vital signs, physical abnormalities) 
 ECG recording 
 Laboratory 
analyses: 
haematology, 
blood 
chemistry, cotinine, urinalysis, virology and 
serum pregnancy test (women only) 
 Urine multi-drug kit test 
 AE monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two 
letters 
of 
the 
surname 
followed 
by the first two 
letters of the first 
name will be used in 
the Phase I Unit 
source 
document 
only and will not be 
transferred to the 
sponsor 
Period 1 
Visit 2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women only) 
 AE and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomisation 
Arrival at the Phase I 
Unit in the evening 
Confinement 
until 
the evening of Day 2 
Standardised low-fat 
dinner 
Fasting for at least 10 
h (overnight) up to 
dosing 
Visit 3 
Day 1 
 IMP administration at 08:00 ± 1 h 
 Palatability of the test product immediately 
after administration 
 Mouth visual inspections after administration of 
the test investigational medicinal product, at 
pre-dose and 0.5 and 1 h post-dose  
 Vital signs measurement (§  7.1.2) 
 Blood sample collection for PK analysis (§ 
7.3.1) 
 AE and concomitant medications 
Fasting until about 5 
h post-dose 
Standardised lunch at 
about 13:00  
Standardised dinner 
at about 20:00 (12 h 
post-dose)  
Day 2 
 Vital signs measurement (§  7.1.2) 
 Blood sample collection for PK analysis (§ 
7.3.1) 
 AE and concomitant medications 
Standardised 
breakfast at about 
8:00 and lunch at 
about 13:00  
Discharge from the 
Phase I Unit in the 
evening after the 36-
h 
post-dose 
blood 
sample collection and 
vital signs check 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 32 
 
 
Day 
Procedures/Assessments 
Notes 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 2 
Visit 4 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 5 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 3 
Visit 6 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 7 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 4 
Visit 8 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 9 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 33 
 
 
Day 
Procedures/Assessments 
Notes 
Period 4 
Visit 9 
Day 2 
As visit 3 
As visit 3 
Final phase  
Visit 10 - Final Visit or ETV 
Day 2 of 
period 4 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight and 
physical abnormalities; also vital signs in case 
of ETV) 
 Laboratory analyses as at screening, with the 
exception of cotinine, virology, urine drug test 
and pregnancy test 
 AE and concomitant medications 
 
In case of clinically significant results at the final 
visit, the subjects will be followed-up by the 
investigator until the normalisation of the 
concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
investigator in case 
of occurrence of any 
adverse reactions 
 
6.2 
Diet and lifestyle 
 
During confinement, the subjects will not take any food or drinks (except water) for about 10 
h (i.e. overnight) before IMP administration and for about 5 h afterwards. On Day -1 of each 
study period, a standardised low-fat dinner will be served. Water will be allowed as desired, 
except for one h before and one h after IMP administration. In order to maintain an adequate 
hydration, the subjects will be encouraged to drink at least 150 mL of still mineral water every 
2 h for 5 h post-dose, starting at 1 h post-dose. 
 
On Day 1 of each study period, the subjects will remain fasted until about 5 h post-dose. 
Standardised lunch and dinner will be served at approximately 5 h and 12 h post-dose. 
On Day 2 of each study period, standardised breakfast and lunch will be served at about 8:00 
and 13:00, respectively. The meals’ composition will be standardised on Days -1 and 1 in 
each study period, as summarised in the table below.  
 
Table  6.2.1 
Meals’ composition on Day -1 and Day 1 in the four study periods 
Study day 
Lunch 
Dinner 
Day -1 
NA 
Bread  
Tomato pasta 
Fruit 
Day 1 
Bread 
Pasta Bolognaise  
Roasted turkey  
Green beans  
Bread  
Tomato pasta  
Bresaola and salad 
Fruit 
NA: Not applicable 
Meals will be served as standardised portions prepared by a selected catering provider 
 
Coffee, tea or food containing xanthines (i.e. coke, chocolate, etc.), smoking, alcohol and 
grapefruit will be forbidden during confinement. In particular, alcohol and grapefruit will be 
forbidden for 24 h before the first IMP administration until the end of the study.  
 
Only non-smokers will be included in the study. 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 34 
 
During confinement, routine ambulant daily activities will be strongly recommended. 
 
6.2.1 
Restrictions 
 
During each study period, the subjects will be confined from the evening preceding the IMP 
administration (study Day -1) until the evening of Day 2.  
 
For the 4 h following each administration, when not involved in study activities, the subjects 
will remain seated. They will not be allowed to lie down.  
 
During confinement, hazardous, strenuous or athletic activities will not be permitted. 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 35 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations will be performed at the screening and final visit/ ETV. 
Information about the physical examination will be recorded by the investigator. Any 
abnormalities will be recorded. 
 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see §  11), will be recorded in the subject source documents. 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
 
7.1.1 
Body weight 
 
Body weight will be recorded at the screening and final visit/ ETV. 
 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and BMI will be recorded. BMI will be calculated as weight [kg]/(height [m] x 
height [m]). 
 
7.1.2 
Vital signs 
 
Subjects blood pressure (BP) and heart rate will be measured at rest (5 min in sitting position) 
by the investigator or his deputy at: 
 Screening 
 In each period, at pre-dose and 2 and 36 h post-dose 
 ETV (if applicable) 
 
7.1.3 
ECGs 
 
One 12-Leads ECG will be performed (in supine position) at screening visit.  
 
7.1.4 
Mouth visual inspections 
 
The investigator or deputy will inspect the subjects’ mouth to check for mucosal irritation at 
the application site at the following times: 
 After each administration of the test IMP, at pre-dose and 0.5 and 1 h post-dose 
 
7.1.5 
Palatability 
 
The subjects will be asked about the palatability of the test product immediately after 
administration. 
Palatability will be scored according to the following scale:  


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 36 
Table  7.1.5.1 Palatability evaluation scores 
JUDGEMENT 
SCORE 
very unpleasant 
0 
unpleasant 
1 
acceptable 
2 
good 
3 
very good 
4 
 
7.2 
Clinical laboratory assays 
 
Samples of blood (12.5 mL) and urine will be collected. The following laboratory analyses 
will be performed at the screening visit at the centralised clinical laboratory (§  16.4): 
 
Haematology 
Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, haemoglobin (conv. units), haemoglobin (IS units), haematocrit, MCV, MCH, 
MCHC, thrombocytes. 
 
Blood chemistry 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, glucose, urea, uric acid, total cholesterol, 
triglycerides, cotinine 
Proteins: total proteins 
 
Serum pregnancy test (women). 
 
Urine analysis 
Urine chemical analysis (stick): pH, specific weight, appearance, colour, nitrites, proteins, 
glucose, urobilinogen, bilirubin, ketones, haematic pigments, leukocytes 
Urine sediment (analysis performed only if positive): leukocytes, erythrocytes, flat cells, 
round cells, crystals, cylinders, mucus, bacteria 
 
Serum virology  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
A urine drug test will be performed at the Phase I Unit at screening, using a urine multi-drug 
kit. The following drugs will be assayed: cocaine, amphetamine, methamphetamine, 
cannabinoids (delta-9-tetrahydrocannabinol - THC), opiates and ecstasy.  
 
A serum pregnancy test will be performed at the clinical laboratory (§  16.4) at screening. 
Urine pregnancy tests will be performed on Day -1 of each study period at the Phase I Unit.  
 
The same analyses, with the exception of cotinine, urine drug test, virology and pregnancy 
test, will be performed at the final visit/ETV at the centralised clinical laboratory (§  16.4). 
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 37 
findings (if any) will be reported in the individual CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. Hard copies of the laboratory 
print-outs will be attached to the CRFs. 
 
7.3 
Sampling for pharmacokinetic analysis 
 
7.3.1 
Venous blood sampling 
 
In each period, venous blood samples (7 mL) will be collected from a forearm vein at the 
following times:  
 
 0 h (pre-dose), 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h post-dose. 
 
Actual sampling times for each subject will be recorded in the individual case report forms 
(CRFs). The actual sampling times should not exceed the recommended tolerance ranges 
presented in the following table. Any deviation outside the recommended ranges will be 
verified through Data Clarification Forms and, if confirmed, will be reported as protocol 
deviation, although it will not automatically lead to the exclusion of the concerned subjects 
from the PK Sets. 
 
Table  7.3.1.1 Tolerance ranges for the scheduled sampling times 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 30 minutes before IMP administration 
0.25 h (15 min) 
0 min 
0.5 h (30 min) 
± 1 min 
0.75 h (45 min) 
± 2 min 
1, 1.25, 1.5 h 
± 3 min 
2, 3, 4 h 
± 5 min 
6, 8, 12, 24, 36 h 
± 10 min 
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch 
valve. The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline 
solution containing 20 I.U./mL Na-heparin. The first 1.5 mL of blood will be discarded at 
each collection time to wash the cannula out of saline solution and to avoid contamination of 
the sample with heparin. 
 
The remaining 5.5 mL will be collected from the catheter and transferred with a syringe into 
pre-labelled Li-heparinised polypropylene tubes. 
 
The samples will be stored on ice for a maximum of 60 min. Then the samples will be 
centrifuged at 4° C for 10 min at 2500 g to obtain plasma. Each plasma sample will be 
immediately divided into 3 aliquots, P1 (1 mL), P2 and P3 (remaining plasma), in pre-labelled 
polypropylene tubes, and stored frozen until analyses.  
 
If any clinical assessment, such as vital signs measurement is foreseen at the same time-point 
as blood sampling for PK analysis, blood collection will be performed at the scheduled time. 
However, vital signs can be influenced by blood sampling. Therefore, these measurements 
can be performed within 30 min before the pre-dose PK time point (0 h) and within 10 min 
before the other scheduled PK time-points. Any deviations outside the recommended time 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 38 
will be verified through Data Clarification Forms. However, since vital signs measurements 
will be performed for safety reasons only, deviations from the planned time schedule will be 
considered not relevant. 
 
7.3.2 
Analytics  
 
The concentration of riluzole in plasma will be determined at Accelera S.r.l., Italy, (§  16.3), 
using a fully validated LC-MS/MS method with a lower quantification limit (LQL) of 5 
ng/mL. 
 
Analyses will be performed according to the general Principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81) 30 (final) and GCP. 
 
The method validation report and the analytical report will be attached to the final report. 
 
7.3.3 
Labelling, storage and transport of samples 
 
7.3.3.1 
Samples labelling 
 
Each sample tube will be clearly and unequivocally identified with a label resistant to the 
storage temperature and reporting: 
Study code 
Study CRO-PK-20-344 - Sponsor code Z7251J01 
Subject number 
P001-P054 
Tube identification 
P1/P2/P3 
Period  
1/2/3/4 
Study day 
1/2 
Scheduled sampling time as h; see §  7.3.1 
 
7.3.3.2 
Samples storage and transport 
 
At the Phase I Unit, the study samples will be stored at ≤-20° C. At the end of each collection 
day, aliquots 1 and 3 will be stored in freezers separate from aliquots 2. 
 
All aliquots 1, packed in sufficient solid CO2, will be shipped by an authorised courier from 
the Phase I Unit, Switzerland, to Accelera S.r.l., Italy. Aliquots 1 will remain stored at 
Accelera S.r.l. for a maximum time of 6 months after finalisation of the bioanalytical report. If 
not otherwise indicated, the samples will be destroyed and a certificate of destruction will be 
provided to the sponsor. 
 
The counter-samples (aliquot 2 and 3) will remain stored at CROSS Research S.A., 
Switzerland. These samples could either be: 
 sent to the laboratory for reanalysis should this become necessary for analytical reasons 
or if any problems occur during the delivery of aliquots 1, or 
 destroyed at an authorised site, or 
 transferred to the sponsor upon written request, or 
 stored at CROSS Research S.A., for a maximum time of 5 years 


CONFIDENTIAL 
 
Study protocol CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
CROSS Research S.A. 
Page 39 
 
No analyses different from those stated in this protocol and agreed by the subjects when 
signing the informed consent form will be performed unless a new informed consent and a 
new approval from the Ethical Committee is obtained. The subjects may ask to destroy their 
own samples at any time. 
 
7.4 
Total number of samples and blood withdrawn 
 
During the study the following volume of blood will be collected:  
 
For routine laboratories analysis: 
Screening visit: 
12.5 mL 
Final visit/ETV: 12.5 mL 
 
For PK analysis: 
Treatment T:  
15x2x7=210 mL 
Treatment R: 
15x2x7=210 mL 
 
In total, 445 mL of blood (not exceeding a normal blood donation) will be withdrawn from 
each subject. 
 


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Riluzole orodispersible film replicate bioavailability 
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8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The randomisation list will be computer-generated by the Biometry Unit of the Clinical 
Contract Research Organization (CRO), using the PLAN procedure of the SAS® version 9.3 
(TS1M1) ( 13) or higher (the actual version will be stated in the final report). The 
randomisation list will be supplied to the study site and to STM Pharma PRO Srl., Italy 
(§  16.5) for the preparation of the IMP individual kits before study start and will be attached 
to the final clinical study report. 
 
8.2 
Treatment allocation 
 
The study subjects will be assigned to one of 2 sequences of treatments (either RTRT or 
TRTR) according to their randomisation number. Randomisation number will be given to the 
subjects on study Day -1, period 1, as soon as they are definitely enrolled in the study. 
 
8.3 
Blinding 
 
This is an open study. No masking procedure will be applied.  
 
 
 
 
 


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9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary variables 
 
 Cmax and AUC0-t of plasma riluzole after replicate single dose administration of test and 
reference formulation. 
 
9.1.2 
Secondary variables 
 
 AUC0-∞, t1/2, tmax, AUCextra, λz, of riluzole after replicate single dose administration of test 
and reference; 
 Palatability score 
 TEAEs, vital signs (BP, HR), laboratory parameters, physical examination including BW 
 
9.2 
Pharmacokinetic assessments 
 
9.2.1 
Pharmacokinetic parameters 
 
The following PK parameters will be measured and/or calculated for plasma riluzole, using 
the validated software Phoenix WinNonlin® version 6.3 ( 12) or higher (actual version will be 
stated in the final report): 
 
Cmax: 
Maximum plasma concentration 
 
tmax: 
Time to achieve Cmax 
 
λz: 
Terminal elimination rate constant, calculated, if feasible, by log-linear 
regression using at least 3 points 
 
t1/2: 
Half-life, calculated, if feasible, as ln2/λz 
 
AUC0-t: 
Area under the concentration-time curve from administration to the last 
observed concentration time t, calculated with the linear trapezoidal method 
 
AUC0-∞: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration 
 
%AUCextra: 
Percentage of the residual area (Ct/λz) extrapolated to infinity in relation to 
the total AUC0-∞, calculated, if feasible, as 100×[(Ct/λz)/AUC0-∞] 
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0-∞ equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that the primary variable AUC0-t covers a sufficient percentage of the theoretical total 
extent of exposure.  
 


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The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
9.3 
Safety assessments 
 
Safety and general tolerability of the IMP will be based on TEAEs, physical examinations 
including body weight, vital signs and routine haematology, blood chemistry and urinalysis 
laboratory tests. 
 


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Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 28APR20 
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10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. geometric mean (PK data only), arithmetic 
mean, SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of 
demographic and safety data will be performed using SAS® version 9.3 (TS1M1) ( 13) or 
higher (the actual versions will be stated in the final report). 
The statistical analysis of PK parameters will be performed using Phoenix WinNonlin® 
version 6.3 ( 12) or higher and SAS® version 9.3 (TS1M1) or higher. 
 
10.1 
Analysis Sets 
 
10.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to one 
treatments sequence. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomised in the study when he/she is assigned to one 
randomised treatments sequence. 
 
The following analysis sets are defined: 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
 Safety set: all subjects who receive at least one dose of the investigational medicinal 
products. This analysis set will be used for the safety analyses 
 PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal product intake and have evaluable PK data readouts for the 
planned treatment comparisons, with no major deviations that may affect the PK results. 
This analysis set will be used for the statistical analysis of the PK results 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Safety set 
and the PK set. Subjects will be evaluated according to the treatment they actually receive. 
 
 
 


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10.1.2 
Reasons for exclusion from the PK set before bioanalysis 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 vomiting and diarrhoea after drug intake which could render the plasma concentration-
time profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
10.1.3 
Reasons for exclusion from the PK set after bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 subjects with lack of any measurable concentrations or only very low plasma 
concentrations for the reference medicinal product. A subject is considered to have very 
low plasma concentrations if his/her AUC is less than 5% of the reference medicinal 
product geometric mean AUC (which should be calculated without inclusion of data from 
the outlying subject) 
 subjects with implausible concentrations (i.e. different from the known, expected 
concentration profiles) for the reference medicinal product. The exclusion of these 
subjects must be justified on the basis of sound scientific reasons and mutually agreed 
between the CRO and the Sponsor 
 subjects with non-zero baseline concentrations > 5% of Cmax 
The samples from the subjects excluded from the PK set should still be assayed and the 
results listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 
80% of the AUC0-∞. 
 
10.2 
Sample size and power considerations 
 
Data from previous PK studies of the test product, 1897 and 162020 (§  1.4.1and  1.4.2) were 
used to calculate the sample size of the present study, as shown in the table below.  
 
Table  10.2.1 Sample size calculation  
Parameter 
δ 
CVWR 
α 
β 
n 
N=2n 
Cmax 
1.11 
0.3266 
0.1 
0.2 
26 
52 
AUC0-t 
1.0917 
0.1265 
0.1 
0.2 
4 
9 
δ: ratio of geometric means of the considered parameter; CVWR%: within-subject variability; α: type 1 error; β: 
type 2 error; n: number of subjects per sequence; N: total sample size 
 
Variability of AUC0-t and Cmax (CVWR) actually observed in study 162020 (§  1.4.2) was used 
in the calculation. The actual ratio of geometric means of AUC0-t of study 162020 was 1.0917, 


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whilst that of Cmax observed in study 162020 was 1.1582. This high ratio did not prevent the 
demonstration of bioequivalence of the formulations in study 162020 also for Cmax. However, 
the calculation of the sample size for the present study using a δ of 1.1582 would be 126 
subjects. Considering that the enrolment of at least 126 subjects in a bioequivalence study 
would be hardly justifiable, that bioequivalence between the test IMP and Rilutek® 50 mg 
tablets available in US was demonstrated in study 162020 in 30 subjects, who completed the 
study, and that the actual δ of Cmax obtained in the previous pilot study 1897 was 0.9436, 
which is notably nearer the equality, i.e. ratio = 1.00, than the ratio 1.1582 observed later in 
study 162020, a ratio of 1.11 was postulated in the present sample size calculation. Indeed, 
maintaining CVWR, α and β unchanged and assuming as Cmax ratios, alternately, 1.05 and 
1.10, sample sizes of 26 and 46 subjects, respectively, would be necessary to demonstrate 
bioequivalence in terms of Cmax.  
Taking into account this premise, when the sample size in each sequence group is 26 (and the 
total sample size is 52), a replicate crossover design will have 80% power to reject both the 
null hypothesis that the ratio of the test mean to the reference mean of Cmax is below 0.800 
and the null hypothesis that the ratio of test mean to the reference mean of Cmax is above 1.250 
( i.e. that the test and standard are not equivalent, in favour of the alternative hypothesis that 
the means of the two treatments are equivalent) assuming that data will be analysed in the 
natural log scale using t-tests for differences in means and that each t-test will be made at the 
5.0% significance level. 
 
In conclusion, 54 subjects will be enrolled in order to have 52 completed subjects. 
 
10.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics. 
 
10.4 
Drug administration and analysis of film dissolution 
 
The date and time of film placement, of film dissolution, of accidental film swallowing and 
reference tablet administrations will be listed. Dosing time is defined as the time the film is 
placed on the subject’s tongue.  
The actual time of film dissolution will be summarised by descriptive statistics. 
 
The dose per body weight of riluzole will be listed and summarised by descriptive statistics. 
The body weight collected at the screening visit will be used for the calculation. 
 
The minimum and maximum number of days of wash-out between periods will be presented.  
 
10.5 
Test IMP palatability 
 
Test IMP palatability scores will be listed and summarised in tables of frequency. 
 
 
 


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10.6 
Analysis of pharmacokinetic parameters 
 
10.6.1 
Descriptive pharmacokinetics 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables 
and figures. Individual and mean curves (+SD at sampling times), indicating inter-subject 
variability, will be plotted. Data below the lower quantification limit (BLQL) will be 
considered as 0 in the calculations and presented as BLQL in listings and tables. As a 
consequence of BLQL (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). 
 
10.6.2 
Statistical comparison of pharmacokinetic parameters 
 
According to the current European Guideline ( 9), plasma riluzole AUC0-t, AUC0-∞ and Cmax 
will be analysed using analysis of variance (ANOVA). A mixed linear model will be used to 
make statistical inferences about the values of Cmax and AUC0-t. In order to correctly assume 
normality and homoscedasticity, the data will be transformed prior to analysis using a 
neperian logarithmic transformation in compliance with the EMA guideline.  
 
The 90% CI of the ratio of the population means (test/reference), for the parameters under 
consideration will be calculated. This method is equivalent to the corresponding two one-
sided test procedure with the null hypothesis of bioequivalence at the 5% significance level. 
 
 The statistical analysis will take into account treatment, period, sequence and subject 
within sequence as fixed effects.  
 
 Acceptance criterion for bioequivalence in terms of extent of absorption (AUC0-t as 
primary variable and AUC0-∞ as secondary variable) will be that the 90% CI of this ratio 
has to lie within the range 80.00-125.00%. 
 
 Due to the replicate design of the study, if the within-subject variability (CVWR%) of Cmax 
of plasma riluzole after administration of the reference formulation is >30%, the 
reference-scaled BE approach will be used. Bioequivalence acceptance range for Cmax will 
be widened, in compliance with the guideline, as exemplified in Table  10.6.2.1. 
 
 CVWR% will be calculated by applying the formula 
1
100
(%)
2
−
=
WR
S
WR
e
CV
, where S2WR is 
the within-subject variation plasma riluzole after administration of the reference 
formulation only.  
 
 The extent of the widening will be defined on the basis of the within-subject variability 
actually observed in the study according to [U, L] = exp [±k·sWR], where U is the upper 
limit of the acceptance range, L is the lower limit of the acceptance range, k is the 
regulatory constant set to 0.760 and SWR is the within-subject standard deviation of the 
log-transformed values of Cmax of plasma riluzole after administration of the reference 
formulation. 
 


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 Moreover, the widening of the acceptance range for Cmax is justified considering the 
favourable safety and tolerability profile of riluzole as demonstrated for the formulations 
authorised on the market. 
 
Table  10.6.2.1 
Examples of widened bioequivalence acceptance limits of Cmax according to its actual 
CVWR 
CVWR %*  
Lower Limit 
Upper Limit 
30  
80.00 
125.00 
35 
77.23 
129.48 
40 
74.62 
134.02 
45 
72.15 
138.59 
≥50 
69.84 
143.19 
*: 
1
e
100
CVWR(%)
WR
2
S
−
=
; source: reference ( 9) 
 
tmax and t1/2will be compared between treatments by the non-parametric Friedman test. 
 
10.7 
Safety and tolerability evaluation 
 
 AEs 
AEs will be coded by System Organ Class (SOC) and Preferred Term (PT), using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and TEAEs, according to the period of 
occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of IMP and not worsening after the 
first dose of IMP 
 TEAEs: all AEs occurring or worsening after the first dose of IMP 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity.  
 
 Physical examination 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
 Laboratory data  
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be listed. All laboratory results will be listed and a table of all the 
abnormal values will be presented. The overall investigator’s interpretation will be 
summarised using tables of frequency.  
 
 Vital signs 
Vital signs values will be listed and summarised by descriptive statistics.  
 
 
 Body weight  


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Body weight values will be listed and summarised by descriptive statistics. 
 
 Tolerability at the application site   
Date/time of each mouth visual inspection, overall investigator’s interpretation (as normal or 
abnormal and, if abnormal, clinically significant or not clinically significant) and clinically 
significant findings (if any) will be listed. 


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11 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the Sponsor’s SOPs. The AE form 
present in the CRF and the SAE form will also follow the sponsor SOPs.  
 
The full SOP or an operative summary will be made available to the Phase I Unit. 
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definition of Adverse Event (AE) 
 
An AE is “any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with treatment”. 
 
AEs include: 
 worsening (change in nature, severity or frequency) of conditions present at the onset of 
the study 
 patient/subject deterioration due to the primary illness 
 intercurrent illnesses 
 drug interactions 
 events related or possibly related to concomitant medications 
 abnormal laboratory values, as well as significant shifts from baseline within the range of 
normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
 
11.3 
Definition of Adverse Drug Reaction (ADR) 
 
An ADR is “any untoward and unintended response to a medicinal product related to any 
dose administered”.  
All AEs judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression 
reasonable causal relationship means to convey in general that there is evidence or matter to 
suggest a causal relationship. 
 
 Unexpected ADR:  
an unexpected ADR is: “An adverse reaction, the nature or severity of which is not consistent 
with the applicable product information (Reference Safety Information - RSI)” 
 
 Reference Safety Information (RSI): in order to assess whether an ADR is expected, the 
IB will be used. 


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11.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
 
A Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) is: “any 
untoward medical occurrence or effect that at any dose”:  
 results in death 
 is life-threatening (i.e. the subject was at risk of death at the time of the event/reaction; 
it does not refer to an event/reaction which hypothetically might have caused death if 
it were more severe) 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity (where disability is defined as a 
permanent or substantial disruption of ability to carry out normal life functions, either 
reported or defined as per clinical judgement) 
 is a congenital anomaly/birth defect 
 is an important medical event that may not result in death, be life-threatening, or 
require hospitalization but, according to appropriate medical judgment, it may 
jeopardize the subject’s health status and may require intervention to prevent any of 
the outcomes listed in the definition above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home or 
blood dyscrasias or convulsions that do not result in hospitalisation or development of 
drug dependency or drug abuse 
 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event. 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an ADR that is both 
unexpected (not consistent with the RSI) and also meets the definition of a SAE. 
 
A non-serious adverse event is any adverse event that does not meet the criteria listed above 
for a serious adverse event. 
 
11.5 
Definition of Severity of Adverse Events 
 
The term “severe” is used to describe the intensity (severity) of a specific event: 
- 
Mild: causing no limitation of usual activities; the subject may experience slight 
discomfort. 
- 
Moderate: causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
- 
Severe: causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
 
11.6 
Definition of Adverse Event causality 
 
Causality shall be determined according to the definition of ADR given in  11.3. 
 


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All AE judged by either the investigator or the sponsor as having a reasonable suspected 
causal relationship to an investigational medicinal product qualify as adverse reactions. The 
causality assessment given by the investigator should not be downgraded by the sponsor. 
 
The following binary decision for causality will be used: 
 Reasonable possibility that the IMP caused the event 
 No reasonable possibility that the IMP caused the event 
Features supportive of an association include: 
• temporal plausibility 
• pharmacological properties of the drug or of the substance class 
• course of the adverse event after dechallenge and, if applicable, after rechallenge 
• specific tests indicating involvement of the drug in the occurrence/worsening of the 
adverse event  
• alternative explanations 
 
11.7 
Adverse Events recording 
 
Each AE occurring to a subject, either spontaneously revealed by the subject or observed by 
the investigator, whether believed by the investigator to be related or unrelated to the IMP, 
must be recorded on the AE information page of the CRF (for SAEs information must be 
recorded also on the “Serious Adverse Event Form”).  
The investigator will also perform an evaluation with respect to seriousness and causality 
(relationship of any AE to IMP) of the AEs and record it on the appropriate section of the 
CRF and on the ”Serious Adverse Event Form” (if appropriate).  
 
11.8 
AEs monitoring window 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: final visit/ETV  
An AE occurring after the final visit/ETV and coming to knowledge of the investigator (e.g. 
by spontaneous reporting by study subjects) must be recorded only if it is an ADR, according 
to the investigator’s judgment. 
 
11.9 
Adverse Events reporting 
 
The official language for reporting is English. The investigator and clinical staff of the present 
study are familiar with English language. 
 
The investigator must report all AEs which occur during the study, regardless of their 
relationship to the IMP.  
 
 
 


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11.10 
SAEs reporting 
 
The investigator must report the SAEs immediately and not later than 24 h from when he 
becomes aware of the SAE, by faxing the “Serious Adverse Event Form” (back up plan) or e-
mailing as scanned attachment (backup plan) or by Electronic Data Capture to the Drug 
Safety Unit (DSU) personnel of Zambon (preferred method). 
 
The community standards of confidentiality must always be maintained and any relevant 
national legislation on data protection must be followed. 
 
Another copy of the “Serious Adverse Event Form” will be retained by the investigator for the 
investigator’s file. 
 
If the investigator becomes aware of any SAE occurred to a subject within the window 
established in the protocol, he will report the SAE as above. The SAE will be also reported in 
the CRF. 
 
If outside the window established in the protocol the investigator becomes aware of a SAE, it 
is the investigator’s responsibility to report the SAE. The investigator might use the “Serious 
Adverse Event Form” via email or fax, but the SAE must not to be reported in the CRF, as it 
is not an event occurred within the study period. 
 
11.11 
Follow-up for Adverse Events 
 
A follow-up “Serious Adverse Event Form” will be filled in if important follow-up 
information (i.e. diagnosis, outcome, causality assessment, results of specific investigations) 
is made available after submission of the initial SAE Form for immediate reporting. Follow-
up “Serious Adverse Event Form” will be reported to the Sponsor as above-described. 
 
In any case of an AE that, in the opinion of the investigator, requires the subject’s 
discontinuation, follow-up information relating to the subjects subsequent course must be 
collected until the event has subsided or the condition stabilised or when the subject is lost to 
follow up and uncontactable. 
 
When follow-up data on non-serious AE are collected, information should be reported under 
“Comments” in the Final report of the CRF. 
 
11.12 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the Sponsor (day 0).  
For fatal and life-threatening SUSARs the EC and Competent Authority (Swissmedic) should 
be informed as soon as possible and in any case within 7 days. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. Complete follow-up report should 
be sent within 15 calendar days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 


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The minimum information to be reported includes: 
 Sponsor study code 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect IMP (including active substance name, code) 
 A causality assessment. 
 
In addition, in order to properly process the report electronically, the following administrative 
information should be provided: 
 
 the sender’s (case) safety report unique identifier, 
 the receipt date of the initial information from the primary source, 
 the receipt date of the most recent information, 
 the worldwide unique case identification number, 
 the sender identifier. 
 
11.13 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting when they might materially alter the 
current benefit-risk assessment of a medicinal product or would be sufficient to consider 
changes in the medicinal product administration or in the overall conduct of the study, for 
instance: 
 single case reports of an expected serious adverse reaction with an unexpected 
outcome (e.g.: a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical study and are 
reported to the investigator by the subject. 
 new events relating to the conduct of the study or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
− a SAE which could be associated with the study procedures and which could 
modify the conduct of the study 
− a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) or from other clinical study. 
 


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11.14 
SAEs: contacts 
 
The Phase I Unit can be contacted using the phone and fax numbers stated in this protocol or 
calling the mobile phone number +41.79.822.35.07 (operative 24-h/day, 365 days/year). This 
mobile phone can be called by the study participants to communicate to the clinical staff any 
SAE occurring outside the clinical facility. 
 
The Sponsor contact for SAEs is the following: 
 
Dr. Milko Radicioni 
Phone: +41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: milko.radicioni@croalliance.com 
 
The investigator will report any SAE to the sponsor. The sponsor’s details for SAEs are the 
following: 
Phone: 
+39.02.66.524.444 
Fax: 
+39.02.66.524.038 
Email: 
drugsafety@zambongroup.com 
 
11.15 
Pregnancy 
 
Subjects must be instructed that known or suspected pregnancy occurring during the study 
should be confirmed and reported to the investigator, who must then withdraw the subject 
from the study without delay. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after its completion. In the event that a subject is subsequently 
found to be pregnant after inclusion in the study, then any pregnancy will be followed to term 
and the status of mother and child will be reported to the Sponsor after delivery through the 
Pregnancy Report Form provided by the Sponsor. The investigator will send pregnancy 
reports to DSU within the timeframes of SAEs, with follow-up information to be actively 
sought for the outcome of pregnancy.  
- 
Part I of the Form is completed at the time of awareness of foetal exposure during 
pregnancy.  
- 
Part II of the Form is filled in when information on pregnancy outcome becomes 
available. 
If pregnancy results in abnormal outcome that the investigator considers to be due to the IMP, 
this will be treated as an expedited ADR report. 
 


CONFIDENTIAL 
 
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12 
DATA MANAGEMENT PROCEDURES 
 
12.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRFs. He must also check that the data reported in the CRFs correspond to 
those in the subject’s source documents.  
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-
point pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be 
carried out by the investigator or a designated member of staff. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. A single stroke 
must be drawn through the original entry. Corrections have to be dated and initialled. In the 
interest of completeness of data acquisition, the questions which are repeated in each section 
of the CRFs should be answered in full, even if there are no changes from a previous 
examination. The investigator must provide a reasonable explanation for all missing data. 
The CRFs will be completed, signed by the investigator, sent to the CRO Biometry Unit for 
data management procedures and finally sent to the sponsor.  
 
12.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. The unique subject identifier consists of the sponsor study code 
(i.e. Z7251J01), the 3-digit site number (i.e. 001), the 4-digit screening number (e.g. S001, 
S002, etc.) and, if applicable, the 3-digit subject randomisation number (e.g. 001, 002, etc.). 
Study code, site number, screening number and subject randomisation number are separated 
by slashes (“/”). The last 8 digits of the unique subject identifier (enrolled subjects), 
corresponding to the subject screening and subject randomisation numbers separated by a 
slash, or the last 4 digits of the unique subject identifier (not enrolled subjects), corresponding 
to the subject screening number, will appear as subject identifier in the individual listings and 
figures of the clinical study report and will be used to identify the subjects in in-text tables or 
wording (if applicable). 
 
12.3 
Database management 
 
The CRO will provide a double data entry with total re-entry of data and discrepancy 
resolution by a second data entrist and will update and verify the database and create the final 
SAS data sets. The final data file will be transferred to the sponsor in the agreed format with 
all the other study documentation. 
 
12.3.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™). 
Previous and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE). The version of the coding dictionaries will be stated in the study 
report. 


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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff of Clinical Medical Services of 
Maria Pia Savorelli, Switzerland.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOAC principles (Attributable-Legible-
Contemporaneous-Original-Accurate-Complete). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CROs and the sponsor will be responsible for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the sponsor. 
 
 


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13.3 
Applicable SOPs 
 
The Sponsor and the CRO will follow their respective SOPs in the conduct of the respective 
activities as specified in the signed assignment of responsibilities. For definition and handling 
of AEs the Sponsor’s SOP will be used. SOPs will be made available for review, if required. 
 
13.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs 
and all other documentation that is relevant to this study will be made accessible for 
monitoring activities, audits, IEC review, and regulatory inspections. 
 
13.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
 The investigator and the CRO agree, by written consent to this protocol, to fully co-
operate and support audits and inspections compliance checks by allowing authorised 
individuals to have access to all the study documentation. 
 
 
 


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14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The approval of the study protocol by the local (Canton Ticino) IEC and by the Federal 
Health Authorities (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the current revision of Good 
Clinical Practice (GCP), ICH topic E6 (R2), and the applicable local law requirements. 
 
14.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
It will include all the elements required by law according to the ICH-GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
 any potential negative effects attributable to the study product or treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of a subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see §  15.3). 
The investigator will allow inspection of the forms by authorised representatives of the 
sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
A blank copy of the information sheet and the informed consent form is appended to this 
protocol. 
 


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14.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical 
study. The insurance is in compliance with the local regulation and with the requirements of 
the Health Authorities. 
 
14.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a 
subject, study treatment or observations are discontinued, the primary reason for 
discontinuation will be recorded. 
 
14.4.1 
Primary reason for discontinuation 
 
 Adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to §  11.2. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 study terminated by Sponsor or by Swissmedic or EC:  
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
14.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 
assays. This examination will verify that all values tested at screening have remained 
within a clinically acceptable range (i.e. not clinically significant changes compared to 
screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 


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 record the subject decision about the use of collected biological samples 
 report in the CRF date and time of the last dose administration, and date and primary 
reason of study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
Subjects withdrawn from the study will retain their randomisation/study number and will not 
be replaced.  
 
14.5 
Study termination 
 
The study will be considered concluded at the date of the last visit of the last subject (LSLV) 
or upon completion of any follow-up procedure described in protocol.  
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. 
Reasons for discontinuation have to be documented appropriately and immediately reported to 
Swissmedic and EC (i.e. within 15 days).  


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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centre 
 
Beside IMPs, the following study material will be supplied to the clinical centre: 
 final version of the study protocol 
 CRF for each subject plus some spare copies 
 copy of the investigator’s brochure (IB) relative to the IMP 
 informed consent forms 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments 
(if any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
15.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to EC and Swissmedic, as appropriate. The 
amendment will be applicable only when it is approved, unless the changes consist of urgent 
safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  


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These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects including lab tests and ECG tracing, insurance contracts, certificate of analysis of the 
IMP(s), drug accountability records, signed informed consent forms, confidential subjects 
identification code, CRFs, curricula vitae of the investigator and other participants in the 
study, study staff lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited from the volunteers’ database maintained by the CRO. 
This database contains a pool of volunteers that are contacted whenever necessary to enrol 
subjects in a new study. Before the start of the new study, the principal investigator and other 
relevant staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the database, 
contacts potential participants to propose the study and evaluate their interest and availability. 
In addition to the volunteers’ database, new subjects often call or email the CRO asking to 
become a research volunteer, after hearing of the clinical site activities from other volunteers 
or friends or after checking the company web site. 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
15.5 
Confidentiality and data protection 
 
By signing this protocol, the CRO and the investigators agree to keep all the information 
provided by the sponsor in strict confidentiality and to request he same confidentiality from 
his/her staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
In this Phase I study the CRO plays the role usually performed by the Trial Center, 
performing services  like drug assay, clinical monitoring and related drafting of monitoring 
reports; clinical laboratory analysis; reporting and project management; test data management, 
statistics; drug/samples storage and trial document archiving directly or availing itself of 
authorized third parties. 
 


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Data on subjects collected in the CRFs during the study will be documented in a coded way 
(see §  12.2). If, as an exception, for safety or regulatory reasons identification of a subject 
becomes necessary, the monitor, the sponsor and the investigator will be bound to keep this 
information confidential. 
 
With reference to EU Regulation no.679/2016 of European Parliament and of the Council of 
27 April 2016, the General Data Protection Regulation (GDPR), such as Swiss Federal Data 
Protection Act of June, 19 1992, and other local law provisions the data protection roles 
within the Phase I study are the following: 
 the Sponsor and the CRO (that plays the role of the Investigational Center in this Phase I 
study) are Joint Controllers. The data processing activities performed within the Phase I 
clinical trial are jointly designed, addressed and managed by the Parties, pursuant to 
Article 26 of General Data Protection Regulation (EU) 2016/679 on personal data 
protection (hereinafter the “GDPR”). The Joint Controllers  will process the personal and 
study data of the participants exclusively for study related purposes and for 
pharmacovigilance purposes or for other legitimate purposes. 
 The Principal Investigator will process the data as a Data Processor, on behalf of the CRO. 
 
As concerns the data protection information/notice, participants must be informed properly 
about all the data protection elements provided by art. 13 and 14 of GDPR and similar 
provisions of the Swiss Federal Data Protection Act of June, 19 1992 and subsequent 
amendments. Investigator or his/her representative will give to the participant a proper data 
protection information notice compliant with GDPR, and will consequently ask to the 
participant a data protection consent, together with the study informed consent. According to 
the provisions of the GDPR and Swiss Data Protection Law, the level of disclosure in the 
informed consent must also be explained to the participant. The participant must be informed 
that his/her medical records may be examined by Auditors or other authorized personnel 
appointed by the sponsor, by appropriate EC members, and by inspectors from regulatory 
authorities. 
 
As regards the organizational and security measures adopted, the operations of collection, 
storage, circulation of biological samples as well as all the data processing operations 
regarding the study data are performed in compliance with GDPR and Swiss Data Protection 
Law. The investigator or his/her representative will assign to the participants a unique 
identifier. Investigator will be the only one who can match the participant’s identity with the 
data referred to the study. Any participant records or datasets that are transferred to the 
sponsor will contain the identifier code only; participant names or any other information 
which would make the participant identifiable will not be transferred to the Sponsor. 


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15.6 
Publication policy 
 
The sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the investigator publishing in peer 
reviewed journals, presenting results at scientific congresses and posting information and 
results on internet-based public registers and databases. 
Study results will be communicated in full to the competent Health Authorities (Swissmedic) 
by the submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 
 
According to The Federal Act on Research involving Human Beings and the Ordinance on 
Clinical Trials in Human Research, the study will be registered and published in a WHO 
primary register or clinicaltrials.gov as well as in the supplementary federal database.  
 
 


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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Zambon S.p.A., via Lillo del Duca 10, I-20091 Bresso, Italy 
Phone: 
+39.02.66.52.42.99 
Fax: 
+39.02.66.52. 48.87 
Email: 
carlo.cattaneo@zambongroup.com 
 
Sponsor representative 
 
Carlo Cattaneo, Global Head Medical Affairs CNS 
 
Medical Expert 
Paola Castellani, MD 
Global Chief Medical Officer and Patient’s Access Head 
 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centre 
 
CROSS Research S.A. – Phase I Unit, Via F. A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: 
clinic@croalliance.com 
 
Principal investigator 
Milko Radicioni, MD 
 
16.3 
Drug assay 
 
Accelera S.r.l., V.le Pasteur, 10, I-20014 Nerviano, Italy 
Phone: 
+39.0331.1984.444 
Fax: 
+39.0331.1984.200 
Email: 
info@accelera.org 
 
Analytics representative 
Daniele Pezzetta 
Phone: 
+39.0331.1984.355 
Fax: 
+39.0331.1984.325 
Email: 
daniele.pezzetta@accelera.org 
 
Analytical facilities and procedures are in compliance with the general principles of GLP 
regulations. 
 
 
 


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16.4 
Centralised clinical laboratory 
 
Unilabs Ticino, via Rovere 8, CH-6932 Breganzona, Switzerland 
Phone: 
+41.91.960.73.73 
Fax: 
+41.91.960.73.74 
Email: 
bmathis@unilabs.ch 
 
16.5 
Packaging and labelling 
 
STM Pharma PRO Srl., Italy, Via Abruzzi, IT–20056, Grezzago (MI), Italy 
Phone: 
+39.02.9506981 
Email: 
marina.farina@stmpharmapro.it 
 
16.6 
Co-ordination, data analysis & reporting 
 
CROSS Research S.A. 
Via F. A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Coordination 
Angelo Vaccani, Senior Clinical Project Leader 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing 
Andrea Di Stefano, Senior Medical Writer 
Email: 
medicalwriting@croalliance.com 
 
Biometry Unit Representative 
Alessandra Gentili, Biometry Manager, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
Email: 
qau@croalliance.com 
 
16.7 
Monitoring 
 
Clinical Medical Services di Maria Pia Savorelli, Via Indipendenza 29/A, CH-6883 
Novazzano, Switzerland 
Mobile: +41 79 827 27 67 
Email: 
cmed@cmed.ch 


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17 
REFERENCES 
 
1. Bensimon G, Lacomblez L, Meininger V, et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. 
N Engl J Med 1994a; 330:585-591 
2. Anon. Riluzole raises hopes and doubts in amyotrophic lateral sclerosis. Drugs Therapy Perspectives 1994; 
3:6-7 
3. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V, Dose-ranging study of riluzole in 
amyotrophic 
lateral 
sclerosis. 
Amytrophic 
later 
sclerosis/Riluzole 
Study 
Group 
II. 
Lancet. 
1996;347(9013):1425-1431 
4. Bucchia M, Ramirez A, Parente V, Simone C, Nizzardo M, Magri F, Dametti S, Corti S. Therapeutic 
development in amyotrophic lateral sclerosis. Clin Ther. 2015;37(3):668-680 
5. Orsini M, Oliveira AB, Nascimento OJ, Reis CH, Leite MA, de Souza JA, Pupe C, de Souza OG, Bastos 
VH, de Freitas MR et al. Amyotrophic Lateral Sclerosis: New Perspectives and Update. Neurol Int. 
2015;7(2):5885 
6. Riluzole orodispersible film. Investigator’s Brochure, Edition 3.0, Aquestive Therapeutics 
7. Rilutek SmPC, Rilutek EPAR 14 August 2019 - EMEA/H/C/000109 - IAIN/0060, last updated 11 
November 2019  
8. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the 
European Community, Volume 4 
9. Guidance on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr **, 20 January 
2010  
10. European Public Assessment Report (EPAR), Rilutek. EMEA/H/C/109 
11. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: 2015-2020 Dietary Guidelines, Appendix 9 
12. Phoenix 1.3 User’s Guide, Pharsight Corporation 
13. SAS/STAT® User’s Guide 
14. Guidance for Industry.  Bioavailability and bioequivalence studies for orally administered products - general 
considerations. U.S. Department of Health and Human Services. Food and Drug Administration, Center for 
Drug Evaluation and Research. CDER, March 2003 
  

SAP_001.pdf: 
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Statistical analysis plan CRO-PK-20-344 
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SAP template: frm-0097, version 4.0 
STATISTICAL ANALYSIS PLAN 
 
Study CRO-PK-20-344 - Sponsor code Z7251J01 
 
Comparative bioavailability study of a new riluzole orodispersible 
film vs. a marketed oral reference (Rilutek® tablets) in healthy 
male and female volunteers 
 
Single centre, single dose, open-label, randomised, 2-sequence, 4-period replicate 
cross-over study 
 
 
Test formulation: 
Riluzole 50 mg orodispersible film, Aquestive Therapeutics, USA 
Reference formulation: 
Rilutek®, 50 mg riluzole tablets, Sanofi Mature IP, France 
Sponsor: 
Zambon S.p.A., via Lillo del Duca 10, I-20091 Bresso, Italy 
Phone: +39.02.66.52.42.99 
Fax:     +39.02.66.52.48.87 
Email: carlo.cattaneo@zambongroup.com 
Investigator: 
Milko Radicioni, MD - Principal investigator 
CROSS Research S.A., Phase I Unit 
Via F.A. Giorgioli 14 
CH-6864 Arzo, Switzerland 
Phone: +41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: clinic@croalliance.com 
Development phase: 
I 
Version and date: 
Final version 1.0, 31MAY2021 
 
 
This study will be conducted in accordance with current version of Good Clinical Practice (GCP),  
ICH topic E6 (R2) 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 33 pages plus appendices 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 2 
 
 
SAP template: frm-0097, version 4.0 
VERSIONS' HISTORY 
 
Version 
Date of Issue 
Reason for change 
Draft version 0.1 
21MAY2021 
Alice Segantin issued the first draft 
Draft version 0.2 
28MAY2021 
Alice Segantin issued the second draft after revision of MW 
Final version 1.0 
31MAY2021 
Alice Segantin issued the final version after sponsor approval 
 
 






CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 5 
 
 
SAP template: frm-0097, version 4.0 
STUDY/INVESTIGATION SCHEDULE 
 
ACTIVITIES 
Screening 
PERIOD 1, 2, 3, 4 (wash-out≥7 days) 
Final 
visit/ETV12 
Visit 
V1 
V2, V4, V6, V8 
V3, V5, V7, V9 
V1011/ETV 
 Days -14/-2 
Day -1 
Day 1 
Day 2  
Day 211/ETV 
Informed consent 
x 
 
 
 
 
Demography 
x 
 
 
 
 
Lifestyle 
x 
 
 
 
 
Medical/surgical history  
x 
 
 
 
 
Physical abnormalities 
x 
 
 
 
x 
Previous and concomitant 
treatments 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
Body weight 
x 
 
 
 
x 
Laboratory analysis1 
x 
 
 
 
x 
Cotinine 
x 
 
 
 
 
Virology 
x 
 
 
 
 
Drug screening 
x 
x 
 
 
 
Vital signs 
x 
 
x 2 
x 2 
x13 
Pregnancy test  
x3 
x4 
 
 
 
ECG 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
x5 
 
 
 
Eligibility evaluation 
x 
x5 
 
 
 
Alcohol breath test 
 
x 
 
 
 
Enrolment and randomisation 
 
x5 
 
 
 
Confinement 
 
x 
x 
 
 
Discharge 
 
 
 
x 
 
IMP administration 
 
 
x6 
 
 
Palatability 
 
 
x7 
 
 
Mouth visual inspection  
 
 
x8 
 
 
Blood samplings 9 
 
 
x 
x 
 
Standardised meals 
 
x 
x 
x 
 
AEs monitoring10 
x 
x 
x 
x 
x 
 
1. 
Haematology, blood chemistry with the exception of cotinine, urinalysis  
2. 
At pre-dose and 2 and 36 h post-dose 
3. 
Women only - serum β-HCG test  
4. 
Women only - urine test  
5. 
Period 1, visit 2 
6. 
At 08:00 ± 1 h under fasting conditions 
7. 
Immediately after each administration of the test product 
8. 
At pre-dose and 0.5 and 1 h post-dose at each administration of the test product 
9. 
At pre-dose (0) and 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h post-dose 
10. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final 
visit/ETV 
11. Final visit on Day 2 of period 4 after the 36-h post-dose blood sampling 
12. Early termination visit (ETV) in case of subject’s premature discontinuation  
13. At the ETV only  
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 6 
 
 
SAP template: frm-0097, version 4.0 
TABLES OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN 
1 
VERSIONS' HISTORY 
2 
APPROVAL AND ACKNOWLEDGEMENT 
3 
STUDY/INVESTIGATION SCHEDULE 
5 
TABLES OF CONTENTS 
6 
TABLES 
7 
ABBREVIATIONS 
8 
1 
INTRODUCTION 
10 
1.1 
Changes with respect to the study protocol and its amendment 
10 
2 
STUDY OBJECTIVES 
11 
2.1 
Primary end-point 
11 
2.2 
Secondary end-points 
11 
3 
INVESTIGATIONAL PLAN 
12 
3.1 
Overall study design 
12 
3.2 
Discussion of design 
12 
4 
STUDY POPULATION 
13 
4.1 
Target population 
13 
4.2 
Inclusion criteria 
13 
4.3 
Exclusion criteria 
13 
4.3.1 
Not allowed treatments 
14 
5 
STUDY SCHEDULE 
16 
5.1 
Study visits and procedures 
16 
5.2 
Diet and lifestyle 
19 
5.3 
Restrictions 
19 
6 
STUDY 
SUBJECT 
IDENTIFICATION 
METHOD 
AND 
TREATMENT 
ASSIGNMENT METHOD 
20 
6.1 
Unique subject identifier 
20 
6.2 
Subject identifier for the study 
20 
6.3 
Randomisation 
20 
6.4 
Treatment allocation 
20 
6.5 
Blinding 
20 
7 
STUDY EVALUATION PARAMETERS 
21 
7.1 
Study variables 
21 
7.1.1 
Primary variables 
21 
7.1.2 
Secondary variables 
21 
7.2 
Pharmacokinetic assessments 
21 
7.2.1 
Pharmacokinetic parameters 
21 
7.3 
Safety and tolerability parameters 
22 
8 
STATISTICAL METHOD 
23 
8.1 
Tables, listings and figures layout 
23 
8.2 
Analysis sets 
24 
8.2.1 
Definitions 
24 
8.2.1.1 
Reasons for exclusion from the PK Set before bioanalysis 
24 
8.2.1.2 
Reasons for exclusion from the PK Set after bioanalysis 
25 
8.3 
Sample size and power considerations 
25 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 7 
 
 
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8.4 
Demographic, baseline and background characteristics 
26 
8.4.1 
Subjects' disposition 
26 
8.4.2 
Analysis sets 
26 
8.4.3 
Subjects excluded from PK and /or safety analysis 
26 
8.4.4 
Discontinued subjects 
26 
8.4.5 
Protocol deviations 
26 
8.4.6 
Demography 
27 
8.4.7 
Inclusion/exclusion criteria not met 
27 
8.4.8 
ECG 
27 
8.4.9 
Medical and surgical history 
27 
8.4.10 
Prior and concomitant medication 
27 
8.4.11 
Subjects' study visits 
27 
8.4.12 
Fertility status and contraceptive method 
27 
8.4.13 
Alcohol breath test, pregnancy test, cotinine test and urine drug test 
27 
8.4.14 
Tobacco consumption 
28 
8.4.15 
Meals 
28 
8.5 
IMP administration 
28 
8.5.1 
Dose per body weight 
28 
8.5.2 
Wash-out 
28 
8.6 
PK and Palatability analysis 
28 
8.6.1 
PK blood samples collection 
28 
8.6.2 
Descriptive pharmacokinetics/pharmacodynamics 
28 
8.6.3 
Statistical comparison of pharmacokinetic parameters 
29 
8.7 
Safety and tolerability analysis 
30 
8.7.1 
Adverse events 
30 
8.7.2 
Vital signs 
31 
8.7.3 
Laboratory data 
31 
8.7.4 
Physical examination 
31 
8.7.5 
Mouth Visual Inspection 
31 
8.8 
Analysis datasets 
31 
9 
REFERENCES 
32 
10 
APPENDICES 
33 
 
TABLES 
 
Table 9.4.1 - Sample size calculation 
25 
Table 8.9.3.1 
Examples of widened bioequivalence acceptance limits of Cmax according to its 
actual CVWR 
 
30 
 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 8 
 
 
SAP template: frm-0097, version 4.0 
ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUC0-∞ 
Area under the concentration versus time curve up to infinity 
%AUCextra  
Percentage of the residual area extrapolated to infinity in relation to the AUC∞ 
BE 
Bioequivalence 
BLQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm  
Beats per minute 
BW  
Body weight 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
Cmax 
Peak drug concentration 
CPL 
Clinical Project Leader 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CRS 
Clinical Study Report 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
CVWR 
 Coefficient of Variation within-subject 
DIABP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA  
European Medicine Agency 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device  
λz  
Terminal elimination rate constant, calculated, if feasible, by log-linear 
regression using at least 3 points 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
N 
Normal 
NA 
Not Applicable 
NC 
Not calculated 
NCS 
Not clinically significant 
OTC 
Over The Counter 
PK 
Pharmacokinetics 
PT 
Preferred Term 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 9 
 
 
SAP template: frm-0097, version 4.0 
PTAE 
Pre-Treatment Adverse Event 
QTc 
Corrected QT interval 
R 
Reference 
SAE 
Serious Adverse Event 
SYSBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test 
TEAE 
Treatment-Emergent Adverse Event 
t1/2 
Half-life 
tmax 
Time to achieve Cmax 
USDA 
United States Department of Agriculture 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 10 
 
 
SAP template: frm-0097, version 4.0 
1 
INTRODUCTION 
 
Statistical analysis will be performed by the CROSS Research Biometry Unit. The end-points 
and methods of analysis specified in this SAP are consistent with ICH E6 (R2) and E9 
guidelines (1, 2) and with EMA guideline on the investigation of bioequivalence (3, 4). The 
SAP has been compiled by the CRO Biometry Unit on the basis of the final version 1.0 of the 
clinical study protocol and its amendment (5, 6), reviewed by the Sponsor and finalized 
before the database lock. 
 
1.1 
Changes with respect to the study protocol and its amendment 
 
No change with respect to the study protocol and its amendment  (5, 6) was introduced in this 
SAP.


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 11 
 
 
SAP template: frm-0097, version 4.0 
2 
STUDY OBJECTIVES 
 
The objective of the study is to compare the pharmacokinetic profile of riluzole after replicate 
single dose of the novel orodispersible film test formulation and of the marketed reference 
Rilutek® tablets and to evaluate their bioequivalence. 
 
2.1 
Primary end-point 
 
• 
To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of riluzole 
after replicate single dose administration of test and reference. 
 
2.2 
Secondary end-points 
 
• 
To describe the PK profile of riluzole after replicate single dose administration of test 
and reference; 
• 
to evaluate the test product palatability; 
• 
to collect safety and tolerability data of test and reference after replicate single dose 
administration. 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 12 
 
 
SAP template: frm-0097, version 4.0 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Overall study design 
 
Single centre, single dose, open-label, randomised, 2-sequence, 4-period replicate cross-over 
study. 
 
3.2 
Discussion of design 
 
The study was designed in agreement with the EMA guideline “Guidance on the investigation 
of bioequivalence”, CPMP/EWP/QWP/1401/98 Rev. 1 January 2010 (3). The well-known 
high variability of riluzole led to the choice of the replicate cross-over design as suggested by 
the current EMA guideline. According to the guideline, an enlargement of the acceptance 
interval for bioequivalence in terms of Cmax is allowed up to 69.84-143.19% in relation to the 
actual intra-subject variability of riluzole Cmax found in this study with the reference 
treatment, by keeping in consideration the favourable safety profile of the test formulation 
previously observed in 3 clinical studies. In detail, a Cmax within-subject variability >30% was 
found in the previous pilot study and =32.66% in the previous bioequivalence study 
performed in USA (7). According to the 2-arm cross-over study design, each randomised 
subject will be allocated to one of 2 sequences of IMP administrations in the 4 study periods 
according to a computer generated randomisation list (see § 6.3). Balance between the 
sequences will be made so that subjects have the same chances to be assigned to 
either sequence (either RTRT or TRTR in the 4 consecutive periods). 
 
An open-label design will be used since the primary end-point of the study is based on 
objective measurements of riluzole in plasma and the outcome variables could not be 
influenced by the subjects or investigator being aware of the administered products. The 
bioanalysis will be performed under blinded conditions. 
 
The washout period of 7 days was estimated to be adequate. Based upon a half-life of 12 h 
(Rilutek SmPC reference: 8), it is anticipated that minimal plasma levels would be achieved 
in 5 days thus allowing dosing every 7 days. Blood sampling time-points were selected on the 
basis of the known PK profile of riluzole and on the basis of previous Phase I studies of the 
same test formulation administered to healthy volunteers. 
 
The dose for the present study was selected based on EMA Rilutek® European Public 
Assessment Report (EPAR) (9), which recommends a dose regimen of 50 mg (one filmcoated 
tablet) twice a day in the common clinical practice. The dose of 50 mg is the minimal unit 
dose. 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 13 
 
 
SAP template: frm-0097, version 4.0 
 
4 
STUDY POPULATION 
 
4.1 
Target population 
 
Healthy men and women will be enrolled in this study. 
 
4.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
 
1. 
Informed consent: signed written informed consent before inclusion in the study 
2. 
Sex and Age: men/women, 18-55 years old inclusive 
3. 
Tobacco: non-smokers for at least 6 months prior to study screening 
4. 
Body Mass Index (BMI): 18.5-29 kg/m2 inclusive 
5. 
Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure 
(DBP) 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting 
position 
6. 
Full comprehension: ability to comprehend the full nature and purpose of the study, 
7. 
including possible risks and side effects; ability to co-operate with the investigator and 
to comply with the requirements of the entire study 
8. 
Contraception and fertility (women only): women of child-bearing potential must be 
using at least one of the following reliable methods of contraception: 
a. A non-hormonal intrauterine device [IUD] or female condom with 
spermicide or contraceptive sponge with spermicide or diaphragm with 
spermicide or cervical cap with spermicide for at least 2 months before 
the screening visit 
b. A male sexual partner who agrees to use a male condom with spermicide 
c. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at 
least 1 year will be admitted. 
For all women, pregnancy test result must be negative at screening. 
 
4.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
 
1. 
Electrocardiogram 
(ECG) 
12-leads: 
(supine 
position) 
clinically 
significant 
abnormalities; QTc interval > 450 msec 
2. 
Physical findings: clinically significant abnormal physical findings which could 
interfere with the objectives of the study 
3. 
Laboratory analyses: clinically significant abnormal laboratory values indicative of 
physical illness 
4. 
Cotinine: positive cotinine test at screening 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 14 
 
 
SAP template: frm-0097, version 4.0 
5. 
Allergy: ascertained or presumptive hypersensitivity to the active principle and/or 
formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in 
general, which the investigator considers may affect the outcome of the study 
6. 
Diseases: clinically significant history or presence of renal, hepatic, gastrointestinal, 
cardiovascular, cerebrovascular, immunological, musculoskeletal, respiratory, skin, 
haematological, endocrine, psychiatric or neurological diseases or surgeries that may 
interfere with the aim of the study. Gastrointestinal pathologies include any clinically 
significant disorder of the mouth, e.g. impairment of swallowing, lesions, ulcerations, 
deformities, untreated dental caries 
7. 
Dentures: presence of mouth jewellery, dentures, braces, piercings that may interfere 
with successful completion of the dosing 
8. 
Medications: medications, including over the counter (OTC) medications and herbal 
remedies for 2 weeks before study screening; central nervous system depressants, 
including opioids, benzodiazepines, general anaesthetics and anticonvulsants, or CYP 
inhibitors, including cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, 
fluconazole, ketoconazole, diltiazem and antiretroviral agents, or strong CYP inducers, 
including barbiturates, carbamazepine, glucocorticoids, phenytoin, St John’s wort and 
rifampin, or hormonal oral or transdermal contraceptives for 30 days before study 
screening; implanted, injected, intravaginal or intrauterine hormonal contraceptives for 
6 months before study screening 
9. 
Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between 
the first calendar day of the month that follows the last visit of the previous study and 
the first day of the present study 
10. 
Blood donation: blood donations for 3 months before this study 
11. 
Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and 
>2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015 (10)], 
caffeine (>5 cups coffee/tea/day) or tobacco use including any tobacco product like 
ecigarettes and vaping products 
12. 
Drug test: positive result at the drug test at screening or Day -1 
13. 
Alcohol test: positive alcohol breath test at Day -1 
14. 
Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits 
in the 4 weeks before this study; vegetarians and vegans 
15. 
Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, 
pregnant or lactating women 
 
4.3.1 
Not allowed treatments 
 
No medication, including OTC and herbal remedies, will be allowed for 2 weeks before the 
start of the study and during the whole study duration. 
 
Central nervous system depressants, including opioids, benzodiazepines, general anaesthetics 
and anticonvulsants, or CYP inhibitors, including cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and antiretroviral agents, or 
strong CYP inducers, including barbiturates, carbamazepine, glucocorticoids, phenytoin, St 
John’s wort and rifampin, or hormonal oral or transdermal contraceptives will be forbidden 
for 30 days before study screening and during the whole study duration. 
 
Implanted, injected, intravaginal or intrauterine hormonal contraceptives will be forbidden for 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 15 
 
 
SAP template: frm-0097, version 4.0 
6 months before study screening and during the whole study duration. 
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) 
according to the investigator’s opinion. 
 
The intake of any other medication will be reported as a protocol deviation. However, it will 
lead to subject's discontinuation from the study only if the investigator, together with the 
sponsor, considers it could affect the study assessments or outcome 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 16 
 
 
SAP template: frm-0097, version 4.0 
5 
STUDY SCHEDULE 
 
The schedule of the study/investigation is summarised at page 5. 
 
5.1 
Study visits and procedures 
 
Each study subject will undergo 10 visits. 
 
The study protocol foresees 4 periods separated by wash-out intervals of at least 7 days. 
Minimum study duration will be 25 days, screening visit included. A written informed 
consent will be obtained before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the Phase I Unit by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the Phase I Unit by the last subject, i.e. the last visit foreseen by the study protocol, 
independently of the fact that the subject is a completer or a withdrawn subject, and it 
corresponds to the study completion. 
 
The following phases, visits and procedures will be performed: 
 
• 
Screening phase 
 
Screening – visit 1: between Day -14 and Day -2 
 
Period 1 – visit 2: Day -1 
 
• 
Interventional phase 
 
Period 1 – visit 3: Days 1-2 
 
Wash-out interval of at least 7 days 
 
Period 2 – visit 4: Day -1 
 
Period 2 – visit 5: Days 1-2 
 
Wash-out interval of at least 7 days 
 
Period 3 – visit 6: Day -1 
 
Period 3 – visit 7: Days 1-2 
 
Wash-out interval of at least 7 days 
 
Period 4 – visit 8: Day -1 
 
Period 4 – visit 9: Days 1-2 
 
• 
Final phase 
 
Period 4 – visit 10: Day 2 - Final visit or early termination visit (ETV) in case of 
early discontinuation 
 
 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 17 
 
 
SAP template: frm-0097, version 4.0 
 
 
 
Day 
Procedures/Assessments 
Notes 
Screening phase 
Screening – visit 1 
From Day -14 to 
Day -2 
 Explanation to the subject of study aims, 
procedures and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, 
vital signs, physical abnormalities) 
 ECG recording 
 Laboratory 
analyses: 
haematology, 
blood 
chemistry, cotinine, urinalysis, virology and 
serum pregnancy test (women only) 
 Urine multi-drug kit test 
 AE monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two 
letters 
of 
the 
surname 
followed 
by the first two 
letters of the first 
name will be used in 
the Phase I Unit 
source 
document 
only and will not be 
transferred to the 
sponsor 
Period 1 
Visit 2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women only) 
 AE and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomisation 
Arrival at the Phase I 
Unit in the evening 
Confinement 
until 
the evening of Day 2 
Standardised low-fat 
dinner 
Fasting for at least 10 
h (overnight) up to 
dosing 
Visit 3 
Day 1 
 IMP administration at 08:00 ± 1 h 
 Palatability of the test product immediately 
after administration 
 Mouth visual inspections after administration of 
the test investigational medicinal product, at 
pre-dose and 0.5 and 1 h post-dose  
 Vital signs measurement 
 Blood sample collection for PK analysis  
 AE and concomitant medications 
Fasting until about 5 
h post-dose 
Standardised lunch at 
about 13:00  
Standardised dinner 
at about 20:00 (12 h 
post-dose)  
Day 2 
 Vital signs measurement  
 Blood sample collection for PK analysis  
 AE and concomitant medications 
Standardised 
breakfast at about 
8:00 and lunch at 
about 13:00  
Discharge from the 
Phase I Unit in the 
evening after the 36-
h 
post-dose 
blood 
sample collection and 
vital signs check 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 18 
 
 
SAP template: frm-0097, version 4.0 
 
 
Day 
Procedures/Assessments 
Notes 
Period 2 
Visit 4 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 5 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 3 
Visit 6 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 7 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 
Day 2 
As visit 3 
As visit 3 
Wash-out 
At least 7 days 
A wash-out interval of at least 7 days between 2 
consecutive administrations  
 
Period 4 
Visit 8 
Day -1 
As visit 2, excluding inclusion/exclusion criteria 
evaluation, enrolment and randomisation 
As visit 2 
Visit 9 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
As visit 3 
Period 4 
Visit 9 
Day 2 
As visit 3 
As visit 3 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 19 
 
 
SAP template: frm-0097, version 4.0 
 
 
Day 
Procedures/Assessments 
Notes 
Final phase  
Visit 10 - Final Visit or ETV 
Day 2 of 
period 4 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight and 
physical abnormalities; also vital signs in case 
of ETV) 
 Laboratory analyses as at screening, with the 
exception of cotinine, virology, urine drug test 
and pregnancy test 
 AE and concomitant medications 
 
In case of clinically significant results at the final 
visit, the subjects will be followed-up by the 
investigator until the normalisation of the 
concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
investigator in case 
of occurrence of any 
adverse reactions 
 
5.2 
Diet and lifestyle 
 
During confinement, the subjects will not take any food or drinks (except water) for about 10 
h (i.e. overnight) before IMP administration and for about 5 h afterwards. On Day -1 of each 
study period, a standardised low-fat dinner will be served. Water will be allowed as desired, 
except for one h before and one h after IMP administration. In order to maintain an adequate 
hydration, the subjects will be encouraged to drink at least 150 mL of still mineral water 
every 2 h for 5 h post-dose, starting at 1 h post-dose. 
 
On Day 1 of each study period, the subjects will remain fasted until about 5 h post-dose. 
Standardised lunch and dinner will be served at approximately 5 h and 12 h post-dose. On 
Day 2 of each study period, standardised breakfast and lunch will be served at about 8:00 and 
13:00, respectively. The meals’ composition will be standardised on Days -1 and 1 in each 
study period (see the study protocol (5) for further details). 
 
Coffee, tea or food containing xanthines (i.e. coke, chocolate, etc.), smoking, alcohol and 
grapefruit will be forbidden during confinement. In particular, alcohol and grapefruit will be 
forbidden for 24 h before the first IMP administration until the end of the study. 
 
Only non-smokers will be included in the study. 
 
During confinement, routine ambulant daily activities will be strongly recommended. 
 
5.3 
Restrictions 
 
During each study period, the subjects will be confined from the evening preceding the IMP 
administration (study Day -1) until the evening of Day 2. 
 
For the 4 h following each administration, when not involved in study activities, the subjects 
will remain seated. They will not be allowed to lie down. 
 
During confinement, hazardous, strenuous or athletic activities will not be permitted.


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 20 
 
 
SAP template: frm-0097, version 4.0 
6 
STUDY SUBJECT IDENTIFICATION METHOD AND TREATMENT 
ASSIGNMENT METHOD 
 
6.1 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
"unique subject identifiers" when data are extracted from the study database into the domains 
of the CDISC SDTM and ADaM models. The unique subject identifier consists of the sponsor 
study code (i.e. Z7251J01), the 3-digit centre number (e.g. 001, 002, etc), the 4-digit 
screening number (e.g. S001, S002, etc.) and the 3-digit randomisation number (e.g. 001, 002, 
etc., when applicable). Study code, centre number, screening number and randomisation 
number (when applicable) are separated by slashes ("/"). 
 
6.2 
Subject identifier for the study 
 
The last 8 digits of the unique subject identifier (enrolled subjects), corresponding to the 
subject screening and subject randomisation numbers separated by a slash, or the last 4 digits 
of the unique subject identifier (not enrolled subjects), corresponding to the subject screening 
number, will appear as subject identifier in the individual listings and figures of the clinical 
study report and will be used to identify the subjects in in-text tables or wording (if 
applicable). 
 
6.3 
Randomisation 
 
The randomisation list was computer-generated by the Biometry Unit of the Clinical Contract 
Research Organization (CRO), using the PLAN procedure of the SAS® version 9.3 (TS1M1) 
(11). The randomisation list was supplied to the study site and to STM Pharma PRO Srl., Italy 
for the preparation of the IMP individual kits before study start and will be attached to the 
final clinical study report. 
 
6.4 
Treatment allocation 
 
The study subjects will be assigned to one of 2 sequences of treatments (either RTRT or 
TRTR) according to their randomisation number. Randomisation number will be given to the 
subjects on study Day -1, period 1, as soon as they are definitely enrolled in the study. 
 
6.5 
Blinding 
 
This is an open study. No masking procedure will be applied. 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 21 
 
 
SAP template: frm-0097, version 4.0 
7 
STUDY EVALUATION PARAMETERS 
 
7.1 
Study variables 
 
7.1.1 
Primary variables 
 
• 
Cmax and AUC0-t of plasma riluzole after replicate single dose administration of test and 
reference formulation. 
 
7.1.2 
Secondary variables 
 
• 
AUC0-∞, t1/2, tmax, AUCextra, λz, of riluzole after replicate single dose administration of 
test and reference; 
• 
Palatability score 
• 
TEAEs, vital signs (BP, HR), laboratory parameters, physical examination including 
BW 
 
7.2 
Pharmacokinetic assessments 
 
The following PK parameters will be measured and/or calculated for riluzole, using the 
validated software Phoenix WinNonlin® version 6.3 (12) or higher (actual version will be 
stated in the final report). 
 
7.2.1 
Pharmacokinetic parameters 
 
• 
Cmax 
Maximum plasma concentration 
• 
tmax 
Time to achieve Cmax 
• 
λz 
Terminal elimination rate constant, calculated, if feasible, by log-
linear regression using at least 3 points 
• 
t1/2 
Half-life, calculated, if feasible, as ln(2)/λz 
• 
AUC0-t 
Area under the concentration-time curve from administration to the 
last observed concentration time t, calculated with the linear 
trapezoidal method 
• 
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity, 
calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last 
measurable drug concentration 
• 
%AUCextra 
Percentage of the residual area (Ct/λz) extrapolated to infinity in 
relation to the total AUC0-∞, calculated, if feasible, as 100×[(Ct/λz)/ 
AUC0-∞] 
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0-∞ equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that the primary variable AUC0-t covers a sufficient percentage of the theoretical total 
extent of exposure. 
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 22 
 
 
SAP template: frm-0097, version 4.0 
7.3 
Safety and tolerability parameters 
 
Safety and general tolerability of the IMP will be based on TEAEs, physical examinations 
including body weight, vital signs and routine haematology, blood chemistry and urinalysis 
laboratory tests. 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 23 
 
 
SAP template: frm-0097, version 4.0 
8 
STATISTICAL METHOD 
 
The statistical analysis of demographic and safety data will be performed using SAS® version 
9.3 (TS1M1) (11) or higher (the actual versions will be stated in the final report). 
 
The statistical analysis of PK parameters will be performed using Phoenix WinNonlin® 
version 6.3 (12) or higher and SAS® version 9.3 (TS1M1) or higher. 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. geometric mean (PK data only), arithmetic 
mean, SD, CV (%), minimum, median and maximum values for quantitative variables and 
frequencies for qualitative variables. 
 
8.1 
Tables, listings and figures layout 
 
Tables, listings and figures will be provided according to the following settings: 
 
• 
Background: White 
• 
Foreground: Black 
• 
Font face: Times 
• 
Font style: Roman 
• 
Font size: 10 pt 
• 
Font weight: Medium (data, footers and notes), Bold (titles and headers) 
• 
Font width: Normal 
• 
Layout: Landscape 
• 
Top Margin: 2.5 cm 
• 
Bottom Margin: 2.5 cm 
• 
Left Margin: 0.8 cm 
• 
Right Margin: 0.8 cm 
• 
Test label: Riluzole 50 mg orodispersible film (T) 
• 
Reference/Placebo label: Rilutek®, 50 mg riluzole tablets (R) 
• 
Date format: ddMMMyyyy 
• 
Means, standard deviations, percent coefficient of variations, medians, lower confidence 
limits and upper confidence limits will be rounded to one digit more than the original 
data 
• 
Minima and maxima will keep the same number of decimal digits as the source values 
• 
p-values will be rounded to the fourth decimal digit and will be flagged by an asterisk 
(*) in case of statistical significance (i.e. p-value < 0.05 or, in case of centre by 
treatment interaction, p-value < 0.10) 
• 
p-values lower than 0.0001 will be reported as "<.0001 *". 
 
The data and results of Riluzole 50 mg orodispersible film (T) will be presented before the 
data and results of Rilutek®, 50 mg riluzole tablets (R) in all listings and tables. 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 24 
 
 
SAP template: frm-0097, version 4.0 
8.2 
Analysis sets 
 
8.2.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure. 
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to one 
treatments sequence. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatments sequence. 
 
The following analysis sets are defined: 
 
• 
Enrolled Set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
• 
Safety Set: all subjects who receive at least one dose of the investigational medicinal 
products. This analysis set will be used for the safety analyses 
• 
PK Set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal product intake and have evaluable PK data readouts for the 
planned treatment comparisons, with no major deviations that may affect the PK results. 
This analysis set will be used for the statistical analysis of the PK results 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Safety set 
and the PK set. Subjects will be evaluated according to the treatment they actually receive. 
 
8.2.1.1 
Reasons for exclusion from the PK Set before bioanalysis 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
• 
vomiting and diarrhoea after drug intake which could render the plasma concentration-
time profile unreliable 
• 
intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
• 
AEs which could render the plasma concentration-time profile unreliable 
• 
administration errors which could render the plasma concentration-time profile 
unreliable 
• 
other events which could render the plasma concentration-time profile unreliable 
 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 25 
 
 
SAP template: frm-0097, version 4.0 
8.2.1.2 
Reasons for exclusion from the PK Set after bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 
• 
subjects with lack of any measurable concentrations or only very low plasma 
concentrations for the reference medicinal product. A subject is considered to have very 
low plasma concentrations if his/her AUC is less than 5% of the reference medicinal 
product geometric mean AUC (which should be calculated without inclusion of data 
from the outlying subject) 
• 
subjects with implausible concentrations (i.e. different from the known, expected 
concentration profiles) for the reference medicinal product. The exclusion of these 
subjects must be justified on the basis of sound scientific reasons and mutually agreed 
between the CRO and the Sponsor 
• 
subjects with non-zero baseline concentrations > 5% of Cmax 
 
The samples from the subjects excluded from the PK set should still be assayed and the 
results listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 
80% of the AUC0-∞. 
 
8.3 
Sample size and power considerations 
 
Data from previous PK studies of the test product, 1897 and 162020 (see the study protocol 
(5) for further details) were used to calculate the sample size of the present study, as shown in 
the table below. 
 
Table 9.4.1 - Sample size calculation 
Parameter 
δ 
CVWR 
α 
β 
n 
N=2n 
Cmax 
1.11 
0.3266 
0.1 
0.2 
26 
52 
AUC0-t 
1.0917 
0.1265 
0.1 
0.2 
4 
9 
δ: ratio of geometric means of the considered parameter; CVWR%: within-subject variability; α: type 1 
error; β: type 2 error; n: number of subjects per sequence; N: total sample size 
 
Variability of AUC0-t and Cmax (CVWR) actually observed in study 162020 (§ 1.4.2) was used 
in the calculation. The actual ratio of geometric means of AUC0-t of study 162020 was 1.0917, 
whilst that of Cmax observed in study 162020 was 1.1582. This high ratio did not prevent the 
demonstration of bioequivalence of the formulations in study 162020 also for Cmax. However, 
the calculation of the sample size for the present study using a δ of 1.1582 would be 126 
subjects. Considering that the enrolment of at least 126 subjects in a bioequivalence study 
would be hardly justifiable, that bioequivalence between the test IMP and Rilutek® 50 mg 
tablets available in US was demonstrated in study 162020 in 30 subjects, who completed the 
study, and t hat t he a ctual δ o f C max obtained in the previous pilot study 1897 was 0.9436, 
which is notably nearer the equality, i.e. ratio = 1.00, than the ratio 1.1582 observed later in 
study 162020, a ratio of 1.11 was postulated in the present sample size calculation. Indeed, 
maintaining CVWR, α and β unchanged and assuming as Cmax ratios, alternately, 1.05 and 1.10, 
sample sizes of 26 and 46 subjects, respectively, would be necessary to demonstrate 
bioequivalence in terms of Cmax. 
 
Taking into account this premise, when the sample size in each sequence group is 26 (and the 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 26 
 
 
SAP template: frm-0097, version 4.0 
total sample size is 52), a replicate crossover design will have 80% power to reject both the 
null hypothesis that the ratio of the test mean to the reference mean of Cmax is below 0.800 and 
the null hypothesis that the ratio of test mean to the reference mean of Cmax is above 1.250 
(i.e. that the test and standard are not equivalent, in favour of the alternative hypothesis that 
the means of the two treatments are equivalent) assuming that data will be analysed in the 
natural log scale using t-tests for differences in means and that each t-test will be made at the 
5.0% significance level. 
 
In conclusion, 54 subjects will be enrolled in order to have 52 completed subjects. 
 
8.4 
Demographic, baseline and background characteristics 
 
Demographic, baseline and background characteristics will be reported for all the enrolled 
subjects and analyses will be performed according to the treatment they actually received 
(Safety Set and PK Set). 
 
8.4.1 
Subjects' disposition 
 
The disposition of all subjects enrolled in the study will be listed (Listing 16.2.4.1) and 
summarised (Table 14.1.1.1). The number and proportion of subjects enrolled, randomised, 
treated and completing the study, the number and proportion of withdrawals and the reasons 
for withdrawal will be presented. 
 
8.4.2 
Analysis sets 
 
The subjects included in each analysis sets will be listed (Listing 16.2.4.2) and summarised 
(Table 14.1.1.2) by treatment group. 
 
8.4.3 
Subjects excluded from PK and /or safety analysis 
 
All subjects excluded from the PK and /or safety analysis will be listed (Listing 16.2.3.1) and 
the reasons for exclusion will be reported. 
 
8.4.4 
Discontinued subjects 
 
All subjects who discontinued the clinical trial (if any) will be listed (Listing 16.2.1.1). Last 
IMP administered before discontinuation, gender, age, last visit performed before 
discontinuation, time elapsed from last IMP administration (days), date of premature 
discontinuation and primary reason for subject premature discontinuation will be reported. 
 
8.4.5 
Protocol deviations  
 
All the protocol deviations reported during the clinical trial will be listed (Listing 16.2.2.1) 
and summarised by severity (major and minor) (Table 14.1.1.5). The number and proportion 
of subjects for each deviation will be reported. 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 27 
 
 
SAP template: frm-0097, version 4.0 
8.4.6 
Demography 
 
Demographic data will be listed (Listing 16.2.4.3) and summarised (Table 14.1.1.3). The 
number and proportion of subjects in each category for categorical variables (e.g. race) and 
descriptive statistics (mean, SD, CV%, minimum, median and maximum) for continuous 
variables (e.g. age, weight) will be presented. 
 
8.4.7 
Inclusion/exclusion criteria not met 
 
All the unmet inclusion/exclusion criteria will be listed (Listing 16.2.4.4) and summarised 
(Table 14.1.1.4). 
 
8.4.8 
ECG 
 
The date/time of ECG assessments, the value of parameters and the overall investigator’s 
interpretation (as normal, abnormal, not clinically significant or abnormal, clinically 
significant) will be listed (Listing 16.2.4.5). 
 
The overall investigator's interpretations will be summarised using contingency tables at 
screening (Table 14.1.1.6).  
 
8.4.9 
Medical and surgical history 
 
All the diseases of medical history and the surgeries of all subjects enrolled in the study will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0, 
listed (Listing 16.2.10.1). 
 
8.4.10 
Prior and concomitant medication 
 
All prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary Enhanced (WHODDE) March 2021 and listed (Listing 16.2.10.4). 
 
8.4.11 
Subjects' study visits 
 
The dates of all subjects study visits and date/time of home discharge at the end of each 
period will be listed (Listing 16.2.10.5). 
 
8.4.12 
Fertility status and contraceptive method 
 
The fertility status and the contraceptive method used by the subjects will be listed (Listing 
16.2.10.6). 
 
8.4.13 
Alcohol breath test, pregnancy test, cotinine test and urine drug test 
 
The date/time and the result of alcohol breath test, pregnancy test, cotinine test and urine drug 
test will be listed (Listing 16.2.8.1). 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 28 
 
 
SAP template: frm-0097, version 4.0 
8.4.14 
Tobacco consumption 
 
Individual tobacco consumption habits history collected at screening will be listed (Listing 
16.2.4.6). 
 
8.4.15 
Meals 
 
The start date/time of the standardised meals will be listed (Listing 16.2.10.7). 
 
8.5 
IMP administration 
 
The date and time of all IMP administrations, of film dissolution, of accidental film 
swallowing and reference tablet administrations will be listed (Listing 16.2.5.1). Dosing time 
is defined as the time the film is placed on the subject’s tongue. 
 
The actual time of film dissolution will be summarised by descriptive statistics (Table 
14.2.4.1). 
 
8.5.1 
Dose per body weight 
 
The dose per body weight of riluzole will be listed (Listing 16.2.5.2) and summarised using 
descriptive statistics (Table 14.3.5.5). 
 
The body weight collected at the screening visit will be used for the calculation. 
 
8.5.2 
Wash-out 
 
The minimum and maximum number of days of wash-out between periods will be presented 
(Table 14.3.5.6). 
 
8.6 
PK and Palatability analysis 
 
The date/time and score of palatability (for test only) will be listed (Listing 16.2.6.2) and 
summarised in tables of frequency (Table 14.2.4.2) on the safety set. 
 
The PK analysis will be performed on the subjects included into the PK Set. Subjects will be 
analysed according to the treatment they actually received. 
 
8.6.1 
PK blood samples collection 
 
The actual date/time of PK blood samples collection will be listed (Listing 16.2.5.3). 
 
8.6.2 
Descriptive pharmacokinetics/pharmacodynamics 
 
A descriptive PK will be presented.  
 
Individual subject concentrations of riluzole will be presented in data listings (Listing 
16.2.5.4) and summarised at each time point by treatment (Table 14.2.1.1). 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 29 
 
 
SAP template: frm-0097, version 4.0 
Individual (figures in section 16.2.5) and mean curves (+SD at sampling times) (figures in 
section 14.2.1), indicating inter-subject variability, will be plotted. Mean curves will be 
presented by treatment.  
 
PK parameters of riluzole will be listed (Listing 16.2.6.1) and summarised by treatment 
(Table 14.2.2.1). 
 
Data below the lower quantification limit (BLQL) will be considered as 0 in the calculations 
and presented as BLQL in listings and tables. As a consequence of BLQL (i.e. 0) values, 
calculated geometric means (if requested) could be null. For this reason, in the presence of 
any null value, the geometric mean will be reported as NC. If for an individual PK curve, a 
log-linear regression with a correlation coefficient R2 > 0.8 cannot be obtained, the 
extrapolated PK parameters will be reported as NC and considered missing in the calculations 
of descriptive statistics. 
 
8.6.3 
Statistical comparison of pharmacokinetic parameters 
 
According to the current European Guideline on the Investigation of Bioequivalence (3), 
plasma riluzole AUC0-t, AUC0-∞ and Cmax will be analysed using analysis of variance 
(ANOVA) (Table 14.2.3.1). 
  
A mixed linear model will be used to make statistical inferences about the values of Cmax and 
AUC0-t. In order to correctly assume normality and homoscedasticity, the data will be 
transformed prior to analysis using a neperian logarithmic transformation in compliance with 
the EMA guideline. 
 
The 90% CI of the ratio of the population means (test/reference), for the parameters under 
consideration will be calculated. This method is equivalent to the corresponding two one-
sided test procedure with the null hypothesis of bioequivalence at the 5% significance level. 
 
• 
The statistical analysis will take into account treatment, period, sequence and subject 
within sequence as fixed effects. 
• 
Acceptance criterion for bioequivalence in terms of extent of absorption (AUC0-t as 
primary variable and AUC0-∞ as secondary variable) will be that the 90% CI of this ratio 
has to lie within the range 80.00-125.00%. 
• 
Due to the replicate design of the study, if the within-subject variability (CVWR%) of 
Cmax of plasma riluzole after administration of the reference formulation is >30%, the 
reference-scaled BE approach will be used. Bioequivalence acceptance range for Cmax 
will be widened, in compliance with the guideline, as exemplified in Table 8.9.3.1. 
• 
CVWR% will be calculated by applying the formula 
1
100
(%)
2
−
=
WR
S
WR
e
CV
, where S2WR is 
the within-subject variation plasma riluzole after administration of the reference 
formulation only.  
• 
The extent of the widening will be defined on the basis of the within-subject variability 
actually observed in the study according to [U, L] = exp [±k·SWR], where U is the upper 
limit of the acceptance range, L is the lower limit of the acceptance range, k is the 
regulatory constant set to 0.760 and SWR is the within-subject standard deviation of the 
log-transformed values of Cmax of plasma riluzole after administration of the reference 
formulation. 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
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Table 8.9.3.1 Examples of widened bioequivalence acceptance limits of Cmax according to its actual CVWR 
CVWR %*  
Lower Limit 
Upper Limit 
30  
80.00 
125.00 
35 
77.23 
129.48 
40 
74.62 
134.02 
45 
72.15 
138.59 
≥50 
69.84 
143.19 
*: 
1
e
100
CVWR(%)
WR
2
S
−
=
; source: reference ( 3) 
 
The value of within-subject variability of Cmax (after administration of the reference 
formulation), obtained using the formula above, will be reported in the table 14.2.3.2. 
 
tmax and t1/2 will be compared between treatments by the non-parametric Friedman test (Table 
14.2.3.3). 
 
8.7 
Safety and tolerability analysis 
 
The safety and tolerability analysis will be performed on the subjects included into the Safety 
Set. 
 
Subjects will be analysed according to the treatment they actually received. 
 
8.7.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 
• 
PTAEs: all AEs occurring before the first dose of IMP and not worsening after the first 
dose of IMP 
• 
TEAEs: all AEs occurring or worsening after the first dose of IMP 
 
Individual PTAEs and TEAEs will be listed in subject data listings (Listing 16.2.7.1, Listing 
16.2.7.2). 
 
No summary table will be provided for PTAEs. 
 
TEAEs will be summarised by treatment group and overall. The number and percentage of 
subjects with any TEAE and the number of TEAEs will be tabulated by SOC and PT, 
seriousness, relationship to treatment and severity. 
  
For TEAEs that change intensity during the study (e.g. from mild to moderate or from 
moderate to mild), the most severe intensity will be reported in the summary tables (Table 
14.3.1.1, Table 14.3.1.2, Table 14.3.1.3, Table 14.3.1.4). 
 
Should any serious TEAE occur, the number and percentage of subjects with any serious 
TEAE, the number of serious TEAEs, the number and percentage of subjects with any serious 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 31 
 
 
SAP template: frm-0097, version 4.0 
TEAE related to study drug and the number of serious TEAEs related to study drug will be 
presented (Table 14.3.1.5, Table 14.3.1.6). 
 
All TEAEs leading to death will be listed, all Serious TEAEs will be listed and all TEAEs 
leading to discontinuation will be listed, if applicable (Table 14.3.2.1). 
 
8.7.2 
Vital signs 
 
The date/time of vital signs assessments and the values of vital signs will be listed (Listing 
16.2.9.1) and summarised using descriptive statistics at screening and end of study (Table 
14.3.5.2) and by treatment during the study (Table 14.3.5.3).  
 
A table of all the abnormal vital signs' values will be presented (Table 14.3.5.1). 
 
8.7.3 
Laboratory data 
 
Date/time of samples collection  and all laboratory results will be listed (Listing 16.2.8.1) and 
a table of all the abnormal values will be presented (Table 14.3.4.1). 
 
Overall Investigator’s interpretation (as normal or abnormal and, if abnormal, clinically 
significant or not clinically significant) and clinically significant findings (if any) will be 
listed (Listing 16.2.8.2).  
The overall Investigator’s interpretation will be summarised using tables of frequency (Table 
14.3.4.2). 
 
8.7.4 
Physical examination 
 
Date of the physical examination, overall Investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed (Listing 16.2.10.2). 
 
8.7.5 
Mouth Visual Inspection  
 
The date/time of  mouth visual inspection, overall Investigator’s interpretation (as normal or 
abnormal and, if abnormal, clinically significant or not clinically significant) and clinically 
significant abnormalities (if any) will be listed (Listing 16.2.10.3). 
 
The overall Investigator’s interpretation will be summarised using tables of frequency (Table 
14.3.5.4) at each time point. 
 
8.8 
Analysis datasets 
 
Analysis datasets will be created according to the version 2.1 of the ADaM model of CDISC 
(13). 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 32 
 
 
SAP template: frm-0097, version 4.0 
9 
REFERENCES 
 
1 
ICH Topic E6 (R2): Good clinical practice.  
2 
ICH Topic E9: Statistical principles for clinical trials. 
3 
Guidance on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 
1/Corr **, 20 January 2010 
4 
Questions & Answers: Positions on specific questions addressed to the 
pharmacokinetics working party. EMA/618604/2008 Rev. 8, 10 October 2013 
5 
Radicioni M. Protocol CRO-PK-20-344. "Comparative bioavailability study of a new 
riluzole orodispersible film vs. a marketed oral reference (Rilutek® tablets) in healthy 
male and female volunteers". Final version 1.0, 28APR2020, CROSS Research, 
Switzerland, 2020  
6 
Radicioni M. Protocol amendment CRO-PK-20-344. "Comparative bioavailability 
study of a new riluzole orodispersible film vs. a marketed oral reference (Rilutek® 
tablets) in healthy male and female volunteers". Final version 1.0, 17FEB2021, CROSS 
Research, Switzerland, 2020  
7 
Riluzole orodispersible film. Investigator’s Brochure, Edition 3.0, Aquestive 
Therapeutics 
8 
Rilutek SmPC, Rilutek EPAR 14 August 2019 - EMEA/H/C/000109 - IAIN/0060, last 
updated 11 November 2019 
9 
European Public Assessment Report (EPAR), Rilutek. EMEA/H/C/109 
10 
U.S. Department of Health and Human Services and U.S. Department of Agriculture, 
Nutrition and your health: 2015-2020 Dietary Guidelines, Appendix 9 
11 
SAS/STAT® User's Guide 
12 
Phoenix 1.3 User's Guide, Pharsight Corporation 
13 
CDISC Analysis Data Model Version 2.1 
 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-20-344 
Sponsor code Z7251J01 
Riluzole orodispersible film replicate bioavailability 
Final version 1.0, 31MAY2021 
CROSS Research S.A. 
Page 33 
 
 
SAP template: frm-0097, version 4.0 
10 
APPENDICES 
 
1. 
Section 14 - Tables and Figures Shells 
2. 
Section 16.2 - Individual Subject Data Listings and Figures Shells 
 
 
 


CROSS Research S.A.
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Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Section 14 - Tables Shells
Table 14.1.1.1 - Subjects' disposition - Enrolled set
Table 14.1.1.2 - Analysis sets - Enrolled set
Table 14.1.1.3 - Demography - Enrolled set, Safety set and PK set
Table 14.1.1.4 - Inclusion/exclusion criteria not met - Enrolled set, Safety set, PK set
Table 14.1.1.5 - Protocol deviations - Enrolled set, Safety set and PK set
Table 14.1.1.6 - Contingency tables of investigator's interpretation of ECG at screening - Enrolled set
Table 14.2.1.1 - Riluzole concentrations (ng/mL) measured in plasma - PK Set
Table 14.2.2.1 - Riluzole plasma PK parameters - PK Set
Table 14.2.3.1 - Statistical analysis on Riluzole plasma PK parameters - PK set
Table 14.2.3.2 - Within-subject variability of Cmax (after administration of the reference formulation) - PK Set
Table 14.2.3.3 - Non-parametric Friedman test on tmax and t1/2 - PK set
Table 14.2.4.1 - Descriptive statistics of dissolution time - Safety set
Table 14.2.4.2 - Contingency tables of palatability - Safety set
Table 14.3.1.1 - Global incidence of subjects with treatment-emergent adverse events - Safety set
Table 14.3.1.2 - Subjects with treatment-emergent adverse events by system organ class and preferred term - Safety set
Table 14.3.1.3 - Subjects with treatment-emergent adverse events by intensity, system organ class and preferred term - Safety set
Table 14.3.1.4 - Subjects with treatment-emergent adverse events related to the IMP by system organ class and preferred term - Safety set
Table 14.3.1.5 - Subjects with serious treatment-emergent adverse events by system organ class and preferred term - Safety set
Table 14.3.1.6 - Subjects with serious treatment-emergent adverse events related to the IMP by system organ class and preferred term - Safety set
Table 14.3.2.1 - Treatment emergent adverse events leading to death, serious adverse events or treatment emergent adverse events leading to discontinuation - Safety set
Table 14.3.4.1 - Abnormal laboratory values - Safety set
Table 14.3.4.2 - Contingency tables of investigator's interpretation of laboratory test results - Safety set
Table 14.3.5.1 - Abnormal vital signs - Safety set
Table 14.3.5.2 - Descriptive statistics of vital signs and body weight at screening and end of study - Safety set
Table 14.3.5.3 - Descriptive statistics of vital signs during the study - Safety set
Table 14.3.5.4 - Contingency tables of investigator's interpretation of mouth visual inspection during the study - Safety set
Table 14.3.5.5 - Descriptive statistics of dose per body weight - Safety set
Table 14.3.5.6 - Descriptive statistics of wash-out - Safety set


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.1 - Subjects' disposition - Enrolled set
Overall
n (%)
Enrolled
nn
Enrolled but not randomised 1
nn (xx.x)
Randomised 1
nn (xx.x)
Discontinued before treatment 2
nn (xx.x)
Treated 2
nn (xx.x)
Completed 3
nn (xx.x)
Discontinued 3
nn (xx.x)
Adverse event 3
nn (xx.x)
Withdrawal by subject 3
nn (xx.x)
...
nn (xx.x)
Note: The number and the proportion of subjects of each disposition event are reported
Note 1: The denominator for calculating the proportion is the number of enrolled subjects
Note 2: The denominator for calculating the proportion is the number of randomised subjects
Note 3: The denominator for calculating the proportion is the number of randomised and treated subjects
Source: Listing 16.2.4.1 - Subjects' disposition
Program: Tables\k344-ds-tbl.sas


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Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.2 - Analysis sets - Enrolled set
Enrolled Set
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%)
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%)
Overall
N=XX
n (%)
Safety Set
nn (xx.x)
nn (xx.x)
nn (xx.x)
PK Set
nn (xx.x)
nn (xx.x)
nn (xx.x)
Note: Subjects are summarised according to the product they were assigned to
The number and the proportion of subjects included in each analysis set are reported
The denominator for calculating the proportions is the number of subjects in the enrolled set of each treatment group and overall
Source: Listing 16.2.4.2 - Analysis sets
Program: Tables\k344-ds-tbl.sas


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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.3 - Demography - Enrolled set, Safety set and PK set
Statistics
Enrolled Set
N=XX
Safety Set
N=XX
PK Set
N=XX
Sex
Female
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Male
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Race
American Indian or Alaska Native
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Asian
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Native Hawaiian or Other Pacific Islander
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Black or African American
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
White
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Other
n (%)
nn (xx.x)
nn (xx.x)
nn (xx.x)
Age (years)
N
nn
nn
nn
Mean
xx.x
xx.x
xx.x
SD
xx.x
xx.x
xx.x
CV%
xx.x
xx.x
xx.x
Min
xx
xx
xx
Median
xx.x
xx.x
xx.x
Max
xx
xx
xx
Body Weight (kg)
N
nn
nn
nn
Mean
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
CV%
xx.xx
xx.xx
xx.xx
Min
xx.x
xx.x
xx.x
Median
xx.xx
xx.xx
xx.xx
Max
xx.x
xx.x
xx.x
Note: The number and the proportion of subjects of each sex and race are reported
The denominator for calculating the proportions is the number of subjects in each analysis set
Source: Listing 16.2.4.3 - Demography
Program: Tables\k344-dm-tbl.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.3 - Demography - Enrolled set, Safety set and PK set
Statistics
Enrolled Set
N=XX
Safety Set
N=XX
PK Set
N=XX
Body Mass Index (kg/m2)
N
nn
nn
nn
Mean
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
CV%
xx.xx
xx.xx
xx.xx
Min
xx.x
xx.x
xx.x
Median
xx.xx
xx.xx
xx.xx
Max
xx.x
xx.x
xx.x
Note: The number and the proportion of subjects of each sex and race are reported
The denominator for calculating the proportions is the number of subjects in each analysis set
Source: Listing 16.2.4.3 - Demography
Program: Tables\k344-dm-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.4 - Inclusion/exclusion criteria not met - Enrolled set, Safety set, PK set
Enrolled Set
N=XX
Safety Set
N=XX
PK Set
N=XX
Number of subjects with any inclusion/exclusion criteria not met
nn (xx.x)
nn (xx.x)
nn (xx.x)
Inclusion
nn (xx.x)
nn (xx.x)
nn (xx.x)
Inclusion criterion 1
nn (xx.x)
nn (xx.x)
nn (xx.x)
Inclusion criterion 2
nn (xx.x)
nn (xx.x)
nn (xx.x)
...
...
...
...
Exclusion
nn (xx.x)
nn (xx.x)
nn (xx.x)
Exclusion criterion 1
nn (xx.x)
nn (xx.x)
nn (xx.x)
Exclusion criterion 2
nn (xx.x)
nn (xx.x)
nn (xx.x)
...
...
...
...
Note: The number and the proportion of subjects for any criterion not met are reported
The denominator for calculating the proportions is the number of subjects in each analysis set
Source: Listing 16.2.4.4 - Inclusion/Exclusion criteria not met
Program: Tables\k344-ie-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.5 - Protocol deviations - Enrolled set, Safety set, PK set
Enrolled Set
N=XX
Safety Set
N=XX
PK Set
N=XX
Number of subjects with any protocol deviation
nn (xx.x)
nn (xx.x)
nn (xx.x)
Major
nn (xx.x)
nn (xx.x)
nn (xx.x)
Treatment deviation
nn (xx.x)
nn (xx.x)
nn (xx.x)
Inclusion criteria violation
nn (xx.x)
nn (xx.x)
nn (xx.x)
Exclusion criteria violation
nn (xx.x)
nn (xx.x)
nn (xx.x)
Medication not admitted
nn (xx.x)
nn (xx.x)
nn (xx.x)
...
...
...
...
Minor
nn (xx.x)
nn (xx.x)
nn (xx.x)
Deviation from scheduled sampling time
nn (xx.x)
nn (xx.x)
nn (xx.x)
...
...
...
...
Note: The number and the proportion of subjects for any protocol violation are reported
The denominator for calculating the proportions is the number of subjects in each analysis set
Source: Listing 16.2.2.1 - Protocol deviations
Program: Tables\k344-dv-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.1.1.6 - Contingency tables of investigator's interpretation of ECG at screening - Enrolled set
Time Point
Investigator's interpretation
Enrolled Set
N=XX
Screening
Normal
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
Note: The number and the proportion of subjects for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the enrolled set
Source: Listing 16.2.4.5 - Investigator's interpretation of ECG
Program: Tables\k344-eg-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.1.1 - Riluzole concentrations (ng/mL) measured in plasma - PK Set
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Statistics
Pre
dose
0.25 h
0.5 h
0.75 h
1 h
1.25 h
1.5 h
2 h
3 h
4 h
6 h
8 h
12 h
18 h
24 h
N
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
Geo.Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
SD
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
CV%
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Min
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Median
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Max
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
BLQL: Below Lower Quantification Limit (x.xx ng/mL)
Source: Listing 16.2.5.4 - Riluzole concentrations (ng/mL) measured in plasma
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.1.1 - Riluzole concentrations (ng/mL) measured in plasma - PK Set
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Statistics
Pre
dose
0.25 h
0.5 h
0.75 h
1 h
1.25 h
1.5 h
2 h
3 h
4 h
6 h
8 h
12 h
18 h
24 h
N
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
Geo.Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
SD
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
CV%
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Min
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Median
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Max
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
BLQL: Below Lower Quantification Limit (x.xx ng/mL)
Source: Listing 16.2.5.4 - Riluzole concentrations (ng/mL) measured in plasma
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.2.1 - Riluzole plasma PK parameters - PK Set
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Statistics
Cmax
(ng/mL)
tmax
(h)
AUC0-t
(h*ng/mL)
AUC0-inf
(h*ng/mL)
t½
(h)
λ z
(1/h)
N
xx
xx
xx
xx
xx
xx
Geo.Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
SD
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
CV%
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Min
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Median
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Max
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Source: Listing 16.2.6.1 - Riluzole plasma PK parameters
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.2.1 - Riluzole plasma PK parameters - PK Set
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Statistics
Cmax
(ng/mL)
tmax
(h)
AUC0-t
(h*ng/mL)
AUC0-inf
(h*ng/mL)
t½
(h)
λ z
(1/h)
N
xx
xx
xx
xx
xx
xx
Geo.Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Mean
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
SD
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
CV%
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Min
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Median
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Max
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Source: Listing 16.2.6.1 - Riluzole plasma PK parameters
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.3.1 - Statistical analysis on riluzole plasma PK parameters - PK set
Analysis
Dependent Variable
Comparison
Point Estimate
90% Confidence Interval
Lower Limit
90% Confidence Interval
Upper Limit
Effect
p Value
ANOVA
Ln(AUC0-inf)
T vs R
xxx.xx
xxx.xx
xxx.xx
Sequence
x.xxxx
Treatment
x.xxxx
Period
x.xxxx
ANOVA
Ln(AUC0-t)
T vs R
xxx.xx
xxx.xx
xxx.xx
Sequence
xxxxx
Treatment
x.xxxx
Period
x.xxxx
ANOVA
Ln(Cmax)
T vs R
xxx.xx
xxx.xx
xxx.xx
Sequence
x.xxxx
Treatment
x.xxxx
Period
x.xxxx
T: Riluzole 50 mg orodispersible film (T)
R: Rilutek®, 50 mg riluzole tablets (R)_
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.3.2 - Within-subject variability of Cmax (after administration of the reference formulation) - PK Set
AINGR
Dependent Variable
S2
WR
Within-subject variability
CVWR(%)
Riluzole
Ln(Cmax)
xxx.xxx
xx.xx
Note: CVWR% was calculated by applying the formula 100*sqrt[exp(S2
WR)-1]
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.3.3 - Non-parametric Friedman test on tmax and t1/2 - PK set
Analysis
Dependent Variable
Comparison
p Value
Friedman
tmax
T vs R
x.xxxx
t1/2
T vs R
x.xxxx
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.4.1 - Descriptive statistics of dissolution time (Safety set)
Safety Set
Statistics
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Was the film accidentally swallowed within 5 min after dosing?
Yes
n (%)
nn (xx.x)
nn (xx.x)
No
n (%)
nn (xx.x)
nn (xx.x)
Was the film undissolved at 5 min after dosing and had to be swallowed?
Yes
n (%)
nn (xx.x)
nn (xx.x)
No
n (%)
nn (xx.x)
nn (xx.x)
Dissolution Time [min]
N
nn
nn
Mean
xxx.xx
xxx.xx
SD
xxx.xx
xxx.xx
CV%
xxx.xx
xxx.xx
Min
xxx.x
xxx.x
Median
xxx.xx
xxx.xx
Max
xxx.x
xxx.x
Note: Subjects are summarised according to the product they actually received
The number and the proportion of subjects for each question are reported
The denominator for calculating the proportions is the number of subjects in the safety set of Riluzole 50 mg orodispersible film (T) of each administration
Source: Listing 16.2.5.1 - Investigational medicinal products administration
Program: Tables\k344-ex-tbl.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.2.4.2 - Contingency tables of palatability - Safety set
Safety Set
Time Point
Palatability Score
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Immediately after administration
0 - very unpleasant
xx (xx.x)
nn (xx.x)
1 - unpleasant
xx (xx.x)
nn (xx.x)
2 - acceptable
xx (xx.x)
nn (xx.x)
3 - good
xx (xx.x)
nn (xx.x)
4 - very good
xx (xx.x)
nn (xx.x)
Note: The number and the proportion of subjects for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of Riluzole 50 mg orodispersible film (T) of each administration
Source: Listing 16.2.6.2 - Palatability
Program: Tables\k344-fa-tbl.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.1 - Global incidence of subjects with treatment-emergent adverse events - Safety set
Safety Set
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Treatment-emergent Adverse Events
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Relationship
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Related
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Not related
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Intensity
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Mild
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Moderate
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Severe
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Leading to discontinuation
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Note: Subjects are summarised according to the product they actually received
Subjects are summarised according to the each level of relationship and intensity reported in each treatment group and overall
The number and the proportion of subjects with any adverse event and the number of adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-01-tbl.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.1 - Global incidence of subjects with treatment-emergent adverse events - Safety set
Safety Set
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Serious Treatment-emergent Adverse Events
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Relationship
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Related
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Not related
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Intensity
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Mild
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Moderate
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Severe
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Leading to discontinuation
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Note: Subjects are summarised according to the product they actually received
Subjects are summarised according to the each level of relationship and intensity reported in each treatment group and overall
The number and the proportion of subjects with any adverse event and the number of adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-01-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.2 - Subjects with treatment-emergent adverse events by system organ class and preferred term - Safety set
Safety Set
System Organ Class 1
Preferred Term 1
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Treatment-emergent Adverse Events
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Nervous system disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Headache
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Gastrointestinal disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Abdominal pain upper
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Diarrhoea
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Note: Subjects are summarised according to the product they actually received
The number and the proportion of subjects with any adverse event and the number of adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Note 1: MedDRA version 24.0
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-02-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.3 - Subjects with treatment-emergent adverse events by intensity, system organ class and preferred term - Safety set
Safety Set
Riluzole 50 mg orodispersible film (T)
N=XX
Rilutek®, 50 mg riluzole tablets (R)
N=XX
Overall
N=XX
System Organ Class 1
Preferred Term 1
Mild
n (%) [n AE]
Moderate
n (%) [n AE]
Severe
n (%) [n AE]
Mild
n (%) [n AE]
Moderate
n (%) [n AE]
Severe
n (%) [n AE]
Mild
n (%) [n AE]
Moderate
n (%) [n AE]
Severe
n (%) [n AE]
Treatment-emergent Adverse Events
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Nervous system disorders
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Headache
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
...
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Gastrointestinal disorders
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Abdominal pain upper
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Diarrhoea
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
...
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
nn (x.x) [kk]
Note: Subjects are summarised according to the treatment they actually received
The number and the proportion of subjects with any adverse event and the number of adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Note 1: MedDRA version 24.0
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-02-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.4 - Subjects with treatment-emergent adverse events related to the IMP by system organ class and preferred term - Safety set
Safety Set
System Organ Class 1
Preferred Term 1
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Treatment-emergent Adverse Events related to the IMP
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Nervous system disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Headache
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Gastrointestinal disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Abdominal pain upper
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Diarrhoea
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Note: Subjects are summarised according to the product they actually received
The number and the proportion of subjects with any related adverse event and the number of related adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Note 1: MedDRA version 24.0
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-02-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.5 - Subjects with serious treatment-emergent adverse events by system organ class and preferred term - Safety set
Safety Set
System Organ Class 1
Preferred Term 1
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Serious Treatment-emergent Adverse Events
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Nervous system disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Headache
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Gastrointestinal disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Abdominal pain upper
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Diarrhoea
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Note: Subjects are summarised according to the product they actually received
The number and the proportion of subjects with any serious adverse event and the number of serious adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Note 1: MedDRA version 24.0
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-02-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.1.6 - Subjects with serious treatment-emergent adverse events related to the IMP by system organ class and preferred term - Safety set
Safety Set
System Organ Class 1
Preferred Term 1
Riluzole 50 mg
orodispersible film (T)
N=XX
n (%) [n AE]
Rilutek®, 50 mg
riluzole tablets (R)
N=XX
n (%) [n AE]
Overall
N=XX
n (%) [n AE]
Serious Treatment-emergent Adverse Events related to the IMP
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Nervous system disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Headache
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Gastrointestinal disorders
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Abdominal pain upper
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
Diarrhoea
nn (xx.x) [kk]
nn (xx.x) [kk]
nn (xx.x) [kk]
...
...
...
...
Note: Subjects are summarised according to the product they actually received
The number and the proportion of subjects with any serious related adverse event and the number of serious related adverse events for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of each treatment group and overall
Note 1: MedDRA version 24.0
Source: Listing 16.2.7.1 - Treatment-emergent adverse events
Program: Tables\k344-ae-02-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.2.1 - Treatment emergent adverse events leading to death, serious adverse events or treatment emergent adverse events leading to discontinuation - Safety set
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Adverse
Event
ID
S001/001
1
Description:
Headache
Body Area Affected:
Head
Preferred Term 1:
Headache
System Organ Class 1:
Nervous system disorders
Acknowledgment Date/Time (Day)
ddMMMyyyy hh:mm (j)
Start - End Date/Time (Day):
ddMMMyyyy hh:mm (k) - ddMMMyyyy hh:mm (k+n)
Has the Adverse Event Started After the Administration of the Study Drug?
Y
Last Study Drug Administration Date/Time Before Onset
ddMMMyyyy hh:mm
Reasonable Possibility of a Causal Relationship with the Study Drug?
Y
Other Causal Relationship
---
Severity:
Severe
Pattern:
Continuous
Serious?
N
Seriousness criteria:
---
Action taken with Study Drug:
None
Concomitant therapy?
N
Caused Study Discontinuation?
Y
Other Action Taken:
None
Outcome:
Recovered/Resolved
Comments:
---
...
...
...
...
Note: Subjects are listed according to the product they actually received
Note 1: MedDRA version 24.0.
Sources: Listing 16.2.7.1 - Treatment-emergent adverse events, Listing 16.2.7.2 - Pre-treatment adverse events (for serious adverse events only)
Program: Tables\k344-ae-03-tbl.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.2.1 - Treatment emergent adverse events leading to death, serious adverse events or treatment emergent adverse events leading to discontinuation - Safety set
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
Adverse
Event
ID
S001/001
2
Description:
Headache
Body Area Affected:
Head
Preferred Term 1:
Headache
System Organ Class 1:
Nervous system disorders
Acknowledgment Date/Time (Day)
ddMMMyyyy hh:mm (j)
Start - End Date/Time (Day):
ddMMMyyyy hh:mm (k) - ddMMMyyyy hh:mm (k+n)
Has the Adverse Event Started After the Administration of the Study Drug?
Y
Last Study Drug Administration Date/Time Before Onset
ddMMMyyyy hh:mm
Reasonable Possibility of a Causal Relationship with the Study Drug?
Y
Other Causal Relationship
---
Severity:
Severe
Pattern:
Continuous
Serious?
N
Seriousness criteria:
---
Action taken with Study Drug:
None
Concomitant therapy?
N
Caused Study Discontinuation?
Y
Other Action Taken:
None
Outcome:
Recovered/Resolved
Comments:
---
...
...
...
...
Note: Subjects are listed according to the product they actually received
Note 1: MedDRA version 24.0.
Sources: Listing 16.2.7.1 - Treatment-emergent adverse events, Listing 16.2.7.2 - Pre-treatment adverse events (for serious adverse events only)
Program: Tables\k344-ae-03-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.4.1 - Abnormal laboratory values - Safety set
Category of Laboratory Parameters: BLOOD CHEMISTRY
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Phosphate [mmol/L]
0.84 [L]
0.87 - 1.45
N
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Phosphate [mmol/L]
0.84 [L]
0.87 - 1.45
N
...
...
...
...
...
...
...
Note 1: H=Higher than upper normal limit, L=Lower than lower normal limit
Source: Listing 16.2.8.1 - Individual laboratory measurements
Program: Tables\k344-lb-tbl.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.4.1 - Abnormal laboratory values - Safety set
Category of Laboratory Parameters: HEMATOLOGY
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Leukocytes [10^9/L]
10.02 [H]
4.00 - 10.00
N
...
...
...
...
...
...
...
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Leukocytes [10^9/L]
10.02 [H]
4.00 - 10.00
N
...
...
...
...
...
...
...
Note 1: H=Higher than upper normal limit, L=Lower than lower normal limit
Source: Listing 16.2.8.1 - Individual laboratory measurements
Program: Tables\k344-lb-tbl.sas


CROSS Research S.A.
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CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.4.1 - Abnormal laboratory values - Safety set
Category of Laboratory Parameters: URINE ANALYSIS
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Hemoglobin
+++ [A]
Absent
N
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Hemoglobin
+++ [A]
Absent
N
...
...
...
...
...
...
...
Note 1: A=Different from reference value
Source: Listing 16.2.8.1 - Individual laboratory measurements
Program: Tables\k344-lb-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.4.2 - Contingency tables of investigator's interpretation of laboratory test results - Safety set
Time Point
Investigator's interpretation
Safety Set
N=XX
Screening
Normal
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
End of Study
Normal
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
Note: The number and the proportion of subjects for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set
Source: Listing 16.2.8.2 - Investigator's interpretation of laboratory test results
Program: Tables\k344-lb-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.1 - Abnormal vital signs - Safety set
Subject
ID
Time
Point
Assessment
Date/Time
Parameter
Value and
Abnormality 1
Normal Range
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 3 - Pre-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
...
...
...
...
...
...
...
Note 1: H=Higher than upper normal limit, L=Lower than lower normal limit
Source: Listing 16.2.9.1 - Vital signs and body weight
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.2 - Descriptive statistics of vital signs at screening and end of study - Safety set
Parameter
Time Point
Statistics
Safety Set
N=XX
Systolic Blood Pressure [mmHg]
Screening
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Systolic Blood Pressure [mmHg]
End of Study
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Diastolic Blood Pressure [mmHg]
Screening
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Note: End of Study = Visit 9 - Day 2 - 36 hours post-dose or early termination visit for vital signs, final visit or early termination visit for body weight
Source: Listing 16.2.9.1 - Vital signs
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.2 - Descriptive statistics of vital signs at screening and end of study - Safety set
Parameter
Time Point
Statistics
Safety Set
N=XX
Diastolic Blood Pressure [mmHg]
End of Study
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Heart Rate [beats/min]
Screening
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Heart Rate [beats/min]
End of Study
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Note: End of Study = Visit 9 - Day 2 - 36 hours post-dose or early termination visit for vital signs, final visit or early termination visit for body weight
Source: Listing 16.2.9.1 - Vital signs
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 3
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.2 - Descriptive statistics of vital signs at screening and end of study - Safety set
Parameter
Time Point
Statistics
Safety Set
N=XX
Weight [kg]
Screening
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Weight [kg]
End of Study
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Note: End of Study = Visit 9 - Day 2 - 36 hours post-dose or early termination visit for vital signs, final visit or early termination visit for body weight
Source: Listing 16.2.9.1 - Vital signs
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.3 - Descriptive statistics of vital signs during the study - Safety set
Safety Set
Parameter
Time Point
Statistics
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
1st adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
2nd adm.
N=XX
Systolic Blood Pressure [mmHg]
Pre-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Systolic Blood Pressure [mmHg]
2 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Systolic Blood Pressure [mmHg]
36 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Note: Subjects are summarised according to the product they actually received
Source: Listing 16.2.9.1 - Vital signs and body weight
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.3 - Descriptive statistics of vital signs during the study - Safety set
Safety Set
Parameter
Time Point
Statistics
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
1st adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
2nd adm.
N=XX
Diastolic Blood Pressure [mmHg]
Pre-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Diastolic Blood Pressure [mmHg]
2 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Diastolic Blood Pressure [mmHg]
36 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Note: Subjects are summarised according to the product they actually received
Source: Listing 16.2.9.1 - Vital signs and body weight
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 3
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.3 - Descriptive statistics of vital signs during the study - Safety set
Safety Set
Parameter
Time Point
Statistics
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
1st adm.
N=XX
Rilutek®, 50 mg
riluzole tablets (R)
2nd adm.
N=XX
Heart Rate [beats/min]
Pre-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Heart Rate [beats/min]
2 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Heart Rate [beats/min]
36 hours post-dose
N
nn
nn
nn
nn
Mean
xxx.x
xxx.x
xxx.x
xxx.x
SD
xxx.x
xxx.x
xxx.x
xxx.x
CV%
xxx.x
xxx.x
xxx.x
xxx.x
Min
xxx
xxx
xxx.x
xxx.x
Median
xxx.x
xxx.x
xxx.x
xxx.x
Max
xxx
xxx
xxx.x
xxx.x
Note: Subjects are summarised according to the product they actually received
Source: Listing 16.2.9.1 - Vital signs and body weight
Program: Tables\k344-vs-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.4 - Contingency tables of investigator's interpretation of mouth visual inspection during the study - Safety set
Safety Set
Time Point
Investigator's interpretation
Riluzole 50 mg
orodispersible film (T)
1st adm.
N=XX
Riluzole 50 mg
orodispersible film (T)
2nd adm.
N=XX
Pre-dose
Normal
nn (xx.x)
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
nn (xx.x)
0.5 hour post-dose
Normal
nn (xx.x)
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
nn (xx.x)
1 hour post-dose
Normal
nn (xx.x)
nn (xx.x)
Abnormal, Not Clinically Significant
nn (xx.x)
nn (xx.x)
Abnormal, Clinically Significant
nn (xx.x)
nn (xx.x)
Note: The number and the proportion of subjects for each classification level are reported
The denominator for calculating the proportions is the number of subjects in the safety set of Riluzole 50 mg orodispersible film (T) of each administration
Source: Listing 16.2.10.3 - Mouth Visual Inspection
Program: Tables\k344-pe-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.5 - Descriptive statistics of dose per body weight - Safety set
Parameter
Sex
Statistics
Safety Set
N=XX
Dose per body weight [mg/kg]
Females
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Dose per body weight [mg/kg]
Males
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Dose per body weight [mg/kg]
Females and males
N
nn
Mean
xxx.x
SD
xxx.x
CV%
xxx.x
Min
xxx
Median
xxx.x
Max
xxx
Note: The dose per body weight was calculated using the screening body weight
Source: Listing 16.2.5.2 - Dose per body weight
Program: Tables\k344-ex-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Table 14.3.5.6 - Descriptive statistics of wash-out - Safety set
Parameter
Statistics
Safety Set
N=XX
Wash-out between IMP administration of Period 1 and Period 2 [days]
N
nn
Min
xxx
Max
xxx
Wash-out between IMP administration of Period 2 and Period 3 [days]
N
nn
Min
xxx
Max
xxx
Wash-out between IMP administration of Period 3 and Period 4 [days]
N
nn
Min
xxx
Max
xxx
Note: The wash-out is calculated as the difference in days between the dates of product administrations
Source: Listing 16.2.5.1 - Investigational medicinal products administration
Program: Tables\k344-ex-tbl.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Section 16.2 - Individual Subject Data Listings Shells
Listing 16.2.1.1 - Discontinued subjects
Listing 16.2.2.1 - Protocol deviations
Listing 16.2.3.1 - Subjects excluded from PK and/or safety analysis
Listing 16.2.4.1 - Subjects' disposition
Listing 16.2.4.2 - Analysis sets
Listing 16.2.4.3 - Demography
Listing 16.2.4.4 - Inclusion/Exclusion criteria not met
Listing 16.2.4.5 - Investigator's interpretation of ECG
Listing 16.2.4.6 - Tobacco consumption
Listing 16.2.5.1 - Investigational medicinal products administration
Listing 16.2.5.2 - Dose per body weight
Listing 16.2.5.3 - PK samples collection dates and times
Listing 16.2.5.4 - Riluzole concentrations (ng/mL) measured in plasma
Listing 16.2.6.1 - Riluzole plasma PK parameters
Listing 16.2.6.2 - Palatability
Listing 16.2.7.1 - Treatment-emergent adverse events
Listing 16.2.7.2 - Pre-treatment adverse events
Listing 16.2.8.1 - Individual laboratory measurements
Listing 16.2.8.2 - Investigator's interpretation of laboratory test results
Listing 16.2.9.1 - Vital signs and body weight
Listing 16.2.10.1 - Medical and surgical history
Listing 16.2.10.2 - Physical examination
Listing 16.2.10.3 - Mouth Visual Inspection
Listing 16.2.10.4 - Prior and concomitant medications
Listing 16.2.10.5 - Subjects study visits
Listing 16.2.10.6 - Fertility status and contraception
Listing 16.2.10.7 - Meals


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.1.1 - Discontinued subjects
Subject
ID
Last IMP
before discontinuation
Sex
Age
(years)
Last
visit
Time elapsed from
last drug administration
(days)
Date of
premature
discontinuation
Primary reason for subject
premature study termination
S001/001
Riluzole 50 mg orodispersible film (T)
M
30
Visit 3
1
ddMMMyyyy
Withdrawal by subject
S003/002
Rilutek®, 50 mg riluzole tablets (R)
F
27
Visit 5
2
ddMMMyyyy
Adverse event
S005/004
Rilutek®, 50 mg riluzole tablets (R)
M
18
Visit 3
2
ddMMMyyyy
Physician decision
S007/006
Riluzole 50 mg orodispersible film (T)
F
27
Visit 5
2
ddMMMyyyy
Adverse event
S011/010
Rilutek®, 50 mg riluzole tablets (R)
M
18
Visit 3
2
ddMMMyyyy
Physician decision
...
...
...
...
...
...
...
Note: Subjects are listed according to the last product they actually received before discontinuation
Program: Listings\k344-ds-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.2.1 - Protocol deviations
Subject
ID
Deviation
Number
Deviation
Category
Deviation
Coded
Term
Deviation
Description
S001/001
1
Minor
Deviation from scheduled sampling time
Sample number 2 was collected outside the window of 15 min post-dose
S007/006
1
Major
Inclusion criteria violation
Inclusion criteria violation
...
...
...
...
Program: Listings\k344-dv-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.3.1 - Subjects excluded from PK and/or safety analysis
Subject
ID
Sex
Age
(years)
Enrolled
Set
Safety
Set
PK
Set
Reason for the exclusion
S010/008
F
30
Y
N
N
Lack of IMP administration
S015/013
F
20
Y
Y
N
Major protocol deviations
...
...
.
.
.
...
Program: Listings\k344-ds-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.1 - Subjects' disposition
Subject
ID
Date of
Informed
Consent
Date of
Screening
Date of
Enrolment
Date of
First
Administration
Date of
Last
Administration
Completed
or
Discontinued
Date of Study
Completion or
Discontinuation
Date of
End of
Participation
Reason for discontinuation
S001/001 ddMMMyyyy ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
Discontinued
ddMMMyyyy
ddMMMyyyy
Withdrawal by subject
S002/002 ddMMMyyyy ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
Completed
ddMMMyyyy
ddMMMyyyy
S005/003 ddMMMyyyy ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
ddMMMyyyy
Discontinued
ddMMMyyyy
ddMMMyyyy
Adverse event
...
...
...
...
...
...
...
...
...
...
Program: Listings\k344-ds-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.2 - Analysis sets
Subject
ID
Planned Sequence
Enrolled
Set
Safety
Set
PK
Set
Reason for the exclusion
S001/001
TRTR
Y
N
N
Lack of IMP intake
S003/002
RTRT
Y
Y
Y
...
...
.
.
.
...
Note: Subjects are listed according to the sequence they were assigned to
T: Riluzole 50 mg orodispersible film (T)
R: Rilutek®, 50 mg riluzole tablets (R)
Program: Listings\k344-ds-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.3 - Demography
Subject
ID
Sex
Race
Birth
Year
Age
(years)
Height
(cm)
Body Weight
(kg)
Body Mass Index
(kg/m2)
S001/001
F
White
2001
20
170
55.0
19.0
S002/002
M
White
1990
31
187
91.0
26.0
...
...
...
...
...
...
...
Note:Program:Listings\k344-dm-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.4 - Inclusion/Exclusion criteria not met
Subject
ID
Criterion
Verbatim
S001/001
Inclusion criterion 4
Body Mass Index (BMI): 18.5-29 kg/m2 inclusive
...
...
...
Program: Listings\k344-ie-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.5 - Investigator's interpretation of ECG
Subject
ID
Time
Point
Assessment
Date/Time
Investigator's
Interpretation
Clinically
Significant
Abnormalites
S001/001
Screening
ddMMMyyyy hh:mm
Abnormal, Not Clinically Significant
---
S005/002
Screening
ddMMMyyyy hh:mm
Normal
---
...
...
...
...
...
Program: Listings\k344-eg-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.4.6 - Tobacco consumption
Subject
ID
Tobacco Consumption
End of consumption Date
S001/001
Non smoker
---
S003/003
Ex Smoker
2019
...
...
...
Program: Listings\k344-su-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.1 - Investigational medicinal products administration
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Adm.
Nr.
Adm.
Visit
Administration
Date/time
Dissolution
Start
Time
Dissolution
End
Time
Film
swallowed
within 5
min?
If yes,
accidental
swallowing
time
Film
undissolved
at 5 min
after Adm.?
Fasting
Conditions
From 10 h
before
IMP Adm.?
Fasting Conditions
Start Date/time
Time from
Start of
Fasting
Conditions
S001/001
1
Visit 3
ddMMMyyyy hh:mm
hh:mm:ss
hh:mm:ss
N
---
N
Y
ddMMMyyyy hh:mm
xx min
S001/001
3
Visit 7
ddMMMyyyy hh:mm
hh:mm:ss
hh:mm:ss
N
---
N
Y
ddMMMyyyy hh:mm
xx min
...
...
...
...
...
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-ex-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.1 - Investigational medicinal products administration
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
Adm.
Nr.
Adm.
Visit
Administration
Date/time
Dissolution
Start
Time
Dissolution
End
Time
Film
swallowed
within 5
min?
If yes,
accidental
swallowing
time
Film
undissolved
at 5 min
after Adm.?
Fasting
Conditions
From 10 h
before
IMP Adm.?
Fasting Conditions
Start Date/time
Time from
Start of
Fasting
Conditions
S001/001
2
Visit 5
ddMMMyyyy hh:mm
---
---
---
---
---
Y
ddMMMyyyy hh:mm
xx min
S001/001
4
Visit 9
ddMMMyyyy hh:mm
---
---
---
---
---
Y
ddMMMyyyy hh:mm
xx min
...
...
...
...
...
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-ex-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.2 - Dose per body weight
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Active
Ingredient
Dose
Administered
(mg)
Body Weight
at Screening
(kg)
Dose per
Body Weight
(mg/kg)
S001/001
Riluzole
200
55.0
3.63
...
...
...
...
...
Note: The dose per body weight is calculated using the screening body weight
Program: Listings\k344-ex-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.3 - PK samples collection dates and times
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
IMP Administration
Date/Time
IMP
Adm.
Nr.
Time Point
Sample
Number
Collection
Date/time
Time from
IMP Administration
S001/001
ddMMMyyyy hh:mm
1
Pre-dose - Within 30 min before IMP administration
1
ddMMMyyyy hh:mm
-xx min
S001/001
ddMMMyyyy hh:mm
1
15 min post-dose
2
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
1
30 min post-dose ± 1 min
3
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
1
45 min post-dose ± 2 min
4
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
1
1 hour post-dose ± 3 min
5
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
1.25 hours post-dose ± 3 min
6
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
1.5 hours post-dose ± 3 min
7
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
2 hours post-dose ± 5 min
8
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
3 hours post-dose ± 5 min
9
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
4 hours post-dose ± 5 min
10
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
6 hours post-dose ± 10 min
11
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
8 hours post-dose ± 10 min
12
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
12 hours post-dose ± 10 min
13
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
24 hours post-dose ± 10 min
14
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
1
36 hours post-dose ± 10 min
15
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
Pre-dose - Within 30 min before IMP administration
31
ddMMMyyyy hh:mm
-xx min
S001/001
ddMMMyyyy hh:mm
3
15 min post-dose
32
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
3
30 min post-dose ± 1 min
33
ddMMMyyyy hh:mm
xx min
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-pc-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.3 - PK samples collection dates and times
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
IMP Administration
Date/Time
IMP
Adm.
Nr.
Time Point
Sample
Number
Collection
Date/time
Time from
IMP Administration
S001/001
ddMMMyyyy hh:mm
3
45 min post-dose ± 2 min
34
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
3
1 hour post-dose ± 3 min
35
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
1.25 hours post-dose ± 3 min
36
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
1.5 hours post-dose ± 3 min
37
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
2 hours post-dose ± 5 min
38
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
3 hours post-dose ± 5 min
39
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
4 hours post-dose ± 5 min
40
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
6 hours post-dose ± 10 min
41
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
8 hours post-dose ± 10 min
42
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
12 hours post-dose ± 10 min
43
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
24 hours post-dose ± 10 min
44
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
3
36 hours post-dose ± 10 min
45
ddMMMyyyy hh:mm
xx h xx min
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-pc-lst.sas


CROSS Research S.A.
Page 3
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.3 - PK samples collection dates and times
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
IMP Administration
Date/Time
IMP
Adm.
Nr.
Time Point
Sample
Number
Collection
Date/time
Time from
IMP Administration
S001/001
ddMMMyyyy hh:mm
2
Pre-dose - Within 30 min before IMP administration
16
ddMMMyyyy hh:mm
-xx min
S001/001
ddMMMyyyy hh:mm
2
15 min post-dose
17
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
2
30 min post-dose ± 1 min
18
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
2
45 min post-dose ± 2 min
19
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
2
1 hour post-dose ± 3 min
20
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
1.25 hours post-dose ± 3 min
21
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
1.5 hours post-dose ± 3 min
22
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
2 hours post-dose ± 5 min
23
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
3 hours post-dose ± 5 min
24
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
4 hours post-dose ± 5 min
25
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
6 hours post-dose ± 10 min
26
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
8 hours post-dose ± 10 min
27
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
12 hours post-dose ± 10 min
28
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
24 hours post-dose ± 10 min
29
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
36 hours post-dose ± 10 min
30
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
Pre-dose - Within 30 min before IMP administration
46
ddMMMyyyy hh:mm
-xx min
S001/001
ddMMMyyyy hh:mm
4
15 min post-dose
47
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
4
30 min post-dose ± 1 min
48
ddMMMyyyy hh:mm
xx min
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-pc-lst.sas


CROSS Research S.A.
Page 4
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.3 - PK samples collection dates and times
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
IMP Administration
Date/Time
IMP
Adm.
Nr.
Time Point
Sample
Number
Collection
Date/time
Time from
IMP Administration
S001/001
ddMMMyyyy hh:mm
4
45 min post-dose ± 2 min
49
ddMMMyyyy hh:mm
xx min
S001/001
ddMMMyyyy hh:mm
4
1 hour post-dose ± 3 min
50
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
1.25 hours post-dose ± 3 min
51
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
1.5 hours post-dose ± 3 min
52
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
2 hours post-dose ± 5 min
53
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
3 hours post-dose ± 5 min
54
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
4 hours post-dose ± 5 min
55
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
6 hours post-dose ± 10 min
56
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
8 hours post-dose ± 10 min
57
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
12 hours post-dose ± 10 min
58
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
24 hours post-dose ± 10 min
59
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
4
36 hours post-dose ± 10 min
60
ddMMMyyyy hh:mm
xx h xx min
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-pc-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.4 - Riluzole concentrations (ng/mL) measured in plasma
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Period
Pre
dose
0.25 h
0.5 h
0.75 h
1 h
1.25 h
1.5 h
2 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
S001/001
1
BLQL
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
S001/001
3
BLQL
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
BLQL: Below Lower Quantification Limit (xx.xx ng/mL)
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.5.4 - Riluzole concentrations (ng/mL) measured in plasma
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
Period
Pre
dose
0.25 h
0.5 h
0.75 h
1 h
1.25 h
1.5 h
2 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
S001/001
2
BLQL
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
S001/001
4
BLQL
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
BLQL: Below Lower Quantification Limit (xx.xx ng/mL)
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.6.1 - Riluzole plasma PK parameters
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Period
Cmax
(ng/mL)
tmax
(h)
AUC0-t
(h*ng/mL)
AUC0-inf
(h*ng/mL)
AUCextra
(%)
t½
(h)
λz
(1/h)
Points
R2
S001/001
1
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
S001/001
3
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
...
...
...
...
...
...
...
...
...
...
Note: Only subjects included in PK Set are listed
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.6.1 - Riluzole plasma PK parameters
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
Period
Cmax
(ng/mL)
tmax
(h)
AUC0-t
(h*ng/mL)
AUC0-inf
(h*ng/mL)
AUCextra
(%)
t½
(h)
λz
(1/h)
Points
R2
S001/001
2
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
S001/001
4
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
...
...
...
...
...
...
...
...
...
...
Note: Only subjects included in PK Set are listed
Program: pk-analysis\k344-tlf.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.6.2 - Palatability
Subject
ID
IMP Administration
Date/Time
IMP Administration
Number
Time
Point
Assessment
Date/Time
Palatability
Score
S001/001
ddMMMyyyy hh:mm
1
Visit 3 - Day 1 - Immediately after administration
ddMMMyyyy hh:mm
0 - Very unpleasant
S001/001
ddMMMyyyy hh:mm
3
Visit 7 - Day 1 - Immediately after administration
ddMMMyyyy hh:mm
1 - Unpleasant
...
...
...
...
...
...
Note: Palatability has been evaluated only for Riluzole 50 mg orodispersible film (T)
Program: Listings\k344-pc-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.7.1 - Treatment-emergent adverse events
Investigational Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
Adverse
Event
ID
S001/001
1
Description:
Headache
Body Area Affected:
Head
Preferred Term 1:
Headache
System Organ Class 1:
Nervous system disorders
Acknowledgment Date/Time (Day)
ddMMMyyyy hh:mm (j)
Start - End Date/Time (Day):
ddMMMyyyy hh:mm (k) - ddMMMyyyy hh:mm (k+n)
Has the Adverse Event Started After the Administration of the Study Drug?
Y
Last Study Drug Administration Date/Time Before Onset
ddMMMyyyy hh:mm
Reasonable Possibility of a Causal Relationship with the Study Drug?
Y
Other Causal Relationship
---
Severity:
Mild
Pattern:
Continuous
Serious?
N
Seriousness criteria:
---
Action taken with Study Drug:
None
Concomitant therapy?
N
Caused Study Discontinuation?
N
Other Action Taken:
None
Outcome:
Recovered/Resolved
Comments:
---
...
...
...
...
Note: Subjects are listed according to the product they actually received
Note 1: MedDRA version 24.0
Program: Listings\k344-ae-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.7.1 - Treatment-emergent adverse events
Investigational Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
Adverse
Event
ID
S001/001
2
Description:
Headache
Body Area Affected:
Head
Preferred Term 1:
Headache
System Organ Class 1:
Nervous system disorders
Acknowledgment Date/Time (Day)
ddMMMyyyy hh:mm (j)
Start - End Date/Time (Day):
ddMMMyyyy hh:mm (k) - ddMMMyyyy hh:mm (k+n)
Has the Adverse Event Started After the Administration of the Study Drug?
Y
Last Study Drug Administration Date/Time Before Onset
ddMMMyyyy hh:mm
Reasonable Possibility of a Causal Relationship with the Study Drug?
Y
Other Causal Relationship
---
Severity:
Mild
Pattern:
Continuous
Serious?
N
Seriousness criteria:
---
Action taken with Study Drug:
None
Concomitant therapy?
N
Caused Study Discontinuation?
N
Other Action Taken:
None
Outcome:
Recovered/Resolved
Comments:
---
...
...
...
...
Note: Subjects are listed according to the product they actually received
Note 1: MedDRA version 24.0
Program: Listings\k344-ae-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.7.2 - Pre-treatment adverse events
Subject
ID
Adverse
Event
ID
S001/001
1
Description:
Headache
Body Area Affected:
Head
Preferred Term 1:
Headache
System Organ Class 1:
Nervous system disorders
Acknowledgment Date/Time (Day)
ddMMMyyyy hh:mm (j)
Start - End Date/Time (Day):
ddMMMyyyy hh:mm (k) - ddMMMyyyy hh:mm (k+n)
Has the Adverse Event Started After the Administration of the Study Drug?
N
Last Study Drug Administration Date/Time Before Onset
---
Reasonable Possibility of a Causal Relationship with the Study Drug?
N
Other Causal Relationship
Other, stress period
Severity:
Mild
Pattern:
Continuous
Serious?
N
Seriousness criteria:
---
Action taken with Study Drug:
None
Concomitant therapy?
N
Caused Study Discontinuation?
N
Other Action Taken:
None
Outcome:
Recovered/Resolved
Comments:
---
...
...
...
...
Note 1: MedDRA version 24.0
Program: Listings\k344-ae-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: BLOOD CHEMISTRY
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Sodium [mmol/L]
138 [N]
136 - 145
N
S001/001
Screening
ddMMMyyyy hh:mm
Potassium [mmol/L]
4.4 [N]
3.5 - 5.1
N
S001/001
Screening
ddMMMyyyy hh:mm
Calcium [mmol/L]
2.27 [N]
2.10 - 2.55
N
S001/001
Screening
ddMMMyyyy hh:mm
Chloride [mmol/L]
103 [N]
96 - 110
N
S001/001
Screening
ddMMMyyyy hh:mm
Phosphate [mmol/L]
0.84 [L]
0.87 - 1.45
N
S001/001
Screening
ddMMMyyyy hh:mm
Alkaline Phosphatase [U/L]
95 [N]
<= 129
N
S001/001
Screening
ddMMMyyyy hh:mm
Gamma Glutamyl Transferase [U/L]
17 [N]
<= 66
N
S001/001
Screening
ddMMMyyyy hh:mm
Aspartate Aminotransferase [U/L]
24 [N]
<= 50
N
S001/001
Screening
ddMMMyyyy hh:mm
Alanine Aminotransferase [U/L]
30 [N]
<= 50
N
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Sodium [mmol/L]
138 [N]
136 - 145
N
S001/001
End of Study
ddMMMyyyy hh:mm
Potassium [mmol/L]
4.4 [N]
3.5 - 5.1
N
S001/001
End of Study
ddMMMyyyy hh:mm
Calcium [mmol/L]
2.27 [N]
2.10 - 2.55
N
S001/001
End of Study
ddMMMyyyy hh:mm
Chloride [mmol/L]
103 [N]
96 - 110
N
S001/001
End of Study
ddMMMyyyy hh:mm
Phosphate [mmol/L]
0.84 [L]
0.87 - 1.45
N
S001/001
End of Study
ddMMMyyyy hh:mm
Alkaline Phosphatase [U/L]
95 [N]
<= 129
N
S001/001
End of Study
ddMMMyyyy hh:mm
Gamma Glutamyl Transferase [U/L]
17 [N]
<= 66
N
S001/001
End of Study
ddMMMyyyy hh:mm
Aspartate Aminotransferase [U/L]
24 [N]
<= 50
N
S001/001
End of Study
ddMMMyyyy hh:mm
Alanine Aminotransferase [U/L]
30 [N]
<= 50
N
...
...
...
...
...
...
...
Note 1: N=Normal, H=Higher than upper normal limit, L=Lower than lower normal limit
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: HEMATOLOGY
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Leukocytes [10^9/L]
10.02 [H]
4.00 - 10.00
N
S001/001
Screening
ddMMMyyyy hh:mm
Erythrocytes [10^12/L]
5.19 [N]
4.30 - 5.90
N
S001/001
Screening
ddMMMyyyy hh:mm
Hemoglobin [g/dL]
15.4 [N]
14.0 - 18.0
N
S001/001
Screening
ddMMMyyyy hh:mm
Hemoglobin [mmol/L]
9.6 [N]
8.7 - 11.2
N
S001/001
Screening
ddMMMyyyy hh:mm
Hematocrit [%]
44 [N]
42 - 52
N
S001/001
Screening
ddMMMyyyy hh:mm
Ery. Mean Corpuscular Volume [fL]
84 [N]
83 - 100
N
S001/001
Screening
ddMMMyyyy hh:mm
Ery. Mean Corpuscular Hemoglobin [pg]
30 [N]
27 - 34
N
S001/001
Screening
ddMMMyyyy hh:mm
Ery. Mean Corpuscular HGB Concentration [g/dL]
35 [N]
32 - 36
N
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Leukocytes [10^9/L]
10.02 [H]
4.00 - 10.00
N
S001/001
End of Study
ddMMMyyyy hh:mm
Erythrocytes [10^12/L]
5.19 [N]
4.30 - 5.90
N
S001/001
End of Study
ddMMMyyyy hh:mm
Hemoglobin [g/dL]
15.4 [N]
14.0 - 18.0
N
S001/001
End of Study
ddMMMyyyy hh:mm
Hemoglobin [mmol/L]
9.6 [N]
8.7 - 11.2
N
S001/001
End of Study
ddMMMyyyy hh:mm
Hematocrit [%]
44 [N]
42 - 52
N
S001/001
End of Study
ddMMMyyyy hh:mm
Ery. Mean Corpuscular Volume [fL]
84 [N]
83 - 100
N
S001/001
End of Study
ddMMMyyyy hh:mm
Ery. Mean Corpuscular Hemoglobin [pg]
30 [N]
27 - 34
N
S001/001
End of Study
ddMMMyyyy hh:mm
Ery. Mean Corpuscular HGB Concentration [g/dL]
35 [N]
32 - 36
N
...
...
...
...
...
...
...
Note 1: N=Normal, H=Higher than upper normal limit, L=Lower than lower normal limit
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 3
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: COTININE
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Cotinine
Negative [N]
Negative
N
...
...
...
...
...
...
...
Note 1: N=Normal, A=Different from reference value
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 4
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: URINE ANALYSIS
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Urobilinogen
Normal [N]
Normal
N
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Bilirubin
Absent [N]
Absent
N
S001/001
Screening
ddMMMyyyy hh:mm
Ketones
Absent [N]
Absent
N
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Hemoglobin
+++ [A]
Absent
N
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Leukocytes
Absent [N]
Absent
N
S001/001
Screening
ddMMMyyyy hh:mm
Sediment Examination
Checked
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Sediment Leukocytes
Absent [N]
Absent or 0-2 per field
N
S001/001
Screening
ddMMMyyyy hh:mm
Urinary Sediment Erythrocytes
0-2 per field [N]
Absent or 0-2 per field
N
...
...
...
...
...
...
...
S001/001
End of Study
ddMMMyyyy hh:mm
Urobilinogen
Normal [N]
Normal
N
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Bilirubin
Absent [N]
Absent
N
S001/001
End of Study
ddMMMyyyy hh:mm
Ketones
Absent [N]
Absent
N
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Hemoglobin
+++ [A]
Absent
N
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Leukocytes
Absent [N]
Absent
N
S001/001
End of Study
ddMMMyyyy hh:mm
Sediment Examination
Checked
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Sediment Leukocytes
Absent [N]
Absent or 0-2 per field
N
S001/001
End of Study
ddMMMyyyy hh:mm
Urinary Sediment Erythrocytes
0-2 per field [N]
Absent or 0-2 per field
N
...
...
...
...
...
...
...
Note 1: N=Normal, A=Different from reference value
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 5
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: URINE DRUG SCREENING
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Amphetamine
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Cannabinoids
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Cocaine
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Ecstasy
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Methamphetamine
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Opiate
Negative [N]
Negative
N
...
...
...
...
...
...
...
Note 1: N=Normal, A=Different from reference value
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 6
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: VIROLOGY
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Hepatitis B Virus Surface Antigen
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
Hepatitis C Virus Antibody
Negative [N]
Negative
N
S001/001
Screening
ddMMMyyyy hh:mm
HIV Ag/Ab Combo
Negative [N]
Negative
N
...
...
...
...
...
...
...
Note 1: N=Normal, A=Different from reference value_
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 7
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.1 - Individual laboratory measurements
Category of Laboratory Parameters: ALCOHOL BREATH TEST AND PREGNANCY TEST
Subject
ID
Time
Point
Collection
Date/time
Parameter
Value and
Abnormality 1
Normal Range or
Reference Value
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Pregnancy Test
Negative [N]
Negative
N
S001/001
Visit 2 - Day -1
ddMMMyyyy hh:mm
Pregnancy Test
Negative [N]
Negative
N
S001/001
Visit 2 - Day -1
ddMMMyyyy hh:mm
Alcohol Breath Test
Negative [N]
Negative
N
...
...
...
...
...
...
...
Note 1: N=Normal, A=Different from reference value
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.8.2 - Investigator's interpretation of laboratory test results
Subject
ID
Time
Point
Assessment
Date
Investigator's
Interpretation
Clinically
Significant
Abnormalites
S001/001
Screening
ddMMMyyyy
Abnormal, Not Clinically Significant
---
S001/001
End of Study
ddMMMyyyy
Abnormal, Not Clinically Significant
---
...
...
...
...
...
Program: Listings\k344-lb-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.9.1 - Vital signs and body weight
Subject
ID
Time
Point
Assessment
Date/Time
Parameter
Value and
Abnormality 1
Normal
Range
Clinically
Significant?
S001/001
Screening
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Screening
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Screening
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Screening
ddMMMyyyy hh:mm
Weight [kg]
55.5
---
N
S001/001
Visit 3 - Pre-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 3 - Pre-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 3 - Pre-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 3 - 2 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 3 - 2 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 3 - 2 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 3 - 36 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 3 - 36 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 3 - 36 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 5 - Pre-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 5 - Pre-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 5 - Pre-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 5 - 2 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 5 - 2 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 5 - 2 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 5 - 36 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 5 - 36 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 5 - 36 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 7 - Pre-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 7 - Pre-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 7 - Pre-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
Note 1: N=Normal, H=Higher than upper normal limit, L=Lower than lower normal limit
Program: Listings\k344-vs-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.9.1 - Vital signs and body weight
Subject
ID
Time
Point
Assessment
Date/Time
Parameter
Value and
Abnormality 1
Normal
Range
Clinically
Significant?
S001/001
Visit 7 - 2 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 7 - 2 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 7 - 2 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 7 - 36 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 7 - 36 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 7 - 36 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 9 - Pre-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 9 - Pre-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 9 - Pre-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 9 - 2 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 9 - 2 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 9 - 2 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
Visit 9 - 36 hours post-dose
ddMMMyyyy hh:mm
Systolic Blood Pressure [mmHg]
96 [L]
100-139
N
S001/001
Visit 9 - 36 hours post-dose
ddMMMyyyy hh:mm
Diastolic Blood Pressure [mmHg]
58 [N]
50-89
N
S001/001
Visit 9 - 36 hours post-dose
ddMMMyyyy hh:mm
Heart Rate [beats/min]
88 [N]
50-90
N
S001/001
End of Study
ddMMMyyyy hh:mm
Weight [kg]
55.5
---
N
...
...
...
...
...
...
...
Note 1: N=Normal, H=Higher than upper normal limit, L=Lower than lower normal limit
Program: Listings\k344-vs-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.1 - Medical and surgical history
Subject
ID
Category
Disease/Surgery
ID
S001/001
Medical History
M1
Verbatim:
Left shoulder luxation
Preferred Term 1:
Joint dislocation
System Organ Class 1:
Injury, poisoning and procedural complications
Disease Start - End Date:
2012 - 2012
Surgery
S1
Verbatim:
Right knee meniscectomy
Preferred Term 1:
Meniscus removal
System Organ Class 1:
Surgical and medical procedures
Surgery Date:
04NOV1980
...
...
...
...
Note 1: MedDRA version 24.0
Program: Listings\k344-mh-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.2 - Physical examination
Subject
ID
Time Point
Physical
Examination
Date
S001/001
Screening
ddMMMyyyy
Investigator's Interpretation
Normal
End of Study
ddMMMyyyy
Investigator's Interpretation:
Abnormal, Clinically Significant
Clinically Significant Abnormalities: Left shoulder luxation
Preferred Term 1:
Joint dislocation
System Organ Class 1:
Injury, poisoning and procedural complications
...
...
...
...
...
Note 1: MedDRA version 24.0
Program: Listings\k344-pe-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.3 - Mouth Visual Inspection
Subject
ID
Time Point
Physical
Examination
Date
S001/001
Visit 3 - Pre-dose
ddMMMyyyy
Investigator's Interpretation
Normal
S001/001
Visit 3 - 0.5 hour post-dose
ddMMMyyyy
Investigator's Interpretation
Abnormal, Not Clinically Significant
S001/001
Visit 3 - 1 hour post-dose
ddMMMyyyy
Investigator's Interpretation:
Abnormal, Clinically Significant
Clinically Significant Abnormalities: Left shoulder luxation
Preferred Term 1:
Joint dislocation
System Organ Class 1:
Injury, poisoning and procedural complications
S001/001
Visit 7 - Pre-dose
ddMMMyyyy
Investigator's Interpretation
Normal
S001/001
Visit 7 - 0.5 hour post-dose
ddMMMyyyy
Investigator's Interpretation
Abnormal, Not Clinically Significant
S001/001
Visit 7 - 1 hour post-dose
ddMMMyyyy
Investigator's Interpretation:
Abnormal, Clinically Significant
Clinically Significant Abnormalities: Left shoulder luxation
Preferred Term 1:
Joint dislocation
System Organ Class 1:
Injury, poisoning and procedural complications
...
...
...
...
...
Note: Mouth visual inspection has been evaluated only for Riluzole 50 mg orodispersible film (T)
Note 1: MedDRA version 24.0
Program: Listings\k344-pe-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.4 - Prior and concomitant medications
Subject
ID
Category
Medication
ID
S001/001
Prior
1
Verbatim:
Alerid
Standardised Medication Name 1:
Alerid
Active Ingredients 1:
Cetirizine hydrochloride
Medication Class 1, 2:
Piperazine derivatives (R06AE)
Indication:
Pollinosis
Dose:
10 mg
Start - End Date/Time:
2013 - Ongoing
Frequency - Dosage Form - Route:
1 time per day - Tablet - Oral
Related to:
Disease M1
Concomitant
2
Verbatim:
Paracen
Standardised Medication Name 1:
Paracen
Active Ingredients 1:
Paracetamol
Medication Class 1, 2:
Anilides (N02BE)
Indication:
Headache
Dose:
500 mg
Start - End Date/Time:
15JUN2016 19:08 - 15JUN2016 19:08
Frequency - Dosage Form - Route:
Once - Tablet - Oral
Related to:
Adverse Event 1
...
...
...
...
Note 1: WHO Drug Dictionary Enhanced March 1, 2021
Note 2: Anatomical Therapeutic Chemical classification, 4th level term
Program: Listings\k344-cm-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.5 - Subjects study visits
Subject
ID
Visit
Visit Start Date (Day)
Visit End Date (Day)
Home discharge
Date/time
S001/001
Visit 1 - Screening - Day -14/-2
ddMMMyyyy (-j)
---
---
S001/001
Period 1 - Visit 2 - Day -1
ddMMMyyyy (-1)
---
---
S001/001
Period 1 - Visit 3 - Days 1-2
ddMMMyyyy (1)
ddMMMyyyy (2)
ddMMMyyyy (2) hh:mm
S001/001
Period 1 - Visit 4 - Day -1
ddMMMyyyy (k-1)
---
---
S001/001
Period 2 - Visit 5 - Days 1-2
ddMMMyyyy (k)
ddMMMyyyy (k+1)
ddMMMyyyy (k+1) hh:mm
S001/001
Period 1 - Visit 6 - Day -1
ddMMMyyyy (n-1)
---
---
S001/001
Period 2 - Visit 7 - Days 1-2
ddMMMyyyy (n)
ddMMMyyyy (n+1)
ddMMMyyyy (n+1) hh:mm
S001/001
Period 1 - Visit 8 - Day -1
ddMMMyyyy (p-1)
---
---
S001/001
Period 2 - Visit 9 - Days 1-2
ddMMMyyyy (p)
ddMMMyyyy (p+1)
---
S001/001
Final Visit
ddMMMyyyy (p+1)
---
ddMMMyyyy (p+1) hh:mm
...
...
...
...
...
Program: Listings\k344-sv-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.6 - Fertility status and contraception
Subject
ID
Chilbearing
Potential?
Non-childbearing
Potential
Status Onset
Menopausal
Status?
Date of
Menopause
Surgical
Sterilisation?
Surgical
Sterilisation
Date
Reliable
Contraceptive
Method Used?
S001/001
No
ddMMMyyyy
Yes
MMMyyyy
Yes
ddMMMyyyy
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...
...
...
...
...
...
...
...
Note: Only female subjects are listed
Program: Listings\k344-rp-lst.sas


CROSS Research S.A.
Page 1
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.7 - Meals
Investigational Medicinal Product: Riluzole 50 mg orodispersible film (T)
Subject
ID
IMP
Administration
Date/Time
Meal
Nr
Standardised
Meal
Time Point
Meal
Served?
Meal Start
Date/time
Elapsed
Time
S001/001
ddMMMyyyy hh:mm
1
Lunch
Visit 3 - Day 1 –5 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
2
Dinner
Visit 3 - Day 1 –12 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
---
3
Breakfast
Visit 3 - Day 2 –at about 08:00
Y
ddMMMyyyy hh:mm
---
S001/001
---
4
Lunch
Visit 3 - Day 2 - at about 13:00
Y
ddMMMyyyy hh:mm
---
S001/001
ddMMMyyyy hh:mm
9
Lunch
Visit 7 - Day 1 –5 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
10
Dinner
Visit 7 - Day 1 –12 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
---
11
Breakfast
Visit 7 - Day 2 –at about 08:00
Y
ddMMMyyyy hh:mm
---
S001/001
---
12
Lunch
Visit 7 - Day 2 - at about 13:00
Y
ddMMMyyyy hh:mm
---
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-ml-lst.sas


CROSS Research S.A.
Page 2
CONFIDENTIAL
Statistical analysis plan CRO-PK-20-344
Sponsor code Z7251J01
Riluzole orodispersible film replicate bioavailability
Final version 1.0, 31MAY21
Listing 16.2.10.7 - Meals
Investigational Medicinal Product: Rilutek®, 50 mg riluzole tablets (R)
Subject
ID
IMP
Administration
Date/Time
Meal
Nr
Standardised
Meal
Time Point
Meal
Served?
Meal Start
Date/time
Elapsed
Time
S001/001
ddMMMyyyy hh:mm
5
Lunch
Visit 5 - Day 1 –5 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
6
Dinner
Visit 5 - Day 1 –12 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
---
7
Breakfast
Visit 5 - Day 2 –at about 08:00
Y
ddMMMyyyy hh:mm
---
S001/001
---
8
Lunch
Visit 5 - Day 2 - at about 13:00
Y
ddMMMyyyy hh:mm
---
S001/001
ddMMMyyyy hh:mm
13
Lunch
Visit 9 - Day 1 –5 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
ddMMMyyyy hh:mm
14
Dinner
Visit 9 - Day 1 –12 hours post-dose
Y
ddMMMyyyy hh:mm
xx h xx min
S001/001
---
15
Breakfast
Visit 9 - Day 2 –at about 08:00
Y
ddMMMyyyy hh:mm
---
S001/001
---
16
Lunch
Visit 9 - Day 2 - at about 13:00
Y
ddMMMyyyy hh:mm
---
...
...
...
...
...
...
...
Note: Subjects are listed according to the product they actually received
Program: Listings\k344-ml-lst.sas