Clinical trial NCT03110458
Conditions: Acute Unilateral Vestibulopathy (AUV)
Keywords: Acute unilateral vestibulopathy, AUV
Sponsor: Sensorion
Start date: 2017-08-16; Completion date: 2019-10-15
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 2 dose-regimens of orally administered SENS-111 (100mg and 200mg) given during 4 days in patients suffering from Acute Unilateral Vestibulopathy (AUV)

Detailed description:

Arms: arm 1: SENS-111 100mg: 2 Oral Dispersible Tablets (1 SENS-111 100 mg and 1 placebo) arm 2: SENS-111 200mg: 2 Oral Dispersible Tablets (SENS-111 100 mg) arm 3: Placebo: 2 placebo Oral Dispersible Tablets
Interventions: intervention 1: SENS-111 100mg intervention 2: SENS-111 200mg intervention 3: Placebo Oral Tablet
Intervention descriptions: intervention 1: SENS-111 100mg is presented as 1 Oral Dispersible Tablet of SENS-111 100mg + 1 Oral Dispersible Tablet of placebo given twice on Day 1, second intake given approximately 12 hours (9 to 15 hours) after the first intake and thereafter given once daily on Days 2 to 5 inclusive. The corresponding total dose will be 500 mg for the entire study. intervention 2: SENS-111 200mg is presented as 2 Oral Dispersible Tablet of SENS-111 100mg given twice on Day 1,second intake given approximately 12 hours (9 to 15 hours) after the first intake and thereafter given once daily on Days 2 to 5 inclusive. The corresponding total dose will be 1000 mg for the entire study. intervention 3: Placebo is presented as 2 Oral Dispersible Tablets of placebo given twice on Day 1, second intake given approximately 12 hours (9 to 15 hours) after the first intake and thereafter given once daily on Days 2 to 5 inclusive. The corresponding total dose will be 0 mg for the entire study.

Protocol documents:
Prot_001.pdf: 
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AMENDED CLINICAL TRIAL PROTOCOL 
 
 
 
STUDY COMPOUND: SENS-111 
 
STUDY Number: SENS 111-201 
NCT03110458 
 
 
 
A multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 2 
dose regimens of orally administered SENS-111 (100 mg and 200 mg) given during 4 days in patients 
suffering from Acute Unilateral Vestibulopathy 
 
 
 
Version date: 9 February-2017 
 
 
 
EudraCT number: 2016-003927-45 
IND number: 129 922 
 
 
« The information presented in this document is strictly confidential and is the exclusive property of 
Sensorion. It shall not be used, published or disclose to any unauthorized person, in any form, without the 
written authorization from Sensorion. » 
 
 


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CLINICAL TRIAL PROTOCOL APROVAL FORM 
 
The protocol, entitled: “A multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of 2 dose regimens of orally administered SENS-111 (100 mg and 200 mg) given during 
4 days in patients suffering from Acute Unilateral Vestibulopathy “ has been reviewed and approved by:  
 
and I have fully discussed the objectives of this clinical trial and the contents of this protocol with the 
Sponsor's representative(s). 
 
I agree to conduct the clinical trial according to this protocol and to comply with its requirements, subject 
to ethical and safety considerations. 
 
I understand that, should the decision be made by the Sponsor to terminate prematurely or suspend the 
clinical trial at any time for whatever reasons, such decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the clinical trial I will communicate 
immediately such decision in writing to the Sponsor. 
 
INVESTIGATOR/ International Coordinator 
 
Name:  
 
DATE: ____________ (e.g.:  05 February 2000)  
SIGNATURE: 
______________ 
 
 
FOR THE SPONSOR 
 
Company:  
 
Name:  
 
DATE: ____________ (e.g.:  05 February 2000)  
SIGNATURE: 
______________ 
 
 


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1 TABLE OF CONTENT  
1 
TABLE OF CONTENT ........................................................................................................................... 3 
2 
LIST OF ABBREVIATIONS ..................................................................................................................... 8 
3 
CLINICAL TRIAL SUMMARY ................................................................................................................ 10 
4 
FLOW-CHARTS ............................................................................................................................... 19 
5 
INTRODUCTION AND RATIONALE ......................................................................................................... 22 
5.1 
Acute Unilateral Vestibulopathy ....................................................................................................................................... 22 
5.2 
Histamine 4 receptor ............................................................................................................................................................. 22 
5.3 
SENS-111 ..................................................................................................................................................................................... 23 
5.3.1 
Pharmacology studies ................................................................................................................................................................. 23 
5.3.2 
Preclinical pharmacokinetics .................................................................................................................................................. 23 
5.4 
Non clinical safety pharmacology and toxicology studies ...................................................................................... 24 
5.5 
Clinical experience with SENS-111 .................................................................................................................................. 25 
5.6 
Study Rationale ......................................................................................................................................................................... 26 
5.7 
Dose selection ........................................................................................................................................................................... 26 
5.8 
Endpoints selection ................................................................................................................................................................ 27 
6 
STUDY OBJECTIVES AND END-POINTS ................................................................................................... 28 
6.1 
Study Objectives ....................................................................................................................................................................... 28 
6.1.1 
Primary objective: ......................................................................................................................................................................... 28 
6.1.2 
Secondary objectives: .................................................................................................................................................................. 28 
6.2 
Study End points ...................................................................................................................................................................... 28 
6.2.1 
Primary efficacy end point ........................................................................................................................................................ 28 
6.2.2 
Secondary efficacy endpoints .................................................................................................................................................. 28 
6.2.3 
Exploratory efficacy endpoints ............................................................................................................................................... 29 
6.2.4 
Safety endpoints: ........................................................................................................................................................................... 29 
6.2.5 
Pharmacokinetics.......................................................................................................................................................................... 29 
7 
STUDY DESIGN ............................................................................................................................... 30 
7.1 
Description of the protocol .................................................................................................................................................. 30 
7.2 
Study diagram ........................................................................................................................................................................... 31 
7.3 
Number of subjects and duration of study participation ........................................................................................ 31 
7.4 
Determination of end of clinical trial (all patients) ................................................................................................... 32 


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8 
INCLUSION AND EXCLUSION CRITERIA ................................................................................................... 33 
8.1 
Inclusion criteria ...................................................................................................................................................................... 33 
8.2 
Exclusion criteria ..................................................................................................................................................................... 33 
9 
TREATMENT ................................................................................................................................. 36 
9.1 
Study treatment........................................................................................................................................................................ 36 
9.2 
Description of blinding methods ....................................................................................................................................... 36 
9.3 
Randomization process ......................................................................................................................................................... 36 
9.4 
Packaging and labeling .......................................................................................................................................................... 37 
9.5 
Storage conditions ................................................................................................................................................................... 37 
9.6 
Drug Accountability ................................................................................................................................................................ 37 
9.7 
Responsibilities ........................................................................................................................................................................ 38 
9.8 
Management of treatment at the end of the study ..................................................................................................... 38 
9.9 
Concomitant therapy.............................................................................................................................................................. 38 
9.9.1 
Authorized concomitant medication ................................................................................................................................... 38 
9.9.2 
Not permitted concomitant medication ............................................................................................................................. 38 
9.9.3 
Other prohibited therapy: ......................................................................................................................................................... 39 
9.9.4 
Rescue medication ........................................................................................................................................................................ 39 
10 STUDY ASSESSMENTS ................................................................................................................ 40 
10.1 
Efficacy assessments .............................................................................................................................................................. 40 
10.1.1 
Vertigo intensity visual analog scale (VI-VAS) .......................................................................................................... 40 
10.1.2 
Nausea Intensity Visual analog scale ............................................................................................................................. 40 
10.1.3 
The Dizziness Handicap Inventory (DHI) ..................................................................................................................... 41 
10.1.4 
Time to unassisted walking ................................................................................................................................................ 41 
10.1.5 
The Vestibular Disorders Activities of Daily Living ................................................................................................. 42 
10.1.6 
Videooculography (VOG): .................................................................................................................................................... 42 
10.1.7 
The Romberg tests ................................................................................................................................................................... 42 
10.1.8 
The caloric test .......................................................................................................................................................................... 43 
10.1.9 
The video Head Impulse Test ............................................................................................................................................. 44 
10.2 
Safety assessments .................................................................................................................................................................. 45 
10.2.1 
Physical examination ............................................................................................................................................................. 45 
10.2.2 
Vital signs .................................................................................................................................................................................... 45 
10.2.3 
Electrocardiogram (ECG) .................................................................................................................................................... 45 
10.2.4 
Laboratory safety .................................................................................................................................................................... 46 
10.2.5 
Adverse event collection ....................................................................................................................................................... 46 
10.3 
Pharmacokinetic evaluation ............................................................................................................................................... 46 
10.4 
Health Economic: ..................................................................................................................................................................... 47 
11 STUDY PROCEDURES ....................................................................................................................... 48 
11.1 
Visit ................................................................................................................................................................................................ 48 
11.1.1 
Visit 1 - Screening H-6 (± 6) ................................................................................................................................................ 48 
11.1.2 
Visit 2 - Inclusion H0 .............................................................................................................................................................. 49 


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11.1.3 
Visit 2 - H12 (± 3hours) ......................................................................................................................................................... 50 
11.1.4 
Visit 3 - H24 (± 3hours) ......................................................................................................................................................... 50 
11.1.5 
Visit 4: End of hospitalization visit, From D3 (-1, +25) to D28 ........................................................................... 51 
11.1.6 
Visit 5: End of treatment visit: D5 (-1/+2 days) ........................................................................................................ 52 
11.1.7 
Visit 6: Phone Call; D14 (±2 days) .................................................................................................................................... 52 
11.1.8 
Visit 7: End of study visit; Day 28 (±2 days): ............................................................................................................... 53 
11.1.9 
Unscheduled Visit: Visit 99 .................................................................................................................................................. 53 
11.2 
Definition of source data ...................................................................................................................................................... 54 
11.3 
Subject withdrawal ................................................................................................................................................................. 54 
11.3.1 
Removal of subjects from therapy or assessment ..................................................................................................... 54 
11.3.2 
Withdrawal criteria ............................................................................................................................................................... 54 
11.3.3 
Decided by the sponsor ......................................................................................................................................................... 55 
11.3.4 
Decided by the investigator ................................................................................................................................................ 55 
12 SAFETY ........................................................................................................................................ 56 
12.1 
Definitions .................................................................................................................................................................................. 56 
12.1.1 
Adverse event (AE) .................................................................................................................................................................. 56 
12.1.2 
Serious adverse event (SAE) ............................................................................................................................................... 56 
12.1.3 
Unexpected adverse reaction ............................................................................................................................................. 56 
12.2 
Overdose ..................................................................................................................................................................................... 57 
12.3 
Reporting of adverse events ............................................................................................................................................... 57 
12.3.1 
Adverse events ........................................................................................................................................................................... 57 
12.3.2 
Serious adverse events........................................................................................................................................................... 57 
12.3.3 
Severity and causality of events ........................................................................................................................................ 58 
12.4 
Premature study discontinuation due to adverse event ......................................................................................... 59 
12.5 
Safety follow-up ....................................................................................................................................................................... 59 
12.6 
Unblinding procedure ............................................................................................................................................................ 59 
12.7 
General Safety Monitoring ................................................................................................................................................... 60 
12.7.1 
Safety steering committee ................................................................................................................................................... 60 
12.7.2 
Data Monitoring Committee .............................................................................................................................................. 60 
13 STATISTICAL CONSIDERATIONS ........................................................................................................... 61 
13.1 
Determination of sample size ............................................................................................................................................. 61 
13.2 
Subject description ................................................................................................................................................................. 61 
13.2.1 
Disposition of subjects ........................................................................................................................................................... 61 
13.2.2 
Protocol deviations ................................................................................................................................................................. 62 
13.3 
Analysis populations .............................................................................................................................................................. 62 
13.3.1 
Efficacy populations ............................................................................................................................................................... 62 
13.3.2 
Safety population ..................................................................................................................................................................... 62 
13.4 
Statistical methods .................................................................................................................................................................. 62 
13.4.1 
Analysis of primary efficacy endpoint ............................................................................................................................ 62 
13.4.2 
Analysis of secondary efficacy endpoints ...................................................................................................................... 63 
13.4.3 
Analysis of safety endpoints ................................................................................................................................................ 64 


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14 ETHICAL AND REGULATORY CONSIDERATIONS ......................................................................................... 66 
14.1 
Good clinical practice (GCP) ................................................................................................................................................ 66 
14.2 
Informed consent..................................................................................................................................................................... 66 
14.3 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) .......................................................... 66 
15 STUDY MONITORING ....................................................................................................................... 67 
15.1 
Responsibilities of the Investigator ................................................................................................................................. 67 
15.2 
Responsibilities of the Sponsor ......................................................................................................................................... 67 
15.3 
Source document requirements ........................................................................................................................................ 67 
15.4 
Protocol amendments ............................................................................................................................................................ 68 
16 ADMINISTRATIVE RULES ................................................................................................................... 69 
16.1 
Curriculum Vitae ...................................................................................................................................................................... 69 
16.2 
Record retention in study sites .......................................................................................................................................... 69 
16.3 
Confidentiality........................................................................................................................................................................... 69 
16.4 
Ownership of data and use of the study results .......................................................................................................... 69 
16.5 
Insurance compensation ...................................................................................................................................................... 70 
16.6 
Premature discontinuation of the study or premature close out of a center ................................................. 70 
16.6.1 
Decided by the Sponsor in the following cases ........................................................................................................... 70 
16.6.2 
Decided by the Investigator ................................................................................................................................................ 70 
17 BIBLIOGRAPHIE ......................................................................................................................... 71 
18 APPENDICES .............................................................................................................................. 74 
APPENDIX 1. 
STANDING VERTIGO INTENSITY VISUAL ANALOG SCALE ............................................................. 74 
APPENDIX 2. 
WORST VERTIGO INTENSITY VISUAL ANALOG SCALE ................................................................. 75 
APPENDIX 3. 
NAUSEA INTENSITY VISUAL ANALOG SCALE ............................................................................ 76 
APPENDIX 4. 
DHI – DIZZINESS HANDICAP INVENTORY ............................................................................... 77 
APPENDIX 5. 
VESTIBULAR DISORDERS ACTIVITIES OF DAILY LIVING SCALE ....................................................... 79 
APPENDIX 6. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE: SPECIFIC HEALTH PROBLEM V2.0 
(WPAI:SHP) 
80 
APPENDIX 7. 
UNASSISTED WALKING ...................................................................................................... 82 
APPENDIX 8. 
VIDEOOCULOGRAPHY ....................................................................................................... 83 


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APPENDIX 9. 
VIDEO HEAD IMPULSE TEST ................................................................................................ 84 
APPENDIX 10. 
ROMBERG TESTS PROCEDURE ............................................................................................. 85 
APPENDIX 11. 
HIGHLY EFFECTIVE BIRTH CONTROL METHODS .......................................................................... 87 
19 LIST OF RAW DATA.......................................................................................................................... 89 
 
 
 


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2 LIST OF ABBREVIATIONS 
AE: adverse event 
AUC: area under the curve 
AUV: acute unilateral vestibulopathy 
BP: blood pressure 
BPPV: benign paroxysmal positional vertigo 
CBC: complete blood count   
Cmax: maximum concentration 
CNS: central nervous system 
CRF: case report Form 
CRP: C reactive protein   
CSR: clinical study report 
CYP: cytochrome 
DB: double blind 
DDI: drug drug interaction   
DHI: disability handicap Index 
ECG: electrocardiogram 
F: fraction 
GLP: good Laboratory Practice 
H: histamine 
H4R: Histamine 4 receptor  
Hb: hemoglobin 
Hct: hematocrit 
HIT: head impulse test 
HR: heart rate 
IEC: independent ethics committee.   
IRB: institutional review board.  
ITT: Intent to treat 
LOAEL: lowest observed adverse effect level  
LOCF: last observation carried forward 
MedDRA: medical dictionnary of regulatory affairs 
MRI: magnetic resonance imaging 
NOAEL: no observed adverse effect level  
ODT: orally dispersible tablet 
PK: pharmacokinetic 
PP: per protocol 
R: randomized   
SAE: serious adverse event 


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SP: sway path 
TEAE: treatment-emergent adverse event.   
VADL: vestibular disorder activities of daily living scale 
VAS: visual analog scale 
VI-VAS: vertigo intensity visual analog scale 
VOR: vestibulo-ocular reflex 
WBC: white blood count 
WOCBP: woman of child-bearing potential 


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3 CLINICAL TRIAL SUMMARY 
 
NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
Study Title:  
A multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy 
and safety of 2 dose-regimens of orally administered SENS-111 (100mg and 200mg) given 
during 4 days in patients suffering from Acute Unilateral Vestibulopathy (AUV) 
 
Study Code Numbers: 
SPONSOR ref.:  
SENS 111-201 
International Coordinator: Michael Strupp, MD, FANA, FEAN, Prof. of Neurology 
(Munich, Germany) 
Clinical Study Sites:  28 sites in Asia; Australia; Europe; US 
Objectives: 
Primary objective:  
• To demonstrate the efficacy of SENS-111 in Acute Unilateral Vestibulopathy 
(AUV) 
Secondary objectives:  
• To explore the effect of SENS-111 on quality of life  
• To determine the optimal dose regimen of SENS-111 
• To evaluate safety and tolerability of SENS-111 in patients with AUV 
• To evaluate the effect of SENS-111 on long term recovery of vestibular function 
• To characterize the plasma exposure to SENS-111 in patients with AUV 
• To preliminary evaluate the health economics of SENS-111 
Methodology/Study Design: 
Multicenter, double-blind, randomized, placebo-controlled 3 parallel arm study comparing 
SENS-111 (100 mg or 200 mg) to placebo  
Treatment administered once daily for 4 days with an additional dose 12 hours after the first 
dose intake. 
 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
Number of Subjects: 
Randomised:  207 (69 patients/ treatment group) 
Randomization 1:1:1, stratified by duration of vertigo before being treated (≤ 24 hours, > 
24 hours) 
Diagnosis and Main Criteria for Inclusion: 
Strict adherence to the inclusion and exclusion criteria is critical to ensure that only patients 
suffering from AUV are included. 
Inclusion criteria: 
1. Male or female 
2. Aged ≥18 years and <75 years 
3. Suffering from an acute episode of vertigo of peripheral origin defined as: 
a. Severe (≥ 60mm on the standing vertigo intensity visual analog scale) 
b. Prolonged (more than 6 hours),  
c. Associated with imbalance (and/or postural imbalance) and nausea (and/or 
vomiting)  
d. Spontaneous nystagmus toward the unaffected ear (fast phase) which is 
suppressed or reduced by visual fixation confirmed by oculography 
e. Gain of the vestibulo ocular reflex (VOR) <0.7, measured by the video- head 
impulse test (HIT) and/or difference between the 2 labyrinths >25% 
according to the caloric test (de Jongkees’ formula).  
4. Affiliated or is a beneficiary to a health insurance system (if applicable per 
national regulations) 
5. Signed and dated written informed consent.  
 
Exclusion criteria: Patients with the following criteria must not be included 
1. Vertigo duration of less than 6 hours before randomization 
2. Acute continuous vertigo lasting more than 72 hours prior to randomization 
3. Acute hearing loss during or after the onset of vertigo. 
4. Acute unilateral tinnitus during or after the onset of vertigo 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
5. History of acute or chronic vestibular diseases (including Ménière’s disease, acute 
labyrinthitis, vestibular migraine...), vestibular dysfunction, previous episode of 
acute unilateral vestibulopathy or prolonged vertigo. 
6. Ongoing Benign paroxysmal positional vertigo (BPPV)  
7. History of prior acute central vestibular lesion. 
8. Acute or chronic disease of middle ear (infections, otitis) 
9. Concurrent Varicella Zoster Virus (VZV) ear infection (Herpes zoster oticus) 
10. History of cochlear implants  
11. Neurological disorders including stroke, brainstem or cerebellar dysfunction within 
the last 3 months (In case of possible stroke of the brainstem or cerebellum, the 
diagnosis should have been excluded by a MRI performed within the last 48 hours) 
12. Past or concomitant treatment with ototoxic chemotherapy  
13. Past history of seizures or convulsions 
14. Head trauma within the last 10 days prior to randomization 
15. Aminoglycosides in the past 6 months given via systemic or transtympanic 
administration 
16. Concomitant treatment with any of the followings within the last 24 hours prior to 
randomization if more than 2 doses have been taken:  
a. Antihistamines: diphenhydramine, cyclizine, dimenhydrinate, meclizine, 
hydroxyzine, promethazine,  
b. Cinnarizine, flunarizine  
c. Central anti-dopaminergics: neuroleptics, unless the dose is stable for at least 
1 month prior to randomization and no changes are expected during the 
course of the study  
d. Benzodiazepines  
e. Histaminergics (e.g., betahistine) 
f. Scopolamine, homatropine 
g. Gabapentin, pregabalin 
h. Acetylleucine, 5HT3 antagonists (ondensetron, granisetron, palonosetron 
etc…) 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
i. Piracetam, piribedil, trimetazidine,  
j. Corticosteroids (oral or injectable) unless the dose is stable for at least 1 
month prior to randomization and no changes are expected during the course 
of the study 
17. Treatment with any investigational agent within 4 weeks prior to randomization or 
5 half-lives of the investigational drug (whichever is longer)  
18. Prior participation in a clinical trial with SENS-111 
19. History of malignancy other than effectively treated carcinoma in-situ of the cervix, 
or adequately treated non-metastatic squamous or basal cell carcinoma of the skin, 
within 5 years  
20. Known history of, or concomitant severe hepatic, gastrointestinal, cardiovascular, 
respiratory, neurological, psychiatric, hematological, renal, or dermatological 
disease, or any condition, psychiatric, substance abuse, or otherwise, that, in the 
opinion of the Investigator might interfere with the evaluation of study treatment or 
warrant exclusion. 
21. Pregnancy (a negative pregnancy test is required for all women of childbearing 
potential (WOCBP) before initiation of treatment  
22. Male and female patients of child-bearing potential who are unwilling to use an 
highly effective contraception while enrolled on study and receiving the 
experimental drug, and for at least 1 month after the last intake of the investigational 
product. Highly effective therapy includes:  
a. combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal or transdermal 
b. progestogen-only hormonal contraception associated with inhibition of 
ovulation 1 : oral, injectable or implantable  
c. intrauterine device (IUD) 
d. intrauterine hormone-releasing system ( IUS) 
e. bilateral tubal occlusion 
f. vasectomised partner 
g.  sexual abstinence  


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
(see appendix 11 for complete guidance) 
23. Nursing mothers 
24. Severe abnormal laboratory findings  
a. Creatininemia >1.5 upper limit of normal (ULN))  
b. INR >1.7 ULN, Total bilirubin >2 ULN  
c. ALAT and/or ASAT > 3 x ULN  
d. Hemoglobin <0.9 Giga/L and/or  
e. Neutrophils <1,5 Giga/L and/or  
f. Platelets <100 Giga/L 
25. Patients who, in the opinion of the Investigator, have significant medical or 
psychosocial findings that warrant exclusion.  Examples of significant problems 
include, but are not limited to other serious non-malignancy-associated medical 
conditions that may be expected to limit life expectancy or significantly increase the 
risk of serious adverse event (SAEs) and any condition, psychiatric, substance 
abuse, or otherwise, that, in the opinion of the Investigator, would preclude informed 
consent, consistent follow-up, or compliance with any aspect of the study 
26. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, 
study coordinator, other staff or relative thereof directly involved in the conduct of 
the protocol.   
Test Product: 
Product name: SENS-111  
Unit dose: 100 mg Oral Dispersible Tablet (ODT)  
Regimen: Once a day for 4 days + one additional dose 12 hours after first intake 
Mode/route: Oral. The drug should be kept in the mouth until complete dispersion 
Drug Being Tested, Dose, Method of Administration: 
SENS-111 100mg: 2 ODT (1 ODT SENS-111 and 1 ODT placebo)  
SENS-111 200mg: 2 ODTs SENS-111 
Placebo: 2 placebo ODTs  


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
Duration of Treatment: 4 days 
Criteria for Evaluation: 
Primary endpoint: 
The primary endpoint is the vertigo intensity measured by the AUC of the Vertigo Intensity 
Visual Analogue Scale (VI-VAS) in standing position over the 4 treatment days (8 post 
baseline assessments) 
Main secondary efficacy endpoints: comparison between groups of 
• Worst spontaneous vertigo intensity measured by the AUC of the worst vertigo 
visual analogue scale (VI-VAS) over the 4 treatment days (8 post baseline 
assessments) 
• Change from baseline of the total score of the Romberg tests at the end of the 
treatment (D5) and end of study (D28). 
• Peak slow phase velocity of the peripheral vestibular spontaneous nystagmus, 
measured by oculography in darkness at the end of the treatment (D5) and end of 
study (D28). 
• Nausea severity measured by the AUC of the Nausea Intensity Visual Analogue 
Scale over the 4 treatment days (8 post baseline assessments) 
• The functional disability at the end of study (D28) assessed by the Dizziness 
Handicap Inventory (DHI) functional subscale score and the Vestibular Disorders 
Activities of Daily Living Scale (VADL)  
Exploratory efficacy endpoints: comparison between groups of 
• Vertigo Intensity while standing and worst spontaneous at the end of the study (Day 
28) assessed by the Vertigo Intensity VAS.   
• Time to unassisted walk assessed by a specific question.  
Safety Endpoints 
• Adverse events, laboratory, vital signs and ECG 
Health Economic end-point: 
• Health economic evaluation assessed with the Work Productivity and Activity 
Impairment (WPAI-SH) questionnaire at the end of study 
Pharmacokinetics: 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
• SENS-111 pharmacokinetic parameters 
Data Monitoring Committee (DMC): 
An independent DMC will be organized to regularly evaluate the safety of SENS-111 
during the study.  The DMC will be regularly provided with safety data. Safety data will be 
provided by patient with relevant information every 75 patients (around 25 patients/ group) 
or at least once a year.  The first review will be performed after 30 patients have completed 
the study. The DMC will remain blinded for its evaluation but may ask for un-blinding if 
required.  
Statistical methods:  
Sample size calculations: 207 patients (69 patients per group: 20% improvement of the 
AUC VAS versus placebo, = 2.5%, =85%). It is based on the area under the curve (AUC) 
of the Vertigo Intensity Visual Analog Scale (VI-VAS) from first evaluation after baseline 
to end of treatment (8 measurements).  
The assumptions are the following: 
• Each comparison to placebo performed at 2.5% two-sided significance level 
• Power of each comparison to placebo set to 85%. 
• Randomization ratio 1:1:1 
• Intra-group standard deviation of 71 mm*day 
• Difference to placebo of 40 mm*day (i.e. 20% of an average AUC of 200 mm*day 
on placebo). 
Analysis sets: 
• The intent-to-treat (ITT) analysis set will comprise all randomized patients 
according to randomization group. All efficacy analyses will be performed on the 
ITT analysis set. 
• The safety analysis set will comprise all treated patients according to treatment 
received. 
Primary efficacy endpoint: 
The VI-VAS AUC will be compared between treatment groups within an analysis of 
covariance model with the stratification factor (duration of vertigo before being treated) and 
the baseline score as covariates.  The two comparisons to placebo will be tested with an 
alpha adjusted to the Dunnett's multiple comparison procedure in order to preserve an 
overall type I error of 5%, the corresponding confidence intervals will be presented. 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
As a complementary analysis in order to get a better insight of the treatment effect over 
time, the 8 post-baseline VI-VAS scores will be analyzed using a restricted maximum 
likelihood (REML)-based repeated measures approach.  Analyses will include the fixed, 
categorical effects of treatment, time, and treatment-by-time interaction, as well as the 
binary stratification factor (duration of vertigo before being treated) and the continuous, 
fixed covariates of baseline score and baseline score-by-time interaction.  An unstructured 
covariance structure will be used to model the within-patient errors.  If this analysis fails to 
converge, simpler structures (e.g. first-order ante-dependent or heterogeneous compound 
symmetry structures) will be tested in a model without treatment effect; the covariance 
structure converging to the best fit, as determined by Akaike’s information criterion, will 
be used in the full model. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. Within this model the test of interest will be the treatment-
by-time interaction performed at significance level of 5%.  In a second step, the two 
comparisons to placebo will be tested at each time using an alpha adjusted according to the 
Dunnett's multiple comparison procedure in order to preserve an overall type I error of 5% 
within the time considered and the corresponding confidence intervals will be presented. 
Secondary efficacy endpoints: 
The baseline and the 8 post-baseline assessments of the Worst VI-VAS will be analyzed 
using the approach described for the primary endpoint. 
The change from baseline of the total score of the Romberg tests at the end of treatment will 
be compared between treatment groups within an analysis of covariance model. Patients 
without data available at the end of treatment will be excluded from the analysis. The 
covariates will be the stratification factor (duration of vertigo before being treated) and the 
baseline total score. The two comparisons to placebo will be tested with an alpha adjusted 
according to the Dunnett's multiple comparison procedure in order to preserve an overall 
type I error of 5%, the corresponding confidence intervals will be presented. The same 
approach will be applied to the change from baseline at the end of study. 
The change from baseline of the peak slow phase velocity at the end of treatment and the 
change from baseline at the end of study will be analyzed using the approach described for 
the total score of the Romberg tests. 
The baseline and the 8 post-baseline assessments of the Nausea intensity VAS will be 
analyzed using the approach described for the primary endpoint.  
The change from baseline of the DHI functional sub-score scale at the end of study will be 
compared between treatment groups within an analysis of covariance model. Patients 


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NAME 
OF 
COMPANY: 
Sensorion 
NAME OF FINISHED PRODUCT: 
NA® 
NAME 
OF 
ACTIVE 
INGREDIENT: 
SENS-111 
without data available at the end of study will be excluded from the analysis. The two 
comparisons to placebo will be tested with an alpha adjusted to the Dunnett's multiple 
comparison procedure in order to preserve an overall type I error of 5%, the corresponding 
confidence intervals will be presented. The same approach will be applied to the change 
from baseline of the VADL score at the end of study. 
 
Safety endpoints: 
All safety analyses will be performed on the safety analysis set using descriptive statistics. 
Adverse events (AEs) will be evaluated for severity and coded using MedDRA. They will 
be summarized by system organ class and preferred term. Separate summaries of treatment-
emergent AEs (TEAEs) will be generated for the following: 
• All TEAEs 
• Severe TEAEs 
• Serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs resulting in death 
Summary statistics of haematology, blood chemistry and liver function test parameters are 
presented by treatment group for baseline, post-baseline and change from baseline 
measurements.  Number and percentage of patients presenting at least one post-baseline 
potentially clinically significant abnormality are presented by treatment group for selected 
parameters.  The same kind of approach is used for vital signs and ECGs. 
Study timelines:  
Duration of patient’s participation: 4 days of treatment and 24 days of follow-up 
Urgent safety measures: 
In case of voluntary or involuntary overdose, it is recommended to carefully monitor the 
signs and symptoms.  As there is no antidote for SENS-111, intensive care admission should 
be considered according to clinical status, and the treatment would be the standard one for 
unspecific drug intoxication, including general support which may include immediate 
gastric lavage within the first hour after intake to diminish the amount absorbed, continuous 
monitoring of vital signs, supportive care for cardiovascular function, respiratory aid in case 
of compromise, electrolyte balance and other measures as clinically indicated.  


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4 FLOW-CHARTS 
 
 
Double-blind Treatment 
 
Follow-up 
Visit 
V1 
Screening 
V2  
Inclusion 
V3 
 
V4 
End of 
Hospitalization 
Visit 4, 5 
 
V5 
End of Treatment Visit 
V6 
(Phone Call) 
V7 
End of study visit 
H-6 (± 6) 
D1 (H0) 
D2( H24±3) 
 
D3 (-1, +25)  
D5 (-1,+2)  
D14 (±2) 
 
D28  (±2) 
Informed Consent/Demography/Medical 
History 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Physical Examination  
X 
 
 
 
X 
 
X 
Vital signs (BP standing and supine, HR), 
Temperature 
X 
X 
X 
X 
X 
 
X 
ECG 
 
X 
 
 
X 
 
X 
Neuro Otologic examination 
X 
 
 
 
X 
 
X 
Prior Medication History  
X 
X 
 
 
 
 
 
Routine serum Hematology and Chemistry 
X 
 
 
 
X 
 
 
Pregnancy test/Pregnancy status 
X6 
 
 
 
X6 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
Standing vertigo intensity 12 
---- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Worst vertigo intensity (VAS) 1 
 
----------- 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Nausea Intensity (VAS)1  
---- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Walking assessment1  
 
----------- 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Disability Handicap Inventory (DHI) 
 
X 
 
 
 
 
X 
VADL 
 
 
 
 
 
 
X 
Romberg tests8 
 
---- 
------------ 
---------→ 
X 
 
X 


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Double-blind Treatment 
 
Follow-up 
Visit 
V1 
Screening 
V2  
Inclusion 
V3 
 
V4 
End of 
Hospitalization 
Visit 4, 5 
 
V5 
End of Treatment Visit 
V6 
(Phone Call) 
V7 
End of study visit 
H-6 (± 6) 
D1 (H0) 
D2( H24±3) 
 
D3 (-1, +25)  
D5 (-1,+2)  
D14 (±2) 
 
D28  (±2) 
VideoOculography (spontaneous 
nystagmus) 
 
X 
X7 
X 
X 
 
X 
Hospitalization (Yes/No) 
 
X 
X 
X 
X 
X 
X 
Health Economic questionnaire 
 
 
 
 
 
 
X 
Ancillary Efficacy Study 
 
 
 
 
 
 
 
Video-head impulse test (function of the 
vestibulo-ocular reflex 
 
X10 
 
 
X 
 
X11 
Caloric test (optional) 
 
X10 
 
 
 
 
X11 
Treatment 
 
 
 
 
 
 
 
Study Drug Intake 
 
X2---- 
-------- 
-------------→3,4 
 
 
 
Compliance 
 
 
X 
X 
X 
 
 
Safety 
 
 
 
 
 
 
 
Adverse events 
 
----- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
----------→ 
Pharmacokinetics 9 
 
X 
X 
 
X 
 
 
 
1. 
VAS and walking assessment will be completed at the inclusion visit prior to the first study drug intake and then twice daily in the morning at 10 am and in the 
evening just after dinner from the inclusion visit to end of study visit. 
2. 
The first dose should be given at the site after all assessments have been performed. The second dose will be given 12 hours after (+3 h) 
3. 
The last dose will be given either in the morning or evening of D4 according to the time of first intake.  
4. 
Patients will receive the remaining tablets to be taken home if he/she is discharged from the hospital prior to the last scheduled intake: Total intake of 2 tablets x 5. 
5. 
If the patient remains hospitalized after Day 28, the end of hospitalization visit will not be completed. The end of hospitalization visit has to be completed if it does 
not occur at the same time as another scheduled visit (D5: end of treatment visit or D28, the end of study visit The reason for not performing the end of hospitalization 
visit will be filled in the e CRF. 


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6. 
Pregnancy tests will be both urine and blood test, except at end of study visit (urine test only. If the test is positive a blood test will be done for confirmation).  
7. 
Video oculography will be performed daily until the end of hospitalization  
8. 
The Romberg tests will be performed at the inclusion visit prior to the first study drug intake and twice daily in the morning and evening while hospitalized, and at 
all subsequent onsite visits.  
9. 
12 hours after the first study drug intake, Vital signs will be measured and a blood sample will be taken for PK just before the second study drug intake. Two other 
blood samples will be taken at H24 and end of treatment visit. 
10. Either HIT or caloric test are needed for confirmation of the diagnosis 
11. The caloric test and HIT at the end of study visit are optional and part of an ancillary study 
12. The standing vertigo VAS will be completed under condition 1 of the Romberg tests at the site twice daily. At home, it will be performed twice daily in standing 
position, eyes open, feet together on a firm surface. 
 


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5 INTRODUCTION AND RATIONALE 
5.1 
Acute Unilateral Vestibulopathy 
Acute unilateral vestibulopathy (AUV) (previously called acute vestibular neuritis) is the third most 
frequent cause of peripheral vestibular vertigo, after benign paroxysmal positional vertigo and 
Menière’s disease. It is caused by a sudden unilateral isolated vestibular deficit. The annual incidence is 
about 3.5 to 15 cases/100,000 according to sparse epidemiological data (3)(17)(18)(21). Onset usually 
occurs in the mid age. There is no gender difference. 
Clinically, AUV is a severe condition, characterized by an acute or subacute onset of severe sustained 
spinning vertigo associated with nystagmus, postural and gait unsteadiness, nausea and often vomiting. 
There is no acute hearing loss, tinnitus, and no other neurological symptoms. Patients are unable to cope 
with their usual daily activities. Most symptoms usually abate spontaneously within several days but 
they may last one or two weeks. AUV occurs usually once during the life span. It is estimated that about 
40% of patients will suffer from sequelae: long term unsteadiness and benign paroxysmal positioning 
vertigo (15% of patients) (5)(10)(11)(15)(22)(24). 
Recovery results from a combination of peripheral restoration of labyrinthine function – usually not 
complete; contralateral vestibular and somatosensory and visual substitution for the unilateral vestibular 
deficit and central compensation of the vestibular tone imbalance (2)(33). 
The pathophysiology of AUV is unknown. Several hypotheses have been proposed: infection due to the 
reactivation of a latent Herpes Simplex I infection but also an autoimmune reaction, or acute thrombosis 
following an acute inflammation (12)(16). 
There is no approved therapy for AUV. Many patients are severely impaired by vertigo, nausea and 
vomiting in the acute phase: these symptoms are major targets for treatment. Nausea and vomiting are 
usually treated with antihistamins, mostly dimenhydrinate or even benzodiazepines in severe cases 
(23)(36). However, these treatments induce sedation. Based on theoretical considerations, it has been 
postulated that they may delay or even reduce central compensation of the vestibular tone imbalance 
between the two labyrinths, limiting their use to two to three days (3). 
The effects of corticosteroids and vestibular exercises (28)(37) are still debated. Shupak et al. (38) 
showed that corticosteroids might enhance earlier recovery but do not improve long term recovery in 
contrast to a recent study showing some efficacy on long tem compensation, but not on the acute phase 
(23). 
5.2 
Histamine 4 receptor 
Histamine is a well-known neurotransmitter and modulator of neural activity in the central and 
peripheral nervous system such as the peripheral vestibular apparatus. 
Histamine is found in central vestibular structures and centrally acting antihistamines modulate 
symptoms of motion sickness (35) (25) (26). 


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The histamine H4 receptor is a G-coupled protein receptor that was initially identified on immune cells, 
mast cells and eosinophils. Histamine-induced eosinophil and mast cell chemotaxis, and calcium 
response were shown to be mediated by H4R. In human mast cells, H4R mediates the release of 
leukotrienes, cytokines and chemokines (1) (30). 
Recent findings have shown that H4 receptors are present in the inner ear. They are expressed on 
peripheral neurons including vestibular neurons (20) (28) (27). The H4 receptor affects primary 
vestibular neurons (9). 
H4R Knock-Out mice and the administration of H4R antagonists have demonstrated anti-inflammatory 
properties in various inflammatory models (8). They were described to modulate vestibular neural 
activity in ex vivo models and alleviate the induced vestibular deficits in in vivo models. 
5.3 
SENS-111 
SENS-111 is a new highly selective and specific antagonist of the histamine H4 receptor (H4R) 
discovered and initially developed by Palau Pharma (former identification UR-63325). It is developed 
as a potential novel therapy for patients suffering from AUV with the aim of improving associated 
symptoms without preventing long tem recovery (see additional information in the Investigator’s 
brochure). 
In vitro, SENS-111 binds to human H4 receptor with high affinity (Ki: 15 nM) and high selectivity, 
acting as a potent antagonist for this receptor in native cells (IC50: 10 nM). SENS-111 has shown similar 
binding affinity to H4 receptor from the main pharmacological and toxicological species, i.e. rat, and 
monkey, but low affinity for dog H4 receptor.  
5.3.1 Pharmacology studies 
The anti-inflammatory effect of SENS-111 was shown in various inflammatory models. Also, 
preclinical experiments have confirmed the ability of SENS-111 to inhibit vestibular neuron activity 
(action potential firing) in ex vivo and in vitro tissue preparations.  
 In rat models of unilateral vestibular lesion, SENS-111 consistently reduced spontaneous nystagmus 
(measured with videonystagmography VNG) and vestibular deficits (measured with a vestibular 
behavior rating scale) in a dose-dependent manner after single IV dose (10 to 30 mg/kg).  
5.3.2 Preclinical pharmacokinetics 
SENS-111 is well absorbed by oral route in mice (F=71%), rats (F=38%) and dogs (F=127%). Protein 
binding is low. A low extent of metabolism was observed in in-vitro studies. About 50% of SENS-111 
is eliminated as unchanged form in urine. Two main metabolites have been observed with a low biliary 
and urinary excretion. SENS-111 crosses the blood brain barrier in rats and mice with brain/plasma 
ratios of about 6. SENS-111 reaches the inner ear tissues surrounded by the blood labyrinth barrier with 
an inner ear/plasma ratio of around 0.3.  


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Based on non-clinical data in the rat, the target plasma concentrations for vestibular indications in man 
range between 100 and 300 ng/mL.  
In vitro studies have not shown any inhibition or induction of human cytochromes by SENS-111 at 
expected therapeutic concentrations. 
 
5.4 
Non clinical safety pharmacology and toxicology studies  
The toxicology of SENS-111 has been studied up to 28 days dosing under GLP conditions. Acute 
toxicity showed a Minimum Lethal Dose (MLD) after single dosing of 250 mg/kg orally and 50 mg/kg 
IV in mice, and of 250 mg/kg orally and 70 mg/kg IV in rats.  
Oral daily dosing for 28 days to rats and monkeys showed No Observed Adverse Effect Level (NOAEL) 
of 20 mg/kg/day (Cmax: 1138 ng/mL AUC: 3748 ng•h/mL) in rats, and 12 mg/kg/day (Cmax: 2148 ng/mL 
AUC: 14890 ng•h/mL) in monkeys, respectively.  
Central nervous system (CNS) toxicity was observed at very high doses with SENS-111, notably in the 
primate; convulsions occurred prior to death at a dose of 80mg/kg (after eight daily doses). Tonic and 
clonic convulsions were also observed at high doses in mice (50 mg/kg) and rats (70 mg/kg).  
A slight depressant CNS effect at the dose of 200 mg/kg was observed at 1 h after administration, in the 
functional observational battery, a neuro-behavioral assessment test in rats. No other adverse clinical 
signs suggestive of any CNS toxicity were observed in mice, rats and monkeys. 
Repeated dosing up to 28 days in rats and monkeys did not identify any relevant toxicity. SENS-111 
was otherwise well tolerated.  
Substantial margins (between 27 and 33 fold based upon Cmax) to the no effect dose level give 
assurance that the proposed dose levels in humans should not induce serious CNS effects in humans 
following either acute or repeated dosing. 
GLP compliant safety pharmacology core battery studies have been performed with SENS-111. No 
effects on the respiratory function of conscious rats were observed at doses up to 90 mg/kg.  
SENS-111 caused elevated heart rate and blood pressure possibly associated with emesis and prolonged 
QRS complex at the dose of 30 mg/kg (AUC0-inf: 40807 ng•h/mL) in the dog telemetry study. No effect 
was observed at 10 mg/kg (AUC0-inf: 10272 ng•h/mL). No effects on QTc have been observed. 
Additional studies to further characterize any potential CNS and cardiovascular effects included an 
Irwin test after a single dose and repeated administration, with slight depression effect on the central 
nervous system after multiple doses of 200 mg/kg, sodium thiopental-induced sleep test in mice and 
ethanol-induced sleep test in mice, neither of which showed effects at doses up to the highest dose 
tested. Specific studies in rats and mice to examine the pro-convulsive potential of SENS-111 confirmed 
high doses to be associated with increased incidence of convulsions but the studies were compromised 
by lack of an expected effect with the positive controls.  


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o Finally, SENS-111 inhibited in vitro hERG and Nav1.5 ion channel at very high 
concentrations (IC50 of 242 M (56,900 ng/mL) and >300 M (70,000 ng/mL 
respectively). 
o There was no effect on QTc in telemetered beagle dogs at doses up to 30mg/kg, the 
highest dose evaluated (Cmax: 6500 ng/mL, AUC0-inf: 40,807 ng•h/mL). Only a slight 
increase in QRS was observed at 30 mg/kg, which was attributed to one metabolite (UR-
67147) present at high concentrations in dogs. There was no in vivo cardiac effect at 
high concentrations in rats and monkeys. 
No target organs and histopathological findings were identified. 
So far, fertility or teratology studies have not been conducted. The effect of SENS-111 on pregnancy 
and newborns is unknown.   
SENS-111 is considered to be non-mutagenic according to the standard GLP genotoxic battery that 
included bacterial reverse mutation, chromosomal aberration test and in vivo micronucleus test. 
 
5.5 
Clinical experience with SENS-111 
SENS-111 has been tested in 4 clinical studies. Three studies were conducted in healthy subjects as 
single dose and multiple doses and one study was conducted in subjects with asymptomatic allergic 
rhinitis otherwise healthy.   
SENS-111 has been administered to 172 healthy subjects (men and women not at childbearing 
potential): 78 received single doses from 2 to 500 mg, and 94 were administered SENS-111 for 4 to 7 
days at doses ranging from 5 to 250 mg/day. SENS-111 was well tolerated and the maximal tolerated 
dose was not reached. The most frequent adverse events were headaches, somnolence and 
nasopharyngitis observed in both placebo and SENS-111 groups. No dose-dependent adverse event has 
been observed. There were no cardiac effects.  
The pharmacokinetic profile was linear at doses from 5 to 200 mg/day and was slightly over-
proportional starting at 250 mg/day. During the single dose part, the highest mean Cmax and AUC0-inf 
were observed at 500 mg (respectively 1135ng/ml and 17419 ng•h/mL). During repeated 
administration, the highest mean Cmax was 1088 ng/mL and maximum AUC0-192 was 26,121 ng•h/mL 
(250 mg/day for 7 days).  
T1/2 elimination was between 21.8h to 29.9h after single dose and increased with the duration of 
administration up to 56h after 7 days of SENS-111 250 mg/day.  
− Plasma concentrations of the metabolites UR-67147 and UR-64250 were quantifiable at all doses; 
UR-64167 and UR-64250 exposure respectively amounts to about 5% and 1% of SENS-111 
exposure. This percentage did not increase or decrease depending on dose or after a repeated 
administration. Half-lives were not longer than the parent compound. 
 


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5.6 
Study Rationale  
The proposal to test the efficacy on a H4 antagonist in the treatment of AUV is based on a scientific 
rationale: 
a) Modulation of vestibular neural activity was shown to be highly effective for treating vertigo of 
peripheral origin. (Astemizole, a H1R antagonist not crossing the brain blood barrier). 
b) In the inner ear and particularly in the vestibular apparatus, histamine and its metabolites modulate 
the neural activity through the specific activation of histamine receptors. Such activation can be 
antagonized by specific histamine- receptors antagonists.   
c) Histamine receptors antagonists have shown mild efficacy in peripheral and central vestibular 
disorders. However their dosage is limited by the induced sedation (e.g., meclizine, 
dimenhydrinate). 
d) Antagonists to H4R were able to decrease peripheral vestibular imbalance (and thus vertigo 
symptoms) in animal models,  
Based on preclinical data, it is expected that SENS-111 will improve vertigo and associated symptoms 
of AUV and would reduce the risk of side effects such as sedation with no deleterious effect on central 
compensation.   
In addition, SENS-111 has shown activity on a well-established biomarker model of H4R antagonism 
in humans (the histamine-induced eosinophil shape change). In the phase 1 single dose study, SENS-
111 was able to reverse the histamine induced eosinophil shape changes at all doses. In the first repeated 
dose administration study, a dose-dependent effect duration was observed, with a one week activity 
after 50mg.  
A first pharmacology study using cold water-induced nystagmus in healthy subjects did not demonstrate 
effect on nystagmus at any of the 5 tested doses (50, 100, 150, 200, and 250 mg/day) for 4-7 days. A 
post-hoc pharmacokinetic/pharmacodynamics evaluation confirmed that SENS-111 was able to delay 
the onset, and duration of induced vertigo. 
5.7 
Dose selection 
An oral dispersible tablet will be used in this study. Pharmacokinetic parameters confirmed no 
difference between the ODT and capsules in a dog study. 
The dose for this study has been selected from in vitro and in vivo models and from the phase 1 safety 
studies in human that confirmed the good safety up to 500 mg single dose and 250 mg repeated-dose.  
Based on nonclinical data generated in vestibular models in the rat (see Section 5.3.1), the range of 
targeted plasma concentrations is 100 to 300 ng/mL for a vestibular indication. 
Phase I pharmacokinetic data in healthy volunteers showed that these concentrations are achieved at 
doses between 100 and 200 mg/day repeated doses. The dose of 200 mg/d administered for 7 days 
resulted in plasma Cmin (at 24 h post dosing) of 260 ng/mL.  


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Also, in healthy subjects, the nystagmus-induced test demonstrated the more consistent 
pharmacodynamic effect at 100-200 mg/day. 
SENS-111 100mg and 200mg have been selected for the proposed study. However, it is proposed to 
start the treatment with 100 or 200 mg administered twice, 12h apart during the first 24 hours to rapidly 
achieve an active concentration then continue with a once-daily administration for 3 additional days. 
Pharmacokinetic simulation confirmed that the steady-state is more rapidly achieved with a twice daily 
(b.i.d.) administration on the first treatment day, and that the Cmax remains below the highest Cmax. The 
duration of treatment was established from the course of the acute vertigo (lasting approximately 1 
week) and the half -life of SENS-111.  
 
5.8 
Endpoints selection 
There are no validated objective tests to assess the efficacy of pharmacotherapy in AUV. Since vertigo 
is the hallmark symptom of AUV, it has been taken as a marker of the efficacy.  
The Vertigo Intensity Visual analog scale (VI-VAS) has been used by several authors to assess vertigo 
in AUV (34) (31) (32). The scale has been shown to have good test-retest reliability (ICC 0.93–0.96) in 
subjects with remaining symptoms after AUV. It was confirmed also that the baseline values are 
correlated with long-term residual symptoms and that the reduction is the greatest during the first week. 
From a patient perspective, two parameters are important: the severity and the duration of the vertigo; 
improvement in either is clinically relevant. The AUC of VI-VAS during the first 5 days after the 
occurrence of AUV is the best way to capture either the severity, the duration or both. Given the natural 
course of AUV, it is assumed that in the placebo group, the vertigo intensity at the end of treatment will 
be too small to detect any statistical difference with the active group. For this reason, a rapid decline in 
vertigo intensity is thought clinically more relevant than low vertigo intensity at the end of the treatment. 
To account for this dynamic effect, the AUV of the 8 first VAS assessments (including baseline to first 
evaluation after the last study drug intake) will be used as the primary end-point. In this study the VI-
VAS will be evaluated under a standardized condition in each patient to reduce inter-individual 
variability: standing upright, eyes open, feet close together  
The main secondary endpoints will include objective measures of functional impairment (quantified by 
Romberg tests and a standardized nystagmus evaluation), and measures of disability using two well 
validated instruments: the DHI (the dizziness handicap inventory) and a more specific to AUV the 
Vestibular Disorders Activities of Daily Living Scale (VADL) as one of the major consequence of AUV 
is inability to cope with daily activities, and an objective measure of the ability to walk without support. 
The later has been shown to directly relate to a physiologic measure of compensation. Also, an 
additional evaluation of the worst vertigo over the last 2 hours will be also assessed twice daily to 
account for cyclic variation.  


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6 STUDY OBJECTIVES AND END-POINTS  
6.1 
Study Objectives 
6.1.1 Primary objective: 
To demonstrate the efficacy of SENS-111 in Acute Unilateral Vestibulopathy. 
6.1.2 Secondary objectives: 
• To explore the effect of SENS-111 on quality of life 
• To determine the optimal dose regimen of SENS-111 
• To evaluate safety and tolerability of SENS-111 in patients with AUV 
• 
To evaluate the effect of SENS-111 on long-term recovery of vestibular function 
• To characterize the plasma exposure to SENS-111in patients with AUV 
• To preliminary evaluate the health economics of SENS-111 
 
6.2 
Study End points 
The study procedures and outcomes are summarized in the flow chart (Section 4) and described in the 
following paragraphs. 
6.2.1 Primary efficacy end point  
The primary endpoint is the standing vertigo intensity measured by the AUC of the Vertigo Intensity 
Visual Analogue Scale (VI-VAS) over the 4 treatment days (8 post-baseline assessments) 
6.2.2 Secondary efficacy endpoints 
Comparison between groups of 
• Worst spontaneous vertigo intensity measured by the AUC of the worst vertigo visual analogue 
scale (VI-VAS) over the 4 treatment days (8 post baseline assessments) 
• Change from baseline of the total score of the Romberg tests at the end of the treatment (D5) 
and end of study (D28). 
• Peak slow phase velocity of the peripheral vestibular spontaneous nystagmus, measured by 
oculography in darkness at the end of the treatment (D5) and end of study (D28). 
• Nausea severity measured by the AUC of the Nausea Intensity Visual Analogue Scale over the 
4 treatment days (8 post baseline assessments) 


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• The functional disability at the end of study (D28) assessed by the Dizziness Handicap Inventory 
(DHI) functional subscale score and the Vestibular Disorders Activities of Daily Living Scale 
(VADL)  
6.2.3 Exploratory efficacy endpoints 
• Vertigo Intensity in standing position and worst spontaneous at the end of the study (Day 28) 
assessed by the Vertigo Intensity VAS.   
• Time to unassisted walk assessed by a specific question.  
• Health economic evaluation assessed with the Work Productivity and Activity Impairment 
(WPAI-SH) questionnaire at the end of study. 
 
6.2.4 Safety endpoints: 
• Adverse events, laboratory, vital signs and ECG 
 
6.2.5 Pharmacokinetics 
• SENS-111 pharmacokinetic parameters  


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7 STUDY DESIGN 
7.1 
Description of the protocol 
This is a double-blind, randomized, 3 parallel-group placebo-controlled, international study. The study 
will assess the efficacy and safety of orally administered SENS-111 in patients with acute unilateral 
vestibulopathy.  
Patients will be included if they are presenting with an acute peripheral vertigo lasting more than 6 
hours and less than 3 days, diagnosed as an AUV, and the intensity is at least 60mm on a 100mm visual 
analog scale measured in standing position feet together.  
It is planned to enroll 207 patients into the study: 69 patients receiving SENS-111 200mg daily for 4 
days, 69 patients receiving SENS-111 100 mg once daily for 4 days, and 69 patients receiving matching 
placebo (1:1:1 ratio). An additional dose (respectively 200 mg, 100 mg and placebo) will be 
administered to the patients approximately 12 hours after the first intake.  
The screening evaluation including vital signs, a complete oto-neurological examination and nausea 
and vertigo evaluation will confirm the diagnosis and no exclusion criteria for past medical history, 
concomitant treatments, laboratory tests or other concomitants diseases. Specific attention will be paid 
to exclude any patient with a stroke (a negative past MRI is needed for inclusion of patients with 
possible stroke of the brainstem or cerebellum). Following this screening phase, eligible patients will 
undergo a nystagmus evaluation with a videooculography (VOG), and either head impulse test or caloric 
test or both to confirm the diagnosis. They will complete vertigo evaluations with visual analog scales 
and questionnaires, assessment of imbalance (Romberg tests), nausea and vomiting scales just before 
the first intake of the investigational drug at the investigational site. Patients will be requested to stay 
under medical supervision for at least 6 hours after the first study drug intake for safety. Approximately 
12 hours after the first study drug intake, patients will be assessed for vital signs and a blood sample 
will be taken for PK evaluation just before the second dose regimen is given.  
Patients will be asked to complete a vertigo visual analog scale for vertigo intensity and nausea intensity 
twice daily in the morning between 10.00 am and 12.00 pm in the evening after dinner until the end of 
the study on a specific electronic device, and to record their ability to walk without support. The worst 
intensity of the spontaneous vertigo over the past 2 hours will be recorded as well as the intensity of the 
vertigo during standing position.  
24 hours after the first study drug intake, Patients will be tested with VOG to measure the severity of 
their spontaneous nystagmus and a blood sample will be taken for PK just before the study drug intake. 
Patients will continue to be monitored for vertigo, nausea and vomiting, vital signs (both supine and 
standing), ability to unassisted walk and imbalance (Romberg tests) until discharge from the hospital 
when a full efficacy assessment will be performed. It will include assessment of the quality of life, and 
VOG. The same assessments will be performed at the following visit on day 5 and at the end of the 
study on Day 28.  


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Patients will be followed for adverse events throughout the study. Inquiry about potential adverse events 
will be done at every on-site visit and on Day 14 when a phone call will be given. 
Safety parameters will include routine blood tests (complete blood count, chemistry, liver function tests 
and lipid profile), urine analysis, pregnancy tests (if applicable), cardiac evaluation by ECG, physical 
exams and vital signs (with orthostatic blood pressure).  
A health economic questionnaire will be completed at the end of the study. 
At some specific sites, an ancillary test using the VOG will be conducted.  
7.2 
Study diagram 
 
 
 
The inclusion and screening are to be done no more than 24 hours apart. 
As soon as eligibility of the patient is confirmed, the investigator will dispense the subject the study 
drug that is to be taken immediately after all baseline assessments are performed.  
 
7.3 
Number of subjects and duration of study participation  
It is planned to enroll a total of 207 patients in the study.  
The study will be conducted in Europe, US and South Asia and Australia.  
Each patient’s participation in the study will be 4 weeks: 


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• 4 days of double blind treatment  
• A follow up with no investigational product until 28 Days after inclusion.  
 
7.4 
Determination of end of clinical trial (all patients) 
The study will be considered complete when all patients have completed all the scheduled procedures 
as described in the flow chart (Section 4), and all data are captured (database lock). Any withdrawal 
from treatment during the 4-day treatment period will be considered as treatment discontinuation.  
 


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8 INCLUSION AND EXCLUSION CRITERIA  
Strict adherence to the inclusion and exclusion criteria is critical to ensure that only patients suffering 
from AUV are included. 
8.1 
Inclusion criteria  
13. Subjects male or female aged 18 years and above, and below 75 years 
14. Suffering from an acute episode of vertigo of peripheral origin defined as follows:  
a. Severe (≥ 60mm on the standing vertigo intensity VAS) 
b. Prolonged (more than 6 hours)  
c. Associated with imbalance and/or postural imbalance, nausea and/or vomiting  
d. Spontaneous nystagmus toward the unaffected ear (fast phase) which is suppressed or 
reduced by visual fixation confirmed by VOG  
e. Gain of the VOR <0.7 on the video HIT and/or difference between the 2 labyrinths >25% 
according to the caloric test (de Jongkees’ formula).  
15. Affiliated or is a beneficiary to a health insurance system (if applicable per national 
regulations) 
16. Having signed and dated written informed consent.  
 
8.2 
Exclusion criteria 
Patients who have met all the above inclusion criteria listed in Section 8.1 will be screened for the 
following exclusion criteria: 
1. Vertigo duration of less than 6 hours before randomization 
2. 
Acute continuous vertigo lasting more than 72 hours prior to randomization 
3. 
Acute hearing loss during or after the onset of vertigo. 
4. 
Acute unilateral tinnitus during or after the onset of vertigo 
5. 
History of acute or chronic vestibular diseases (Meniere’s disease, acute labyrinthitis vestibular 
migraine..,) vestibular dysfunction, previous episode of acute unilateral vestibulopathy or 
prolonged vertigo. 
6. 
On-going benign paroxysmal positional vertigo (BPPV)  
7. 
History of prior acute central vestibular lesion. 
8. 
Acute or chronic disease of middle ear (infections, otitis) 


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9. 
Concurrent Varicella Zoster Virus ear infection (Herpes zoster oticus) 
10. History of cochlear implants  
11. Neurological disorders including stroke, brain stem or cerebellar dysfunction within the last 3 
months. (In case of possible stroke of the brainstem or cerebellum, the diagnosis should have 
been excluded by a MRI performed in the past 48 hours) 
12. Past or concomitant treatment with ototoxic chemotherapy 
13. Past history of seizures or convulsions 
14. Head trauma within the last 10 days prior to randomization 
15. Aminoglycosides in the past 6 months given via systemic or transtympanic administration 
16. Concomitant treatment with any of the followings within the last 24 hours prior to 
randomization, if more than 2 doses have been taken:  
a. Antihistamines: diphenhydramine, cyclizine, dimenhydrinate, meclizine, hydroxyzine, 
promethazine,  
b. Cinnarizine, flunarizine  
c. Central anti-dopaminergics: neuroleptics, unless the dose is stable for at least 1 month 
prior to randomization and no changes are expected during the course of the study 
d. Benzodiazepines  
e. Histaminergics (e.g., betahistine) 
f. Scopolamine, homatropine 
g. Gabapentin, pregabalin 
h. Acetylleucine, 5HT3 antagonists (ondensetron, granisetron, palonosetron etc..) 
i. Piracetam, piribedil, trimetazidine,  
j. Corticosteroids (oral or injectable) unless the dose is stable for at least 1 month prior to 
randomization and no changes are expected during the course of the study 
17. Treatment with any investigational agent within 4 weeks prior to randomization or 5 half-lives 
of the investigational drug (whichever is longer)  
18. Prior participation in a clinical trial with SENS-111 
19. History of malignancy other than effectively treated carcinoma in-situ of the cervix, or 
adequately treated non-metastatic squamous or basal cell carcinoma of the skin, within 5 years  
20. Known history of, or concomitant severe hepatic, gastrointestinal, cardiovascular, respiratory, 
neurological, psychiatric, hematological, renal, or dermatological disease, or any condition, 
psychiatric, substance abuse, or otherwise, that, in the opinion of the Investigator might 
interfere with the evaluation of study treatment or warrant exclusion. 


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21. Pregnancy (a negative pregnancy test is required for all women of childbearing potential before 
initiation of treatment on Day 1)  
22. Male and female patients of child-bearing potential who are unwilling to use an highly effective 
contraception while enrolled on study and receiving the experimental drug, and for at least 1 
month after the last intake of the investigational product. Highly effective therapy includes  
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal or transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable or implantable  
c. Intrauterine device (IUD),  
d. Intrauterine hormone-releasing system (IUS)  
e. Bilateral tubal occlusion  
f. Vasectomised partner  
g. Sexual abstinence  
(see complete list in Appendix 11) 
23. Nursing mothers 
24. Severe abnormal laboratory findings  
k. Creatininemia >1.5 upper limit of normal (ULN))  
l. INR >1.7 ULN, Total bilirubin >2 ULN  
m. ALAT and/or ASAT > 3 x ULN  
n. Hemoglobin <0.9 Giga/L and/or  
o. Neutrophils <1,5 Giga/L and/or  
p. Platelets <100 Giga/L 
25. Patients who, in the opinion of the Investigator, have significant medical or psychosocial 
findings that warrant exclusion.  Examples of significant problems include, but are not limited 
to other serious non-malignancy-associated medical conditions that may be expected to limit 
life expectancy or significantly increase the risk of SAEs and any condition, psychiatric, 
substance abuse, or otherwise, that, in the opinion of the Investigator, would preclude informed 
consent, consistent follow-up, or compliance with any aspect of the study 
26. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol.  


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9 TREATMENT  
9.1 
Study treatment 
SENS-111 100 mg orally disintegrating tablets (ODT), with a matching placebo 
dose:  
• SENS-111 200mg  (100 mg ODT + 100 mg ODT) or  
• SENS-111 100mg  (100 mg ODT + Placebo ODT) or  
• Matching Placebo (2 ODTs)  
Given once daily for 4 days.  
An additional dose will be given approximately 12 hours (9 to 15 hours) after the first intake. The 
corresponding total dose will be 1000 mg or 500 mg or 0 mg for the entire study. 
Administration Route: The tablet should not be swallowed immediately, nor taken with water. The tablet 
should be kept in the mouth for a few seconds until dispersion is complete. 
There is no food restriction.  
 
9.2 
Description of blinding methods 
The orally disintegrating placebo tablets match SENS-111 (100 mg) tablets, and are identical. The list 
of randomization will be generated centrally by Catalent. 
Pharmacokinetic parameters that could potentially unblind the study team will not be disclosed during 
the conduct of the study 
Investigators will have no access to the randomization code except under the special circumstances. In 
case of an emergency, when knowledge of the randomization status is deemed necessary for the medical 
care of the patient, the randomization code can be unblinded for a specific patient. (see section 12.6 for 
unblinding method) 
 
9.3 
Randomization process 
The randomization will be managed centrally using an interactive web system response (IWRS). 
A total of 207 eligible patients will be randomized in a 1:1:1 ratio to one of the 3 treatment groups, 
stratified by duration of vertigo before being treated (≤ 24 hours, > 24 hours). 
A patient will be considered randomized when the IWRS has given the treatment number to be allocated. 
All randomized subjects (Day 1) will receive either SENS 100mg x 2 ODT, or SENS 100mg x 1 ODT 
and Placebo x 1 ODT, or Placebo x 2 ODT at the study site according to the IWRS allocation.  


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• The treatment will be given once daily.  
• The first dose (2 ODT) will be given at the site  
• An additional dose (2 ODT) will be given approximately 12 hours after the first dose (not less 
than 9 hours and no more than 15 hours after the first dose).  
 
9.4 
Packaging and labeling 
SENS-111 and matching placebo will be inserted in child resistant aluminium blisters. The blisters are 
packaged and labeled into a child resistant sealed clinical pack that includes 6 dose regimens (12 tablets) 
of the investigational product for a 4-day administration and 1 extra day. Each patient will be 
administered the tablets from the assigned kit. The patient will take the kit at home with the remaining 
tablets at discharge from the hospital if it occurs prior to the last scheduled intake.  
The content of the labeling is in accordance with the local regulatory specifications and requirements. 
 
9.5 
Storage conditions 
SENS-111 and matching placebo should be stored in a secure location with restricted access to 
authorized study staff at room temperature as described on the investigational product labeling. The 
investigational product is under the responsibility of the study site, and should be handled according to 
local regulations and procedures.  
Patients discharged from the investigational site prior to end of treatment visit (D5) should be warned 
to store the treatment according to the labeling and out of reach of children. They will be requested to 
return the wallet within the pack with the remaining tablets at the following on site visit (End of 
treatment visit). 
9.6 
Drug Accountability 
The Investigator is responsible for the accountability of all used and unused study drug. Drug 
accountability records must be kept current.  These records should contain the dates, quantities and 
identification numbers (or lot numbers) of study drug received by the Investigator, dispensed or 
administered to specified subjects, returned from subjects (if applicable), disposed of at the site or 
returned to Sensorion or its designee. These inventories, along with shipment receipts, shipment 
temperature recordings (if applicable) and storage temperature logs, and IWRS confirmation reports (if 
applicable), must be made available for inspection by Sensorion’s monitoring and QA auditing staff or 
designees and regulatory agency inspectors.  At the conclusion of the study, photocopies of all drug 
accountability records will be provided to Sensorion. 
 


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9.7 
Responsibilities 
The Investigator, the Hospital Pharmacist, or any other staff member allowed to store and dispense 
Investigational Product will be responsible for ensuring that the investigational product used in the study 
is securely maintained as specified by the Sponsor and in accordance with the applicable regulatory 
requirements. 
The investigational product should not be supplied to any non-authorized person, and should not be 
used other than as described in this protocol.  
 
9.8 
Management of treatment at the end of the study 
All unused investigational product (IP) will be returned to the designated Clinical Research 
Organization at the end of the study, as described in the shipment procedure. The site should not destroy 
any treatment without a specific written information from the sponsor. 
In case of destruction of the IP, the information about date and location of destruction, sort and amount 
of the IP, reason and contact details of the person who destroyed the IP should be recorded. 
 
9.9 
Concomitant therapy 
9.9.1 Authorized concomitant medication 
Any drugs other than those listed below are permitted, if considered necessary for the subject and 
administered at a stable dose, at the discretion of the Investigator.  
Any concomitant medication (started prior to the study and/or prescribed during the study) should be 
recorded on the case report form. In case of treatment given for any untoward event, an adverse event 
form should be completed in the CRF. 
The highly effective contraception method should be kept unchanged during the study and up to 1 month 
after the end of the study.  
9.9.2 Not permitted concomitant medication 
• The medications listed below are not permitted, unless in exceptional circumstances: see below 
rescue medication  
• Antihistamines: diphehydramine, cyclizine, dimenhydrinate, meclizine, hydroxyzine, 
promethazine 
• Cinnarizine, flunarizine 
• Central antidopaminergics: Neuroleptics unless the dose is stable for at least 1 month prior to 
randomization and no changes are expected during the course of the study  


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• Histaminergics: betahistine 
• Scopolamine, homatropine 
• Gabapentin, pregabalin 
• Acetylleucine, 5HT3 antagonists (ondensetron, granisetron, palonosetron etc..) 
• Piracetam, piribedil, trimetazidine 
• Non-selective systemic antihistamines (e.g., chlorpheniramine, dexchlorpheniramine, 
cyproheptadine, diphenhydramine, hydroxyzine, …)  
• Corticosteroids, unless the dose is stable for at least 1 month prior to randomization and no 
changes are expected during the course of the study 
• Note: new "generation" antihistamines (cetirizine, loratadine, desloratadine, ebastine, 
mizolastine, fexofenadine, …) are allowed. 
9.9.3 Other prohibited therapy: 
No specific vestibular rehabilitation, except the Romberg test, should be performed during the study. 
Patients will be informed, that staying in bed without stimulating the vestibular organ will prolong 
central vestibular compensation. 
9.9.4 Rescue medication 
• In exceptional circumstances, when the patient is presenting with a severe, unbearable vertigo 
lasting more than 4 days after the first study drug intake, a rescue medication can be given to 
the patient from Day 5 and onwards: It is recommended to use non sedative standard of care 
therapy, even listed in the above not permitted concomitant medication. The rescue medication 
(date, dose, indication) should be recorded on the e-CRF. 
 


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10 STUDY ASSESSMENTS 
10.1 Efficacy assessments 
10.1.1  Vertigo intensity visual analog scale (VI-VAS) 
The Vertigo Intensity VAS is a non-anchored 100 mm horizontal line. Patients will be asked to rate the 
intensity of the vertigo placing the cursor of the electronic device on the 100 mm line to indicate the 
severity from 0 – 100 when 0 indicates no severity and 100 indicates worst severity. Patients will be 
requested to rate their vertigo at screening for inclusion criterion, just before the first study drug intake 
for baseline, and then twice daily in the morning between 10am and 12pm and in the evening just after 
dinner up to the end of study. An electronic device will be given to the patient for rating. The date and 
exact time of the rating will be captured together with the intensity.  
Two conditions will be tested:   
• Standing vertigo intensity (see Appendix 1): Patients will be asked to rate the intensity of the 
vertigo while standing up, eyes open, feet together twice daily. The vertigo assessment will be 
performed under condition 1 of the Romberg test on site to make sure that there is no risk of 
falling. When the patient is at home, he will be asked to try to stand up, to rate the standing 
vertigo intensity. He/she should be warned against the unability to stand up without support and 
the risk of falling. The patient should be recommended to try to stand up, close to his/her bed, 
to get support if needed, and if possible with someone close by to prevent any fall.  
• Spontaneous worst vertigo (See Appendix 2): Patients will be asked to rate the worst intensity 
of the vertigo over the last 2 hours, if possible prior to the Romberg tests or to the standing 
vertigo 
At baseline, and on site visits if the subject is unable to rate the vertigo due to severity of nausea and/or 
vertigo, or inability to stand up, the VAS will be verbally assessed (0 to 100), the reason for the patient 
not rating and the rating will be captured in the eCRF. 
At time points other than baseline, in case the patient is unable to complete the test, the reason should 
be reported within 24 hours (eg: Severe vertigo, Severe nausea, other) on the electronic device.  
 
10.1.2  Nausea Intensity Visual analog scale  
The nausea Intensity Visual analog scale is a non-anchored 100 mm horizontal line. Patients will be 
asked to rate the worst intensity of their nausea over the past 2 hours placing the cursor of the electronic 
device on the 100 mm line to indicate the severity from 0 – 100 when 0 indicates no severity and 100 
indicates worse severity (see Appendix 3). 


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The nausea intensity will be rated just before the first study drug intake, and then twice daily in the 
morning and in the evening up to the end of study.  An electronic device will be given to the patient for 
rating. The date and exact time of the rating will be captured together with the intensity.  
 
10.1.3  The Dizziness Handicap Inventory (DHI)  
DHI is widely used to evaluate self-perceived handicap due to dizziness, and is known to correlate with 
vestibular function tests in chronic dizziness (13) (29). First described by Jacobsen and Newman, the 
original DHI comprises 25 questions designed to assess the patient’s disability displayed by functional 
(DHI-F) (9 questions), emotional (9 questions) and physical (7 questions) limitations. The patient is 
asked to answer each question using "yes" (4 points), "sometimes" (2 points) and "no" (0 points) (See 
Appendix 4). The functional aspects investigated by the DHI-F evaluate the interference of dizziness 
on the performance of some eye, head and body movements, although focusing on the capacity of 
performing professional, domestic, social and pleasure activities and on the independency of performing 
tasks such as walking without help and walking around the house in the dark. The score of the functional 
disability subscale ranges from 0 suggesting the absence of any functional handicap to 36 points 
indicating the worst functional disturbance.  
 
The DHI has been reported to have good psychometric properties: high test-retest reliability (interclass 
correlation coefficient [ICC] 0.72-0.97) and internal consistency reliability (Cronbach  = 0.72- 0.89) 
responsiveness.  
In case the patient is unable to complete the test, the investigator will complete the e CRF with the 
reason of missing data (eg: Severe vertigo, Severe nausea, other). 
Patients will be requested to complete the DHI at baseline (prior to the first study drug intake), and end 
of study visit (D28). Comparison in the functional subscore will be considered.  
 
10.1.4 Time to unassisted walking 
Patient will have to express their ability to walk without assistance on the electronic device (see 0). 
They will have to tick a box “yes” or “no” corresponding to their response to the following question: 
“Because of your vertigo (or disequilibrium) problem, do you have difficulty walking 10 meters (32,8 
feet) at your usual speed without using support?” Walking as usual without support will be considered 
at the first time when the patient is ticking “yes” and all further assessments are “yes”.  
 
 
 


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10.1.5 The Vestibular Disorders Activities of Daily Living  
The Vestibular Disorders Activities of Daily Living scale (VADL) (see Appendix 5) (39) assesses the 
impact of vestibular impairment on every day activities. The test evaluates self-perceived functional 
limitations regardless of the underlying pathophysiology. Functional performance was shown to directly 
relate to a physiologic measure of compensation (40). It includes 28 items grouped into three 
dimensions: functional (self-care and intimate activities), ambulation (walking and stair climbing), and 
instrumental (home management and leisure activities).Each item is scored from 1 to 11. 1 to rate for 
independent, to 10 (too difficult, no longer performed). Rating 11 corresponds to not applicable. This 
scale has been recently validated in a population of Acute Unilateral vestibulopathy. It will be performed 
only at the end of study visit. 
 
10.1.6 Videooculography (VOG):   
Eye movements will be recorded using a standardized portable videooculography (VOG). Usually, 
AUV cause a jerk nystagmus with linear or constant velocity slow phase drifts. Characteristically, the 
nystagmus increases when the eyes are turned in the direction of the fast phases (opposite to the side of 
the lesion), and can be markedly suppressed by visual fixation. A change in head position often 
exacerbates the nystagmus. 
The experiment is a non-invasive, video-based method to measure the fast and slow phase of the 
nystagmus. It is based on pupil tracking through infrared cameras. Patients will be in complete darkness 
for the experiment (see Appendix 8). 
The nystagmus intensity defined as the slow-phase velocity (SPV) will be recorded. The SPV is 
automatically calculated by the apparatus. It corresponds to the distance that the eye travels during the 
slow phase divided by the duration (SPV = ΔΘ/Δt). Several eye movements are analyzed to calculate 
the maximum SPV: the nystagmus beat with the highest speed as reported during the experiment.  
The test will be performed at baseline (prior to the first study drug intake for inclusion), and daily until 
the end of hospitalization visit and at the end of treatment visit (D5) and End of study visit (D28).  
In case the patient is unable to complete the test, the investigator will complete the eCRF with the reason 
of missing data (eg: Severe vertigo, Severe nausea, other). 
 
10.1.7 The Romberg tests 
The modified Romberg test of Standing Balance was described by Agrawal Y and al. in 2011 (4). It is 
a static balance testing the patient’s ability to stand unassisted under several test conditions with the 
eyes successively open and closed. This test specifically evaluates the sensory inputs that contribute to 
balance: the vestibular system, vision, and proprioception. 
 


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In order to assess the potential risk of falls and imbalance related to vestibular function, a derived 
procedure of the modified Romberg test of Standing Balance is proposed (see Appendix 10) The patient 
is asked to stand, shoes off, in six successive conditions of increasing difficulties, eyes open, and eyes 
closed, feet together on a firm then foam surface or in tandem position. 
Condition 1: Standing on the floor, feet together (or at a distance for them to be steady) with the eyes 
open looking straight ahead 
Condition 2: Standing on the floor, feet together (or at a distance for them to be steady) with the eyes 
closed 
Condition 3: Standing on a foam pad, feet together (or at a distance for them to be steady) with the eyes 
open looking straight ahead  
Condition 4: Standing on a foam pad, feet together (or at a distance for them to be steady) with the eyes 
closed  
Condition 5: Standing, on a foam pad, feet heel to the toes with the eyes open looking straight ahead 
(dominant foot directly in front of the non-dominant foot in tandem) 
Condition 6: Standing on a foam pad, feet heel to the toes with the eyes closed (dominant foot directly 
in front of the non-dominant foot in tandem). 
Importantly, after condition 1, the patient will be requested to fill in the standing vertigo intensity VAS 
on his/her electronic device. 
 
Each condition is scored as a success or a failure; the failure being defined as one of the following:  
• The subject cannot stand up, and is unable to do the test or  
• Any occurrence of any of the following within 5 seconds: 
o Movement of the subject's feet from the initial test position (falling, side-stepping, 
hopping, pivoting, etc.); 
o Eyes open during an eyes-closed condition (i.e., Conditions 2, 4 and 6);  
o Requirement of the operator intervention to prevent the subject from falling or to 
maintain balance. 
 
The Romberg test will be repeated twice daily during hospitalization and will be performed at every on 
site visits. The total score will be calculated by summing the rate of each condition with 1 as a success 
and 0 as a failure. Subscores will be calculated for eyes closed on one hand and eyes open on the other 
hand 
10.1.8 The caloric test 
This test is usually performed with the subject reclining, head inclined 30° up from horizontal so as to 
make the lateral canal horizontal. Water is introduced into the ear canal on one side, either 7°C above 


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or below assumed body temperature. The flow rate is such that the ear rapidly equilibrates with the 
water. The water is stopped after 20 seconds, and nystagmus is observed. Nystagmus commonly builds 
for about 30 – 60 seconds, then gradually decays away over roughly 2 minutes. After a rest of at least 2 
minutes, the procedure is repeated with either the opposite temperature water, or on the other side. 
Eye movements are usually recorded with either electronystagmography or video.  
From the peak slow-phase velocity of nystagmus four numbers are obtained  
- 
cold right : RC  
- 
cold left : LC  
- 
warm right : RW  
- 
warm left : LW  
Spontaneous nystagmus should be subtracted from these, and then the absolute value taken. From these 
responses, LC, LW, RC, RW, three additional numbers are derived: The total response is the absolute 
sum of all appropriately directed responses. TR= (RC+LC+RW+LW). The goal is to detect bilateral 
weakness. The total response should be 20 or greater. When responses are corrected for spontaneous 
nystagmus, the procedure here is to sum the absolute value of responses that go in the right direction - 
i.e. left cold and right warm should be right-beating, right cold and left warm should be left beating.  
Unilateral paresis or RVR (relative vestibular reduction), RVR = (RC+RW-LC+LW)/TR is called "de 
Jongkees’ formula". If all responses are appropriately directed, one can simply take the sum of the 
absolute values of responses due to the right ear, subtract the sum of the absolute responses due to the 
left, and normalize to the sum of the absolute values of all responses. If spontaneous nystagmus is not 
subtracted off first, peculiar results may appear, such as greater than 100% paresis (which is obviously 
impossible). 
The test can be performed at baseline for inclusion if the vHIT is negative and all other criteria are met. 
The RVR should be > 25% (de Jongkees’ formula).  
Caloric tests at baseline and end of study visit will be performed in some centers participating in an 
ancillary study. 
 
10.1.9  The video Head Impulse Test  
The video Head Impulse Test (vHIT) (see Appendix 9) provides a quick and objective measure of the 
vestibular ocular reflex (VOR) in response to head movements in the natural range of daily motions. 
AUV patients are reported to have reduced horizontal canal VOR gain (6)(7). 
vHIT is an easy  tool to determine corrective saccades (overt and covert) in patients, when delivering 
manually graded head impulses and to objectively analyze the stimulus-response characteristics of the 
VOR.  
This procedure provides the clinician with a video recording of eye movement for spontaneous, dynamic 
positional and positioning maneuvers. It also allows a “bedside” type of neurovestibular evaluation of 


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the patient's ability to hold gaze and the presence or absence of nystagmus in the aforementioned 
subtests. 
Eye movements are recorded via VOG goggles to quantify eye and head movements and to calculate 
gain as a ratio of angular eye velocity to angular head velocity. The vHIT will be conducted at baseline 
to confirm the peripheral origin of the vertigo.  AUV is confirmed if the VOR gain is <0.7 or if there is 
a pathological caloric testing and all other criteria are met. (see Appendix 8) 
An additional vHIT will be performed at the end of treatment and end of study visits in some centers 
participating in the ancillary study.  
10.2 Safety assessments 
Clinical safety will be routinely assessed by the medically-qualified study investigator.  
10.2.1  Physical examination 
A physical examination including evaluation of main body systems/regions: skin and mucous, 
ears/nose/throat, pulmonary, cardiac, gastro-intestinal and neurological systems is to be conducted at 
the Screening visit, on Day 5 (Visit 5, EOT), and Day 28 (Visit 7, EOS). Care should be taken to 
examine and assess any abnormalities that have been indicated as potentially present by medical history.   
10.2.2 Vital signs 
Vital signs including temperature, systolic (SBP) and diastolic (DBP) blood pressures, heart rate, and 
respiration will be collected after 10 minutes rest in the supine and after 2 minutes in the standing 
position. Orthostatic blood pressure is part of the symptomatology described in patients with AUV. If 
possible, vital signs will be measured prior to blood draw. 
Vital signs and orthostatic hypotension will be measured at screening, at baseline (prior to the first study 
drug intake, 12 and 24 hours after the first intake, at the end of treatment visit (D5) and End of study 
visit (D28). 
10.2.3  Electrocardiogram (ECG) 
A standard 12-lead electrocardiogram (ECG) will be performed at the Screening visit, on Day 5 (visit 
5, EOT), and Day 28 (Visit 7, EOS). Heart rate will be recorded from the ventricular rate and the PR, 
QRS and QTc (QTc=QT/[60/heart rate]1/2) intervals will be recorded.  The Investigator medical 
opinion and automatic values will be recorded in the eCRF .The ECG strips or reports will be stored as 
source document. 
 
 


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10.2.4  Laboratory safety 
A standard laboratory blood test will be performed at the screening visit and at D5 (visit 5 EOT visit). 
Routine serum hematology and chemistry samples will be collected in EDTA tubes and according to 
the study flow chart and kept at the local laboratory as per laboratory requirements  
The standard laboratory blood test comprises: 
• hematology : complete blood count (CBC), including hematocrit, hemoglobin, red blood cell 
count, white blood cell count with differential count,platelets, and INR 
• serum chemistry including: sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, albumin, lactate dehydrogenase (LDH), alanine 
amino transferase (ALT), aspartate serine transferase (AST), alkaline phosphatase, GGT and 
total bilirubin, fasting glycaemia (at screening glycaemia will not be necessarily fasting), 
creatine phosphokinase(CPK). 
• C Reactive Protein (CRP). 
• HCG will be performed in women of childbearing potential at screening, and at the end of 
treatment visit, with a urine pregnancy test performed at the screening visit. A subject cannot be 
included with a positive urine test. Blood sample will be taken for confirmation of the pregnancy 
status at baseline and end of study visit. In case of positive results, the pregnancy outcome should 
be reported on a specific form.  
No centralized laboratory procedure is planned.. Biological samples will be analysed locally and 
destroyed immediately after the analyses. 
10.2.5  Adverse event collection 
Adverse events will be collected throughout the study and at every visit after screening. The medically-
qualified investigator will be available to provide clinical judgment on all trial-related medical issues 
including adverse events and clinical laboratory values. 
 
10.3 Pharmacokinetic evaluation 
Serum samples will be collected for pharmacokinetic (PK) analysis. A 3 mL blood sample will be drawn 
into a Vacutainer tube, at H12, H24, and at end of treatment visit. The blood samples must be gently 
inverted a few times for complete mixing with the anticoagulant (lithium heparin). The exact date and 
time of sample collection will be recorded on the eCRF. Within 30 minutes following blood collection, 
each blood sample will be centrifuged at 1500 g for 10 minutes at 4°C. 
Samples will be stored at the site in a secure location at -20°C as per laboratory requirements and 
outlined in the laboratory manual which will be available at each investigational site, until shipment in 
dry ice to Atlanbio (Saint-Nazaire, France) that will perform the pharmacokinetic analyses.  


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Several samples will be batched together in the same shipment. The person in charge of the shipment 
will be contacted by the CRO who will organize samples’ shipment. If the site needs to transfer the 
samples rapidly (due to storage constraint for instance), the CRO should be contacted.  
PK samples will be destroyed after the finalization of the complete Clinical Study Report. No further 
uses of biological samples are planned, i.e for additional research. 
 
10.4 Health Economic: 
Health impairment often leads to work impairment in the form of both absenteeism and presenteeism 
(i.e. reduced productivity while at work). The Work Productivity and Activity Impairment (WPAI-SH) 
questionnaire (see Appendix 6) is a well-validated instrument (19) that measures impairments in work 
and activities over the past 7 days. It is the most frequently used instrument.  
The patient will be requested to fill-in the WPAI questionnaire at the End of study visit (D28).  
 
WPAI is expressed as impairment percentages, with higher numbers indicating greater impairment and 
less productivity, i.e., worse outcomes.  


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11 STUDY PROCEDURES 
11.1 Visit  
Study procedures are described in the flow chart (Section 4)) The following are general guidance 
relating to all visits. 
Every attempt should be made to complete all visits during the defined window periods. 
An end of study visit is required for all patients. In the rare cases a final follow-up visit cannot occur 
within the 30-day timeframe following the scheduled study end date, any attempt to contact should be 
recorded on a special contact form, until/unless appropriate information is obtained which will allow 
completion of final end of study visit CRF, even after the anticipated timeframe. 
Blood is collected by venipuncture. The exact time of sample collection should be transferred into 
database and should be collected on the laboratory request form for local blood sampling. 
Important note: Any abnormal laboratory value, abnormal ECG parameter, SAE will be immediately 
rechecked for confirmation before making a decision of permanent discontinuation of IP for the 
corresponding patient. 
• Patient will be provided with an electronic device for assessment of the VAS during the study. 
The use of the device will be explained to the patient by the investigator’s team and tested prior 
to the first use.  
• Patient may not be able to complete all tests due to the severity of the vertigo. In case of missing 
data, the reason should be specified in the eCRF (severe vertigo, severe nausea, or other) or in 
the electronic device if the patient is already discharged. 
 
11.1.1  Visit 1 - Screening H-6 (± 6) 
Before any screening assessment is performed, complete and detailed information about the aim, the 
consequences and the constraints of the trial will be given by a physician, both verbally and by 
reviewing the information leaflet and consent form. If the subject agrees to perform the study, he will 
sign and date the Informed Consent form prior to any study-specific procedure. He will be given a copy 
of the information leaflet and consent form. 
After obtaining consent, the investigator will connect to the site http://www.prgrand.com secured by an 
SSL certificate to create the patient in the database data (patient attribution of code).  
The following tests and procedures will be performed:  
• Assessment of eligibility by review of inclusion and exclusion criteria 
• Recording of the subject demography 
• Complete Physical examination: Special attention should be paid to dizziness, migraine, nausea, 
vomiting (start and duration)  


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• Previous Medical and surgical history including neurological and psychiatric history 
• Neuro-Otologic examination  
• Concomitant medications (over the past 3 months). Specific attention will be paid to medication 
and doses that might have been taken during transportation. 
• Vital signs: supine blood pressure and heart rate, Temperature 
• Blood collection for routine hematology  
• Blood collection for serum chemistry  
• C Reactive Protein (CRP). 
• Urinary Pregnancy test: both and blood (for WOCBP) 
• Standing Vertigo intensity (VAS)  
• Nausea intensity (VAS) 
 
11.1.2  Visit 2 - Inclusion H0 
If the patient meets all inclusion and no exclusion criteria (per history, exam and laboratory) the patient 
can be included in the study.  
 
The following tests and procedures will be performed: 
• Re-Confirmation of medical history (dizziness, migraine, nausea, vomiting (start and duration)  
• Vital signs: supine and standing blood pressure and heart rate, Temperature 
• 12-lead ECG 
• Checking for Concomitant medication and doses of unauthorized medication;  
• Re-confirmation of eligibility by reviewing inclusion/exclusion criteria 
• Inquiring about adverse event and fill an adverse event form if any 
• The patient will be provided with an electronic device. He will be instructed to fill in the worst 
vertigo intensity VAS and the nausea intensity VAS, and to answer to unassisted walking ability 
question. 
• The patient will be asked to complete specific tests  
o Romberg tests with a standing vertigo intensity VAS under condition 1. 
o Videooculography 
o Video Head Impulse test and/ or Caloric test 
o DHI 
• Recording of the Hospitalization status of the patient (yes/no) 
• After all assessments have been completed, the investigator will connect to the IWRS for 
allocation of a randomized treatment kit number. The investigator will dispense to the subject 
the corresponding study drug that is to be taken at the site, immediately after all baseline 
assessments are performed. Patient should be instructed to take 2 tablets and to keep the tablets 


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in the mouth until complete dispersion.  Date and time of the intake should be recorded on the 
e-CRF. 
• The patient remains under medical supervisions for at least six hours after the study drug intake. 
11.1.3 Visit 2 - H12 (± 3hours) 
• Patient will be instructed to continue to fill in the worst vertigo intensity VAS and the nausea 
intensity VAS, and answer to the walking ability question twice daily in the morning between 
10.00 am and 12.00 pm and in the evening just after dinner. 
• Inquiring about adverse event and fill an adverse event form if any   
• The investigator will dispense the second dose of the investigational product, 12 hours (+3 h) 
after the first intake, if there is no adverse event leading to discontinuation, and after  
o Vital signs are assessed and  
o a blood sample taken for PK 
o Romberg tests are performed with the standing vertigo VAS to complete under condition 
1.  
Date and time of the intake should be recorded on the e-CRF. 
 
11.1.4 Visit 3 - H24 (± 3hours) 
The following tests and procedures will be performed: 
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• Vital signs: supine and standing blood pressure and heart rate, Temperature 
• The electronic device information for VAS completion will be checked  
• Patient will be asked to complete specific tests 
o The Romberg tests that will be repeated twice daily until the patient is discharged with 
the standing vertigo intensity VAS just after condition 1. 
o Videooculography 
• Hospitalization status (Yes/No) 
• Drug accountability 
• A blood sample will be taken for PK. 
• Patient will be instructed to take the third dose of the investigational product and to continue 
once daily for the fourth, and the fifth doses in the morning or evening depending on the time 
of the first intake. 
• Patient will be reminded to fill in the Vertigo intensity VAS and the nausea intensity VAS on 
the electronic device and to answer to the unassisted walking ability question twice daily in the 
morning between 10.00 am and 12.00pm and in the evening just after dinner. 


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• If the patient is discharged, he will be instructed to record also a standing vertigo intensity VAS 
while standing on a firm surface, eyes open, feet together. 
• An appointment for Visit 5 D5 (end of treatment visit) will be scheduled.  
 
11.1.5  Visit 4: End of hospitalization visit, From D3 (-1, +25) to D28 
The discharge visit has to be done the day of discharge from the hospital. If it occurs on D5 (-1; +2) 
(end of treatment visit) or on Day 28 (+2) (end of study visit), only the information about date and time 
of hospital discharge will be captured in the e CRF.  
 
The following tests and procedures will be performed: 
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• Vital signs: supine and standing blood pressure and heart rate, Temperature 
• The electronic device information for VAS completion will be checked  
• Patient will be asked to complete specific tests 
o The Romberg tests with a standing vertigo intensity VAS after condition 1 
o Videooculography 
• He will be requested to return the device to the site at the following visit.  
• Hospitalization status (Yes/No) 
• Drug accountability 
• If the discharge visit occurs prior to Day 5, Patient will be provided with the treatment kit with 
the remaining tablets to be taken home. He will be instructed to take 2 tablets in the morning or 
evening depending on the time of the first intake the last intake being on D4 (if relevant). 
• Patient will be provided with the electronic device to be taken home and he will be reminded to 
fill in the worst vertigo intensity VAS and the nausea intensity VAS, as well as to answer to the 
unassisted walking ability question twice daily in the morning between 10am and 12pm and in 
the evening just after dinner. He will be instructed to record also a standing vertigo intensity 
VAS while standing on a firm surface, eyes open, feet together twice daily. 
• If the patient is still at the study site (hospital) at the time of end of study visit, or if the end of 
hospitalization visit is within the window of the end of treatment visit, the end of hospitalization 
visit will not be completed and the reason clearly mentioned in the e CRF. . 
• An appointment for the following visit will be scheduled, and the patient will be instructed to 
bring the investigational product kit with the remaining tablets together with the electronic 
device, and to come in fasting condition. 
 


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11.1.6 Visit 5: End of treatment visit: D5 (-1/+2 days) 
This visit includes: 
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any  
• Physical examination including the body weight 
• Vital signs: supine and standing blood pressure and heart rate, Temperature 
• 12-lead ECG 
• Drug accountability 
• A blood sample will be taken for PK. 
• Routine hematology  
• Routine biochemistry  
• C Reactive Protein (CRP) 
• Pregnancy tests both urinary and blood for WOCBP 
• The patient will be asked to complete specific tests:  
• The Romberg tests with a standing vertigo intensity VAS after condition 1 
• Videooculography 
• Recording of the Hospitalization status of the patient (yes/no) 
• The electronic device information for VAS and unassisted walking ability question completion 
will be checked  
• Patient will be reminded to fill in the Vertigo intensity VAS and the nausea intensity VAS as 
well as to answer to the walking ability question twice daily in the morning between 10am and 
12pm and in the evening just after dinner. He will be instructed to record also a standing vertigo 
intensity VAS while standing on a firm surface, eyes open, feet together twice daily. 
• He will be requested to return the device to the site at the following visit.  
• Appointment to the following visits will be scheduled (end of study visit at the site, and phone 
call). 
• Ancillary study: An additional test may be performed at sites participating in the ancillary study: 
Video-head impulse test (function of the vestibule-ocular reflex) 
 
11.1.7 Visit 6: Phone Call; D14 (±2 days) 
A call will be given to ensure safety of the patient. The visit can be performed by phone if the patient is 
no longer hospitalized. It will include:  
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any; In case an event is identified 
during the phone call, a subsequent visit at the site may be required in order to allow appropriate 
documentation of the safety event. 


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• The patient will be reminded to complete the VAS and unassisted walking ability question twice 
daily in the morning between 10am and 12pm and in the evening just after dinner. He will be 
also reminded to record also a standing vertigo intensity VAS while standing on a firm surface, 
eyes open, feet together twice daily. 
• Recording of the Hospitalization status 
• Appointment to the following visit will be reminded (end of study visit at the site, and phone 
call), and the patient will be reminded to return the electronic device back to the site, and to be 
in fasting condition for the V7.  
 
11.1.8  Visit 7: End of study visit; Day 28 (±2 days): 
This visit includes: 
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any  
• Physical examination  
• Vital signs: supine and standing blood pressure and heart rate, Temperature 
• Drug accountability (if relevant) 
• Urinary Pregnancy tests for WOCBP (In case of positive test, a blood sample will be taken for 
confirmation) 
• The patient will be asked to complete specific questionnaires and tests :  
o VADL  
o DHI 
o The Romberg tests with a standing vertigo intensity VAS after condition 1 
o Videooculography  
o Health economic questionnaire: WPAI 
• Recording of the Hospitalization status of the patient (yes/no) 
• The electronic device information for VAS completion will be checked, and the device stored 
at the site 
Ancillary study: An additional test will be performed at sites participating in the ancillary study  
 
• Video-head impulse test (function of the vestibule-ocular reflex) and/or a caloric test  
11.1.9  Unscheduled Visit: Visit 99 
In case of adverse event, or in case of abnormal values, an additional visit may be needed to repeat the 
test or document an adverse event. 
 


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11.2 Definition of source data 
The list of information considered to be raw data which must be shown in the subject’s file are listed in 
the section 19. 
The results of certain investigations or assessments included in the CRF may be considered to be raw 
data. Direct CRF data entries, if any, should be defined during initiation visits at the latest, by the 
investigational team and implemented for the rest of the study. 
11.3 Subject withdrawal 
11.3.1  Removal of subjects from therapy or assessment 
In accordance with the current revision of the Declaration of Helsinki and current US Food and Drug 
law, a subject has the right to withdraw from the study at any time for any reason without prejudice to 
his/her future medical care by the physician or at the institution.  The Investigator and Sponsor also 
have the right to withdraw subjects from the study in the event of intercurrent illness, adverse events, 
treatment failure, protocol violation, or other reasons.  Should a subject (or a subject’s legally authorized 
representative) decide to withdraw, all efforts will be made to follow the patient and to complete and 
report the observations as thoroughly as possible on the appropriate case report form. 
Subjects who discontinue treatment should be assessed in accordance with the assessments/tests 
specified normally for the end of study visit.  
Subjects who have been withdrawn from the study cannot be re-included in the study. Their subject 
number and treatment number must not be re-used. They should not be replaced. 
 
11.3.2  Withdrawal criteria 
The subjects could withdraw from the study if they decided to do so, at any time and irrespective of the 
reason, or this could be the Investigator’s decision. All drops out must be documented and the 
investigator must give the reason (adverse event, subject request, other reason…). 
Subjects may be removed from the study by the investigator or the sponsor, if one or more of the 
following occurs: 
• Noncompliance with protocol by the subject. 
• Adverse event (decision to be removed from study made by either the Investigator or subject). 
All adverse events, both serious and non-serious, that result in the subject’s withdrawal from the 
study (either by subject request or Investigator decision) must be reported to the CRO (Sensorion 
designee) within 24 hours for serious events, and within 7 days for non-serious events. 


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• Worsening of the disease : 
o Worsening of nausea of more than 20 mm compared to baseline on the nausea intensity 
VAS on 2 consecutive evaluations 
o Worsening of vertigo of more than 20 mm compared to baseline on the VI-VAS scale 
standing position on 2 consecutive evaluations 
Any worsening is considered an adverse event and must be reported to the CRO (Sensorion 
designee) within 24 hours for serious events, and within 7 days for non-serious events. 
• Onset of new neurological symptoms (such as but not limited to diplopia, slurred speech, gait 
disturbances, localised weakness or numbness)  
• Hearing Loss. 
• Positive serum pregnancy test 
• Decision by the Investigator or Sponsor that termination is in the subject’s best medical interest 
or administrative decision for a reason other than that of an adverse event. 
• Request for withdrawal by the subject for reasons other than an intolerable adverse event. 
• Lost to follow-up: For subjects considered lost to follow-up, the CRF must be filled in up to the 
last visit performed. The Investigator should make every effort to re-contact and to identify the 
reason why the subject failed to attend the visit and to determine his/her health status. 
 
11.3.3  Decided by the sponsor 
The Sponsor could decide premature discontinuation of the study in the following cases: 
• The study was not conducted in accordance with the procedures defined in the approved protocol 
(i.e. low rate of recruiting - protocol deviations - failure to ensure the quality of the data collected). 
• Information on the Investigational Medicinal Product (IMP) that could change the current benefit-
risk profile of the IMP or that would be sufficient to require changes in the IMP administration or 
in the overall conduct of the trial. 
• Left at the discretion of the Sponsor. 
11.3.4  Decided by the investigator 
The Investigator could stop the research if in his judgment the participating subjects were exposed to 
risks that were not ethically or scientifically justifiable and must notify in writing the Sponsor of this 
decision providing the reason thereof. 
In all cases IRBs and Health Authorities should be informed by sponsor, within 15 days after the 
decision was taken. 


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12 SAFETY 
12.1 Definitions 
12.1.1  Adverse event (AE)  
An AE is any untoward medical event in a patient or clinical investigation subject administered a 
pharmaceutical product.  An AE does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. 
12.1.2  Serious adverse event (SAE) 
A Serious AE is any untoward medical occurrence that at any dose: 
• Results in death - Includes all deaths, even those that appear to be completely unrelated to study 
drug (e.g., car accident where subject is a passenger). 
• Is life-threatening - In the view of the Investigator, the subject is at immediate risk of death at the 
time of the event.  This does not include an AE that had if occurred in a more severe form, might 
have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  Prolongation of 
existing hospitalization is defined as hospital stay longer than originally anticipated for the event or 
development of a new AE as determined by the Investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event – Important medical events may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent one of the other serious outcomes listed above (e.g., intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse).  
 
12.1.3  Unexpected adverse reaction  
An unexpected adverse reaction is an adverse reaction, whose nature, severity or outcome is not 
consistent with the applicable medicinal product information i.e. the Investigator's Brochure. 
The occurrence of a pregnancy of a partner of a trial subject discovered within 10 days after last 
administration of the IMP, is to be communicated to the Sponsor in an expedited manner with the same 
procedure and timelines as for serious adverse events, independently from the occurrence of an AE. 


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12.2 Overdose 
In case of voluntary or involuntary overdose, it is recommended to carefully monitor the signs and 
symptoms. As there is no antidote for SENS-111, intensive care admission should be considered 
according to clinical status, and the treatment would be the standard one for unspecific drug 
intoxication, including general support which may include immediate gastric lavage within the first 
hour after intake to diminish the amount absorbed, continuous monitoring of vital signs, supportive care 
for cardiovascular function, respiratory aid in case of compromise, electrolyte balance and other 
measures as clinically indicated. 
12.3 Reporting of adverse events 
12.3.1  Adverse events 
Any AE occurring after the patient has signed the informed consent must be fully recorded in the 
patient’s eCRF. The AE form should be supported by a complete documentation available in the 
patient’s file. Any abnormal laboratory test considered medically meaningful (e.g., causing the patient 
to withdraw from the study, requiring treatment or causing apparent clinical manifestations, or judged 
medically relevant by the investigator) should be reported as an AE. The AE should be fully described 
along with start and stop dates, severity, relationship to the investigational product, action taken and 
outcome in the AE form. 
For any adverse event, the investigator has to follow-up the case to determine the outcome of the adverse 
event. He should also try to get all necessary information to assess whether the AE meets the criterion 
definition of a non-serious or a serious adverse event (SAE). In the later case, it will trigger immediate 
notification to the Sponsor (see below). Whichever the seriousness criterion, follow-up of the AE is 
requested until final outcome in case of ongoing adverse event or ongoing complication even after the 
treatment is discontinued. 
Final outcome includes complete resolution or stabilization at a level acceptable to the investigator and 
the Sponsor. For subjects withdrawn from the study and subjects experiencing AE at the end of the 
study and within 30 days following the last treatment day, the investigator will manage the appropriate 
follow up (if required until the AEs are resolved or attributed to a cause other than the study drug). 
12.3.2  Serious adverse events 
SAEs or suspected adverse event must be reported on the specific SAE form. This SAE form must be 
completed and forwarded to the designated CRO immediately and no later than 24 hours of learning of 
the event.  
The Sponsor will ensure that all legal reporting requirements are met. 
The initial report must be as complete as possible, including all details of the current illness and 
(serious) AE, and an assessment of the causal relationship between the event and the study 


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medication.  
The serious adverse event or medically important event should be fully documented. All 
additional information not available at the time of the initial report (e.g., AE end, date 
laboratory values received after the report) must be reported on a follow-up SAE form and 
transmitted to the designated CRO as soon as possible.  
Whatever relationship to the study drug any serious adverse event occurring within 30 days following 
the last treatment day must be reported. 
Contact details for SAE reporting to the designated CRO are the following:  
For US sites: 
fax xxxxxx OR e-mail GlobalPV-US@xxxxxx.com 
  
For all other countries sites: 
Fax xxxxxx OR e-mail PVDS-ROW@ xxxxxx.com 
 
An inquiry will then be conducted by the designated CRO in order to determine whether the event was 
caused by the treatment to make all necessary submission. In any case, and as a conservative measure, 
Sensorion will re-assess only cases that were considered not related to the study drug by the investigator. 
Sensorion (or designated CRO) will inform the Health Authorities and the Ethics Committees in writing 
in accordance with current regulations.  
12.3.3 Severity and causality of events 
The Investigator should assess any event with regard to its severity and causality.  
The severity of the adverse events is determined in the following manner: 
• mild: no interference with the subject’s daily activities 
• moderate: moderate interference with the subject’s daily activities 
• severe: major and unacceptable interference with the subject’s daily activities 
 
Both the investigator and the sponsor will assess the possible relationship between the adverse event 
and the study drug: 
• 
Probable: assuming a causal relationship; 
• 
Possible: a causal relationship cannot be excluded  
• 
Unlikely: a causal relationship with another origin is more likely Unrelated; 


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• 
Not assessable: impossible to assess, because of insufficient evidence, conflicting data or poor 
documentation. 
Any adverse event for which, either the Investigator or the Sponsor considers that a causal link with the 
study product could reasonably be envisaged, is considered a suspected adverse effects. Both the 
Sponsor and the Investigator’s assessment with regard to causality will be reported in the declaration of 
suspected adverse effect. In no case Sensorion will provide a downgrade relationship as compared to 
the investigator’s assessment.  
Unrelated adverse events are those that are judged to be not related to the study or to the study drug by 
the investigator and the sponsor. 
12.4 Premature study discontinuation due to adverse event 
In the case of premature study treatment discontinuation due to an adverse event, the Investigator must 
immediately notify the monitoring team using the specific eCRF form. 
12.5 Safety follow-up 
• The Investigator should take all appropriate measures to ensure the safety of the subjects. All 
patient presenting with any AE should be followed up until normalization or the return to 
baseline conditions. Follow up may continue after the end of study visit 
• In case of severe laboratory abnormalities, abnormal ECG, the test should be immediately 
repeated to confirm the value. If confirmed, the treatment should be discontinued and all 
appropriate measures should be taken to ensure the safety of the patient. 
12.6 Unblinding procedure 
In case of an emergency, the Investigator can unblind the treatment for a specific Patient. 
Before breaking a Patient’s blind, the Investigator must contact with the Medical Monitor or his/her 
Backup (available 24H/24, 7 days a week) to obtain a PIN code for unblinding in the IWRS.  
In the event the system is unavailable, the investigator can call the IWRS helpdesk (the telephone 
numbers for the Helpdesk are listed in the IWRS Site User Guide) and provide the PIN. Helpdesk will 
break the blind and provide treatment nature to the investigator over the phone and a confirmation by 
email. 
Unblinded subjects must be discontinued from the study 
 
 
 
 


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MEDICAL MONITOR CONTACT INFORMATION 
 
 
 
 
BACKUP MEDICAL MONITOR 
 
 
 
 
12.7 General Safety Monitoring 
12.7.1  Safety steering committee 
Sensorion Safety Steering Committee, independent from the monitoring study team, will meet 
periodically as determined appropriate for the individual protocol to review blinded safety data. These 
data will include but not be limited to: 
• AEs of a Grade  3 
• Non-serious AEs that result in an early study withdrawal 
• Serious AEs 
• Selected laboratory tests, as deemed appropriate by the Safety Steering Committee 
The steering committee may ask for un-blinding of the data if needed. Appropriate action, if needed, 
will be taken based upon this review and in consultation with the study clinical team, as appropriate. 
The steering committee minutes and charter that will be established before the first patient will be 
included in the study documentation file for consultation by health authorities if needed. The steering 
committee may contact directly the DMC if there is any concern with regard to safety. 
12.7.2  Data Monitoring Committee 
An external data monitoring committee (DMC), independent from the sponsor and the monitoring team 
will be set up to review the safety of the product throughout the conduct of the study.  
The committee consisting of two or more physicians and a statistician will be provided with the blinded 
safety information on a regular basis. Safety data will be provided by patient with relevant information 
according to the DMC charter that will be established before the first patient is included. The DMC may 
ask a total or partial un-blinding of the data. The first review is expected to be done after 30 patients 
have completed the study. The DMC will be responsible for providing recommendation for the 
continuation of the study, amendment or discontinuation. The DMC minutes and final recommendation 
will be included in the study documentation file.  
 


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13 STATISTICAL CONSIDERATIONS  
The statistical considerations summarized in this section outline the plan for data analysis of this study. 
A statistical analysis plan (SAP) will be finalized prior to the database lock. 
For continuous variables, descriptive statistics will include at least the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
For categorical data, frequencies and percentages will be displayed for each category. 
SAS Version 9.2 or later will be used for statistical programming.  
 
13.1 Determination of sample size 
It was based on the area under the curve (AUC) of the Vertigo Intensity Visual Analogue Scale (VI-
VAS) from baseline included to second measurement of Day 4 included. A sample size of 207 patients 
(69 patients per treatment group) was retained corresponding to the following assumptions: 
• Each comparison to placebo performed at 2.5% two-sided significance level 
• Power of each comparison to placebo set to 85%. 
• Randomization ratio 1:1:1 
• Intra-group standard deviation of 71 mm*day 
• Difference to placebo of 40 mm*day (i.e. 20% of an average AUC of 200 mm*day on placebo). 
 
13.2 Subject description 
13.2.1  Disposition of subjects 
The total number of subjects for each one of the following categories will be presented in the clinical 
study report (CSR) using a flow-chart diagram: 
• Screened subjects,  
• Included subjects (= randomized: those who receive a treatment number), 
• Exposed subjects (those who take at least one dose of randomized study drug), 
• Completed subjects, 
• Reasons for treatment discontinuation. 
 
In summary tables, a breakdown by center and randomized treatment group (3 groups as defined in 
section 7.1) will be given. 


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The total number of subjects screened and the reasons for screen failure will be presented separately. 
The overall number of subjects who completed the study normally will be described by center. In 
addition, the number and percentage of subjects in each randomized treatment group who completed 
the study will be displayed in a table. 
Reasons for study withdrawal will be supplied in tables giving numbers and percentage, broken down 
by randomized treatment group and in individual data listings, sorted by center and by subject. 
For all categories of subjects but screened and included, percentages will be calculated using the number 
of randomized subjects as denominator. 
13.2.2  Protocol deviations 
Protocol deviations will be identified and classified. Only subjects with major deviations will be 
discussed in the clinical study report [CSR]. The deviations will also be considered in defining the PP 
population (major deviations only). 
 
13.3 Analysis populations 
13.3.1  Efficacy populations 
13.3.1.1 Intent-to-Treat 
The intent-to-treat (ITT) analysis set will comprise all randomized patients according to randomization 
group. All efficacy analyses will be performed on the ITT analysis set. 
13.3.1.2 Per-protocol 
The per-protocol (PP) analysis set will comprise all patients of the ITT analysis set without major 
protocol deviation. Selected efficacy analyses (primary efficacy endpoint, secondary endpoints) will be 
repeated on the PP analysis set. 
13.3.2  Safety population 
The safety analysis set will comprise all treated patients according to first treatment actually received. 
 
13.4 Statistical methods 
13.4.1  Analysis of primary efficacy endpoint 


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The VI-VAS AUC will be compared between treatment groups within an analysis of covariance model 
with the stratification factor (duration of vertigo before being treated) and the baseline score as 
covariates. Missing intermediate measurements won't be replaced in the calculation of the AUC, 
missing final measurement(s) (e.g. in case of patient's withdrawal) will be replaced by BOCF (baseline 
observation carried forward) if the reason for missing data is severe vertigo or by LOCF last observation 
carried forward (i.e. absence of improvement) if the reason for missing data is nausea or other.   
The two comparisons to placebo will be tested with an alpha adjusted to the Dunnett's multiple 
comparison procedure in order to preserve an overall type I error of 5%, the corresponding confidence 
intervals will be presented. 
As a complementary analysis in order to get a better insight of the treatment effect over time, the 8 post-
baseline VI-VAS scores will be analyzed, without replacement of missing values, using a restricted 
maximum likelihood (REML)-based repeated measures approach. Analyses will include the fixed, 
categorical effects of treatment, time, and treatment-by-time interaction, as well as the binary 
stratification factor (duration of vertigo before being treated) and the continuous, fixed covariates of 
baseline score and baseline score-by-time interaction. An unstructured covariance structure will be used 
to model the within-patient errors. If this analysis fails to converge, simpler structures (e.g. first-order 
ante-dependent or heterogeneous compound symmetry structures) will be tested in a model without 
treatment effect; the covariance structure converging to the best fit, as determined by Akaike’s 
information criterion, will be used in the full model. The Kenward-Roger approximation will be used 
to estimate denominator degrees of freedom. Within this model the test of interest will be the treatment-
by-time interaction performed at significance level of 5%. In a second step, the two comparisons to 
placebo will be tested at each time using an alpha adjusted according to the Dunnett's multiple 
comparison procedure in order to preserve an overall type I error of 5% within the time considered and 
the corresponding confidence intervals will be presented. 
13.4.2  Analysis of secondary efficacy endpoints 
13.4.2.1 Worst spontaneous vertigo intensity over the 4 treatment days 
The baseline and the 8 post-baseline assessments of the Worst VI-VAS will be analyzed using the 
approach described in section 13.4.1 for the primary endpoint. 
13.4.2.2 Change from baseline of the total score of the Romberg tests at the end of treatment and end 
of study 
The change from baseline of the total score of the Romberg tests (see section 10.1.7) at the end of 
treatment (D5) will be compared between treatment groups within an analysis of covariance model. 
Patients without data available at the end of treatment will be excluded from the analysis. The covariates 
will be the stratification factor (duration of vertigo before being treated) and the baseline total score. 
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multiple comparison procedure in order to preserve an overall type I error of 5%, the corresponding 
confidence intervals will be presented. 
The same approach will be applied to the change from baseline at the end of study (D28). 
13.4.2.3 Peak slow phase velocity at the end of treatment and end of study 
The change from baseline of the peak slow phase velocity (degrees/second, see section 10.1.7) at the 
end of treatment (D5) and the change from baseline at the end of study (D28) will be analyzed using 
the approach described in section 13.4.2.2 for the total score of the Romberg tests. 
13.4.2.4 Nausea severity over the 4 treatment days 
The baseline and the 8 post-baseline assessments of the Nausea Intensity VAS (see section 10.1.2) will 
be analyzed using the approach described in section 13.4.1 for the primary endpoint. 
 
13.4.2.5 Functional disability at the end of study 
The change from baseline of the DHI functional sub-score scale (see section 10.1.4) at the end of study 
(D28) will be compared between treatment groups within an analysis of covariance model. Patients 
without data available at the end of study will be excluded from the analysis. The two comparisons to 
placebo will be tested with an alpha adjusted to the Dunnett's multiple comparison procedure in order 
to preserve an overall type I error of 5%, the corresponding confidence intervals will be presented. 
The same approach will be applied to the change from baseline of the VADL score (see section 10.1.5) 
at the end of study (D28). 
13.4.3 Analysis of safety endpoints 
The summary of safety will be presented by treatment group on the basis of the safety population. The 
analysis will be essentially descriptive and no hypothesis testing is planned. 
13.4.3.1 Adverse events 
Each adverse event will be coded to a “Preferred Term” and associated “System-Organ Class” according 
to an established and validated adverse reaction dictionary (MedDRA) before the randomized treatment 
code is broken. The adverse event endpoints are number of subjects experiencing: 
• at least one event, 
• an event under each recorded Preferred Term, 
• an event under each recorded System-Organ Class. 
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All safety analyses will be performed on the safety analysis set using descriptive statistics. 
Adverse events (AEs) will be evaluated for severity and coded using MedDRA. They will be 
summarized by system organ class and preferred term. Separate summaries of treatment-emergent AEs 
(TEAEs) will be generated for the following: 
• All TEAEs 
• Severe TEAEs 
• Serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs resulting in death 
Treatment-emergent adverse events (TEAE) are defined as events occurring after the first dose intake 
of randomized study drug, and up to and including five half-lives after the last dose of study drug. 
Additionally, events present before the first dose of randomized study drug, but worsening under 
treatment are considered as TEAE. Events with treatment status unclear because the onset date and/or 
the dates of first/last study drug intake are missing or incomplete will be considered as TEAEs. 
An AE that will not qualify as a TEAE will be considered as a Non-TEAE. 
To understand the impact of subjects who withdraw from the study prior to completion, the FAS will 
be partitioned into groups of subjects who complete the study (completers) and subjects who do not 
complete the study (dropouts). 
13.4.3.2 Clinical laboratory evaluations 
Summary statistics for baseline, each post-baseline measurement, and change from baseline for each 
post-baseline measurement will be presented by treatment group for each haematology, blood chemistry 
and liver function testparameter. 
The potentially clinically significant abnormality values will be defined as abnormal values considered 
medically important by the sponsor according to predefined criteria/thresholds based on literature 
review Number and percentage of patients presenting at least one post-baseline potentially clinically 
significant abnormality will be presented by treatment group for selected parameters. 
Listings will be provided with flags indicating the out of laboratory range values and the potentially 
clinically significant abnormality values 
13.4.3.3 Vital signs  
The same approach as for the analysis of clinical laboratory evaluations will be used. 
 
13.4.3.4 ECG 
The same approach as for the analysis of clinical laboratory evaluations will be used. 


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14 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 Good clinical practice (GCP) 
This clinical trial is conducted in accordance with the principles of the Declaration of Helsinki (1964), 
the International Conference on Harmonization Good Clinical Practice guideline. This clinical trial is 
also conducted in accordance with the laws and regulations of the countries in which the study is 
performed, as well as any applicable guidelines. 
 
14.2 Informed consent 
According to applicable regulatory requirements, the investigator or a fully designated person should 
provide the patient with a complete and detailed information about the aim, the consequences, the 
constraints of the trial, the favorable opinion given by the IRB, and any information deemed necessary 
both verbally and by reviewing the information leaflet and consent form.  The subject must agree to 
perform the study, sign and date the Informed Consent form prior to any study-specific procedure. He 
will be given a copy of the information leaflet and consent form.  
 
14.3 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The Investigator must submit the protocol and all the necessary documents (informed consent document 
and any materials provided to the patient) to the appropriate Ethics Committee (IRB/IEC), for review 
and approval, prior to any patient enrollment. Approval by IRBs is required for each participating site.  
The investigator should notify the sponsor of the IRB’s approval date. He should forward to the Sponsor 
a copy of the written and dated approval / favorable opinion signed by the Chairman with Ethics 
Committee (IRB/IEC) composition, prior to any investigational product drug shipment to the site. 
Any amendment to the protocol should be submitted for approval to the Ethics Committee (IRB/IEC) 
prior to its implementation, unless there are overriding safety reasons. 
 
 


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15 STUDY MONITORING 
15.1 Responsibilities of the Investigator 
The Investigator undertakes to perform the study in accordance with this protocol, Good Clinical 
Practice and the applicable regulatory requirements. 
The Investigator is required to ensure compliance with the Investigational Product schedule, visit 
schedule and procedures required by the protocol. No protocol waivers will be accepted.  
The Investigator agrees to complete all information requested in the electronic Case Report Form 
according to the instructions provided and to ensure direct access to source documents to Sponsor 
representatives. 
The investigator is also responsible for recording all observations and other data pertinent to the clinical 
investigation.  
The computerized handling of the data by the CRO after the data have been entered on the e CRFs may 
generate additional requests. The Investigator agrees to answer to these requests in a timely manner or 
to correct directly the e CRF when relevant.  
15.2 Responsibilities of the Sponsor 
The Sponsor of this study is responsible to Health Authorities for taking all reasonable steps to ensure 
the proper conduct of the study as regards ethics, protocol compliance, integrity and validity of the data 
recorded on the Case Report Forms. Thus, the main duty of the Monitoring Team is to help the 
Investigator and the Sponsor maintain a high level of ethical, scientific, technical and regulatory quality 
in all aspects of the study. 
At regular intervals during the study, the center will be contacted, through site visits, letters or telephone 
calls, by a representative of the Monitoring Team to review study progress, Investigator and subject 
compliance to protocol requirements and any emergent problems. During monitoring visits, the 
following points will be scrutinized with the Investigator: subject informed consent, subject recruitment 
and follow-up, study drug allocation, subject compliance with the Investigational Product, 
Investigational Product accountability, concomitant therapy use, Adverse Event documentation and 
reporting, and quality of data. Sections of Case Report Forms may be collected on a visit-by-visit basis. 
Any protocol deviation will be assessed by the sponsor. In the event of breach of fundamental 
obligations including but not limited to breach of the clinical trial protocol, breach of the applicable 
laws and regulations or breach of the ICH guidelines on good clinical practice, the sponsor will report 
major non-compliance to health authorities.  
15.3 Source document requirements 
According to the guidelines on Good Clinical Practice, the Monitoring Team must check the Case 
Report Form entries against the source documents, except for the pre-identified source data directly 


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recorded in the Case Report Form. The Informed Consent Form will include a statement by which the 
subject allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the 
regulatory authorities to have direct access to source data which supports the data on the Case Report 
Forms (e.g. subject's medical file, appointment books, original laboratory records, etc.). This personnel, 
bound by professional secrecy, will not disclose any personal identity or personal medical information. 
 
15.4 Protocol amendments 
All appendices attached hereto and referred to herein are made part of this protocol. 
No change or amendment to this protocol may be made by the Investigator or by the Sponsor after the 
protocol has been agreed to and signed by both parties unless such change(s) or amendment(s) has/have 
been fully discussed and agreed upon by the Investigator and the Sponsor. Any change agreed upon will 
be recorded in writing, the written amendment will be signed by the Investigator and by the Sponsor 
and the signed amendment will be filed with this protocol. 
No change or amendment to the protocol will be implemented prior to approval is received to the Ethics 
Committee (IRB/IEC) prior to its implementation, unless there are overriding safety reasons. 
Any change or amendment to the protocol should be submitted for approval to the Ethics Committee 
(IRB/IEC) and regulatory authorities, and implemented only after approval is received, unless there are 
overriding safety reasons. 


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16 ADMINISTRATIVE RULES 
16.1 Curriculum Vitae 
An updated copy of the curriculum vitae limited to the experience, qualification and training for each 
Investigator and Sub-Investigator (and completed FDA 1572 form and Financial Disclosure Form study 
under an IND) will be provided to the Sponsor prior to the beginning of the study. 
16.2 Record retention in study sites 
The Investigator must maintain all study documentation, and take measures to prevent accidental or 
premature destruction of these documents. 
The Investigator must keep the study documentation for at least15 years, or longer if required by local 
regulatory requirements. The investigator should take all necessary measures to prevent accidental 
destruction of this documentation. The sponsor should be informed by the site prior to final destruction. 
16.3 Confidentiality  
The current protocol and any unpublished document referring to SENS-111 or to the current clinical 
trial provided by the sponsor (or any institution acting on their behalf) to the investigator or 
investigational staff member remains the exclusive property of Sensorion. They should not be disclosed 
to any person without prior written authorization from Sensorion.  
The same confidentiality rules apply to all results, discoveries, data obtained from this clinical trial.  
Only, submission of this protocol and necessary documents to the Ethics Committee (IRB/IEC) is 
authorized. Any documentation, record or result that may be requested by the sponsor or representatives 
of health authorities in the context of inspection is also authorized.   
The investigator must ensure that the subject’s anonymity is maintained, and keep in strict confidence 
documents not de-identified (e.g., signed informed consent form).   
In case of an inspection by the authorities, the investigator shall inform the sponsor as soon as possible 
and authorized the sponsor to participate at this audit.  
16.4 Ownership of data and use of the study results 
All data, results, findings resulting from this clinical trial are the exclusive property of Sensorion. They 
can be used by Sensorion in any form for submission to health authorities of any country. In no case, 
the investigator or his/her staff member is authorized to file patent application referring to the results or 
discoveries generated by this clinical trial.  
The investigator or any staff member participating in the study is authorized to present or to publish the 
study results after they have received a formal written and signed authorization from Sensorion. This 
authorization will be delivered after the review made by Sensorion. The authors should forward a copy 


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of the abstract or the text and slides of the presentation at least 7 days in advance prior to the submission. 
Sensorion may request to add the sponsor’s name or the name of some employees on the manuscript.  
 
16.5 Insurance compensation 
The Sponsor certifies that it has taken out a liability insurance policy which covers the liability of the 
Investigator and his/her coworkers and which is in accordance with local laws and requirements. 
Specific statements will be contained in an appendix where needed. 
An insurance certificate will be provided to the Investigator in countries requiring this document. 
16.6 Premature discontinuation of the study or premature close out of a center 
16.6.1 Decided by the Sponsor in the following cases 
• The study is not conducted in accordance with the procedures defined in the approved 
protocol (i.e., low rate of recruitment - protocol deviations - failure to ensure the quality of 
the data collected). 
• Information on the Investigational Product causing doubt as to the benefit/risk ratio. 
• The total number of subjects included earlier than expected. 
• Left at the discretion of the Sponsor. 
 
16.6.2  Decided by the Investigator 
The Investigator must notify the Sponsor of his/her decision and give the reason in writing. 
In all cases Ethics Committees (IRB/IEC) and Health Authorities should be informed. 
In some instances, an amendment may require a change to the Informed Consent Form. The Investigator 
must receive an IRB/IEC approval / favorable opinion concerning the revised Informed Consent Form 
prior to implementation of the change. 
 


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25. Takeda N, Morita M, Hasegawa S, Horii A, Kubo T, Matsunaga T. Neuropharmacology of motion 
sickness and emesis. A review. Acta Otolaryngol Suppl. 1993, 501:10-5. Review. 
26. Takeda N, Morita M, Horii A, Nishiike S, Kitahara T, Uno A. Neural mechanisms of motion 
sickness. J Med Invest. 2001, 48 (1-2):44-59. Review. 
27. Takumida M, Takumida H, Anniko M: Localization of histamine (H1, H2, H3 and H4) receptors in 
mouse inner ear. Acta Otolaryngol. 2016, 136 (6):537-44. 
28. Yardley L, Burgneay J, Andersson G, Owen N, Nazareth I, Luxon L:  Feasibility and effectiveness 
of providing vestibular rehabilitation for dizzy patients in the community. Clin Otolaryngol 1998, 
23:442-448.  
29. Yardley L, Masson E, Verschuur C, Haacke N, Luxon L. Symptoms, anxiety and handicap in dizzy 
patients: development of the vertigo symptom scale. J Psychosom Res. 1992, 36(8):731–41.  
30. Cowden JM, Yu F, Banie H, Farahani M, Ling P, Nguyen S, Riley JP, Zhang M, Zhu J, Dunford 
PJ, Thurmond RL. The histamine H4 receptor mediates inflammation and Th17 responses in 
preclinical models of arthritis. Ann Rheum Dis. 2014, 73(3):600-8. 
31. Son EJ Lee DH, Oh JH, Seo JH, Jeon EJ. Correlation between the dizziness handicap inventory and 
balance performance during the acute unilateral vestibulopathy. Am J Otolaryngol. 2015, 36(6):823-
7 
32. Kammerlind A-S, Larsson PB, Ledin T, Skargren E. Reliability of clinical balance tests and 
subjective ratings in dizziness and disequilibrium. Advances in Physiotherapy. 2005, 7(3):96–107 
33. Kammerlind AS, Ledin TE, Odkvist LM, Skargren EI. Recovery after acute unilateral vestibular 
loss and predictors for remaining symptoms. Am J Otolaryngol. 2011, 32(5):366-75. 
34. Dannenbaum E, Chilingaryan G, Fung J. Visual vertigo analogue scale: an assessment questionnaire 
for visual vertigo. J Vestib Res. 2011, 21(3):153–9. 
35. Housley GD, Norris CH, Guth PS. Hear Res. 1988, 35(1):87-97 


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36. Beck R, Gunther L, Xiong G et al. The mixed blessing of treating symptoms in acute vestibular 
failure - Evidence from a 4-aminopyridine experiment. Exp Neurol. 2014, 261:638-45. 
37. Strupp, M. MD; Arbusow, V. MD; Maag, K. P. MD, PhD; Gall, C. MD; Brandt, T. Vestibular 
exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology. 1998, 
51(3):838-844.  
38. Shupak A, Issa A, Golz A, Margalit Kaminer, Braverman I. Prednisone treatment for vestibular 
neuritis. Otol Neurotol. 2008, 29(3):368-74.  
39. Cohen H.S., Kimball K.T., Development of the Vestibular Disorders Activities of Daily Living 
Scale. Arch Otolaryngol Head Neck Surg. 2000, 126:881–887. 
40. Helmchen C., Klinkenstein J.C., Krüger A., Gliemroth J., Mohr C. and Sander T., Structural brain 
changes following peripheral vestibulo-cochlear lesion may indicate multisensory compensation. J 
Neurol Neurosurg Psychiatr. 2011, 82:309– 316. 
 


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18 APPENDICES 
Appendix 1. 
 Standing Vertigo Intensity Visual Analog Scale 
Patients should rate the intensity of the vertigo just after the Romberg test condition 1 (eyes open, feet 
together, standing on a firm surface) performed in the morning between 10am and 12pm, and in the evening 
while at the study site just after dinner using the electronic device*. An alert will remind the patient to 
complete the VAS. 
The study staff will be responsible to instruct the patient how to complete the VAS before the first inquiry 
using the test page. The patient should move the virtual cursor to place the mark on the VAS horizontal 
line, on the electronic device. 
If the patient is unable to complete the VAS while hospitalized, the nurse or the investigator should ask the 
patient how much he would rate the severity of his/her vertigo on a 0 to 100 scale. The figure should be 
reported on the eCRF and the reason of missing data completed as follows: not able to stand up, severe 
vertigo, severe nausea or other 
When the patient is at home, the patient will be instructed to continue to rate the intensity of the vertigo 
when he/she is standing up, feet together, eyes open, in the morning between 10am and 12pm, and in the 
evening just after dinner using the electronic device. An alert will remind the patient to complete the VAS. 
If the patient is unable to complete the VAS, he/she will have to provide the reason in the electronic device 
no later than 24 hours later.  
 
Place a mark on the line to indicate the severity of your vertigo (when you stand up, feet together, eyes 
open) 
 
 
 
No vertigo                                                                          Worst vertigo ever 
 
 
 
 
The line should measure exactly 100 mm 
 
Example: 
 
 
 
 
 
 
 
 
 
* Patients will be provided with an electronic device Samsung Galaxy TAB E:  9.6" (243.4mm) screen 
size and 1280 x 800 (WXGA)resolution with a blocked zooming function.  This is to ensure the VAS line 
measures exactly 100mm, along the study. 
 
 


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Appendix 2. 
Worst Vertigo Intensity Visual Analog Scale 
Patients should rate the intensity of the most severe vertigo over the last 2 hours in the morning between 
10am and 12pm, and in the evening just after dinner using the electronic device*. An alert will remind the 
patient to complete the VAS twice daily. 
The study staff will be responsible to instruct the patient how to complete the VAS before the first inquiry 
using the test page. The patient should move the virtual cursor to place the mark on the VAS horizontal 
line, on the electronic device. 
If the patient is unable to complete the VAS while hospitalized, the nurse or the investigator should ask the 
patient how much he would rate the severity of his/her vertigo on a 0 to 100 scale. The figure should be 
reported on the e CRF and the reason of missing data completed as follows: severe vertigo, severe nausea 
or other 
If the patient is unable to complete the VAS at home, he/she will have to provide the reason in the electronic 
device no later than 24 hours later.  
 
Place a mark on the line to indicate the intensity of your worst vertigo over the past 2 hours 
 
 
 
No vertigo                                                                          Worst vertigo ever 
 
 
 
 
The lines should measure exactly 100 mm 
 
 
 
 
* Patients will be provided with an electronic device Samsung Galaxy TAB E: 9.6" (243.4mm) screen size 
and 1280 x 800 (WXGA)resolution with a blocked zooming function. This is to ensure the VAS line 
measures exactly 100mm, along the study. 
 
 


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Appendix 3. 
Nausea Intensity Visual Analog Scale 
Patients should rate the intensity of the nausea in the morning between 10am and 12pm, and in the evening 
just after dinner using the electronic device*, considering the worst intensity over the past 2 hours. An alert 
will remind the patient to complete the VAS. The patient should place a vertical line on the VAS horizontal 
line that will be shown on an electronic tablet. 
The study staff will be responsible to show how to complete the VAS before the first inquiry using the test 
page.  
 
Place a mark on the line to indicate the severity of your nausea (the worst over the last 2 hours) 
 
 
 
 
No nausea                                                                         Worst nausea ever 
 
 
 
 
The line should measure exactly 100 mm 
 
 
Example: 
 
 
 
 
 
 
* Patients will be provided with an electronic device Samsung Galaxy TAB E:  9.6" (243.4mm) screen 
size and 1280 x 800 (WXGA)resolution with a blocked zooming function.  This is to ensure the VAS line 
measures exactly 100mm along the study. 


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Appendix 4. 
 DHI – Dizziness Handicap Inventory 
Instructions: The purpose of this scale is to identify difficulties that you may be experiencing because of 
your dizziness. Please check “yes”, or “no” or “sometimes” to each question. Answer each question only 
as it pertains to your dizziness problem. 
 
 
 
 
Questions 
Yes 
Sometimes 
No 
P1 
Does looking up increase your problem? 
 
 
E2 
Because of your problem, do you feel 
frustrated? 
  
 
 
F3 
Because of your problem, do you restrict your 
travel for business or recreation? 
 
 
 
P4 
Does walking down the aisle of a supermarket 
increase your problem? 
    
 
 
F5 
Because of your problem, do you have 
difficulty getting into or out of bed? 
  
 
 
F6 
Does your problem significantly restrict your 
participation in social activities, such as going 
out to dinner, going to movies, dancing or 
going to parties? 
 
 
 
F7 
Because of your problem, do you have 
difficulty reading? 
  
 
P8 
Does performing more ambitious activities 
such as sports, dancing, and household chores, 
such as sweeping or putting dishes away 
increase your problem? 
 
 
 
E9 
Because of your problem, are you afraid to 
leave your home without having someone 
accompany you? 
 
 
 
E10 
Because of your problem, have you been 
embarrassed in front of others? 
 
 
P11 
Do quick movements of your head increase 
your problem? 
  
 
F12 
Because of your problem, do you avoid 
heights? 
 
 
 
P13 
Does turning over in bed increase your 
problem? 
    
 
 
F14 
Because of your problem, is it difficult for you 
to do strenuous housework or yard work? 
 
 
 
E15 
Because of your problem, are you afraid 
people may think you are intoxicated? 
  
 
 


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F16 
Because of your problem, is it difficult for you 
to go for a walk by yourself? 
  
 
 
P17 
Does walking down a sidewalk increase your 
problem? 
 
 
E18 
Because of your problem, is it difficult for you 
to concentrate? 
 
 
F19 
Because of your problem, is it difficult for you 
to walk around your house in the dark? 
 
 
 
E20 
Because of your problem, are you afraid to 
stay home alone? 
 
 
 
E21 
Because of your problem, do you feel 
handicapped? 
 
 
E22 
Has your problem placed stress on your 
relationship with members of your family or 
friends? 
 
 
 
E23 
Because of your problem, are you depressed?  
 
F24 
Does your problem interfere with your job or 
household responsibilities? 
 
 
 
P25 
Does bending over increase your problem? 
 
 
 
 
Scoring for the Dizziness Handicap Inventory:  
 
The sum of each rating calculated with Always = 4 Sometimes = 2 No = 0  is the perceived disability 
scoring. The highest score is 100 (maximum perceived disability), and the minimum score is 0 (no 
perceived disability).   
3 subscales are established to track the specific changes:   
P = physical  
E = emotional  
F = function 


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Appendix 5. 
Vestibular Disorders Activities of Daily Living Scale  
 


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Appendix 6. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) 
The following questions ask about the effect of your VERTIGO on your ability to work and perform regular 
activities.  Please fill in the blanks or select a number, as indicated. 
 1. Are you currently employed (working for pay)?                         _____NO ___ YES 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. During the past seven days, how many hours did you miss from work because of problems associated 
with your VERTIGO?  Include hours you missed on sick days, times you went in late, left early, etc., 
because of your VERTIGO.  Do not include time you missed to participate in this study.               
_____HOURS 
 
3. During the past seven days, how many hours did you miss from work because of any other reason, such 
as vacation, holidays, time off to participate in this study? 
_____HOURS 
 
4. During the past seven days, how many hours did you actually work? 
_____HOURS   
(If “0”, skip to question 6.) 
 
5. During the past seven days, how much did your VERTIGO affect your productivity while you were 
working? 
 
Think about days you were limited in the amount or kind of work you could do, days you accomplished 
less than you would like, or days you could not do your work as carefully as usual.  If VERTIGO affected 
your work only a little, choose a low number.  Choose a high number if VERTIGO affected your work a 
great deal.   
Consider only how much VERTIGO affected productivity while you were working. 
VERTIGO 
had 
no effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
VERTIGO 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
SELECT A NUMBER 
 
6. During the past seven days, how much did your VERTIGO affect your ability to do your regular daily 
activities, 
other 
than 
work 
at 
a 
job?   
 
By regular activities, we mean the usual activities you do, such as work around the house, shopping, 
childcare, exercising, studying, etc.  Think about times you were limited in the amount or kind of activities 
you could do and times you accomplished less than you would like.  If VERTIGO affected your activities 
only a little, choose a low number.  Choose a high number if VERTIGO affected your activities a great 
deal.   
 
Consider only how much VERTIGO affected your ability to do your regular daily activities, other than 
work at a job. 


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VERTIGO 
had 
no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
VERTIGO 
completely 
prevented me from 
doing 
my 
daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
                           
SELECT A NUMBER 
 
 
Questions: 
1 = currently employed  
2a = hours missed due to specified problem  
2b = hours missed due to other health problems  
2c = hours missed other reasons  
3 = hours actually worked 
4a = degree problem affected productivity while working  
4b = degree other health problems affected productivity while working  
5a = degree problem affected regular activities 
5b = degree other health problems affected regular activities 
 
 
 
Scores: 
Percent work time missed due to problem: Q2a/(Q2a+Q2b+Q3)  
 
Percent impairment while working due to problem: Q4a/10  
 
Percent overall work impairment due to problem:  Q2a/(Q2a+Q2b+Q3) + {(1-(Q2a+Q2b)/(Q2a+Q2b+Q3)) 
x Q4a/10 
 
Percent activity impairment due to problem: Q5a/10  
 
Percent work time missed due to all health: (Q2a+Q2b)/(Q2a+Q2b+Q3)  
 
Percent impairment while working due to all health: (Q4a+Q4b)/10 
 
Percent overall work impairment due to all health:  (Q2a+Q2b)/(Q2a+Q2b+Q3) + {(1-
(Q2a+Q2b)/(Q2a+Q2b+Q3)) x (Q4a+Q4b)/10 
 
Percent activity impairment due to all health: (Q5a+Q5b)/10  
WPAI:SHP V2.0 (US English) 
 
 
 


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Appendix 7. 
Unassisted walking 
 
Patient will have to express their ability to walk without assistance on the electronic device twice daily in 
the morning and in the evening at the time of the VAS completion.  
. 
 
 
“Because of your vertigo (or disequilibrium) problem, do you have difficulty walking 10 meters (32,8 feet) 
at your usual speed without using support? “ 
 
 
 
 
 
. 
 
YES 
NO 


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Appendix 8. 
Videooculography 
VOG testing is used to determine if a vestibular (inner ear) disease may be causing a balance or dizziness 
problem, and is one of the only tests available today that can distinguish between a unilateral (one ear) and 
bilateral (both ears) vestibular loss.  In non-compensated unilateral vestibular dysfunction, the difference 
in the strength and nature of the nystagmus of the undermost vs. the uppermost ear during positional and 
positioning tasks can be observed and recorded. 
A standardized portable VOG will be used by all centers to assess the spontaneous nystagmus intensity. 
Recordings will be considered as row data. 
The portable VOG/EOG system is a goggle head mounted system with at least one digital camera connected 
to and powered by a computer (laptop) through a firewire connection. 
Eye movements are recorded and converted to digital data. For analysis of horizontal and vertical 
components, the XY center of the pupil is first calculated. The use of digital centering eliminates the need 
for a mechanical adjustment mechanism (e.g. a slide) in the given direction. Using digital centering for both 
the X and Y (yaw and pitch) directions eliminates any gross adjustment in those directions. 
The VOG system also incorporates a head fixed calibration mechanism in the form of an integrated laser 
pointer on the goggle base or camera housing. The calibration mechanism is incorporated directly into the 
goggle base and powered from the same source powering the digital cameras.  
To monitor the movements of the eyes, infrared goggles are placed around the eyes to record eye 
movements during testing. Eye position will be calibrated using laser targets projected forward from the 
goggles 
VOG testing is non-invasive, and only minor discomfort is felt by the patients during testing as a result of 
wearing goggles. Patients with dark eyelashes, drooped eyelids, may require their eye to be taped. 
 
 
 


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Appendix 9. 
Video head impulse test  
The examiners will need to have training and experience, and their accuracy in performing h-HIT VOR 
measures will be monitored for consistency by assessing the rate of failed HIT maneuvers (i.e. those 
automatically rejected by the device software).  
Patients will be asked to fix their gaze on a distant target (>1.5 m) while seated.  
A series of inward HITs (i.e. centripetal, lateral-to- center head rotations) toward each ear will be performed 
by the examiner placing his/her hand on the patient’s jaw or holding the patient’s head on the top depending 
on the examiner’s position either in front or behind the patient.  
Target head velocity should be between 100 and 200°/s and head displacement between 5 and 20°. At least 
10 finally non-rejected (captured and automatically processed) HITs will be required. If spontaneous 
nystagmus is present, VOR gain measures will be calculated accounting for the spontaneous slow-phase 
drift of the eye, with the device software operating in the nystagmus-adjusted interpretation mode.  
 
 
 


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Appendix 10. 
Romberg tests procedure 
The procedure is designed to assess the patient’s ability to stand unassisted under six successive test 
conditions of increasing difficulty. 
Before starting the first test, the operator will identify the patient’s dominant foot by asking which foot the 
patient would use to kick a ball. It will be recorded on the e CRF. 
 
The operator will ask the patient to stand, shoes off, with his (or her) arms hanging down, and to not speak 
during the time interval. The patient should breathe normally and try to relax as much as possible, 
concentrating on the procedure. In case of talking, the trial is stopped and repeated.  
The first 2 condition tests will be performed on the floor (hard surface). The 4 subsequent conditions will 
be performed on a foam pad standardized across sites.  
 
Condition 1: Standing on the floor, feet together (or at a distance for them to be steady) with the eyes open 
looking straight ahead 
Condition 2: Standing on the floor, feet together (or at a distance for them to be steady) with the eyes closed 
Condition 3: Standing on a foam pad, feet together (or at a distance for them to be steady) with the eyes 
open looking straight ahead  
Condition 4: Standing on a foam pad, feet together (or at a distance for them to be steady) with the eyes 
closed  
Condition 5: Standing, on a foam pad feet heel to the toes with the eyes open looking straight ahead 
(dominant foot directly in front of the non-dominant foot in tandem) 
Condition 6: Standing on a foam pad feet heel to the toes with the eyes closed (dominant foot directly in 
front of the non-dominant foot in tandem). 
 
Each of the condition will last for at least 5 seconds. They will be timed using a stop watch.  
 
In order to prevent any fall, the operator will stand in front of the patient with his arms extended on either 
side of the patient but without touching him. If possible the patient will be close to a wall. 
 
Each condition is scored 1 for a success and 0 for a failure. 
The failure is defined as: 
• The subject cannot stand up, and is unable to do the test or  


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• Any occurrence of any of the following within 5 seconds: 
o Movement of the subject's feet from the initial test position (falling, side-stepping, hopping, 
pivoting, etc.); 
o Eyes open during an eyes-closed condition (i.e., Conditions 2 and 4); or 
o Requirement of the operator intervention to prevent the subject from falling or to maintain 
balance. 
 
Increased sway without movement of the feet do not constitute a failure:  
 
In case of failure, the patient will have one more attempt to pass.  
Because each successive condition is more difficult that the preceding one, the test will be considered 
complete when the subject fails a condition (after re-test), and the patient will be considered unable to pass 
the subsequent more difficult conditions, that will be scored as failed conditions.   
 
The balance test will be repeated twice daily until the end of hospitalization, and then on Day 5 and Day 
28 at the investigational site.  
 
While the mentality that an examinee could fall at any time is critical to being ready to prevent a fall, note 
that the following times during the test pose the greatest risk of destabilization: 
• While the examinee is stepping onto the foam and placing his or her feet together; 
• While the examinee is stepping off the foam; 
• During the first 3 seconds of a new test condition; and 
• During Test Conditions 3 to 6 (with greater risk during Condition 4 and 6). 
 
 


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Appendix 11. 
 Highly effective birth control methods 
Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are 
considered as highly effective birth control methods. Such methods include:  
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation  
o oral  
o intravaginal 
o transdermal  
• progestogen-only hormonal contraception associated with inhibition of ovulation :  
o o oral  
o o injectable  
o o implantable  
• intrauterine device (IUD)1  
• intrauterine hormone-releasing system ( IUS) 1  
• bilateral tubal occlusion1  
• vasectomised partner 1 2  
• sexual abstinence 3 
 
Birth control methods that result in a failure rate of more than 1% per year are considered not highly 
effective and are therefore not accepted per protocol. They include:  
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action  
• Male or female condom with or without spermicide4  
• Cap, diaphragm or sponge with spermicide4  
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. 
Female condom and male condom should not be used together. 
 
1. 
Contraception methods that in the context of this guidance are considered to have low user dependency. 
2. 
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. 
3. 
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period study and 1 month after the end of the study drug intake. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the subject.  


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4. 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective birth control methods 
 
  
 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 
 
 
 
 


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19 LIST OF RAW DATA 
 
Study data which should be included in the source dossier: 
 
• Subject’s identity. 
• Pathology studied, date of diagnosis. 
• Medical history, associated diseases (dates of onset). 
• Dates and time of administration of the study drug. 
• Previous and concomitant treatments. 
• Dates of participation in the study. 
• A statement that the informed consent form was signed by the subject. 
• Dates of study visits. 
• Examinations or assessments carried out during the study: 
• Vital signs:  temperature, systolic (SBP) and diastolic (DBP) blood pressures, heart rate, and 
respiration after 10 minutes rest in the supine and after 2 minutes in the standing position.  
• Questionnaires scores 
• Romberg tests results 
• Oculography tracings 
• Adverse events (+ follow-up). 
• Date of drop-out and reason. 
• Pregnancy test results 
• Laboratory test results 
• ECG 
 

SAP_000.pdf: 
Version 0.4018 
Version 1.2 |12-Nov-2019 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 1 of 58 
 
 
 
 
 
Sponsor 
Sensorion 
Protocol Title: 
A multicenter, randomized, double-blind, placebo-controlled study 
to assess the efficacy and safety of 2 dose regimens of orally 
administered SENS-111 (100 mg and 200 mg) given during 4 days 
in patients suffering from Acute Unilateral Vestibulopathy 
Protocol Number: 
SENS 111-201/ NCT03110458 
xxxxxxxxxxxxxx: 
SENP 154816 
Document Version: 
Final, 1.2 
Document Date: 
12-Nov-2019 
 
Approvals 
 
 
 
 
 
 
 
 
 
 
 
ST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ST 
 
 
 
AD-ST-33.05 Effective date: 22-Jan-2018 
Statistical Analysis Plan 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Biostatistician 
Print Name: xxxxxxxxxxxxxx 
Principal Biostatistician, xxxxxxxx 
13-Nov-2019 | 05:08:21 E 
Sign Name: 
 
Sensorion 
Representative 
Print Name: xxxxxxxx 
Clinical Research Director, Sensorion 
13-Nov-2019 | 02:59:15 P
Sign Name: 
 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 2 of 58 
 
 
 
 
Document History 
 
Reasons for Amendment 1 
 
Updated to clarify some minor ambiguities and inconsistencies and incorporate some decisions 
made during the study about the analysis populations and the AUC calculation. Typos and 
updates to the TLF shells are not included in this summary. 
 
Summary of Amended Sections (Amendment 1) 
 
Section 2.2.3 Pharmacokinetic/Pharmacodynamic Variable(s) 
Added text: 
In cases where PK sample cannot be taken at H12 or H24, it is also 
acceptable to take a PK sample before the 4th intake (H48). 
 
Section 3 Overall Study Design and Plan 
Text formerly read: 
Patients will be included if they are presenting with an acute peripheral 
vertigo lasting more than 6 hours and less than 3 days, diagnosed as an 
AUV, and the intensity is at least 60 mm on a 100 mm VAS measured in 
standing position feet together. 
Now reads: 
Patients will be included if they are presenting with an acute peripheral 
vertigo lasting more than 6 hours and less than 3 days, diagnosed as an 
AUV, and the intensity of the vertigo is at least 60 mm on a 100 mm VAS 
measured in standing position feet together. 
 
Section 3 Overall Study Design and Plan 
Text formerly read: 
Approximately 12 hours after the first study drug intake, patients will be 
assessed for vital signs and a blood sample will be taken for PK evaluation 
just before the second dose regimen is given. 
Patients will be asked to complete a vertigo VAS for vertigo intensity and 
nausea intensity twice daily in the morning between 10:00 am and 12:00 
pm in the evening after dinner until the end of the study on a specific 
electronic device, and to record their ability to walk without support. The 
worst intensity of the spontaneous vertigo over the past 2 hours will be 
recorded as well as the intensity of the vertigo during standing position. 
Twenty-four hours after the first study drug intake, patients will be tested 
with VOG to measure the severity of their spontaneous nystagmus and a 
blood sample will be taken for PK just before the study drug intake. 
Patients will continue to be monitored for vertigo, nausea and vomiting, 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 3 of 58 
 
 
vital signs (both supine and standing), ability to unassisted walk, and 
imbalance assessment (Romberg tests) until discharge from the hospital 
when a full efficacy assessment will be performed. It will include 
assessment of the quality of life, and VOG. The same assessments will be 
performed at the following visit on day 5 and at the end of the study on 
day 28. 
Now reads: 
Approximately 12 hours after the first study drug intake, patients will be 
assessed for vital signs and a blood sample will be taken for PK evaluation 
just before the second dose regimen is given. In cases where PK sample 
cannot be taken at H12 or H24, it is also acceptable to take a PK sample 
before the 4th intake (H48). 
Patients will be asked to complete a vertigo VAS for vertigo intensity and 
nausea intensity twice daily in the morning between 10:00 am and 12:00 
pm in the evening after dinner until the end of the study on a specific 
electronic device, and to record their ability to walk without support. The 
worst intensity of the spontaneous vertigo over the past 2 hours will be 
recorded as well as the intensity of the vertigo during standing position. 
Twenty-four hours after the first study drug intake, patients will be tested 
with VOG to measure the severity of their spontaneous nystagmus and a 
blood sample will be taken for PK just before the study drug intake. 
Patients will continue to be monitored for vertigo, nausea and vomiting, 
vital signs (both supine and standing), ability to unassisted walk, and 
imbalance assessment (Romberg tests) until discharge from the hospital 
when a full efficacy assessment will be performed. It will include 
assessment of the quality of life, and VOG. The same assessments will be 
performed at the following visit on day 5 and at the end of the study on 
day 28. Only the assessments planned during the visits are mandatory. The 
additional assessments planned during the hospitalization period (i.e. 
Romberg test twice a day and VNG once a day) are considered optional. 
In case some of these assessments cannot be performed (for example 
during the week-end), this should not prevent from including a patient. 
 
Section 3.5 Method of Assigning Subjects to Treatment Groups 
Text formerly read: 
A total of 105 eligible patients will be randomized in a 1:1:1 ratio to one 
of the 3 treatment groups, stratified by duration of vertigo before being 
treated (≤ 24 hours, > 24 hours). 
 
Now reads: 
A total of 105 eligible patients will be randomized in a 1:1:1 ratio to one 
of the 3 treatment groups, stratified by duration of vertigo before being 
treated (≤ 24 hours, > 24 hours), as determined at the time of 
randomization. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 4 of 58 
 
 
Section 4.1 Introduction 
Added text: 
The number of missing values will be calculated as difference of the total 
number of subjects in the study population for the treatment group minus 
the number of non-missing values. 
 
Section 4.2 Interim Analysis and Data Monitoring 
Text formerly read: 
The DMC meetings will be held: 
• (first meeting) after 30 patients have completed the study 
• thereafter, every 35 patients have completed the study or 
annualy (whichever comes first) 
Now reads: 
The DMC meetings will be held: 
• (first meeting) after 30 patients have completed the study 
• thereafter, when a further 35 patients (approximately) have 
completed the study or annualy (whichever comes first) 
 
Section 5 Analysis Populations 
Text formerly read: 
Enrolled Population (Enrolled): The Enrolled Population includes all 
screened, consented, and eligibility validated subjects. This population 
will be used for disposition and major protocol deviations only. 
Now reads: 
Screened Population ( Screened): The Screened Population includes all 
screened and consented subjects. This population will be used for 
disposition only. 
 
Section 5 Analysis Populations 
Text formerly read: 
Modified Intention-To-Treat Population (mITT): The mITT population 
includes all patients of the ITT population with a baseline standing VI- 
VAS ≥ 60 mm and with at least one study drug intake. 
Now reads: 
Modified Intention-To-Treat Population (mITT): The mITT population 
includes all patients of the ITT population with a unilateral AUV 
(diagnosed before or after randomization), a baseline standing VI-VAS ≥ 
60 mm and with at least one study drug intake. 
 
Section 5 Analysis Populations 
Text formerly read: 
Per-Protocol Population (PP): The PP population includes all patients of 
the ITT population without a major protocol deviation. 
Now reads: 
Per-Protocol Population (PP): The PP population includes all patients of 
the mITT population with the primary efficacy endpoint (AUC for the 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 5 of 58 
 
 
standing VI-VAS) available and without a protocol deviation likely to 
impact the primary efficacy endpoint. 
 
Section 5 Analysis Populations 
Added text: 
Subjects to be included in the PP Population will be determined by the 
Sponsor prior to the unblinding of the study. A subject with a protocol 
deviation who is classified as ‘major’ per the Protocol Deviation Guidance 
Plan will be excluded from the PP Population only if the protocol 
deviation may directly impact the primary efficacy endpoint. Subjects with 
a major protocol deviation may be excluded from the PP Population if any 
of the following are met: 
• Failure to meet inclusion/exclusion criteria that may impact the 
primary efficacy endpoint 
• Intake of any interfering concomitant medication 
• Randomization error 
 
Section 6.1.1 Baseline 
Text formerly read: For all efficacy endpoints, the last non-missing observation recorded prior to 
randomization or during the same day of randomization will be used as the 
baseline observation for all calculations. 
Now reads: 
For the VAS endpoints, the baseline observation is the first observation 
recorded in the ePRO on the day of the randomization or otherwise the last 
observation before the day of the randomization. 
For the Romberg score and sub scores, the Average and Peak Slow phase 
velocity, the baseline observation is the observation recorded in the eCRF 
at Visit 2 hour 0 provided that this visit is before or the same day as the 
randomization. 
For the DHI score and sub scores, the baseline observation is the 
observation recorded in the ePRO on the day of eCRF Visit 2 provided 
that this visit is before or the same day as the randomization. 
 
Section 6.1.6.2 Area under the Curve 
Text formerly read: 
The AUC calculation includes the 4 days of treatment, from baseline to 
96±6 hours. All assessments within baseline and baseline + 102 hours will 
be included in the calculation. 
The interval between baseline and the first post-baseline assessment will 
be included in the AUC calculation. If some or all of the 8 post-baseline 
assessments are recorded after treatment discontinuation then they will be 
included in the AUC calculation. The 9th post-baseline assessment will be 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 6 of 58 
 
 
included in the AUC calculation when recorded not later than 102 hours 
post baseline. 
 
Now reads: 
The AUC calculation includes the 4 days of treatment, from baseline to 
96±6 hours. All assessments within baseline and baseline + 102 hours will 
be included in the calculation. The AUC will not be calculated if no 
baseline value is available or if no VAS assessment is available between 
18 (12+6) hours and 102 (96+6) hours from baseline for reason not linked 
to severe vertigo. 
The interval between baseline and the first post-baseline assessment will 
be included in the AUC calculation. 
 
Section 6.1.6.3 Romberg Total Score and Subscores 
Text formerly read: 
The average scores of the Romberg test in the morning and evening will 
be used when two assessments are available. 
Now reads: 
The average scores of the Romberg test in the morning and evening will 
be used when two assessments are available for the same visit. 
 
Section 6.1.6.4 DHI total score and subscores 
Text formerly read: 
F1, F3, F5, F6, F7, F12, F16, F19, F24 
Now reads: 
F3, F5, F6, F7, F12, F16, F19, F24 
 
Section 6.1.6.5 VADL total score and subscores 
Text formerly read: 
NEED SPECIAL ASSISTANCE = 8 
Now reads: 
NEED PHYSICAL ASSISTANCE = 8 
 
Section 7.1 Disposition of Patients and Withdrawals 
Text formerly read: 
The total number of subjects for each of the following categories will be 
presented for the enrolled population: 
• Enrolled Population 
• Safety Population 
• ITT Population 
• mITT Population 
• PP Population 
• Ancillary Population 
• Expose patients (those who take at least 1 dose of study drug) 
• Completed patients up to visit 7, Day 28 (±2 days) 
• Patients remaining on treatment at each visit 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 7 of 58 
 
 
• Patients withdrawn 
• Reasons for early study termination 
Now reads: 
The total number of subjects for each of the following categories will be 
presented for the screened population: 
• Screened Population 
• Safety Population 
• ITT Population 
• mITT Population 
• PP Population 
• Ancillary Population 
• Completed patients up to visit 7, Day 28 (±2 days) 
• Patients at each visit 
• Patients withdrawn 
• Reasons for early study termination 
 
Section 7.2. Protocol Violations and Deviations 
Text formerly read: Major protocol violations – i.e. those leading to exclusion from the PP 
population – will be summarized by type of violations, overall and by 
center for the enrolled population. 
Now reads: 
Major protocol violations – i.e. those leading to exclusion from the PP 
population – will be summarized by type of violations, overall and by 
center for the ITT population. 
 
Section 8.1 Primary Efficacy Analysis 
Text formerly read: 
The standing VI-VAS will be summarized using descriptive statistics of 
absolute values and changes from baseline at each assessment, and of the 
AUC including the length of the AUC observation period. 
Now reads: 
The standing VI-VAS will be summarized using descriptive statistics of 
absolute values and changes from baseline at each mapped time point, and 
of the AUC including the length of the AUC observation period. Each 
VAS assessment will be mapped to a time point as follows: 
 
Time point 
(mapped value) 
VAS assessment time 
since baseline (hours) 
12 hours 
6 (excluded) to 18 (included) 
24 hours 
18 (excluded) to 30 (included) 
36 hours 
30 (excluded) to 42 (included) 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 8 of 58 
 
 
 
… 
 
When more than one VAS assessment fall within the same time window, then 
only the VAS assessment closest to the middle point will be assigned to the time 
point. In case of values that are equidistant to the middle point, the latest 
assessment only will be assigned to the time point. VAS assessment not mapped 
to time point will not be included in the summary statistics and in the MMRM 
analysis. 
 
Section 8.1 Primary Efficacy Analysis 
Text formerly read: 
The VI-VAS AUC will be compared between treatment groups within an 
analysis of covariance model (ANCOVA) with the stratification factor 
duration of vertigo (≤24 hours, >24 hours before being treated) and the 
baseline VI-VAS as covariates. The two comparisons to placebo (SENS- 
111 at 100 mg vs placebo, and SENS-111 at 200 mg vs placebo) will be 
tested for superiority at 5% one-sided significance level, the corresponding 
90% two-sided confidence intervals will be presented. 
Now reads: 
The VI-VAS AUC will be compared between treatment groups within an 
analysis of covariance model (ANCOVA) with the stratification factor 
duration of vertigo (≤24 hours, >24 hours before being treated) and the 
baseline VI-VAS as covariates. The two comparisons to placebo (SENS- 
111 at 100 mg vs placebo, and SENS-111 at 200 mg vs placebo) will be 
tested for superiority at 5% one-sided significance level, the corresponding 
90% two-sided confidence intervals will be presented. In addition the pool 
of the two active doses (SENS-111 at 100 mg and SENS-111 at 200 mg) 
will also be tested for superiority at 5% one-sided significance level, and 
the corresponding 90% two-sided confidence interval will be presented. 
Section 8.1 Primary Efficacy Analysis 
Text formerly read: 
As a complementary analysis in order to get a better insight of the 
treatment effect over time, the 8 post baseline VI-VAS scores will be 
analyzed, without replacement of missing values, using a restricted 
maximum likelihood (REML) based repeated measures approach. 
Now reads: 
As a complementary analysis in order to get a better insight of the 
treatment effect over time, the 8 post baseline VI-VAS scores at mapped 
time points (12h, 24h, 36h, 48h, 72h, 84h, 96h) will be analyzed, without 
replacement of missing values, using a restricted maximum likelihood 
(REML) based repeated measures approach. 
 
Section 8.1 Primary Efficacy Analysis 
Added text: 
The same MMRM approach will repeated using all mapped time points up 
to 672 h (D28) included excluding the time points where the available 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 9 of 58 
 
 
sample size represents less than 75% of the analysis set. This additional 
analysis will provide some information on the long-term recovery of the 
vestibular function. 
 
Section 8.2.4 Peak slow phase velocity at the end of treatment and end of study 
Added text: 
The analysis for the peak slow phase velocity will be repeated for each 
testing condition: no fixation (30 sec) and fixation (10 sec). 
 
Section 8.3.3 Time to unassisted walking 
Text formerly read: 
Time to unassisted walking from Day 1, i.e. Visit 2 Inclusion H0, in hours 
will be analyzed using a descriptive time-to-event approach (Kaplan- 
Meier).’ 
Now reads: 
Time to unassisted walking from Day 1, i.e. Visit 2 Inclusion H0, in days 
will be analyzed using a descriptive time-to-event approach (Kaplan- 
Meier). 
 
Section 8.3.3 Time to unassisted walking 
Added text: 
A Cox proportional hazard regression model with a categorical variable 
for the treatment arm as independent variable will also be used to estimate 
the hazard ratios for the treatment effects (SENS111 100 mg vs placebo, 
and SENS111 200 mg vs placebo), which will be presented together with 
two sided 90% confidence intervals, as well as the corresponding P value. 
 
Section 9.5.4 Hospitalization due to AUV 
Text formerly read: 
Hospitalization due to AUV, the type of ward, and the length of hospital 
stay will be summarized by treatment arm. 
Now reads: 
Hospitalization due to AUV (including participation in the study), the type 
of ward, and the length of hospital stay will be summarized by treatment 
arm. 
 
Section 10 Changes from Planned Analysis 
Text formerly read: 
The Enrolled Population, the modified Intention-to-Treat Population and 
the Ancillary Population are not described in the protocol and they have 
been added in Section 5. 
Now reads: 
The Screened Population, the modified Intention-to-Treat Population and 
the Ancillary Population are not described in the protocol and they have 
been added in Section 5. 
 
AD-ST-33.05 Effective date: 22-Jan-2018 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 10 of 58 
 
 
 
 
 
Section 10 Changes from Planned Analysis 
Added text: 
The PP Population definiton has been amended. Patients with major 
protocol deviations are excluded from the PP Population in the protocol, 
while patients with major protocol deviation likely to impact the primary 
efficacy endpoint are excluded from the PP Population in this SAP. 
 
 
 
Section 13 Tables, Listings, and Figures 
 
The following tables and listings have been added: 
• 14.2.1.6 
Statistical Analysis of Standing VI-VAS: MMRM (12H to 672H) 
• 14.2.2.6 
Statistical analysis of Worst VI-VAS: MMRM (12H to 672H) 
• 14.2.3.6 
Statistical Analysis of Nausea Intensity VAS: MMRM (12H to 672H) 
• 16.2.9.8 
CT Scan and MRI Scan 
 
Reasons for Amendment 2 
 
Updated to include sensitivity analyses of Standing VI-VAS, Worst VI-VAS, and Nausea 
Intesity VAS and AUCs. Typos and updates to the TLF shells are not included in this summary. 
 
The amended SAP version 1.2 will be finalized and submitted to file prior to the unblinding for 
final analysis. 
 
Section 8.1 Primary Efficacy Analysis 
Added text: 
A sensitivity analysis using the date/time of the first dose intake of 
randomized study drug as the time reference for the AUC calculation will 
also be performed. In this analysis, the baseline will be defined as the last 
observation recorded in the ePRO until the time of the first dose intake 
and the AUC calculation will conducted as defined in section 6.1.6.2 
(using all VAS assessments between baseline and baseline + 102 hours). 
This analysis will be conducted on the mITT and the PP restricted to 
subjects for whom the baseline standing VI-VAS based on first study drug 
intake is available and ≥ 60 mm. 
 
Section 8.1 Primary Efficacy Analysis 
Added text: 
The same analysis using baseline and mapped time points both defined 
with reference to time of first dose intake will be applied on the mITT and 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 11 of 58 
 
 
the PP restricted to subjects for whom the baseline standing VI-VAS 
based on first study drug intake is available and ≥ 60 mm. 
 
Section 8.1 Primary Efficacy Analysis 
 
Text formerly read: 
The same MMRM approach will be repeated using all mapped time points 
up to 672 h (D28) included excluding the time points where the available 
sample size represents less than 75% of the analysis set. 
 
 
Now reads: 
The same MMRM approach will be repeated using all mapped time points 
up to 672 h (D28) included. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 12 of 58 
 
 
Section 13 Tables, Listings, and Figures 
 
The following tables and listings have been added: 
• 14.2.1.7 
Sensitivity Analysis of AUC for Standing VI-VAS: ANCOVA 
• 14.2.1.8 
Sensitivity Analysis of Standing VI-VAS: MMRM (12H to 96H) 
• 14.2.2.7 
Sensitivity Analysis of AUC for Worst VI-VAS: ANCOVA 
• 14.2.2.8 
Sensitivity Analysis of Worst VI-VAS: MMRM (12H to 96H) 
• 14.2.3.7 
Sensitivity Analysis of AUC for Nausea Intensity VAS: ANCOVA 
• 14.2.3.8 
Sensitivity Analysis of Nausea Intensity VAS: MMRM (12H to 96H) 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 13 of 58 
 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Reasons for Amendment 1 .............................................................................................................. 2 
Summary of Amended Sections (Amendment 1) ........................................................................... 2 
Reasons for Amendment 2 ............................................................................................................ 10 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 15 
List of Figures ............................................................................................................................... 15 
1. 
Overview ........................................................................................................................... 16 
2. 
Study Objectives and Endpoints ....................................................................................... 16 
2.1. 
Study Objectives ......................................................................................................... 16 
2.1.1. Primary Objective ....................................................................................................... 16 
2.1.2. Secondary Objectives .................................................................................................. 16 
2.2. 
Study Endpoints .......................................................................................................... 17 
2.2.1. Safety Endpoints ......................................................................................................... 17 
2.2.2. Efficacy Endpoints ...................................................................................................... 17 
2.2.3. Pharmacokinetic/Pharmacodynamic Variable(s) ........................................................ 18 
2.2.4. Ancillary Endpoints .................................................................................................... 18 
3. 
Overall Study Design and Plan ......................................................................................... 18 
3.1. 
Overall Design ............................................................................................................ 20 
3.2. 
Sample Size and Power ............................................................................................... 20 
3.3. 
Study Population ......................................................................................................... 20 
3.4. 
Treatments Administered ............................................................................................ 20 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 20 
3.6. 
Blinding and Unblinding ............................................................................................ 21 
3.7. 
Schedule of Events ...................................................................................................... 21 
4. 
Statistical Analysis and Reporting .................................................................................... 25 
4.1. 
Introduction ................................................................................................................. 25 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 25 
5. 
Analysis Populations ......................................................................................................... 26 
6. 
General Issues for Statistical Analysis .............................................................................. 27 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 27 
6.1.1. Baseline ....................................................................................................................... 27 
6.1.2. Multiple Comparisons ................................................................................................. 27 
6.1.3. Handling of Dropouts or Missing Data ....................................................................... 27 
6.1.4. Analysis Visit Windows ............................................................................................. 28 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
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6.1.5. Pooling of Sites ........................................................................................................... 28 
6.1.6. Derived Variables ....................................................................................................... 28 
6.1.7. Data Adjustments/Handling/Conventions .................................................................. 36 
7. 
Study Patients and Demographics .................................................................................... 36 
7.1. 
Disposition of Patients and Withdrawals .................................................................... 36 
7.2. 
Protocol Violations and Deviations ............................................................................ 37 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 37 
7.4. 
Exposure and Compliance .......................................................................................... 38 
8. 
Efficacy Analysis .............................................................................................................. 38 
8.1. 
Primary Efficacy Analysis .......................................................................................... 38 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 40 
8.2.1. Worst spontaneous vertigo intensity over the 4 treatment days.................................. 40 
8.2.2. Nausea severity over the four treatment days ............................................................. 40 
8.2.3. Change from baseline of the total score of the Romberg tests at the end of 
treatment and end of study .......................................................................................... 40 
8.2.4. Peak slow phase velocity at the end of treatment and end of study ............................ 40 
8.2.5. Functional disability at the end of study ..................................................................... 41 
8.3. 
Exploratory Efficacy Analysis .................................................................................... 41 
8.3.1. The caloric test ............................................................................................................ 41 
8.3.2. The video Head Impulse Test ..................................................................................... 41 
8.3.3. Time to unassisted walking ......................................................................................... 41 
9. 
Safety and Tolerability Analysis ....................................................................................... 42 
9.1. 
Adverse Events ........................................................................................................... 42 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 43 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 43 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 43 
9.3. 
Vital Signs ................................................................................................................... 43 
9.4. 
Electrocardiograms ..................................................................................................... 44 
9.5. 
Further Safety Evaluations .......................................................................................... 44 
9.5.1. Physical Examination ................................................................................................. 44 
9.5.2. Neuro Otologic Examination ...................................................................................... 44 
9.5.3. AUV diagnosis ............................................................................................................ 45 
9.5.4. Hospitalization due to AUV ....................................................................................... 45 
9.5.5. Hospitalization due to Serious Adverse Event............................................................ 45 
9.6. 
Concomitant Medication ............................................................................................. 45 
10. 
Changes from Planned Analysis ....................................................................................... 45 
11. 
Other Planned Analysis .................................................................................................... 46 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 15 of 58 
 
 
11.1. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem ....................................................................................................................... 46 
11.2. 
Pharmacokinetic Analysis ........................................................................................... 46 
12. 
References ......................................................................................................................... 46 
13. 
Tables, Listings, and Figures ............................................................................................ 46 
13.1. 
Planned Table Descriptions ........................................................................................ 46 
13.2. 
Planned Listing Descriptions ...................................................................................... 52 
13.3. 
Planned Figure Descriptions ....................................................................................... 54 
14. 
Tables, Listings, and Listing Shells .................................................................................. 55 
14.1. 
Standard Layout for all Tables, Listings, and Figures ................................................ 55 
Appendix 1: xxxxxxxxxx Library of Abbreviations ..................................................................... 56 
 
List of Tables 
Table 1 Schedule of Events ........................................................................................................... 22 
Table 2 AUC estimation ............................................................................................................... 30 
Table 3 Planned Tables ................................................................................................................. 46 
Table 4 Planned Listings ............................................................................................................... 52 
Table 5 Planned Figures ................................................................................................................ 54 
List of Figures 
Figure 1 AUC estimation .............................................................................................................. 31 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 16 of 58 
 
 
 
1. 
Overview 
 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Sensorion 
protocol number SENS 111-201 (A multicenter, randomized, double-blind, placebo-controlled 
study to assess the efficacy and safety of 2 dose regimens of orally administered SENS-111 
(100 mg and 200 mg) given during 4 days in patients suffering from Acute Unilateral 
Vestibulopathy), dated 05-Nov-2018 version #4.0. Reference materials for this statistical plan 
include the protocol and the accompanying sample data collection documents. Operational 
aspects related to collection and timing of planned clinical assessments are not repeated in this 
SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Sensorion’s study SENS 111- 
201. 
 
2. 
Study Objectives and Endpoints 
 
2.1. 
Study Objectives 
 
2.1.1. Primary Objective 
 
The primary objective is to assess the efficacy of SENS-111 in Acute Unilateral Vestibulopathy 
(AUV). 
 
2.1.2. Secondary Objectives 
 
The secondary objectives are: 
• 
To explore the effect of SENS-111 on quality of life 
• 
To determine the optimal dose regimen of SENS-111 
• 
To evaluate safety and tolerability of SENS-111 in patients with AUV 
• 
To evaluate the effect of SENS-111 on long-term recovery of vestibular function 
• 
To characterize the plasma exposure to SENS-111 in patients with AUV 
• 
To preliminary evaluate the health economics of SENS-111 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
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2.2. 
Study Endpoints 
 
2.2.1. Safety Endpoints 
 
The safety endpoints are adverse events (AEs), laboratory, vital signs, and ECG. 
Each AE will be coded to a Preferred Term and associated System Organ Class (SOC) according 
to an established and validated adverse reaction dictionary (MedDRA, version 20.0) before the 
randomized treatment code is broken. 
The AE endpoints are number of patients experiencing: 
• at least 1 event 
• an event under each recorded Preferred Term 
• an event under each recorded SOC 
These endpoints apply to all AEs, regardless of relationship of the event to the study drug. 
 
2.2.2. Efficacy Endpoints 
 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the vertigo intensity measured by the area under the curve 
(AUC) of the Vertigo Intensity Visual Analogue Scale (VI-VAS) in standing position over the 4 
treatment days (8 post-baseline assessments). 
 
2.2.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints deal with the comparison between treatment groups of: 
1. Worst spontaneous vertigo intensity measured by the AUC of the worst VI-VAS over the 
4 treatment days (8 post baseline assessments) 
2. Change from baseline of the total score of the Romberg tests at the end of the treatment 
(D5) and at the end of study (D28) 
3. Change from baseline of the peak slow phase velocity (SPV) of the peripheral vestibular 
spontaneous nystagmus, measured by oculography in darkness at the end of the treatment 
(D5) and end of study (D28) 
4. Nausea severity measured by the AUC of the Nausea Intensity Visual Analogue Scale 
(NI-VAS) over the 4 treatment days (8 post baseline assessments) 
5. Change from baseline of the functional disability at the end of study (D28) assessed by 
the Dizziness Handicap Inventory (DHI) functional subscale score 
6. The functional disability at the end of study (D28) assessed the Vestibular Disorders 
Activities of Daily Living Scale (VADL) 
 
 
2.2.2.3. 
Exploratory Efficacy Endpoint(s) 
The exploratory efficacy endpoints of this study include the following: 


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Sensorion 
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PCN SENP 154816 
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1. Vertigo Intensity in standing position at the end of the study (D28) assessed by the 
VI-VAS 
2. Worst spontaneous vertigo at the end of the study (D28) assessed by the VI-VAS 
3. Time to unassisted walk assessed by a specific question 
4. Health economic evaluation assessed with the Work Productivity and Activity 
Impairment (WPAI-SHP) questionnaire at the end of study. 
 
2.2.3. Pharmacokinetic/Pharmacodynamic Variable(s) 
 
Serum samples are collected for pharmacokinetic (PK) analysis at 3 time points: H12, H24, and 
at end of treatment visit (D5). In cases where PK sample cannot be taken at H12 or H24, it is also 
acceptable to take a PK sample before the 4th intake (H48). Plasma concentration of SENS-111 
will be used as the parameter to describe the plasma exposure to SENS-111. 
No pharmacodynamic (PD) variables are being investigated in this study. 
 
2.2.4. Ancillary Endpoints 
 
Additional tests will be performed at baseline and at the end of the study in sites participating in 
the ancillary study: 
• Video-head impulse test (vHIT) which provides a quick and objective measure of the 
vestibular ocular reflex (VOR) in response to head movements 
• Caloric test which provides two parameters: total response (TR) and relative vestibular 
reduction (RVR) 
 
3. 
Overall Study Design and Plan 
 
The study is a double-blind, randomized, 3 parallel-group placebo-controlled, international study 
in patients with acute unilateral vestibulopathy. 
This study will be a multicenter international study conducted in about 38 sites in Europe, Israel, 
US, and South Korea. Each patient’s participation in the study will be 28 days: 4 days of double 
blind treatment, and a 24-day follow-up with no investigational product. 
The study will assess the efficacy and safety of orally administered SENS-111 in patients with 
acute unilateral vestibulopathy. 
Patients will be included if they are presenting with an acute peripheral vertigo lasting more than 
6 hours and less than 3 days, diagnosed as an AUV, and the intensity of the vertigo is at least 
60 mm on a 100 mm VAS measured in standing position feet together. 
It is planned to enroll 105 patients into 3 arms in a 1:1:1 ratio: 
• 
35 patients receiving SENS-111 200 mg daily for 4 days 
• 
35 patients receiving SENS-111 100 mg daily for 4 days 
• 
35 patients receiving matching placebo 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
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This study includes a screening/inclusion phase, a treatment phase, and a follow-up phase. The 
screening and inclusion are to be done no more than 12 hours apart. As soon as eligibility of the 
patient is confirmed, the investigator will dispense the study drug to the subject; the study drug is 
to be taken immediately after all baseline assessment are performed. 
The screening evaluation includes: vital signs, a complete oto-neurological examination, a 
nausea and vertigo evaluation that will confirm the diagnosis and the absence of exclusion 
criteria for past medical history, concomitant treatments, laboratory tests, or other concomitant 
diseases. Specific attention will be paid to exclude any patient with a stroke in the last 3 months 
(a negative past MRI is needed for inclusion of patients with possible stroke of the brainstem or 
cerebellum). 
Following this screening phase, eligible patients will undergo a nystagmus evaluation with a 
videooculography (VOG), and either a head impulse test or caloric test or both to confirm the 
diagnosis. They will complete vertigo evaluations with VAS scores and questionnaires, 
assessment of imbalance (Romberg tests), nausea and vomiting scales just before the first intake 
of the investigational drug at the investigational site. Patients will be requested to stay under 
medical supervision for at least 6 hours after the first study drug intake for safety. Approximately 
12 hours after the first study drug intake, patients will be assessed for vital signs and a blood 
sample will be taken for PK evaluation just before the second dose regimen is given. In cases 
where PK sample cannot be taken at H12 or H24, it is also acceptable to take a PK sample before 
the 4th intake (H48). 
Patients will be asked to complete a vertigo VAS for vertigo intensity and nausea intensity twice 
daily in the morning between 10:00 am and 12:00 pm in the evening after dinner until the end of 
the study on a specific electronic device, and to record their ability to walk without support. The 
worst intensity of the spontaneous vertigo over the past 2 hours will be recorded as well as the 
intensity of the vertigo during standing position. 
Twenty-four hours after the first study drug intake, patients will be tested with VOG to measure 
the severity of their spontaneous nystagmus and a blood sample will be taken for PK just before 
the study drug intake. Patients will continue to be monitored for vertigo, nausea and vomiting, 
vital signs (both supine and standing), ability to unassisted walk, and imbalance assessment 
(Romberg tests) until discharge from the hospital when a full efficacy assessment will be 
performed. It will include assessment of the quality of life, and VOG. The same assessments will 
be performed at the following visit on day 5 and at the end of the study on day 28. Only the 
assessments planned during the visits are mandatory. The additional assessments planned during 
the hospitalization period (i.e. Romberg test twice a day and VNG once a day) are considered 
optional. In case some of these assessments cannot be performed (for example during the week- 
end), this should not prevent from including a patient. 
Patients will be followed for AEs throughout the study. Inquiry about potential AEs will be done 
at every on-site visit and on day 14 when a phone call will be given. 
Safety parameters will include routine blood tests (complete blood count, chemistry, liver 
function tests and lipid profile), pregnancy tests (if applicable), cardiac evaluation by ECG, 
physical exams and vital signs (with orthostatic blood pressure). 
The WPAI-SHP questionnaire will be requested at the end of study visit (D28). 
Additional tests will be conducted at some specific sites participating in an ancillary study: 


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• video Head Impulse Test at the end of treatment visit (D5) and end of study visit (D28) 
• caloric test at the baseline and end of study visit (D28) 
For full details of the study design, please refer to the protocol. 
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The sample size calculation is based on the AUC of the VI-VAS from baseline included to 
second measurement of Day 4 included. 
The assumptions are the followings: 
• Each comparison to placebo performed at 5% one-sided-significance level 
• Power of each comparison to placebo set to 75% 
• Randomization ratio 1:1:1 
• Intra-group standard deviation of 71 mm/day 
• Difference to placebo of 40 mm/day (i.e. 20% of an average AUC of 200 mm/day on 
placebo) 
3.3. 
Study Population 
Men and women aged 18-75 years, suffering from Acute Unilateral Vestibulopathy. 
3.4. 
Treatments Administered 
Orally disintegrating tablets (ODT) will be given once daily for 4 days: 
• SENS-111 200 mg: 100 mg ODT + 100 mg ODT 
• SENS-111 100 mg: 100 mg ODT + placebo ODT 
• Matching placebo: placebo ODT + placebo ODT 
The orally disintegrating placebo tablets match SENS-111 (100 mg) tablets, and are identical in 
appearance. An additional dose (respectively 200 mg, 100 mg and placebo) will be administered 
to the patients approximately 12 hours after the first intake. The corresponding total dose for the 
3 arms will be 1000 mg, 500 mg, 0 mg, respectively. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
The randomization will be managed centrally using an interactive web system response (IWRS). 
A total of 105 eligible patients will be randomized in a 1:1:1 ratio to one of the 3 treatment 
groups, stratified by duration of vertigo before being treated (≤ 24 hours, > 24 hours), as 
determined at the time of randomization. 
A patient will be considered randomized when the IWRS has given the treatment number to be 
allocated. 
All randomized subjects (Day 1) will receive either SENS 100 mg x 2 ODT, or SENS 100 mg x 
1 ODT and Placebo x 1 ODT, or Placebo x 2 ODT at the study site according to the IWRS 
allocation. 


Statistical Analysis Plan 
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• The treatment will be given once daily. 
• The first dose (2 ODT) will be given at the site. 
• An additional dose (2 ODT) will be given approximately 12 hours after the first dose (not 
less than 9 hours and no more than 15 hours after the first dose). 
3.6. 
Blinding and Unblinding 
The orally disintegrating placebo tablets match SENS-111 (100 mg) tablets, and are identical. 
Pharmacokinetic parameters that could potentially unblind the study team will not be disclosed 
during the conduct of the study. 
Investigators will have no access to the randomization code except under the special 
circumstances. In case of an emergency, when knowledge of the randomization status is deemed 
necessary for the medical care of the patient, the randomization code can be unblinded for a 
specific patient. 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 


Statistical Analysis Plan 
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Table 1 Schedule of Events 
 
Double-blind Treatment 
Follow-up 
Visit 
V1 
Screening 
V2 
Inclusion 
V3 
V4 
End of 
Hospitalization 
Visit 4, 4 
V5 
End of Treatment 
Visit 
V6 
(Phone Call) 
V7 
End of study visit 
H-6 (± 6) 
D1 (H0) 
D2( H24±3) 
D3 (-1, +25) 
D5 (-1,+2) 
D14 (±2) 
D28 (±2) 
Informed  
Consent/Demography/Medical 
History 
X 
Inclusion/Exclusion Criteria 
X 
X 
Physical Examination 
X 
X 
X 
Vital signs (BP standing and supine, 
HR), Temperature 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
Neuro Otologic examination 
X 
X 
X 
Prior Medication History 
X 
X 
Routine serum Hematology and 
Chemistry 
X 
X 
Pregnancy test/Pregnancy status 5 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Efficacy 
Standing vertigo intensity 11 
---- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Worst vertigo intensity (VAS) 1 
----------- 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Nausea Intensity (VAS)1 
---- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 
Walking assessment 1 
----------- 
-------- 
---------------- 
--------------------- 
---------------- 
---------→ 


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Double-blind Treatment 
Follow-up 
Visit 
V1 
Screening 
V2 
Inclusion 
V3 
V4 
End of 
Hospitalization 
Visit 4, 4 
V5 
End of Treatment 
Visit 
V6 
(Phone Call) 
V7 
End of study visit 
H-6 (± 6) 
D1 (H0) 
D2( H24±3) 
D3 (-1, +25) 
D5 (-1,+2) 
D14 (±2) 
D28 (±2) 
Disability Handicap Inventory (DHI) 
X 
X 
VADL 
X 
Romberg tests 7 
X 
X 
X 
X 
X 
VideoOculography (spontaneous 
nystagmus) 6 
X 
X 
X 
X 
X 
Hospitalization (Yes/No) 
X 
X 
X 
X 
X 
X 
Health Economic questionnaire 
X 
Ancillary Efficacy Study 
Video-head impulse test (function of 
the vestibulo-ocular reflex 
X9 
X 
X10 
Caloric test 12 (optional) 
X9 
X10 
Treatment 
Study Drug Intake 2, 3 
X---- 
-------- 
-------------→ 
Compliance 
X 
X 
X 
Safety 
Adverse events 
----- 
------------ 
-------- 
---------------- 
--------------------- 
---------------- 
----------→ 
Pharmacokinetics 8 
X 
X 
X 
 
 
1. 
VAS and walking assessment will be completed at the inclusion visit prior to the first study drug intake and then twice daily in the morning at 10 am and in the evening just after dinner from 
the inclusion visit to end of study visit. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
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2. 
The first dose should be taken at the site (H0), immediately after all baseline assessments are performed and the patient is randomized in the IWRS. The second dose will be given 12 hours 
after (+3 h). The following doses will be taken on Day 2 (H24+3h), Day 3 (H48+3h) and Day 4 (H72+3h). 
3. 
Patients will receive the remaining tablets to be taken home if he/she is discharged from the hospital prior to the last scheduled intake: Total intake of 2 tablets x 5. 
The last dose will be given either in the morning or evening of D4 according to the time of first intake. 
4. 
If the patient remains hospitalized after Day 28, the end of hospitalization visit will not be completed. The end of hospitalization visit has to be completed if it does not occur at the same time 
as another scheduled visit (D5: end of treatment visit or D28, the end of study visit The reason for not performing the end of hospitalization visit will be filled in the e CRF. 
5. 
Pregnancy tests will be either urine or blood test (If the urine test is positive a blood test will be done for confirmation). 
6. 
Video oculography will be performed at the inclusion visit prior to the first study drug intake, and at all subsequent onsite visits. In addition, when possible Video oculography will be performed 
daily until the end of hospitalization. 
7. 
The Romberg tests will be performed at the inclusion visit prior to the first study drug intake, and at all subsequent onsite visits. In addition, when possible Romberg test will be performed twice 
daily in the morning and evening while hospitalized. 
8. 
12 hours (± 3) after the first study drug intake, vital signs will be measured and a blood sample will be taken for PK just before the second study drug intake. Two other blood samples will 
be taken. One just before the 3rd study drug intake at H24 and one at the end of treatment visit. In cases where PK sample cannot be taken at H12 or H24, it is also acceptable to take a PK sample 
before the 4th intake (H48). 
9. 
Either HIT or caloric test are needed for confirmation of the diagnosis 
10. The caloric test and HIT at the end of study visit are optional and part of an ancillary study 
11. The standing vertigo VAS will be completed under condition 1 of the Romberg tests at the site twice daily. At home, it will be performed twice daily in standing position, eyes open, feet 
together on a firm surface. 
12. Caloric test can be performed using either water or air according to the usual practice at the site. 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
PCN SENP 154816 
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4. 
Statistical Analysis and Reporting 
 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, the number of missing values, mean, standard deviation (SD), median, 
minimum, and maximum, unless otherwise specified. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment groups, unless otherwise specified. 
The number of missing values will be calculated as difference of the total number of subjects in 
the study population for the treatment group minus the number of non-missing values. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
 
4.2. 
Interim Analysis and Data Monitoring 
 
An independent Data Monitoring Committee (DMC) will independently monitor subject safety 
during the SENS 111-201 study. The primary goal of the DMC is to protect and to promote 
safety of patients participating in the trial. Other goals are to monitor study integrity, to evaluate 
the adequacy of data demonstrating safety of treatments independently from the investigational 
centres and the sponsor and finally to make decision about study continuation based on safety 
data. 
The DMC is an independent multidisciplinary group consisting of at least 2 physicians and a 
statistician that collectively has experience in the management of patients with vestibulopathies 
and in the conduct and monitoring of randomized clinical trials. The DMC does not include 
Sponsor’s personnel or personnel from Contract Research Organizations (CRO) appointed by the 
Sponsor. 
The DMC meetings will be held: 
• (first meeting) after 30 patients have completed the study 
• thereafter, when a further 35 patients (approximately) have completed the study or 
annualy (whichever comes first) 


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The DMC will remain blinded for its evaluation, but may request unblinded or partially blinded 
reports. The unblinded or partially blinded analysis will be performed by an independent 
statistician other than the author of this plan or the person responsible for the primary analysis of 
this study and treatment codes will be revealed to that party only. 
The DMC is empowered to make recommendations on the SENS-111-201 study based on the 
results of their reviews. The possible recommendations the DMC can make are to: 
• Continue the trial without modification 
• Continue the trial with protocol amendments (DMC will provide details of suggested 
modifications and reasons for the modifications according to the benefit/risk ratio) 
• Modify or strengthen safety procedures 
• Suspend enrolment and treatment administration in the trial pending further information 
• Terminate the trial earlier 
The scope of responsibility of the DMC, its membership and its confidentiality, as well as the 
frequency, content, and format of data review meetings, is described in a separate DMC charter 
of operations approved by Sensorion and by the DMC members prior to the first review meeting. 
No other interim analysis, except DMC analysis, is planned. 
 
5. 
Analysis Populations 
 
The followings are planned for this study: 
• Screened Population ( Screened): The Screened Population includes all screened and 
consented subjects. This population will be used for disposition only. 
• Safety Population (SAF): The Safety Population includes all treated patients according 
to first treatment actually received. Note that the Safety population may also be referred 
as Safety Analysis Set. 
• Intention-To-Treat Population (ITT): The ITT population includes all randomized 
patients. 
• Modified Intention-To-Treat Population (mITT): The mITT population includes all 
patients of the ITT population with a unilateral AUV (diagnosed before or after 
randomization), a baseline standing VI-VAS ≥ 60 mm and with at least one study drug 
intake. 
• Per-Protocol Population (PP): The PP population includes all patients of the mITT 
population with the primary efficacy endpoint (AUC for the standing VI-VAS) available 
and without a protocol deviation likely to impact the primary efficacy endpoint. 
• Ancillary Population (ANC): The Ancillary Population includes all patients performing 
ancillary tests, i.e video-head impulse test and/or caloric test. 
The ITT population will be the primary population for efficacy analysis. The PP population will 
be secondary for the efficacy analysis. The mITT population will be used for a sensitivity 


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efficacy analysis in a selection of endpoints: standing VI-VAS, worst VI-VAS, and nausea 
intensity VAS. The SAF will be used for the analyses of safety endpoints. 
 
All efficacy analyses will be conducted according to the randomized treatment assignment by 
IWRS; all safety analyses will be conducted to the treatment actually received. 
 
Subjects to be included in the PP Population will be determined by the Sponsor prior to the 
unblinding of the study. A subject with a protocol deviation who is classified as ‘major’ per the 
Protocol Deviation Guidance Plan will be excluded from the PP Population only if the protocol 
deviation may directly impact the primary efficacy endpoint. 
 
Subjects with a major protocol deviation may be excluded from the PP Population if any of the 
following are met: 
 
• Failure to meet inclusion/exclusion criteria that may impact the primary efficacy endpoint 
• 
Intake of any interfering concomitant medication 
 
• Randomization error 
6. 
General Issues for Statistical Analysis 
 
6.1. 
Statistical Definitions and Algorithms 
 
6.1.1. Baseline 
 
For the VAS endpoints, the baseline observation is the first observation recorded in the ePRO on 
the day of the randomization or otherwise the last observation before the day of the 
randomization. 
For the  Romberg score and sub scores, the Average and Peak Slow phase velocity,  the 
baseline observation is the observation recorded in the eCRF at Visit 2 hour 0 provided that this 
visit is before or the same day as the randomization. 
For the DHI score and sub scores, the baseline observation is the observation recorded in the 
ePRO on the day of eCRF Visit 2 provided that this visit is before or the same day as the 
randomization. 
For all safety endpoints, the last non-missing observation recorded prior to the first drug intake 
will be used as the baseline observation for all calculations. 
 
6.1.2. Multiple Comparisons 
 
No adjustment will be made for multiple comparisons due to the exploratory nature of the 
hypothesis testing. 
 
6.1.3. Handling of Dropouts or Missing Data 
 
In general, no data will be imputed. 
 
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Missing intermediate measurements of the standing VI-VAS, worst VI-VAS, and NI-VAS 
won't be replaced in the calculation of the AUC. Since the trapezoid rule will be used to calculate 
the AUC, linear interpolation of intermediate values or no imputation at all will lead to the same 
AUC estimation. Missing final measurement(s) (e.g. in case of patient's withdrawal) will be 
replaced by BOCF (baseline observation carried forward) if the reason for missing data is severe 
vertigo or by LOCF (last observation carried forward), i.e. absence of improvement, if the reason 
for missing data is nausea, other or unknown. 
A mixed model without replacement of missing values using a restricted maximum likelihood 
(REML) for repeated measures will be conducted to examine whether or not results are robust to 
the data imputation. 
Any subject who withdraws from the study will be considered as study discontinuation. Subjects 
who discontinue study should be assessed in accordance with the assessments/tests specified 
normally for the end of the study visit. 
 
6.1.4. Analysis Visit Windows 
As per protocol a window of ±6 hours is allowed for the screening visit, while a window of ±3 is 
allowed for visit at H12 and H24. For the end of treatment visit, a window of -1 to +2 days is 
allowed. A window of ±2 days is allowed for the phone call visit and the end of study visit. 
Statistical analyses will be based on scheduled visit as collected in the eCRF without further 
realignment. 
 
6.1.5. Pooling of Sites 
 
As there are expected to be relatively few patients per centre, the centre will not be taken into 
account in the analyses. Therefore the question of pooling of centres does not arise. However, a 
breakdown by center will be given in summary tables for patients’ disposition. 
 
6.1.6. Derived Variables 
 
The following derived and computed variables have been initially identified as important for the 
analysis of efficacy. 
It is expected that additional variables will be required. The SAP will not be amended for additional 
variables that are not related to the primary target or key secondary target variables. Any additional 
derived or computed variables will be identified and documented in the SAS programs that create 
the analysis files. If the SAP is not amended, further derivations related to primary and secondary 
target variables will be described in the CSR. 
 
6.1.6.1. 
Treatment-emergent adverse events 
Treatment-emergent adverse events (TEAE) are defined as events occurring after the first dose 
intake of randomized study drug, and up to and including 10 days after the last dose of study drug. 
Additionally, events present before the first dose of randomized study drug, but worsening under 
treatment are considered as TEAE. Events with treatment status unclear because the onset date 
and/or the dates of first/last study drug intake are missing or incomplete will be considered as 
TEAEs. 
 
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If the start date of an AE are partially or completely missing, the AE will be assumed to be 
treatment-emergent if it cannot be definitely shown that the AE did not occur or worsen during 
the treatment-emergent period (worst case approach). Missing dates will not be replaced. 
The following are used for guidance for programmers. 
• If the start date of the AE is complete, the AE will be excluded from treatment-emergent 
AEs if the start day is before day of first treatment or the start day is after end day of the 
treatment-emergent period. 
• If the day is missing but the start month is complete, an AE will only be excluded from 
treatment emergent AEs if the start month is before month of first treatment or the start 
month is after end month of treatment-emergent period or if the stop date is before the 
start of first treatment. 
• If the start day and months are missing but the start year is complete, an AE will only be 
excluded from treatment-emergent AEs if the start year is before year of first treatment or 
if the start year is after end year of treatment-emergent period or if the stop date is before 
the start of first treatment. 
If the start date is completely missing, an AE will not be excluded from treatment-emergent AEs 
unless the stop date is before the start of first treatment. 
 
6.1.6.2. 
Area under the curve 
The baseline assessment and the first 8 first post-baseline assessments will be included in the 
calculation of the AUC. 
The AUC calculation includes the 4 days of treatment, from baseline to 96±6 hours. All 
assessments within baseline and baseline + 102 hours will be included in the calculation. The 
AUC will not be calculated if no baseline value is available or if no VAS assessment is available 
between 18 (12+6) hours and 102 (96+6) hours from baseline for reason not linked to severe 
vertigo. 
The interval between baseline and the first post-baseline assessment will be included in the AUC 
calculation. Skipped assessments do not extend the time interval used. Missing intermediate 
measurements will not be replaced in the calculation of the AUC. Missing final measurements 
will be replaced as described in Section 6.1.3 with time of assessment equal to 96 hours. 
The AUC for the VAS will be calculated using the trapezoidal rule, which is based on the 
formula to find the area of a trapezoid: take the sum of its basis, multiply the sum by the height 
of the trapezoid, and the divide the results by 2. 
Therefore, the VAS-AUC in mm/day will be: 
J−1 
 
 
where: 
1 
AUC = 2 ∑(VASj + VASj+1)(tj+1 − tj) 
j=0 
• the VAS assessments VAS0, VAS1, … , VASj, … , VASJ are made at times t0, t1, … , tj, … , tJ 
• t0 is the time at baseline 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 30 of 58 
 
 
• VAS0 is the VAS assessment at baseline 
• tJ is the latest time with tJ − t0 ≤ 102 hours 
 
An example of the AUC estimation is illustrated in Table 2 and Figure 1. 
Table 2 AUC estimation 
j 
VAS 
score 
(VASj) 
Date and time 
(tj) 
Sum of basis of 
the trapezoid 
(VASj+ VASj+1) 
Height of 
trapezoid 
in days 
(tj+1-tj) 
Area of the trapezoid 
(mm/day) 
0.5 (VASj+ VASj+1) (tj+1-tj) 
0 
72 
31 March 2017, 3:00pm 
142 
0.792 
56.208 
1 
70 
1 April 2017, 10:00am 
135 
0.458 
30.938 
2 
65 
1 April 2017, 9:00pm 
130 
0.563 
36.563 
3 
65 
2 April 2017, 10:30am 
125 
0.438 
27.344 
4 
60 
2 April 2017, 9:00pm 
110 
0.583 
32.083 
5 
50 
3 April 2017, 11:00am 
98 
0.375 
18.375 
6 
48 
3 April 2017, 8:00pm 
98 
0.667 
32.667 
7 
50 
4 April 2017, noon 
95 
0.347 
15.833 
8 
45 
4 April 2017, 8:00pm 
- 
- 
- 
Total 
250.010 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
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0.00 
0.79 
1.25 
1.81 
2.25 
2.83 
3.21 
3.88 
4.21 
Figure 1 AUC estimation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This method will apply to VI-VAS measurements for the standing position and the worst vertigo 
intensity, and NI-VAS as well. 
The estimation of the AUC is complicated by the fact that this parameter is time-dependent; its 
value depends on the length of the observation period: t8-t0. Specific attention will be paid to 
check that the variability of the observation period between treatment arms does not affect the 
calculation of the AUC. 
 
 
6.1.6.3. 
Romberg total score and subscores 
The Romberg test assess the patient’s ability to stand unassisted under 6 successive test 
conditions of increasing difficulty: 
VAS - AUC 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0 
72 
70 
65 
65 
60 
50 
48 
50 
45 
31 Mar 1 Apr 
3pm 
10am 
1 Apr 
2 Apr 
2 Apr 
3 Apr 
3 Apr 
4 Apr 
4 Apr 
9pm    10:30pm 
9pm 
11am 
8pm 
12pm 
8pm 
Calendar time 
VI-VAS 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
PCN SENP 154816 
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Page 32 of 58 
 
 
 
Condition 
Description 
Score 
1 
Standing on the floor, feet together (or at a distance for them to 
be steady) with the eyes open looking straight ahead 
sc1 
2 
Standing on the floor, feet together (or at a distance for them to 
be steady) with the eyes closed 
sc2 
3 
Standing on a foam pad, feet together (or at a distance for them 
to be steady) with the eyes open looking straight ahead 
sc3 
4 
Standing on a foam pad, feet together (or at a distance for them 
to be steady) with the eyes closed 
sc4 
5 
Standing, on a foam pad, feet heel to the toes with the eyes open 
looking straight ahead (dominant foot directly in front of the 
non-dominant foot in tandem) 
sc5 
6 
Standing on a foam pad, feet heel to the toes with the eyes 
closed (dominant foot directly in front of the non-dominant foot 
in tandem) 
sc6 
 
 
Each condition is scored 1 for a success and 0 for a failure. Because each successive condition is 
more difficult that the preceding one, the test will be considered complete when the subject fails 
a condition (after re-test), and the patient will be considered unable to pass the subsequent more 
difficult conditions, that will be scored as failed conditions. 
The total score will be calculated by summing the rate of each condition: 
6 
𝑇𝑜𝑡𝑎𝑙 𝑆𝑐𝑜𝑟𝑒 =  ∑ 𝑠𝑐𝑖 
𝑖=1 
Subscores will be calculated for eyes closed on 1 hand 
𝐸𝑦𝑒𝑠 𝑐𝑙𝑜𝑠𝑒𝑑 𝑆𝑐𝑜𝑟𝑒 = 𝑠𝑐2 + 𝑠𝑐4 + 𝑠𝑐6 
and eyes open on the other hand 
𝐸𝑦𝑒𝑠 𝑜𝑝𝑒𝑛 𝑆𝑐𝑜𝑟𝑒 = 𝑠𝑐1 + 𝑠𝑐3 + 𝑠𝑐5 
 
The average scores of the Romberg test in the morning and evening will be used when two 
assessments are available for the same visit. 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
PCN SENP 154816 
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6.1.6.4. 
DHI total score and subscores 
The purpose of the Dizziness Handicap Inventory (DHI) scale is to identify the difficulties that 
the patient may be experiencing because of dizziness. The scale examines 25 questions and 3 
domains: 
 
Domain 
Number of 
Questions 
Questions 
Physical 
7 
P1, P4, P8, P11, P13, P17, P25 
Emotional 
9 
E2, E9, E10, E15, E18, E20, E21, E22, E23 
Functional 
9 
F3, F5, F6, F7, F12, F16, F19, F24 
 
There are 3 options for each question: 
• Always 
• Sometimes 
• No 
The sum of each rating calculated with 
• Always = 4 
• Sometimes = 2 
• No = 0 
is the perceived total disability scoring. The total score ranges for 0 (no perceived disability) to 
100 (maximum perceived disability). 
Subscores for the 3 domains will be calculated. If a single answer is missing the corrisponding 
subscore and the total score will be missing. 
 
6.1.6.5. 
VADL total score and subscores 
The Vestibular Disorders Activities of Daily Living Scale (VADL) evaluates the effects of 
vertigo and balance disorders on independence in routine activities of daily living. The scale is a 
28 item questionnaire that is broken into 3 subscales: functional, ambulatory, and instrumental: 
 
 
Domain 
Number of 
Questions 
Questions 
Functional 
12 
F1 to F12 
Ambulatory 
9 
A13 to A21 
Instrumental 
7 
I22 to I28 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
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The questionnaire requires to rate self-perceived disablement level on a scale that ranges from 1 
(I am not disabled) to 10 (I no longer perform the activity). 
The overall score and each subscore are calculated by taking both median and mean values over 
the relevant quesitons using the following scores. 
• INDEPENDENT = 1 
• UNCOMFORTABLE, NO CHANGE IN ABILITY = 2 
• DECREASED ABILITY, NO CHANGE IN MANNER OF PERFORMANCE = 3 
• SLOWER, CAUTIOUS, MORE CAREFUL = 4 
• PREFER USING AN OBJECT FOR HELP = 5 
• MUST USE AN OBJECT FOR HELP = 6 
• MUST USE SPECIAL EQUIPMENT = 7 
• NEED PHYSICAL ASSISTANCE = 8 
• DEPENDENT= 9 
• TOO DIFFICULT, NO LONGER PERFORM = 10 
The subscore and the total score will be calculate even if a single answer or more answers are 
missing or not applicable. 
 
 
6.1.6.6. 
Time to unassisted walk 
Walking as usual without support will be considered at the first time when the patient is ticking 
‘no’ to the question “Because of your vertigo (or disequilibrium) problem, do you have difficulty 
walking 10 meters (32,8 feet) at your usual speed without using support?” and all further 
assessments are ‘no’. The time to unassisted walk will be calculated in hours using the following 
formula: 
(date and time of walking as usual without support) - (date and time of baseline visit at H0) 
This time will be censored at the day of the end of study visit (D28). 
6.1.6.7. 
WPAI-SHP 
The Work Productivity and Activity Impairment – Specific Health Problem (WPAI-SHP) 
questionnaire measures impairments in work and activities over the past 7 days. 
The patient will be requested to fill-in the WPAI-SHP questionnaire at the End-of-Study visit 
(D28). 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows: 
 
Questions: 
1 = currently employed 
2 = hours missed due to specified problem 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
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3 = hours missed other reasons 
4 = hours actually worked 
5 = degree problem affected productivity while working 
6 = degree problem affected regular activities 
 
The following scores will be calculated: 
Percent work time missed due to vertigo: 100* Q2/(Q2+Q4) 
Percent impairment while working due to vertigo: 100* Q5/10 
Percent overall work impairment due to vertigo:: 
100*(Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)]) 
Percent activity impairment due to vertigo: 100*Q6/10 
If a single answer is missing the corrisponding subscore and the total score will be missing. 
 
6.1.6.8. 
Compliance 
Study drug intake is planned using the following scheme: 
 
Intake 
When 
1st 
Day 1 H0 
2nd 
Day 1 H12 
3rd 
Day 2 
4th 
Day 3 
5th 
Day 4 
 
The overall compliance for each subject will be calculated as the number of study drug intakes. 
 
6.1.6.9. 
Length of hospital stay 
The length of hospital stay (in hours) due to AUV or due to SAE will be calculated using the 
following duration in hours: (discharge date and time – admission date and time). 
 
6.1.6.10. 
Abnormal and clinically significant results 
The information about abnormal results and clinically significant results for laboratory tests will 
be combined using the following categories: 
• Within normal limits 


Statistical Analysis Plan 
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Protocol Number SENS 111-201 
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• Abnormal- high and clinically significant 
• Abnormal- high, but not clinically significant 
• Abnormal- low and clinically significant 
• Abnormal- low but not clinically significant 
The information about abnormal results and clinically significant results for physical 
examination tests will be combined using the following categories: 
• Normal 
• Abnormal 
6.1.6.11. 
Treatment related adverse event 
A treatment related AE is any AE with a relationship to the study drug of probable or possible. A 
non-treatment related AE is any AE with a relationship to the study drug of unlikely or unrelated. 
An AE with missing or not assessable relationship will be considered as related. 
 
6.1.6.12. 
Prior and concomitant medications 
Medications that started prior to the first study drug intake will be considered prior medications. 
A concomitant medication is defined as any medication that was administered during the 
treatment period. This includes medications that started before the treatment period and 
continued while on treatment and medications that started during the treatment period. 
Any medications continuing or starting post the first study drug intake and before the last drug 
intake will be considered to be concomitant. If a medication starts prior to the first study drug 
intake and continues after the first study drug intake it will be considered both prior and 
concomitant. 
 
If the start/stop dates of a medication are partially or completely missing, then the medication 
will be assumed to be concomitant if it cannot be definitely shown that it was not administered 
during the treatment period. Missing dates will not be replaced. 
 
6.1.7. Data Adjustments/Handling/Conventions 
 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
 
All P values will be displayed in four decimals and rounded using standard scientific notation (eg, 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
 
Adverse events will be coded using the MedDRA version 20.0 thesaurus. 
 
7. 
Study Patients and Demographics 
 
7.1. 
Disposition of Patients and Withdrawals 
 
All patients who provide informed consent will be accounted for in this study. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
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The total number of subjects for each of the following categories will be presented for the 
screened population: 
• Screened Population 
• Safety Population 
• ITT Population 
• mITT Population 
• PP Population 
• Ancillary Population 
• Completed patients up to visit 7, Day 28 (±2 days) 
• Patients at each visit 
• Patients withdrawn 
• Reasons for early study termination 
In summary tables for disposition of patients, a breakdown by center and randomized treatment 
groups will be given. 
 
For all categories of patients percentages will be calculated using the number of randomized 
patients as denominator. 
The total number of screening failures and the reasons for screen failure will be presented 
overall and by center in separate tables. 
 
7.2. 
Protocol Violations and Deviations 
 
Protocol deviations will be identified and classified at the blinded data review meeting before 
defining the analysis populations. 
Only patients with potentially major deviations will be discussed. 
Major protocol violations – i.e. those leading to exclusion from the PP population – will be 
summarized by type of violations, overall and by center for the ITT population. 
Protocol deviations will be listed. 
 
7.3. 
Demographics and Other Baseline Characteristics 
 
Descriptive summaries of the demographic and other baseline characteristics will be completed 
for each population: ITT, mITT, Safety, and PP. 
Descriptive summaries of demographic and other baseline conditions will include: 
• Demographics (age, body weight, gender, ethinicty, race) 
• Medical history 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
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• Prior medications 
Medical history will be coded with MedDRA dictionary. Incidences of findings in medical 
history will be summarized by system organ class (SOC) and preferred term by treatment groups, 
unless otherwise specified. 
The frequency and percentage of prior medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) level 2 within level 1 by treatment group, unless otherwise 
specified. 
 
7.4. 
Exposure and Compliance 
 
Descriptive statistics for the compliance as defined in Section 6.1.6.8 will be presented by 
treatment group on safety population. 
 
8. 
Efficacy Analysis 
 
This study will examine the efficacy of SENS-111 on the VI-VAS AUC. Efficacy analyses will 
be performed based on the treatment group to which the patient was randomized. 
The primary and secondary efficacy analyses will be based on the ITT population. 
For completeness the analyses will be repeated for the PP population. 
The standing VI-VAS, worst VI-VAS, and nausea intensity VAS will be analyzed using an 
ANCOVA model for the mITT population. 
 
8.1. 
Primary Efficacy Analysis 
 
The standing VI-VAS will be summarized using descriptive statistics of absolute values and 
changes from baseline at each mapped time point, and of the AUC including the length of the 
AUC observation period. Each VAS assessment will be mapped to a time point as follows: 
 
Time point 
(mapped value) 
VAS assessment time 
since baseline (hours) 
12 hours 
6 (excluded) to 18 (included) 
24 hours 
18 (excluded) to 30 (included) 
36 hours 
30 (excluded) to 42 (included) 
… 
 
When more than one VAS assessment fall within the same time window, then only the VAS 
assessment closest to the middle point will be assigned to the time point. In case of values that 
are equidistant to the middle point, the latest assessment only will be assigned to the time point. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 39 of 58 
 
 
VAS assessment not mapped to time point will not be included in the summary statistics and in 
the MMRM analysis. 
 
The VI-VAS AUC will be compared between treatment groups within an analysis of covariance 
model (ANCOVA) with the stratification factor duration of vertigo (≤24 hours, >24 hours before 
being treated) and the baseline VI-VAS as covariates. The two comparisons to placebo (SENS- 
111 at 100 mg vs placebo, and SENS-111 at 200 mg vs placebo) will be tested for superiority at 
5% one-sided significance level, the corresponding 90% two-sided confidence intervals will be 
presented. In addition the pool of the two active doses (SENS-111 at 100 mg and SENS-111 at 
200 mg) will also be tested for superiority at 5% one-sided significance level, and the 
corresponding 90% two-sided confidence interval will be presented. 
A sensitivity analysis using the date/time of the first dose intake of randomized study drug as the 
time reference for the AUC calculation will also be performed. In this analysis, the baseline will 
be defined as the last observation recorded in the ePRO until the time of the first dose intake and 
the AUC calculation will conducted as defined in section 6.1.6.2 (using all VAS assessments 
between baseline and baseline + 102 hours). This analysis will be conducted on the mITT and 
the PP restricted to subjects for whom the baseline standing VI-VAS based on first study drug 
intake is available and ≥ 60 mm. 
A sensitivity analysis excluding patients who received treatment related to AUV over the last 3 
months prior to the enrollment will also be performed. 
As a complementary analysis in order to get a better insight of the treatment effect over time, the 
8 post baseline VI-VAS scores at mapped time points (12h, 24h, 36h, 48h, 72h, 84h, 96h) will 
be analyzed, without replacement of missing values, using a restricted maximum likelihood 
(REML) based repeated measures approach. The same analysis using baseline and mapped time 
points both defined with reference to time of first dose intake will be applied on the mITT and 
the PP restricted to subjects for whom the baseline standing VI-VAS based on first study drug 
intake is available and ≥ 60 mm. 
Analyses will include the fixed, categorical effects of treatment, time, and treatment-by-time 
interaction, as well as the binary stratification factor (duration of vertigo before being treated) 
and the continuous, fixed covariates of baseline VI-VAS and baseline score-by-time interaction. 
An unstructured covariance structure will be used to model the within-patient errors. If this 
analysis fails to converge, simpler structures (e.g. first-order ante-dependent or heterogeneous 
compound symmetry structures) will be tested in a model without treatment effect; the 
covariance structure converging to the best fit, as determined by Akaike’s information criterion, 
will be used in the full model. Only the final model will be included in the report. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Within this model the test of interest will be the treatment-by-time interaction performed at 
significance level of 5%. In a second step, the 2 comparisons to placebo will be tested at each 
time at 5% one-sided significal level and the corresponding 90% two-sided confidence intervals 
will be presented. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 40 of 58 
 
 
The same MMRM approach will be repeated using all mapped time points up to 672 h (D28) 
included. This additional analysis will provide some information on the long-term recovery of 
the vestibular function. 
 
 
8.2. 
Secondary Efficacy Analysis 
 
8.2.1. Worst spontaneous vertigo intensity over the 4 treatment days 
The worst VI-VAS will be summarized using descriptive statistics of absolute values and 
changes from baseline at each assessment and of AUC including the length of the AUC 
observation period. 
The AUC for the worst VI-VAS using the baseline and first 8 post baseline assessments will be 
analyzed using the approach described in Section 8.1 for the primary endpoint. 
 
8.2.2. Nausea severity over the four treatment days 
 
The Nausea Intensity VAS will be summarized using descriptive statistics of absolute values and 
changes from baseline at each assessment and of AUC including the length of the AUC 
observation period. 
The AUC for the Nausea Intensity VAS using the baseline and first 8 post-baseline assessments 
will be analyzed using the approach described in Section 8.1 for the primary endpoint. 
 
8.2.3. Change from baseline of the total score of the Romberg tests at the end of treatment 
and end of study 
 
The total score and subscores of the Romberg test will be summarized using descriptive statistics 
at the following visits: baseline, end of treatment (D5), end of study (D28). 
The change from baseline of the total score of the Romberg tests at the end of treatment visit 
(D5) will be compared between treatment groups within an analysis of covariance model. 
Patients without data available at the end of treatment will be excluded from the analysis. The 
covariates will be the stratification factor, duration of vertigo (≤24 hours, >24 hours) before 
being treated and the baseline total score. The 2 comparisons to placebo will be tested at 5% one- 
sided significance level, the corresponding two-sided 90% confidence interval will be presented. 
The same approach will be applied to the change from baseline at the end of study (D28). 
 
8.2.4. Peak slow phase velocity at the end of treatment and end of study 
 
The mean and the peak of the slow phase velocity will be summarized using descriptive statistics 
at the following visits: baseline, end of hospitalization, end of treatment (D5), end of study 
(D28). 
The change from baseline of the peak slow phase velocity (degrees/second) at the end of 
treatment visit (D5) and the change from baseline at the end of study (D28) will be analyzed 
using the approach described in Section 8.2.3 for the Romberg tests. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
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The analysis for the peak slow phase velocity will be repeated for each testing condition: no 
fixation (30 sec) and fixation (10 sec). 
 
8.2.5. Functional disability at the end of study 
 
The DHI total score and subscores will be summarized using descriptive statistics by visit. 
The change from baseline of the DHI functional subscore scale at the end of study (D28) will be 
compared between treatment groups using the approach described in Section 8.2.3 for the 
Romberg tests. Patients without data available at the end of study will be excluded from the 
analysis. The 2 comparisons to placebo will be tested at 5% one-sided significance level, the 
corresponding two-sided 90% confidence interval will be presented. 
The VADL total score and subscores at the end of the study (D28) will be described using 
summary statistics. 
 
8.3. 
Exploratory Efficacy Analysis 
 
8.3.1. The caloric test 
 
The caloric test at baseline and end of study visit (D28) will be performed in some centers 
participating in an ancillary study. The total response (TR), i.e. the absolute sum of all 
appropriately directed responses, and the relative vestibular reduction (RVR) will be analyzed 
using descriptive summaries for each visit. 
 
8.3.2. The video Head Impulse Test 
 
The video Head Impulse Test will be conducted at baseline to confirm the peripheral origin of 
the vertigo. An additional test at the end of treatment visit (D5) and end of study visit (D28) will 
be performed in some centers participating in an ancillary study. The vHIT provides a quick and 
objective measure of the vestibular ocular reflex (VOR). 
The VOR parameter will be analyzed using descriptive summaries for each visit. 
 
8.3.3. Time to unassisted walking 
 
Time to unassisted walking from Day 1, i.e. Visit 2 Inclusion H0, in days will be analyzed using 
a descriptive time-to-event approach (Kaplan-Meier). 
Summaries will include the number of patients experiencing the event and the number of patients 
censored; the median, lower quartile and upper quartile estimates of time-to-event; and point 
estimates for the event-free rate at each visit. 
A Kaplan–Meier graph of time to unassisted walk by treatment group will be presented. The null 
hypothesis of no difference between pairwise comparisons SENS111 100 mg vs placebo, and 
SENS111 200 mg vs placebo will be tested using a log-rank test with a 5% one-sided 
significance level. A Cox proportional hazard regression model with a categorical variable for 
the treatment arm as independent variable will also be used to estimate the hazard ratios for the 
treatment effects (SENS111 100 mg vs placebo, and SENS111 200 mg vs placebo), which will 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 42 of 58 
 
 
be presented together with two sided 90% confidence intervals, as well as the corresponding P 
value. 
Time to unassisted walk will also be analyzed fitting a Cox proportional hazard regression with a 
categorical variable for the treatment arm as independent variable and the stratification factor 
duration of vertigo (≤24 hours, >24 hours before being treated) as covariate. The hazard ratio for 
the treatment effects (SENS111 100 mg vs placebo, and SENS111 200 mg vs placebo) will be 
presented together with two sided 90% confidence intervals, as well as the corresponding P 
value. 
 
9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the Safety population using descriptive statistics. No 
inferential statistical tests will be performed. 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each patient: 
• Adverse events, treatment-emergent AEs (TEAEs), and serious AEs (SAEs) 
• Clinical laboratory investigations (hematology, chemistries, C-reactive protein, βhCG in 
women) 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
• Physical examination 
• 12-lead electrocardiograms (ECG) 
• Neuro-otologic examination 
• AUV diagnosis 
• Hospitalization due to AUV 
9.1. 
Adverse Events 
 
A summary table will present: 
• All AEs 
• AEs leading to withdrawal from the study 
• Non Treatment emergent adverse events (non TEAEs) 
• Treatment emergent adverse events (TEAEs) 
• TEAEs related to study drug 
• Mild TEAEs 
• Moderate TEAEs 
• Severe TEAEs 
• Serious TEAEs 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
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• Serious related TEAEs 
• TEAEs resulting in death 
 
Separate summaries of treatment-emergent AEs (TEAEs) will be generated by SOC and 
preferred terms for the following: 
• All TEAEs 
• All TEAEs by severity 
• TEAEs by relationship to study medication 
9.1.1. Adverse Events Leading to Withdrawal 
 
A summary of incidence rates (frequencies and percentages) of AEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term will be prepared. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the e-CRF. 
 
9.1.2. Deaths and Serious Adverse Events 
 
Any deaths that occur during the study and serious adverse events will be listed and tabulated by 
system organ class and preferred term. 
 
9.2. 
Clinical Laboratory Evaluations 
 
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged, along with corresponding normal ranges. 
Shift table will be presented to show any change from baseline in the clinical laboratory 
findings. In the shift table the number and percentages of clinical laboratory test values that are 
within the limit, low and not clinical significant, low and clinical significant, high and not 
clinical significant, high and clinical significant will be tabulated by treatment group and visit. 
 
9.3. 
Vital Signs 
 
Descriptive summaries of absolute values and change from baseline visit will be calculated for 
each of the following visits: 
• V2, Day 1, H0 
• V2, Day 1, H12 
• V3, Day 2, H24 
• V4, end of hospitalization 
• V5, Day 5, end of treatment 
• V7, Day 28, end of study 
and for each of the following parameters: 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 44 of 58 
 
 
• temperature (T) 
• supine measurements of respiratory rate (RR), heart rate (HR), systolic blood pressure 
(SBP), diastolic blood pressure (DBP) 
• standing measurements of respiratory rate (RR), heart rate (HR), systolic blood pressure 
(SBP), diastolic blood pressure (DBP) 
 
9.4. 
Electrocardiograms 
 
Descriptive summaries will be presented by visit for the 12-lead ECG measures of heart rate, PR 
interval, QRS interval, QT interval, QTcF and QTcB interval (both correction methods). 
The number and percentage of patients with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results will be summarized by treatment group and by visit . 
Categorical analyses of the following ECG parameters will be provided by visit and overall 
showing the number and percentage of patients per treatment group and overall meeting or 
exceeding some predefined upper limit value: 
 
• PR interval <100 msec 
• PR interval >210 msec 
• QRS interval <50 msec 
• QRS interval >120 msec 
• Absolute QTc interval <340 msec 
• Absolute QTc interval >450 msec 
• Absolute QTc interval >480 msec 
• Absolute QTc interval >500 msec 
• QTc interval increases from baseline >30 msec 
• QTc interval increases from baseline >60 msec 
• Heart rate <50 bpm (sinus bradycardia) 
• Heart rate >120 bpm (sinus tachycardia) 
9.5. 
Further Safety Evaluations 
 
9.5.1. Physical Examination 
 
The number and percentage of abnormalities will be tabulated by visit in each body system: 
general appearance, skin and mucous, ears/nose/throat, pulmonary, cardiac, gastro-intestinal, 
neurological, and other. 
 
9.5.2. Neuro Otologic Examination 
 
The number and percentage of abnormalities will be tabulated by visit for: mental status, cranial 
nerves, eye movements (and presence of nystagmus), muscle strength and tone, sensory function, 
coordination, gait, reflexes, external ear, and tympanic membrane/middle ear. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 45 of 58 
 
 
9.5.3. AUV diagnosis 
 
The presence of conditions other than AUV diagnosis, its corresponding examination (CT scan, 
MRI scan, other), and the side concerned (right, left, both) will be described by treatment group 
and visit. Moreover the number of patients with another diagnosis than AUV confirmed will be 
summarized irrespective of study visit. 
 
9.5.4. Hospitalization due to AUV 
Hospitalization due to AUV (including participation in the study), the type of ward, and the 
length of hospital stay will be summarized by treatment arm. 
 
9.5.5. Hospitalization due to Serious Adverse Event 
 
Hospitalization due to SAE, the type of ward, and the length of hospital stay will be summarized 
by treatment arm. 
 
9.6. 
Concomitant Medication 
 
Prior medications will be presented separately from concomitant medications. 
Medications will be coded using WHODD (Version 1-Sep-2016). 
The frequency and percentage of concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) level 2 within level 1 by treatment groups, unless otherwise 
specified. 
 
10. 
Changes from Planned Analysis 
 
The Screened Population, the modified Intention-to-Treat Population and the Ancillary 
Population are not described in the protocol and they have been added in Section 5. 
The efficacy analysis for the mITT population was not planned in the protocol. 
The PP Population definiton has been amended. Patients with major protocol deviations are 
excluded from the PP Population in the protocol, while patients with major protocol deviation 
likely to impact the primary efficacy endpoint are excluded from the PP Population in this SAP. 
There are 3 options for each question of the DHI scale. The option ‘yes’ in the protocol and in 
the electronic patient reported outcomes data should be amended with ‘always’. 
In the AUC calculation, missing final measurements will be replaced by LOCF if the reason for 
missing data is nausea, other or unknown. The option ‘unknown’ was not included in the 
protocol. 
 
The change from baseline of the VADL score will not be analyzed since the VADL score is not 
measured at baseline. The VADL score at the end of study (D28) will be anlayzed using 
descriptive summary. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 46 of 58 
 
 
11. 
Other Planned Analysis 
 
11.1. Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem 
 
The WPAI-SHP questionnaire findings will be presented using descriptive statistics of the 
following scores: 
• Percent work time missed due to vertigo 
• Percent impairment while working due to vertigo 
• Percent overall work impairment due to vertigo 
• Percent activity impairment due to vertigo 
These summaries will be presented by treatment group for the ITT Population. 
 
11.2. Pharmacokinetic Analysis 
 
No derivation of PK parameters is planned for this study as a full PK profile is not measured. 
However, plasma exposure to SENS-111 will be characterized describing summary statistics of 
plasma concentration of SENS-111 by treatment arm and visit. 
 
12. 
References 
 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
 
13. 
Tables, Listings, and Figures 
 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
 
13.1. Planned Table Descriptions 
The following are planned summary tables for protocol SENS 111-201. Tables will be numbered 
according to the nomenclature used to support the clinical study report (CSR) when the 
xxxxxxxxxxxrc CSR template is used. However, the table numbering structure can be modified 
per the sponsor’s request to meet compatibility with the sponsor’s CSR template. 
Table 3 Planned Tables 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 47 of 58 
 
 
 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
Requested for 
the Top-Line 
Results * 
14.1 Demographic Data 
14.1.1.1.1 
Enrolled 
Summary of Patient Enrollment and Disposition 
16.2.1.1 
16.2.1.2 
Yes 
14.1.1.1.2 
Enrolled 
Summary of Patient Enrollment and Disposition by Center 
16.2.1.1 
16.2.1.2 
No 
14.1.1.2.1 
Screen Failures Summary of Reasons for Screening Failure 
16.2.1.3 
No 
14.1.1.2.2 
Screen Failures Summary of Reasons for Screening Failure by Center 
16.2.1.3 
No 
14.1.2.1 
ITT 
Summary of Major Protocol Deviations 
16.2.2.1 
No 
14.1.2.2 
ITT 
Summary of Major Protocol Deviations by Center 
16.2.2.1 
No 
14.1.3 
ITT, mITT, PP, 
SAF 
Summary of Demographic Data 
16.2.4.1 
Yes 
14.1.4 
ITT, mITT, PP, 
SAF 
Medical History by System Organ Class and Preferred Term 
16.2.4.2 
No 
14.1.5 
ITT, mITT, PP, 
SAF 
Prior Medications by ATC Level 2 
16.2.4.3 
No 
14.2 Efficacy Tables 
14.2.1.1 
ITT, mITT, PP 
Summary of Standing VI-VAS Assessments: Absolute Values 
16.2.6.1 
Yes 
14.2.1.2 
ITT, mITT, PP 
Summary of Standing VI-VAS Assessments: Changes from 
Baseline 
16.2.6.1 
Yes 
14.2.1.3 
ITT, mITT, PP 
Summary of AUC for Standing VI-VAS 
16.2.6.1 
Yes 
14.2.1.4.1 
ITT, mITT, PP 
Statistical Analysis of AUC for Standing VI-VAS: ANCOVA 
16.2.6.1 
Yes 
14.2.1.4.2 
ITT, PP 
Statistical Analysis of AUC for Standing VI-VAS: ANCOVA 
excluding patients who received treatment related to AUV 
16.2.6.1 
Yes 
14.2.1.5 
ITT, PP 
Statistical Analysis of Standing VI-VAS: MMRM (12H to 
96H 
16.2.6.1 
Yes 
14.2.1.6 
ITT, PP 
Statistical Analysis of Standing VI-VAS: MMRM (12H to 
672H) 
16.2.6.1 
No 
14.2.1.7 
mITT, PP 
Sensitivity Analysis of AUC for Standing VI-VAS: ANCOVA 16.2.6.1 
No 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 48 of 58 
 
 
 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
Requested for 
the Top-Line 
Results * 
14.2.1.8 
mITT, PP 
Sensitivity Analysis of Standing VI-VAS: MMRM (12H to 
96H) 
16.2.6.1 
No 
14.2.2.1 
ITT, mITT, PP 
Summary of Worst VI-VAS Assessments: Absolute values 
16.2.6.2 
Yes 
14.2.2.2 
ITT, mITT, PP 
Summary of Worst VI-VAS Assessments: Changes from 
Baseline 
16.2.6.2 
Yes 
14.2.2.3 
ITT, mITT, PP 
Summary of AUC for Worst VI-VAS 
16.2.6.2 
Yes 
14.2.2.4.1 
ITT, mITT, PP 
Statistical analysis of AUC for Worst VI-VAS: ANCOVA 
16.2.6.2 
Yes 
14.2.2.4.2 
ITT, PP 
Statistical analysis of AUC for Worst VI-VAS: ANCOVA 
excluding patients who received treatment related to AUV 
16.2.6.2 
Yes 
14.2.2.5 
ITT, PP 
Statistical analysis of Worst VI-VAS: MMRM (12H to 96H) 
16.2.6.2 
Yes 
14.2.2.6 
ITT, PP 
Statistical analysis of Worst VI-VAS: MMRM (12H to 672H) 
16.2.6.2 
No 
14.2.2.7 
mITT, PP 
Sensitivity Analysis of AUC for Worst VI-VAS: ANCOVA 
16.2.6.2 
No 
14.2.2.8 
mITT, PP 
Sensitivity Analysis of Worst VI-VAS: MMRM (12H to 96H) 
16.2.6.2 
No 
14.2.3.1 
ITT, mITT, PP 
Summary of Nausea Intensity VAS Assessments: Absolute 
Values 
16.2.6.3 
No 
14.2.3.2 
ITT, mITT, PP 
Summary of Nausea Intensity VAS Assessments: Changes 
from Baseline 
16.2.6.3 
No 
14.2.3.3 
ITT, mITT, PP 
Summary of AUC for Nausea Intensity VAS 
16.2.6.3 
No 
14.2.3.4.1 
ITT, PP 
Statistical Analysis of AUC for Nausea Intensity VAS: 
ANCOVA 
16.2.6.3 
No 
14.2.3.4.2 
ITT, PP 
Statistical Analysis of AUC for Nausea Intensity VAS: 
ANCOVA excluding patients who received treatment related to 
AUV 
16.2.6.3 
No 
14.2.3.5 
ITT, PP 
Statistical Analysis of Nausea Intensity VAS: MMRM (12H to 
96H) 
16.2.6.3 
No 
14.2.3.6 
ITT, PP 
Statistical Analysis of Nausea Intensity VAS: MMRM (12H to 
672H) 
16.2.6.3 
No 
14.2.3.7 
mITT, PP 
Sensitivity Analysis of AUC for Nausea Intensity VAS: 
ANCOVA 
16.2.6.3 
No 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 49 of 58 
 
 
 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
Requested for 
the Top-Line 
Results * 
14.2.3.8 
mITT, PP 
Sensitivity Analysis of Nausea Intensity VAS: MMRM (12H to 
96H) 
16.2.6.3 
No 
14.2.4.1 
ITT, PP 
Summary of the Total Score and Subscores of the Romberg 
Test: Absolute Values 
16.2.6.4 
No 
14.2.4.2 
ITT, PP 
Summary of the Total Score and Subscores of the Romberg 
Test: Changes from Baseline 
16.2.6.4 
No 
14.2.4.3 
ITT, PP 
Statistical Analysis of the Total Score of the Romberg Test: 
ANCOVA 
16.2.6.4 
No 
14.2.5.1 
ITT, PP 
Summary of the Average and Peak Slow Phase Velocity: 
Absolute Values 
16.2.6.5 
No 
14.2.5.2 
ITT, PP 
Summary of the Average and Peak Slow Phase Velocity: 
Changes from Baseline 
16.2.6.5 
No 
14.2.5.3 
ITT, PP 
Statistical Analysis of the Peak Slow Phase Velocity: 
ANCOVA 
16.2.6.5 
No 
14.2.6.1 
ITT, PP 
Summary of the Total Score and Subscores of the DHI test: 
Absolute Values 
16.2.6.6 
No 
14.2.6.2 
ITT, PP 
Summary of the Total Score and Subscores of the DHI test: 
Changes from Baseline 
16.2.6.6 
No 
14.2.6.3 
ITT, PP 
Change from Baseline of the DHI Functional Subscore Scale at 
the End of Study Visit: ANCOVA 
16.2.6.6 
No 
14.2.7 
ITT, PP 
Summary of the Total Score and Subscores of the VADL Test: 
Absolute Values 
16.2.6.7 
No 
14.2.8 
ANC 
Summary of the Total Response (TR) and the Relative 
Vestibular Reduction (RVR): Absolute Values 
16.2.6.8 
No 
14.2.9 
ANC 
Summary of Video-head Impulse Test: Absolute Values 
16.2.6.9 
No 
14.2.10.1 
ITT, PP 
Statistical Analysis of Time to Unassisted Walk: Event-free 
Rates by Time 
16.2.6.10 
No 
14.2.10.2 
ITT, PP 
Statistical Analysis of Time to Unassisted Walk: Median and 
Quartile Estimates of the Event-free Time 
16.2.6.10 
No 
14.2.10.3 
ITT, PP 
Log-rank Test for Time to Unassisted Walk: Comparison 
between Treatment Groups 
16.2.6.10 
No 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 50 of 58 
 
 
 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
Requested for 
the Top-Line 
Results * 
14.2.10.4 
ITT, PP 
Hazard Ratios of Time to Unassisted Walk: Comparison 
between Treatment Groups (with Covariate Stratification 
Factor Duration of Vertigo) 
16.2.6.10 
No 
14.2.11 
ITT 
Summary of the WPAI-SHP Scores 
16.2.6.11 
No 
14.3 Safety and Tolerability Tables 
14.3.1 Displays of Adverse Events 
14.3.1.1 
SAF 
Summary of all Adverse Events 
16.2.7.1 
No 
14.3.1.2 
SAF 
Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term 
16.2.7.1 
No 
14.3.1.3 
SAF 
Treatment Emergent Adverse Events by Severity, System 
Organ Class, and Preferred Term 
16.2.7.1 
No 
14.3.1.4 
SAF 
Treatment Emergent Adverse Events by Relationship to study 
medication, System Organ Class, and Preferred Term 
16.2.7.1 
No 
14.3.2 Other Serious and Significant Adverse Events 
14.3.2.2 
SAF 
Adverse Events Leading to Withdrawal from the Study by 
System Organ Class and Preferred Term 
16.2.7.3 
No 
14.3.2.3 
SAF 
Treatment Emergent Adverse Events Resulting in Death by 
System Organ Class and Preferred Term 
16.2.7.4 
No 
14.3.2.3 
SAF 
Serious Adverse Events by System Organ Class and Preferred 
Term 
16.2.7.2 
No 
14.3.5 Laboratory Data Tables 
14.3.5.1 
SAF 
Shift Table of Clinical Chemistry Results 
16.2.8.1 
No 
14.3.5.2 
SAF 
Shift Table of Hematology Results 
16.2.8.2 
No 
14.3.6 Other Safety and Tolerability Tables 
14.3.6.1.1 
SAF 
Vital Signs Results: Absolute Values 
16.2.9.1 
No 
14.3.6.1.2 
SAF 
Vital Signs Results: Changes from Baseline 
16.2.9.1 
No 
14.3.6.2.1 
SAF 
ECG Results 
16.2.9.2 
No 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 51 of 58 
 
 
 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
Requested for 
the Top-Line 
Results * 
14.3.6.2.2 
SAF 
ECG Results: Categorical Analysis 
16.2.9.2 
No 
14.3.6.3 
SAF 
Abnormalities and Clinical Significance in Physical 
Examination Results 
16.2.9.3 
No 
14.3.6.4 
SAF 
Abnormalities in Neuro Otologic Examination 
16.2.9.4 
No 
14.3.6.5 
SAF 
Diagnosis of AUV 
16.2.9.5 
No 
14.3.6.6 
SAF 
Hospitalization due to AUV (including participation in the 
study) 
16.2.9.6 
No 
14.3.6.7 
SAF 
Hospitalization due to Serious Adverse Event 
16.2.9.7 
No 
14.3.6.8 
SAF 
Concomitant Medication by ATC Level 2 
16.2.4.3 
No 
14.3.6.9 
SAF 
Compliance 
16.2.5.1 
No 
14.3.6.10 
SAF 
Summary of Plasma Concentration Levels 
16.2.5.2 
No 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 52 of 58 
 
 
13.2. Planned Listing Descriptions 
 
The following are planned data and patient/subject data listings for protocol 2.0. Data listings 
will be numbered according to the nomenclature used to support the CSR when the 
xxxxxxxxxh CSR template is used. However, the listing numbering structure can be modified 
per the sponsor’s request to meet compatibility with the sponsor’s CSR template. 
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (eg, repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Table 4 Planned Listings 
 
Data Listing Number 
Data Listing Title / Summary 
16.2.1 Patient Discontinuation/Completion 
16.2.1.1 
Assignment to Analysis Populations and Treatment Group 
16.2.1.2 
Study Completion Status 
16.2.1.3 
List of Reasons for Screening Failure 
16.2.2 Protocol Deviations 
16.2.2.3 
Major Protocol Deviations 
16.2.3 Patients Excluded from the Efficacy Analysis 
16.2.3.4 
List of Patients Excluded from Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
16.2.4.5 
Demographic data 
16.2.4.6 
Medical History 
16.2.4.7 
Prior and Concomitant Medications 
16.2.5 Drug Compliance and Concentration Data 
16.2.5.8 
Drug Accoountability 
16.2.5.2 
Plasma Concentration Levels 
16.2.6 Individual Efficacy Response Data 
16.2.6.9 
Standing VI-VAS 
16.2.6.2 
Worst VI-VAS 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 53 of 58 
 
 
 
Data Listing Number 
Data Listing Title / Summary 
16.2.6.3 
Nausea Intensity VAS 
16.2.6.4 
Romberg test 
16.2.6.5 
Video Oculography 
16.2.6.6 
Dizziness Handicap Inventory (DHI) test 
16.2.6.7 
Vestibular Disorder Activities of Daily Living Scale (VADL) Test 
16.2.6.8 
Caloric Test 
16.2.6.9 
Video-head Impulse Test 
16.2.6.10 
Unassisted Walk 
16.2.6.11 
Work Productivity and Activity Impairment (WPAI-SHP) 
16.2.7 Adverse Event Listings 
16.2.7.10 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Adverse Events Leading to Withdrawal 
16.2.7.4 
Deaths 
16.2.8 Laboratory Data Listings 
16.2.8.11 
Clinical Chemistry Results 
16.2.8.12 
Hematology Results 
16.2.8.3 
Pregnancy test results 
16.2.9 Listings of Other Clinical Observations and Measurements 
16.2.9.13 
Vital Signs Results 
16.2.9.14 
ECG Results 
16.2.9.15 
Physical Examination Results 
16.2.9.4 
Neuro Otologic Examination Results 
16.2.9.5 
Diagnosis of AUV 
16.2.9.6 
Hospitalization due to AUV (including prticipation in thestudy) 
16.2.9.7 
Hospitalization due to Serious Adverse Events 
16.2.9.8 
CT Scan and MRI Scan 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 54 of 58 
 
 
13.3. Planned Figure Descriptions 
 
The following are planned summary figures for protocol number SENS 111-201. The figure 
numbers and page numbers are placeholders only and will be determined when the figures are 
produced. 
Table 5 Planned Figures 
 
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
table or 
listing 
14.4.1 
ITT 
Kaplan Meier graph of time to unassisted walk 
14.2.26 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 55 of 58 
 
 
14. 
Tables, Listings, and Listing Shells 
 
14.1. 
Standard Layout for all Tables, Listings, and Figures 
Table and listing shells are provided as a separate document. The final statistical tables will be 
produced in the format of the shells and will additionally include “double” page numbering in 
the format “page xx of yy”. Note that programming notes may be added or modified if 
appropriate after each TLF shell. 
The final statistical output will be provided as fully bookmarked pdf file including a table of 
contents. 
No shells are provided for figures. 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 56 of 58 
 
 
 
 
Appendix 1: xxxxxxxxxxxx Library of Abbreviations 
 
Abbreviation 
Definition 
AE 
adverse event 
ANC 
ancillary population 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
AUV 
acute unilateral vestibulopathy 
BOCF 
baseline observation carried forward 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
D 
day 
DBP 
diastolic blood pressure 
DHI 
dizziness handicap inventory 
DMC 
data monitoring committee 
eCRF 
electronical case report form 
ECG 
electrocardiogram 
EMA 
European medicines agency 
FDA 
food and drug administration 
GLM 
generalized linear model 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
Page 57 of 58 
 
 
 
Abbreviation 
Definition 
HR 
heart rate 
ICH 
international conference on harmonisation 
ITT 
Intention-to-treat population 
IWRS 
Interactive web system response 
LOCF 
last observation carried forward 
MedDRA 
medical dictionary for regulatory activities 
MRI 
magnetic resonance imaging 
NI-VAS 
nausea intensity visual analogue scale 
ODT 
orally disintegrating tablet 
PD 
pharmacodynamics 
PP 
Per-protocol population 
PK 
pharmacokinetics 
QTc 
QT-interval for ECG corrected for heart rate 
REML 
restricted maximum likelihood 
RR 
respiratory rate 
RVR 
relative vestibular reduction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SAF 
safety population 


Statistical Analysis Plan 
Sensorion 
Protocol Number SENS 111-201 
PCN SENP 154816 
AD-ST-33.05 Effective date: 22-Jan-2018 
Version1.2 | 12-Nov-2019 | AD-PR-109.01 Effective date: 26-Jun-2017 
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Abbreviation 
Definition 
SOC 
system organ class 
SPV 
slow phase velocity 
T 
temperature 
TEAE 
treatment-emergent adverse event 
TR 
total response 
VADL 
vestibular disorders activities of daily living 
vHIT 
video-head impulse test 
VAS 
visual analogue scale 
VI-VAS 
vertigo intensity visual analogue scale 
VOG 
videooculography 
VOR 
vestibular ocular reflex 
WHO 
world health organization 
WPAI-SHP 
work productivity and activity impairment questionnaire – specific 
health problem