Clinical trial NCT03603314
Conditions: Severe Sudden Sensorineural Hearing Loss
Sponsor: Sensorion
Start date: 2019-02-15; Completion date: 2022-01-12
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective of the study is to assess the efficacy of SENS-401 on hearing loss in comparison to placebo at the end of the 4-week treatment period

Detailed description:
Patients will receive the study drug (SENS-401 or placebo) in the form of tablets by mouth, twice a day (3 tablets in the morning and 3 tablets in the evening), during the first 4 weeks after randomization.

SENS-401 is an investigational medicinal product. It belongs to a family of drugs known as "5 HT3 antagonist".

Arms: arm 1: Patients will receive the study drug (SENS-401) in the form of tablets by mouth, twice a day, during the first 4 weeks after randomization. arm 2: Patients will receive the study drug (SENS-401) in the form of tablets by mouth, twice a day, during the first 4 weeks after randomization. arm 3: Patients will receive the study drug (placebo) in the form of tablets by mouth, twice a day, during the first 4 weeks after randomization.
Interventions: intervention 1: SENS-401 intervention 2: Placebo Oral Tablet intervention 3: SENS-401
Intervention descriptions: intervention 1: 29 mg dose group: tablets of 14.5 mg, oral route, by mouth, twice a day, during 4 weeks intervention 2: placebo, oral route, by mouth, twice a day, during 4 weeks intervention 3: 43.5 mg dose groupe: tablets of 14.5 mg, oral route, by mouth, twice a day, during 4 weeks

Protocol documents:
Prot_000.pdf: 
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CLINICAL TRIAL PROTOCOL 
 
STUDY COMPOUND: SENS-401 
 
 
 
STUDY Number: SENS 401-201 
 
 
 
 
A two- part, randomised, double-blind, placebo-controlled, parallel-
group, efficacy and safety study of SENS-401 in subjects with severe 
or profound sudden sensorineural hearing loss. 
 
AUDIBLE-S 
 
A study to evaluate the Use of SENS-401 in SSNHL DIsease, given 
BID for a 28-day LEngth – by Sensorion 
  
 
Global Clinical Trial Protocol Version 4.0  dated 05 February 2021 
Clinical Trial 
Protocol Version 
Date 
Incorporating 
Amendment# 
Applicable 
country/countries 
2.1 
12 June 2018 
N/A 
All countries, except 
Canada 
2.2 
17 September 
2018 
1 (Country specific) 
Canada only 
3.0 
19 March 2020 
1 (Country specific) and 
2 (Global) 
All countries 
4.0 
05 February 2021 
3 (Global) 
All countries 
 
 
EudraCT number: 2018-000812-47 
 
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 
 
 
I have reviewed the protocol, entitled:  
 
“A two- part, randomised, double-blind, placebo-controlled, parallel-group, efficacy and safety 
study of SENS-401 in subjects with severe or profound sudden sensorineural hearing loss” 
 
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,safety and data protection 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 reason, 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 
 
Name:  
 
DATE:                                                            SIGNATURE: 
 
 
 
 
 
 
SPONSOR 
 
Name:   
 
 
DATE:                
 
 
 
SIGNATURE: 
 
 
 
 
 
 
 
 


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STUDY CONTACT LIST 
 
For questions regarding the conduct of the trial, please contact: 
 
 
SPONSOR 
SENSORION, 375 rue du Professeur Joseph Blayac 
34080 Montpellier - France 
 
Chief Medical Officer:  
 
Clinical Development Director: 
 
 
PROJECT MANAGEMENT 
  
 
DRUG SAFETY:  
 
 
 
 


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1 TABLE OF CONTENTS  
 
1 
TABLE OF CONTENTS ............................................................................................................. 4 
2 
LIST OF ABBREVIATIONS ........................................................................................................ 8 
3 
CLINICAL TRIAL SUMMARY .................................................................................................. 11 
4 
FLOW-CHARTS .................................................................................................................... 22 
5 
INTRODUCTION AND RATIONALE ........................................................................................ 25 
5.1 
SUDDEN SENSORINEURAL HEARING LOSS ............................................................................... 25 
5.2 
PHYSIOPATHOLOGY OF SSNHL ........................................................................................... 26 
5.3 
SENS-401 .................................................................................................................... 27 
5.3.1 
In vitro pharmacology results .................................................................................. 27 
5.3.2 
SENS-401 in vivo pharmacology ............................................................................... 28 
5.3.3 
SENS-401 toxicology ................................................................................................ 28 
5.3.4 
SENS-401 clinical data ............................................................................................. 28 
5.4 
RISK BENEFIT ASSESSMENT ................................................................................................ 29 
5.4.1 
Study Rationale ...................................................................................................... 29 
5.4.2 
Dose selection ......................................................................................................... 29 
5.4.3 
Conclusion .............................................................................................................. 30 
6 
STUDY OBJECTIVES AND END-POINTS .................................................................................. 31 
6.1 
STUDY OBJECTIVES .......................................................................................................... 31 
6.1.1 
Primary Objective ................................................................................................... 31 
6.1.2 
Secondary objectives ............................................................................................... 31 
6.2 
STUDY END POINTS ......................................................................................................... 31 
6.2.1 
Primary efficacy endpoint ....................................................................................... 31 
6.2.2 
Secondary efficacy endpoints .................................................................................. 31 
6.2.3 
Exploratory efficacy endpoints ................................................................................ 31 
6.2.4 
Safety endpoints ..................................................................................................... 32 
6.2.5 
Pharmacokinetics ................................................................................................... 32 
7 
STUDY DESIGN .................................................................................................................... 33 
7.1 
DESCRIPTION OF THE PROTOCOL ......................................................................................... 33 
7.2 
STUDY DESIGN ................................................................................................................ 33 
7.3 
INDEPENDENT REVIEW PROCEDURES.................................................................................... 35 
7.4 
STUDY DIAGRAM ............................................................................................................. 35 
7.5 
NUMBER OF SUBJECTS AND DURATION OF STUDY PARTICIPATION ................................................ 36 
7.6 
DETERMINATION OF END OF CLINICAL TRIAL (ALL PATIENTS) ....................................................... 37 
8 
INCLUSION AND EXCLUSION CRITERIA ................................................................................. 38 
8.1 
INCLUSION CRITERIA ........................................................................................................ 38 
8.2 
EXCLUSION CRITERIA ........................................................................................................ 38 
9 
TREATMENT........................................................................................................................ 41 
9.1 
INVESTIGATIONAL PRODUCT .............................................................................................. 41 
9.2 
NON-INVESTIGATIONAL PRODUCT ....................................................................................... 41 
9.3 
DESCRIPTION OF BLINDING METHODS ................................................................................... 41 


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9.4 
RANDOMISATION PROCESS ................................................................................................ 42 
9.5 
PACKAGING AND LABELING ................................................................................................ 42 
9.6 
ACCOUNTABILITY AND COMPLIANCE .................................................................................... 43 
9.7 
STORAGE CONDITIONS ...................................................................................................... 43 
9.8 
RESPONSIBILITIES ............................................................................................................ 43 
9.9 
MANAGEMENT OF TREATMENT AT THE END OF THE STUDY ........................................................ 43 
9.10 
CONCOMITANT TREATMENT............................................................................................... 43 
9.10.1 
Background therapy ........................................................................................... 43 
9.10.2 
Authorized concomitant medication .................................................................... 44 
9.10.3 
Not permitted concomitant medication ............................................................... 44 
9.10.4 
Rescue medication .............................................................................................. 44 
10 
STUDY ASSESSMENTS .......................................................................................................... 46 
10.1 
EFFICACY ASSESSMENTS .................................................................................................... 46 
10.1.1 
Pure Tone Audiometry ........................................................................................ 46 
10.1.2 
Speech audiometry ............................................................................................. 47 
10.1.3 
Tinnitus .............................................................................................................. 48 
10.1.4 
Vertigo ............................................................................................................... 48 
10.1.5 
QoL .................................................................................................................... 48 
10.1.6 
Otoacoustic emissions (optional) ......................................................................... 49 
10.2 
SAFETY ASSESSMENTS ...................................................................................................... 50 
10.2.1 
Physical examination .......................................................................................... 50 
10.2.2 
Otologic and audiologic examination .................................................................. 50 
10.2.3 
Vital signs ........................................................................................................... 50 
10.2.4 
Electrocardiogram (ECG) ..................................................................................... 50 
10.2.5 
Laboratory safety ............................................................................................... 50 
10.2.6 
Adverse event collection ..................................................................................... 51 
10.2.7 
Suicidality assessment:........................................................................................ 51 
10.3 
PHARMACOKINETIC EVALUATION ........................................................................................ 52 
10.4 
BIOMARKER ................................................................................................................... 52 
11 
STUDY PROCEDURES ........................................................................................................... 53 
11.1 
VISITS .......................................................................................................................... 53 
11.1.1 
Screening visit - Visit 1 (Day-4 to Day 1) ............................................................... 53 
11.1.2 
Baseline visit - Visit 2 (Day 1) ............................................................................... 54 
11.1.3 
Visit 3 (Day 7 ±2) ................................................................................................. 55 
11.1.4 
Visit 4 (Day 14 ±2) ............................................................................................... 55 
11.1.5 
Visit 5: End of Treatment Visit (Day 28±3) ............................................................ 56 
11.1.6 
Visit 6 End Study visit (Day 84±3) ......................................................................... 57 
11.1.7 
Unscheduled Visit: Visit 99 .................................................................................. 57 
11.2 
DEFINITION OF SOURCE DATA ............................................................................................. 57 
11.3 
SUBJECT WITHDRAWAL ..................................................................................................... 58 
11.3.1 
Removal of subjects from therapy or assessment ................................................. 58 
11.3.2 
Withdrawal criteria ............................................................................................. 58 
11.3.3 
Decided by the sponsor ....................................................................................... 59 
11.3.4 
Decided by the investigator ................................................................................. 60 
12 
SAFETY ............................................................................................................................... 61 
12.1 
DEFINITIONS .................................................................................................................. 61 


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12.1.1 
Adverse event (AE) .............................................................................................. 61 
12.1.2 
Serious adverse event (SAE) ................................................................................ 61 
12.1.3 
Unexpected adverse reaction .............................................................................. 61 
12.2 
OVERDOSE .................................................................................................................... 61 
12.3 
PREGNANCY................................................................................................................... 62 
12.4 
REPORTING OF ADVERSE EVENTS ......................................................................................... 62 
12.4.1 
Adverse events ................................................................................................... 62 
12.4.2 
Serious adverse events ........................................................................................ 62 
12.4.3 
Severity and causality of events .......................................................................... 63 
12.5 
PREMATURE STUDY DISCONTINUATION DUE TO ADVERSE EVENT ................................................. 63 
12.6 
SAFETY FOLLOW-UP ......................................................................................................... 64 
12.7 
UNBLINDING PROCEDURE .................................................................................................. 64 
12.8 
GENERAL SAFETY MONITORING .......................................................................................... 64 
12.8.1 
Data Monitoring Committee ............................................................................... 64 
13 
STATISTICAL CONSIDERATIONS ........................................................................................... 66 
13.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................ 66 
13.2 
SUBJECT DESCRIPTION ...................................................................................................... 67 
13.2.1 
Disposition of subjects ........................................................................................ 67 
13.2.2 
Protocol deviations ............................................................................................. 67 
13.3 
ANALYSIS POPULATIONS ................................................................................................... 68 
13.3.1 
Efficacy populations ............................................................................................ 68 
13.3.2 
Safety population ............................................................................................... 68 
13.4 
HANDLING OF MISSING DATA: ............................................................................................ 68 
13.5 
STATISTICAL METHODS ..................................................................................................... 68 
13.5.1 
Analysis of primary efficacy endpoint .................................................................. 68 
13.5.2 
Analysis of secondary efficacy endpoints ............................................................. 70 
13.5.3 
Analysis of exploratory efficacy endpoints ........................................................... 70 
13.5.4 
Analysis of safety endpoints ................................................................................ 71 
14 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................... 73 
14.1 
GOOD CLINICAL PRACTICE (GCP) ........................................................................................ 73 
14.2 
INFORMED CONSENT ........................................................................................................ 73 
14.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC).............................. 73 
14.4 
REGULATORY AUTHORITY APPROVAL ................................................................................... 73 
14.5 
END OF THE TRIAL ........................................................................................................... 73 
STUDY MONITORING .................................................................................................................. 74 
14.6 
RESPONSIBILITIES OF THE INVESTIGATOR ............................................................................... 74 
14.7 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 74 
14.8 
SOURCE DOCUMENTS AND DATA PROTECTION ........................................................................ 74 
14.9 
PROTOCOL AMENDMENTS ................................................................................................. 75 
15 
ADMINISTRATIVE RULES ..................................................................................................... 76 
15.1 
CURRICULUM VITAE ......................................................................................................... 76 
15.2 
RECORD RETENTION IN STUDY SITES ..................................................................................... 76 
15.3 
CONFIDENTIALITY ............................................................................................................ 76 
15.4 
OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS ............................................................. 76 
15.5 
INSURANCE COMPENSATION .............................................................................................. 77 
15.6 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE OUT OF A CENTER ................... 77 


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15.6.1 
Decided by the Sponsor in the following cases ..................................................... 77 
15.6.2 
Decided by the Investigator ................................................................................. 77 
16 
REFERENCES ....................................................................................................................... 78 
17 
APPENDICES ....................................................................................................................... 83 
APPENDIX 1: THE TINNITUS FUNCTIONAL INDEX .......................................................................... 83 
APPENDIX 2: EQ-5D-5L ................................................................................................................ 87 
APPENDIX 3: HIGHLY EFFECTIVE BIRTH CONTROL METHODS ........................................................ 88 
APPENDIX 4: LIST OF COMMONLY PRESCRIBED OTOTOXIC TREATMENTS ..................................... 89 
APPENDIX 5: LIST OF RAW DATA ................................................................................................. 90 
APPENDIX 6: AAO-HNS GUIDELINES ............................................................................................. 91 
APPENDIX 7: NON-EXHAUSTIVE LIST OF SEROTONINERGIC AGENTS ............................................. 92 
APPENDIX 8: CLINICAL INHIBITORS FOR TRANSPORTERS .............................................................. 93 
 
 


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2 LIST OF ABBREVIATIONS 
AAA: American Association of Autology 
AAO-HNS: American Association of Otolaryngology-Head and Neck Surgery  
ABR: Auditory brainstem response 
ADRs: Adverse Drug Reactions 
AE: Adverse event 
ALP: Alanine phosphatase 
ALT: Alanine aminotransferase 
ANCOVA: Analysis covariates 
ANSI: American National Standards Institute 
APD: Action Potential Depolarisation 
ASAT: Aspartate Transaminase 
ASHA: American Speech-Language Hearing Association 
ASNHL: Acute sudden neurosensorial hearing loss 
AUC: Area under the curve 
BID: Bis in die (twice a day) 
BP: Blood Pressure 
CBC: Complete blood count.   
CKD-EPI creatinine equation: Chronic Kidney Disease EPIdemiology collaboration equation 
Cl: Clearance 
Cmax: Maximum concentration 
CNS: Central nervous system 
COMT: Catechol O-methyltransferase 
CRF: Case report Form 
CRO: Clinical research organization 
CRP: C reactive protein   
C-SSRS: Colombia- Suicide Severity Risk score 
CSR: Clinical study report. 
CTCE: Common Terminology Criteria for Adverse Events 
CYP: Cytochrome 
D: Day 
dB: Decibel 
DB: Double-blind 
DDI: Drug-Drug Interaction   
DPOAE: Distortion Products Otoacoustic Emissions 
DMC: Data Monitoring Committee 
ECG: Electrocardiogram 
eCRF: electronic Case Report Form 
ENT: Ear Nose Throat 
F: Bioavailability 
FU: Follow-up 
GCT: Germ Cell Tumours 
GT: Glutamyl transferase 


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GLP: Good Laboratory Practice 
GST: Group Sequential Test 
Hb: hemoglobin 
HCl: Hydrochloride 
Hct: Hematocrit 
HR: Heart rate 
Hz: Hertz 
ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC: Independent ethics committee 
INN: International Non-proprietary Name 
iNOS: inducible nitric oxide synthase 
IP3R: Inositol Triphosphate Receptor 
IRB: Institutional Review Board. 
ISSHL: Idiopathic Sensory hearing loss 
ITT: Intent to treat 
IWRS: Interactive web response system  
LLN: Lower Limit of Normal 
LOAEL: Lowest observed adverse effect level 
LOCF: Last observation carried forward 
MA: Marketing Authorisation 
MCP: monocyte chemo-attractant Protein 
MedDRA: Medical Dictionary for Regulatory Activities 
MHRA: Medicine and Healthcare products related Regulatory Agency 
MDRD equation: Modification of Diet in Renal Disease  
MRI: Magnetic resonance imaging 
NCI: National Cancer Institute 
NISHL: Noise induced Sensorineural hearing Loss 
NOAEL: No observed adverse effect level  
NRS: Numerical rating scale  
OAES: Otoacoustic Emissions  
OHC: Outer hair cell 
PD: Pharmacodynamic 
PK: Pharmacokinetic 
PMDA: Pharmaceuticals and Medical Agency (Japan) 
PP: Per protocol 
PTA: Pure Tone Average of the hearing threshold of 3 contiguous most affected hearing 
frequencies identified at entry in affected ear 
PTS: Permanent threshold shift 
R: Randomised 
ROS: Reactive oxygen species 
SAE: Serious adverse event 
SAP: statistical Analysis Plan 
SHL: Sudden Hearing Loss 
SoC: Standard of Care 
SRAS: Severe Acute Respiratory Syndrome 


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SRT: Speech Recognition Threshold 
SSNHL: Sudden Sensorineural Hearing Loss 
STS: Standard threshold shift 
SUSAR: Suspected Unexpected Serious Adverse Reaction 
t1/2: Elimination half life 
TEAE: Treatment-emergent adverse event.   
TFI: Tinnitus functional index  
tMax: Time to Maximum concentration 
TOEAE: Transient Evoked Otoacoustic Emissions 
ULN: Upper Limit of Normal 
WBC: White blood count 
WOCBP: Woman of child-bearing potential 
WRS: Word Recognition Score 
 


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3 CLINICAL TRIAL SUMMARY 
 
NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
Study Title 
A two- part, randomised, double-blind, placebo-controlled, parallel-group, efficacy and 
safety study of SENS-401 in subjects with severe or profound sudden sensorineural hearing 
loss  
Short Title:  AUDIBLE-S 
A study to evaluate the Use of SENS-401 in SSNHL DIsease, given BID for a 28-day 
LEngth – by Sensorion 
Study Code Number: SENS 401-201 
International Coordinators 
Professor Arne Ernst (Germany) 
Study Phase: 2b/3 
Objectives 
• Primary objective:  
To assess the efficacy of SENS-401 on hearing loss in comparison to placebo at the end of 
the 4-week treatment period. 
• Secondary objectives:  
To confirm the maintenance of any early efficacy on hearing loss at 12-week  
To evaluate the efficacy on tinnitus  
To determine the dose effect on hearing loss 
To confirm the safety of SENS-401 in the studied population/dosage regimen 
Methodology/Study Design 
The study is a 2-part, multicenter, double-blind, randomised, placebo-controlled study of 
SENS-401 administered orally twice daily (BID for 28 days), with an 8-week follow-up. 
The study will be conducted according to an operational seamless design. In the first part, 
2 doses of SENS-401 29 mg/BID and 43.5 mg/BID (respectively 20 mg and 30 mg free 
base) will be tested. In the second part, only the dose that demonstrated efficacy in Part 1 
will be tested.  


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
The selection of the dose will be done by the DMC when all patients have completed 28 
days of treatment in Part 1.  
SENS-401 or placebo will be given on top of the “standard of care” oral corticosteroids 
under the responsibility of the Investigator. 
Moreover, a rescue therapy by intra-tympanic corticosteroids could be administered from 
day 14 in case of non-response under the responsibility of the Investigator. 
Number of Subjects 
The total number of subjects in the study will be 301 or less, broken down as follows: 
Part 1: Randomised:  111  
29 mg dose group:  n = 37 
43.5 mg dose group:  n = 37 
Placebo group:  n = 37 
Part 2: Randomised: 190 
Selected dose group:  n = 95 
Placebo group:  n = 95 
Number of centers: about 50 centers  
Diagnosis and Main Criteria for Inclusion 
Patients will be included if they are presenting with sudden sensorineural hearing loss 
and have met all the following inclusion criteria and no exclusion criteria: 
Inclusion criteria  
1. Male or female 
2. Aged at least 18 years old 
3. Patients with unilateral idiopathic sudden sensorineural hearing loss or 
unilateral/bilateral acute acoustic trauma leading to sudden sensorineural 
hearing loss defined by both: 
3.1. At least 1 hearing threshold of 50 dB or more amongst the 3 most affected 
contiguous frequencies on pure tone audiometric air conduction testing 
performed 24 hours or less prior to first study treatment,  
       and  
3.2  Mean hearing loss of 30 dB or more, averaged across the 3 most affected     contiguous 
frequencies on pure tone audiometric air conduction testing (PTA: Pure Tone Average) 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
performed 24 hours or less prior to first study treatment, compared with the unaffected 
contralateral ear or reference values from a pre-existing audiogram (dated less than 2 years)  
4. Patients with sudden hearing loss with onset within 96 hours prior to first study 
drug intake. 
5. Females must meet one of the following: postmenopausal defined as 12 
consecutive months with no menses without an alternative medical cause, 
surgically sterile, abstinent; or practicing highly effective birth control (must 
agree to use 2 forms of contraception [1 of which must be a barrier method]) 
(Appendix 4) and willing to continue to use highly effective contraception for 
the duration of study participation and for 30 days after the final dose of study 
drug). Women of childbearing potential must have a negative pregnancy test at 
screening before the first dose of study drug is taken. Women of childbearing 
potential are defined as any female who has experienced menarche and who is 
not permanently sterile or postmenopausal. 
6. Male subjects and their female partner(s) must agree to use highly effective 
contraception (must agree to use 2 forms of contraception [1 of which must be a 
barrier method]) (Appendix 4) for the duration of study participation and for 90 
days after the final dose of study drug.  
7. Signed and dated written informed consent.  
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. Bilateral idiopathic hearing loss 
2. Fluctuating hearing loss  
3. History of asymmetric hearing (>20dB difference between ears) to the best 
knowledge of the patient 
4. Severe hearing loss (>90 dB) associated with unilateral (ipsilateral) complete 
vestibular loss   
5. History of Ménière’s disease, autoimmune hearing loss, radiation-induced 
hearing loss, acoustic neuroma (schwannoma) 
6. Previous SSNHL in the affected ear within the past 6 weeks 
7. History of otosclerosis, suspected perilymph fistula or membrane rupture, 
suspected retro-cochlear lesion, barotrauma  
8. Congenital or hereditary hearing loss 
9. History of severe head or neck trauma 
10.  Complete loss of peripheral vestibular function on the affected side 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
11. Any drug-based therapy for inner ear hearing loss that is ongoing or was 
performed in the past 6 weeks, except oral corticosteroids 
12. Any ongoing or planned concomitant medication for the treatment of tinnitus 
until 6 weeks after administration 
13. Any therapy known as ototoxic (e.g. aminoglycosides, cisplatin, loop diuretics, 
quinine etc.) at the current time or in the past 6 months prior to study inclusion 
14. Air-bone gap of greater than 20 dB in 3 contiguous frequencies 
15. Acute chronic otitis media or otitis externa terminated less than 7 days prior to 
randomisation. 
16. History of chronic inflammatory or suppurative ear disease or cholesteatoma,   
17. Prior ear surgery of any kind (except ventilating tubes), or cochlear implants 
18. Patients with moderate to severe renal impairment defined by a creatinine 
clearance ≤ 60 ml/min (calculated with the Cockroft-Gault formula for patients 
<65 years old and with CKD-EPI creatinine equation or with MDRD equation 
for patients ≥65 years old) 
19. Treatment with triptans within the 24 hours before inclusion. 
20. History of drug abuse or alcoholism within the last 2 years 
21. Known or suspected ongoing active infection of HIV, Hepatitis B or C, or herpes 
zoster 
22. Known history of, or concomitant severe hepatic, gastrointestinal, 
cardiovascular, respiratory, neurological (except vertigo or tinnitus),  
hematological, renal, dermatological or psychiatric disease or substance abuse 
or any condition that, in the opinion of the Investigator might interfere with the 
evaluation of study treatment or warrant exclusion (see list of discontinuation 
criteria, section 11.3.2)    
23. Patients who, in the opinion of the Investigator, have any clinically relevant 
findings that warrant exclusion. Examples of clinically relevant problems 
include, but are not limited to, 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 
24. Neurological disorders including stroke, demyelinating disease, brain stem or 
cerebellar dysfunction within the last 3 months. (In case of possible stroke of the 
brainstem or cerebellum, or demyelinating disease the diagnosis should have 
been excluded by a MRI performed in the past 48 hours) 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
25. Known hypersensitivity, allergy or intolerance to the study medication or any 
history of severe abnormal drug reaction 
26. Pregnant or breast-feeding  
27. Mentally unable to understand the nature, objectives and possible consequences 
of the trial, or refusing its constraints 
28. Treatment with any investigational agent within 4 weeks prior to randomisation 
or 5 half-lives of the investigational drug (whichever is longer) 
29. Prior participation in a clinical trial with SENS-401 or any past treatment with 
azasetron  
30. 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 
31. Patients with either a history of significant arrhythmia, or a history of conditions 
known to increase the proarrhythmic risk (e.g., congestive heart failure, long QT 
Syndrome, hypokalemia etc...). 
Test Product 
Product name: SENS-401 
Unit dose: 
14.5 mg Oral Tablet (10mg free base equivalent) 
Regimen: 
Twice daily 
Mode/route: 
Oral 
Drug Being Tested, Dose, Method of Administration 
• 29 mg dose group: 2 tablets of 14.5 mg SENS-401, and 1 tablet of matching placebo, 
twice daily (morning and evening), oral route 
• 43.5 mg dose group: 3 tablets of 14.5 mg SENS-401 twice daily (morning and 
evening), oral route 
• Placebo group: 3 matching placebo tablets twice daily (morning and evening), oral 
route 
Duration of Treatment: 28 days 
Non-Investigational Treatment 
Background treatment: There is no standardized treatment for SSNHL. However, 
corticosteroids are usually given to patients with SSNHL as a standard of care. Therefore, 
oral corticosteroids unless contra-indicated will be given to all patients. Treatment and dose 
to be administered will be the investigator responsibility.  
Rescue therapy:As proposed by the American Association of Otolaryngology-Head and 
Neck Surgery (AAO-HNS) guidelines, in case of no hearing improvement, a rescue 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
treatment consisting of an intra-tympanic administration of corticosteroids starting at the 
earliest on Day 14 will be permitted. The dose to be administered is not standardized as the 
AAO-HNS or EU do not provide any guidance. The decision to use the rescue medication, 
the type of corticosteroid and dose to be administered will be the investigator’s 
responsibility. 
Criteria for Evaluation 
Primary Endpoint 
Change in pure tone audiometry (PTA; average of the hearing threshold of 3 contiguous 
most affected hearing frequencies in decibels as identified at study entry) in affected ear 
from baseline to the end of treatment visit (Visit D28± 3). 
Secondary Endpoints  
• Change in pure tone audiometry (average of the hearing threshold of the 2 most 
affected hearing frequencies identified at study entry) in affected ear from baseline 
to the end of treatment visit (Visit D28± 3). 
•  Change in pure tone audiometry (the most affected hearing frequencies identified 
at study entry) in affected ear from baseline to the end of treatment visit (Visit 
D28± 3). 
• Change in speech discrimination threshold from baseline to Days 28, and 84 
• Frequency and severity of tinnitus at Days 7, 14, 28, and 84 assessed by numerical 
rating scale 
Exploratory Efficacy endpoints 
• % of patients with complete hearing recovery defined as PTA <20 dB or hearing 
similar to the unaffected contralateral ear.  
• % of patients with marked improvement defined as PTA threshold absolute 
improvement > 30 dB  
• % of patients with PTA > 35 dB and > 90 dB on Day 7, Day 14 and end of study 
visit (visit D84± 3) 
• Change in PTA from baseline to Day 7, Day 14 and end of study visit (Visit D84± 
3). 
• % of responders (response defined as an improvement of 10dB or more in PTA) 
• Word recognition score at 80 dB and 60 dB in the affected ear on Day 28 and 84. 
• Relationship between time from onset of symptoms to first study drug intake and  
the primary endpoint 
• Frequency and severity of any vertigo at day 1,7,14, 28 and 84 
• Tinnitus burden based on the change in tinnitus QOL scores at day 1,7,14, 28 and 
84 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
• Change in biomarkers 
• Change in EQ-5D-5L scores between baseline and Day 28 and 84. 
• Change in DPOAE at Days 7, 14, 28, and 84 compared to baseline values 
• Change in TEOAE at Days 7, 14, 28 and 84 compared to baseline values 
 
Safety Evaluation 
• Overall tolerability: incidence, severity and nature of adverse events and SAE 
throughout the study course 
• Clinical chemistry and hematology parameters at baseline and on Days 7, 14, and 
28 
• ECG findings  
• Suicidality assessment (C-SSRS) 
 
Pharmacokinetic evaluations 
Serum samples will be collected for pharmacokinetic (PK) analysis on Day 14 (Visit 4) and 
End of treatment visit (Visit 5).   
Data Monitoring Committee (DMC) 
An independent DMC will be organized to regularly evaluate the safety of SENS-401 
during the study. The DMC will be regularly provided with safety data. Safety data will be 
provided by patient with relevant information after 30 patients have completed the study 
and then after 85 (±5) and 111 (±5)  patients have completed Day 28  during Part 1, every 
50 patients (around 25 patients/group) during Part 2, or at least once a year. The DMC will 
remain blinded for its evaluation but may ask for unblinding if required.  
Following their risk evaluation, the DMC reserves the possibility of alerting the Sponsor in 
the event of observation of highly unexpected events.  
During Part 1, two interim efficacy looks are planned. They will be performed by an 
independent statistician dedicated to the Group Sequential Test (GST). Each of these 
interim looks will lead to an automatically generated recommendation to the sponsor of 
continuing the study or of discontinuing the study for efficacy or futility respectively.  
The committee will review  the results and will provide further recommendation to the 
sponsor for stopping Part 1 for efficacy or futility or continuing Part 1 as planned, until the 
next look or the final analysis of Part 1. No information about these results will be 
communicated to investigators and the International Coordinating Investigator until the 
study is completed or discontinued. 
The committee will be responsible for the recommendation of the dose level of SENS401 
selected in Part 2. The committee will be provided with the unblinded efficacy and safety 
data on the primary endpoint once the sample size used for the final analysis of Part I of  
111 (±5)  patients randomised and will have completed the 4-week treatment. The DMC 


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NAME OF 
COMPANY: 
Sensorion 
NAME OF PRODUCT: SENS-401 
 
ACTIVE INGREDIENT: 
(R)-azasetron besylate 
will review the data provided to evaluate the benefit/risk ratio and recommend appropriate 
measures if needed. The DMC may also recommend to modify the sample size of the Part 
2 study. 
 
 
 


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Statistical methods 
Sample Size Calculation   
The sample size is based on the average change in PTA in dB between the baseline and 
week 4 in each part of the study. 
Part 1: A sample size of 111 patients (37 patients per treatment arm) was retained 
corresponding to following assumptions: 
• Each comparison to placebo performed at 5% one-sided significance level (higher 
dose to be tested first and low dose to be tested conditionally to the high dose 
statistical results) 
• Power of each comparison to placebo set to 75%. 
• Randomisation ratio 1:1:1 
• Intra-group standard deviation of 30 dB 
• Difference to placebo of 15dB. 
• Corresponding fixed sample size design of 105 patients (35 patients per treatment 
arm) inflated to 111 patients (37 patients per treatment arm) to allow the use of GST 
design with 3 looks (2 interim and 1 final look) 
Part 2: A sample size of 190 patients (95 patients per treatment arm) is retained 
corresponding to following assumptions: 
• The comparison to placebo performed at 5% two-sided significance level 
• Power of the comparison to placebo set to 90%. 
• Randomisation ratio 1:1 
• Intra-group standard deviation of 20 dB 
• Difference to placebo of 10 dB. 
• 10% dropout rate 
The sample size of Part 2 will be re-estimated based on Part 1 results when available. 
Analysis sets 
• The intent-to-treat (ITT) analysis set will comprise all randomised patients 
according to randomisation group. All efficacy analyses will be performed on the 
ITT analysis set. 
• 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. 
• The safety analysis set will comprise all treated patients according to treatment 
received. 
Main Efficacy Endpoints 
Mean changes from baseline of the hearing PTA at days 7, 14 and 28 will be analysed using 
a restricted maximum likelihood (REML)-based repeated measures approach. Analyses will 
include the categorical, fixed covariates of duration of disease and oral corticosteroids 
intake at baseline (stratification factors), the fixed, categorical effects of treatment, visit, 
and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline 


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score and baseline score-by-visit 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 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. The estimations 
and standard errors of the contrasts of interest will be derived from this model. The primary 
comparison(s) to placebo will be the ones at week 4; the comparisons to placebo at the other 
visits being seen as secondary. 
Similar approaches will be used for the other efficacy endpoints. 
Safety endpoints 
All safety analyses will be performed on the safety analysis set using descriptive statistics. 
Adverse events (AEs) will be coded and evaluated for severity using MedDRA and 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 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 test parameter. Number and percentage of 
patients presenting at least one post-baseline potentially clinically significant abnormality 
will be presented by treatment group for selected parameters. 
Number and percentage of patients presenting at least one post-baseline potentially 
clinically significant ECG abnormality will be presented by treatment group for selected 
parameters. 
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 vital sign 
parameter. Number and percentage of patients presenting at least one post-baseline 
potentially clinically significant abnormality will be presented by treatment group for 
selected parameters. 
Data from physical exams will be presented in the data listings. 
Study Timelines  
Duration of clinical phase: 12 weeks corresponding to 28 days of investigational product 
(IP) + 8 weeks of follow-up without IP. 


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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-401, 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  
 
Phase 
Screening 
Double-blind Treatment 
Follow-Up 
Day 
Day-4 to Day 1 
Inclusion 
Day 1 
Day 7 (±2) 
Day 14 (±2) 
End of treatment 
Day 28 (±3) 
End of study 
Day 84 (±3) 
Study Visits 
V1 
V2 
V3 
V4 
V5 
V6 
Informed Consent 
X 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
X 
 
 
 
 
Demographic data   
X 
 
 
 
 
 
Medical/Surgical/Otologic History 
X 
 
 
 
 
 
Otoscopy and tympanometry 
X 
X 
X 
X 
X 
X 
Treatment 
 
 
 
 
 
 
Randomisation (IWRS) 
 
X 
 
 
 
 
Study drug administration 
 
 
 
 
 
 
Study drug Compliance1 
 
 
X 
X 
X 
 
Oral Corticosteroids Compliance1,2 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
1 
IP (dose, date, time) and oral corticosteroids intake will be captured daily on a patient diary (with the exception of the IP dose at Visit 1). 
2 
All patients will receive oral corticosteroids, unless contra-indicated. The type, dose and duration will be at the discretion of the investigator. 
 
 


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Day 
Day-4 to Day 1 
Inclusion 
Day 1 
Day 7 (±2) 
Day 14 (±2) 
End of treatment 
Day 28 (±3) 
End of study 
Day 84 (±3) 
Study Visits 
V1 
V2 
V3 
V4 
V5 
V6 
Safety 
 
 
 
 
 
 
Physical Examination  
X 
 
 
 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
12 lead-ECG 
 
X 
X 
X 
X 
 
Laboratory blood test  
X 
 
 
X 
X 
 
Pregnancy test (WOCBP)3 
X 
 
 
X 
X 
X 
Adverse events  
 
 
 
 
 
 
Suicidality assessment (C-SSRS) 
 
X 
X 
X 
X 
 
Efficacy 
 
 
 
 
 
 
Pure Tone Audiometry (air and bone) 
X4 
X5 
X 
X 
X 
X 
DPOAE / TOEAE (optional)  
 
X 
X 
X 
X 
X 
Word Recognition Score 
 
X 
X 
X 
X 
X 
Speech Recognition Threshold 
 
X 
X 
X 
X 
X 
Vertigo Severity (NRS)  
 
X 
X 
X 
X 
X 
Tinnitus Severity (NRS)6 
 
X 
X 
X 
X 
X 
QoL: 5EQ-5D-5L; TFI 
 
X 
X 
X 
X 
X 
3 
Pregnancy test will be urinary test (or blood test if preferred). In case of positive urinary test, a blood test will be performed for confirmation.  
4 
Pure tone audiometry performed within 24 hours prior to the screening visit is valid for screening.  
5 
Baseline Pure tone audiometry should be performed at site, no more than 24 hours before the first study drug intake. If longer, it should be repeated for 
confirmation 
If a Pure tone audiometry has been performed at the study site for the screening visit within 24 hours prior to first study dug intake, there is no need to repeat it.  
6 
In addition, to the record on the e-CRF at each study visit, the patients will be given a diary to record the presence and the severity of the tinnitus on a daily 
basis during the first 14 days of treatment. 
 
 
 


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Day 
Day-3 to Day 1 
Inclusion 
Day 1 
Day 7 (±2) 
Day 14 (±2) 
End of treatment 
Day 28 (±3) 
End of study 
Day 84 (±3) 
Study Visits 
V1 
V2 
V3 
V4 
V5 
V6 
Pharmacokinetics/Biomarker 
 
 
 
 
 
 
Plasma samples for drug concentration  
 
 
 
X 
X 
 
Serum sample: Prestin 
 
X7 
 
X 
X 
 
 
7  Serum sample for baseline prestin concentration measure will be taken before study drug intake (either at inclusion visit or screening visit) 


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5 INTRODUCTION AND RATIONALE 
5.1 
Sudden sensorineural hearing loss 
Sudden hearing loss (SHL) is defined as a rapid-onset, occurring over a 72-hour period, of a 
subjective sensation of hearing impairment in one or both ears. 
Sudden sensorineural hearing loss (SSNHL) is a subset of SHL; sensorineural in nature it is 
diagnosed by audiometric criteria that include (A) abnormality of the cochlea, auditory nerve, 
or other aspects of central auditory perception or processing and (B) a decrease in hearing of 
more than 30 decibels (dB), affecting at least 3 consecutive contiguous test frequencies on pure-
tone audiogram (47, 49).  
Based on American Speech-Language-Hearing Association criteria (ASHA), the hearing loss 
can be slight to profound, with corresponding grades of hearing impairment of 16 to 25 dB 
(slight), 26 to 40 dB (mild), 41 to 55 dB (moderate), 56 to 70 dB (moderately severe), 71 to 90 
dB (severe), or > 91 dB (profound). Because premorbid audiometry is generally unavailable, 
hearing loss is defined as related to the opposite ear’s thresholds.  
The most commonly reported causes of SSNHL include infectious and otologic diseases 
(12.8% and 4.7%, respectively); trauma, including noise-induced, barotrauma or head trauma 
(4.2%); vascular/hematologic (2.8%); neoplastic (2.3%); and other (2.2%). However, 71% of 
cases report an unknown (idiopathic) cause (16). 
A maximum of 32% to 65% of cases of SSNHL may recover spontaneously. Clinical 
experience indicates that even this recovery rate may be an overestimation. Prognosis for 
recovery is dependent on a number of factors, including patient age, presence of vestibular 
symptoms at onset, degree of hearing loss, audiometric configuration, co-morbidities 
(hypertension, diabetes) and time between onset of hearing loss and treatment (15) (41) (58) 
(21) (23) (27).  
SSNHL is a serious and debilitating condition. Hearing loss adversely affects communication, 
speech perception in noisy environments, and social interaction, substantiating that unilateral 
deafness is a serious disability (59).. Disorientation and confusion from the inability to localize 
sound may put patients at risk for accidents and hearing loss is associated with significantly 
increased odds of falling in older adults (27). A psychosocial impact was reported in almost 
75% of patients who had even mild unilateral hearing loss, and feeling frustrated, upset, and 
left out were commonly reported (38). Patients suffering from SSNHL can also experience 
tinnitus and/or vertigo that they consider frightening, debilitating, and negatively impacting 
their QoL (14) (17) (37).   
SSNHL is a rare condition with an average total annual incidence rate of 4 to 160 per 100,000 
and approximately 66,600 new cases reported each year in the United States.  The incidence 
increased with increasing age, ranging from 11 per 100,000 for patients younger than 18 years 
to 77 per 100,000 for patients 65 years and older (3)(39).  
There is currently no treatment to improve or facilitate full, or even partial, recovery of hearing 
and/or symptoms of SSNHL, regardless of the cause. However, a few registered compound that 
treat symptoms such as vertigo or tinnitus may be associated to SSNHL. 


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Therefore, the treatment of SSNHL remains somewhat controversial. It is widely variable and 
often regionally specific.  The American Academy of Otolaryngology-Head and Neck Surgery 
(AAO-HNS) has issued in 2012 clinical practices guidelines for the management of SSNHL 
(49). No European medical society has published clinical guidelines.  
In clinical practice, the most commonly used off-label treatment is corticosteroids (60) 
administered either systemically and/or intratympanically (44). A large number of other 
treatments such as antivirals, antibiotics, diuretics, vasodilators, osmotic agents, plasma 
expanders, anticoagulants, mineral supplements, and hyperbaric oxygen or carbon dioxide–rich 
gases, among others, have been used and/or evaluated without consistent success (45,61).). 
Recent meta-analysis evaluating the efficacy and safety of medical interventions for the 
treatment of SSNHL have not identified effective therapy (18, 19, 32, 33, 20;57). 
Cochlear implant is an invasive procedure and is not a treatment of SSNHL. Hearing aids may 
be used after SSNHL in the absence of recovery but they are not useful in the acute episode.  
Some cases of noise-induced SSNHL can be prevented by using hearing protection but others, 
such as unexpected exposure to gunshots and explosives, are not preventable (13).  For military 
personnel or police officers, exposure to loud noises during training and missions are inevitable.  
In situations such as military operations, hearing is a vital asset during training and military 
operations and the need to communicate is more important than wearing protection  (63)  
5.2 
Physiopathology of SSNHL 
As specified above, SSHNL is usually idiopathic. As such, it is not predictable and cannot be 
reproduced in animal models to determine its pathophysiology and histopathology. It is 
therefore difficult to identify pathways and therapeutic targets for SSHNL. In order to tackle 
this issue, models of noise induced hearing loss (NIHL) have been developed in animals. They 
are considered as reproducing the hearing loss occurring in man after an acute exposure to 
noise.  They are the most reproducible, well-established, commonly used models and are the 
only available translational tools for research and development of new therapies for SSNHL. 
They are used to evaluate mechanisms and efficacy of drug product candidates for the treatment 
of SSNHL.  
Noise levels are measured as sound intensity (0 to over 180 dB).  Levels 90 to 100 dB over 
several hours or sudden levels 115 dB can cause damage to the human ear (5). When exposed 
to noise, the ear protects itself by vasoconstriction, which reduces the blood supply to the 
cochlea's organ of Corti, located in the inner ear (54).).  Insult to hair cells, neurons, and/or 
synapses in the organ of Corti causes a decrease in the ear's sensitivity level, and a temporary 
or permanent shift in hearing threshold occurs (4, 30). 
Sensorineural hearing loss is caused by death of the auditory hair cells in the cochlea and the 
degeneration of their afferent innervation (1). In mammals, these cells are produced only during 
embryonic development (46) and do not regenerate postnatally (51). Therefore, the loss of 
auditory hair cells is an irreversible event that can cumulatively result in profound hearing 
losses and eventually total deafness. Hair cell death following environmental stress has been 
proven to occur via both necrosis and programmed cell death 56, (56 65, 22). 
SSNHL natural history is characterized by frequent partial or complete hearing recovery 
because of cellular defenses and intrinsic repair mechanisms such as neo-synaptogenesis (43). 
Recent animal data suggest that slow degeneration of spiral ganglion cells and delayed hearing 
loss may occur even despite complete short-term recovery. 


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In noise-induced animal studies of SSNHL, cellular mechanisms such as intense metabolic 
stress and damage to many components of the cochlea, including inner and outer hair cells, 
stereocilia, supporting cells, neurons, fibrocytes, and spiral ganglion neurons are involved (56, 
34). Molecular mechanisms, such as calcineurin activation, inflammatory cell infiltration, 
glutamate excitotoxicity, and/or oxidative stress have been incriminated (35, 43, 36). 
Calcineurin is a Ca(2+)/calmodulin -dependent protein phosphatase, expressed in sensorineural 
tissue. Calcineurin is activated after noise-induced trauma to the inner ear and can activate 
mitochondrial-mediated cell death pathways in outer hair cells within the cochlea. It has been 
shown that calcineurin inhibitors are effective at reducing or preventing hair cell damage in 
animals (36, 34,55), and are protective against noise induced cochlear injury (12).  
Calcineurin inhibition directly targets the pathological mechanisms of sensory hair cell death 
and degeneration of the stria vascularis that are key pathways in noise NIHL. Calcineurin 
inhibition is therefore expected to reduce cochlear damage and thus limit the intensity of the 
hearing loss. 
5.3 
SENS-401 
The active ingredient in SENS-401 is the (R)-enantiomer of the racemic mixture of (R/S) 
azasetron, a serotonin type 3 (5-HT3) receptor antagonist marketed in Japan as Serotone®. 
Serotone is approved for the treatment of nausea and vomiting in patients undergoing 
chemotherapy.  
 
5.3.1 In vitro pharmacology results 
Non-clinical pharmacology studies have shown SENS-401 to be a 5-HT3R antagonist as R/S 
azasetron, (Serotone®). In addition, R/S azasetron, has been shown to possess calcineurin 
inhibition properties with an IC50 of about 100 nM (35 ng/mL).  
Calcineurin is a Ca(2+)/calmodulin activated serine/threonine protein phosphatase expressed in 
sensorineural tissue. Pathological activation of calcineurin by excessive calcium influx 
calcineurin activation (24) (49) (64) leads to: 
• increased nuclear NFAT translocation resulting in increased oxidative stress through 
iNOS upregulation 
• increased dephosphorylation of cofilin, leading to actin depolymerization resulting in 
synaptic swelling/uncoupling, neurite retraction and structural degeneration 
• increased mitochondrial translocation of pro-apoptotic BAD (Bcl-2-associated death 
promoter) from the cytosol, resulting in the mitochondrial release of cytochrome C and 
other signalling factors for activation cellular apoptotic cascades.  
A 5HT3 antagonist (tropisetron) was demonstrated to target the Ca(2+)/calmodulin-dependent 
protein phosphatase 2B/calcineurin, and  to inhibit the transcriptional NFAT and AP-1 
activation, and IL-2 production induced by overexpression of an active form of the phosphatase 
calcineurin (21).   
It was expected that the blockade of 5HT3 and inhibition of calcineurin by SENS-401 would 
directly target the mechanisms of SSNHL by reducing the impact of excessive calcium influx, 
limiting increased oxidative stress and countering the activation of pro-apoptotic cascades.  
Based on this mechanism of action, the activity of SENS-401 was evaluated in the rat models 
of the treatment of noise induced hearing loss, in the prevention of cisplatin induced hearing 
loss and in the treatment of unilateral vestibular dysfunction.  


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5.3.2 SENS-401 in vivo pharmacology 
In animal model (rats) of severe acoustic trauma, initial studies showed a treatment effect from 
6.6 mg/kg oral, SENS-401 significantly improving auditory brainstem response (ABR) 
thresholds and DPOAE amplitudes and reducing the average hearing loss. Improvement in 
ABR threshold shifts and DPOAE amplitudes in animal models of NIHL are considered to be 
predictive of a protective and potentially curative effect on SSNHL in patients.  
The improvement was shown to be dose dependent, and time dependent. The effect was shown 
to be present when SENS-401 was given up to 96 hours after the insult. 
Also, the efficacy of SENS-401 was confirmed in a rat model of prevention of cisplatin induced 
hearing loss and demonstrated to start at doses as low as of 6.6 mg/kg (4.55 mg/kg free base 
equivalent) and to increase dose-dependently to the highest tested dose of 26.4 mg/kg.  
In both models, SENS-401 reduced the number of hair cell loss as compared to placebo. 
 
5.3.3 SENS-401 toxicology 
SENS-401 has been administered to rats and dogs for 1 month. The safety was good with a 
NOAEL dose > 25 mg/kg/day (free-base equivalent) in the dog, corresponding to Cmax 
>3200ng/mL and, AUClast >10800ng.h/mL. In the rat, the NOAEL was >157 mg/kg/day (free-
base equivalent), corresponding to a Cmax > 9800 ng/mL, AUClast > 80500 ng.h/mL. In a 
telemetry study, SENS-401 was shown to slightly reduce blood pressure resulting in modest 
dose independent increases in heart rate and then QT interval (<30ms) with no relationship with 
dose or concentrations. No target organ has been identified.  
As SENS-401 is a substrate of MDR1 and BCRP transporters, drugs that are inhibitors of these 
are listed as prohibited. In in vitro experiments using recombinant enzymes, some CYP2B6 
inhibition was observed at 25 µM (approximately 37 %) which did not increase at 100 µM 
(approximately 24 %). This level of inhibition at a very high concentration is unlikely to cause 
any interactions clinically. Therefore, no restrictions are proposed in the protocol. 
Patients will be advised to avoid skin exposure to strong sunlight and to wear sunglasses in 
bright sunlight for the duration of the study and for 1 week after the last dose. 
No specific safety concern was identified from the 3-month oral toxicity studies, and 
reprotoxicology studies performed with the racemic mixture. Genotoxicity studies were 
negative. 
 
5.3.4 SENS-401 clinical data 
In human, a phase 1 study conducted in 36 healthy adult volunteers, confirmed SENS-401 to 
be well tolerated at doses up to 43.5 mg bid for 7 days. In particular no CNS, cardiovascular 
(QT prolongation) or gastrointestinal (constipation) event that is usually observed with 5-HT3R 
antagonists was observed. The PK profile was as expected and linear with dose.  Extensive 
safety information available for the racemate mixture did not identify specific safety concern. 
All available information on SENS-401 is included in the Investigator Brochure  
 


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5.4 
Risk Benefit Assessment 
5.4.1 Study Rationale  
There is currently no approved oral treatment for SSNHL. The pharmacology and the animal 
experiments conducted in animal models suggest that SENS-401 is a candidate compound that 
may be beneficial in this condition that can affect the patient’s life beyond the acute episode on 
the consequences of hearing loss and accompanying tinnitus. 
SENS-401 was selected for clinical development in patients with SSNHL based on the exposure 
to SENS-401 in plasma and inner ear of rats, the ability of SENS-401 to significantly reduce 
hearing loss in the NIHL animal model, and the anticipated effect of SENS401 to inhibit 
calcineurin activation, without the severe side-effects of currently approved, specific 
calcineurin inhibitors (such as cyclosporine or tacrolimus).  
The racemic compound azasetron is marketed for years in Japan and other countries (China, 
Argentina and Korea). To our knowledge, no regulatory actions have been taken on Serotone 
for safety or efficacy reasons.  
SENS-401 possesses 5-HT3 antagonist properties. The main adverse events of this therapeutic 
class are constipation and abdominal pain. They are usually mild or moderate and will 
reasonably not prevent the use of SENS-401 in the treatment of SSNHL, a severe, debilitating 
disease. Furthermore, the oral administration is easy and non-invasive. SENS-401 was safely 
administered during preclinical toxicology studies as well as during the Phase 1 study up to the 
43.5mg twice daily for 7 days. There is a large post marketing safety experience with the 
racemate formulation in Japan.  
Pure tone audiometry is a very-well standardized scientific subjective method to assess the 
hearing capacities in patients suffering from SSNHL. It can be completed by several other 
methods such as speech audiometry, otoacoustic emissions (OAE) (used also in animal models) 
and various scales for tinnitus assessments as proposed to be used in the present study. 
The biological plausibility and the satisfactory safety profile of SENS-401 as well as a complete 
set of validated methods for endpoints assessment form the basis of the present study rationale 
in order to establish the scientific basis for a first oral safe and efficacious treatment of SSNHL. 
 
5.4.2 Dose selection 
The dose selection of SENS-401 was based on dose and allometric scaling including 
pharmacokinetics obtained from animal pharmacology models and human pharmacokinetic.   
Calcineurin is inhibited by azasetron with an IC50 at 100nM (35 ng/ml). In rat models of 
cisplatin induced ototoxicity and noise induced ototoxicity, SENS-401 was shown to be 
effective from 6,6mg/kg, corresponding to Cmax=76ng/ml and AUC0-last=331ng.h/ml.  
Assuming the same distribution in human and rat for the inner ear and perilymph exposure, it 
is considered that SENS-401 43.5 mg (30mg free base) BID will provide concentration that 
demonstrated activity in rats (between Cmin=43,3ng/ml and Cmax=120ng/ml).  
A lower dose 29mg BID will also be tested to assess the concentration effect of SENS-401. The 
mean concentration at this dose (between Cmin-Cmax=21,5-59,9 ng/ml) is in the range of the IC50 
in vitro, and the exposure (AUC) in the range of the rat SENS-401 exposure at active dose.   
The treatment duration is based on the oxidative stress induced by acoustic trauma reported to 
last 10-15 days (61).).).). Recent publications have shown that contrary to existing dogma, noise 
can cause ongoing changes in cochlear structure and function long after it has ceased.  


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5.4.3 Conclusion 
The pharmacology and pharmacokinetic results suggest that SENS-401 29mg BID and 43 mg 
BID for 4 weeks might be effective in patients presenting with SSNHL. The phase 1 results and 
the extent of exposure with the marketed R/S azasetron (Serotone) provides reassurance that 
SENS-401 can be administered safely to patients presenting with SSNHL.  


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6 STUDY OBJECTIVES AND END-POINTS  
6.1 
Study Objectives 
6.1.1  Primary Objective 
To confirm the efficacy of SENS-401 on hearing loss in comparison to placebo after a 4-week 
treatment  
6.1.2  Secondary objectives 
• To confirm the maintenance of any early efficacy on hearing loss at 12-week  
• To evaluate the efficacy on SSNHL related-tinnitus  
• To determine the dose effect on hearing loss 
• To confirm the safety of SENS-401 in the studied population/dosage regimen 
 
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 endpoint  
The primary endpoint is the change in pure tone audiometry (PTA; average of the hearing 
threshold of 3 contiguous most affected hearing frequencies in decibels as identified at study 
entry) in the affected ear from baseline to the end of treatment visit (Visit D28± 3). 
 
6.2.2  Secondary efficacy endpoints 
• Change in pure tone audiometry (average of the hearing threshold of the 2 most affected 
hearing frequencies identified at study entry) in affected ear from baseline to the end of 
treatment visit (Visit D28± 3). 
•  Change in pure tone audiometry (the most affected hearing frequencies identified at 
study entry) in affected ear from baseline to the end of treatment visit (Visit D28± 3). 
• Change in speech discrimination threshold from baseline to Days 28, and 84 
• Frequency and severity of tinnitus at Days 7, 14, 28 and 84  
 
 
6.2.3  Exploratory efficacy endpoints 
• % of patients with complete hearing recovery defined as PTA  <20 dB  
• % of patients with marked improvement defined as PTA absolute improvement > 30 dB  
• % of patients with air PTA> 35 dB and > 90 dB on Day 7, Day 14 and end of study visit 
(visit D84± 3). 
• Change in PTA from baseline to Day 7, Day 14 and end of study visit (Visit D84± 3). 
• % of responders (response is defined as an improvement of 10dB or more in PTA).  
• Word recognition score at 80 dB and 60 dB in the affected ear on Day 28 and 84. 
• Relationship between time of onset of symptoms to first study drug intake and the 
primary endpoint 
• Frequency and severity of any vertigo at days 7, 14, 28 and 84 


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• Tinnitus burden based on the change in tinnitus QOL scores at days 7, 14, 28 and 84 
• Change in biomarkers 
• Change in EQ-5D-5L scores between baseline and Day 28 and 84. 
• Change in DPOAE at Days 7, 14, 28, and 84 compared to baseline values 
• Change in TEOAE at Days 7, 14, 28 and 84 compared to baseline values 
 
6.2.4 Safety endpoints 
• Overall tolerability: incidence, severity and nature of adverse events and SAE 
throughout the study course  
• Clinical chemistry and hematology parameters 
• ECG findings 
• Suicidality assessment using C-SSRS (Colombia- Suicide Severity Risk score) 
 
6.2.5  Pharmacokinetics 
• SENS-401 pharmacokinetic parameters   


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7 STUDY DESIGN 
7.1 
Description of the protocol 
This is a double-blind, randomised, placebo-controlled, international study. The study will 
assess the efficacy and safety of orally administered SENS-401 in patients suffering from 
sudden sensorineural hearing loss (SSNHL). 
 
Patients will be included if they are presenting with sudden hearing loss with onset 96 hours or 
less, ago. Based on inclusion/exclusion criteria, most patients will present with idiopathic or 
noise induced SSNHL. The screening evaluation including ear examination with otoscopic and 
tympanometric examination, will confirm the diagnosis and no exclusion criteria from past 
medical/surgical or otologic history, concomitant treatments, laboratory tests or other 
concomitant diseases. The duration of the disease will be calculated from the reporting time 
onset of  hearing loss. Eligible patients will undergo evaluations including audiometric tests 
(pure tone audiometry) to confirm the eligibility.  
 
Patients will be randomised to receive one of the treatments according to the relevant 
randomisation list (non-ancillary study sites and ancillary study sites) . Audiometric tests, 
speech audiometry, numerical rating scales and questionnaires will be also performed before 
the first intake of the investigational drug at the investigational site. The randomisation will be 
further stratified according to the duration of the hearing loss (≥ 24hours, or < 24 hours) and 
the intake of corticosteroids. 
Patients will be requested to attend 4 additional visits when otologic examination and 
audiometric tests and speech audiometry will be performed on day 7(± 2) and 14 (±2), at the 
end of treatment visit on day 28(±3), and at the follow-up visit (the end of the study visit) on 
Day 84 (±3).  
Patients will be followed for adverse events throughout the study. Inquiry about potential 
untoward events will be done at every on-site visit.  
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 including neurological, otologic examination, tympanometry and vital signs 
(blood pressure, heart rate and body temperature). 
There is no standardized treatment for SSNHL. However, oral corticosteroids are often given 
to the patients with SSNHL as a standard of care. Oral corticosteroids will be administered to 
all patients (unless specific contra indication). The treatment and dose to be administered will 
be the investigator responsibility, and pre-specified at each site.  
As proposed by the AAO-HNS guidelines, a rescue treatment consisting of an intra-tympanic 
administration of corticosteroids after randomisation will be permitted from Day 14 to patients 
who have no hearing improvement (see §9.2). The decision to use the rescue treatment, the type 
of corticosteroid and dosing regimen will be the investigator’s responsibility. 
7.2 
Study design 
The study will be conducted with an operational seamless design and will consist of 2 separate 
parts:  
• Part 1 is a double-blind randomised placebo-controlled Phase 2b/3 study of 28 days of 
treatment that will include 3 arms (2 active doses: SENS-401 29 mg and SENS-401 43.5 


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mg and one placebo) with an 8-week follow-up. The primary end point of Part 1 will be 
the change in PTA at 28 days. At the conclusion of Part 1 treatment, the data for patients 
enrolled in this part of the study will be unblinded by the DMC for the purposes of 
analysis and the dose to be tested in the confirmatory part (Part 2) will be proposed by 
the DMC. Patients included in Part 1 will be completely separated from patients 
included in Part 2. 
 
• Part 2 is a phase 3 study. This study will be a double blind randomised placebo 
controlled study of 28 days of treatment that will include 2 arms with an 8-week follow-
up. SENS-401 dose, either 43.5 mg or 29 mg (selected after completion of Part 1) will 
be tested versus placebo.  
 
  
 Figure 1 - Operational Seamless Design 
 
 
 
 
 
 
 
The principle of the operational design is to continue recruitment without interruption 
successively into Part 1, and Part 2, according to the following steps: 
1. Patients will be randomised in 3 treatment arms in Part 1 (Placebo, SENS-401 29mg, 
SENS-401 43.5mg). A total of 111 subjects (37/treatment arm) will be randomised. 
2. The Part 1 data will be unblinded after 111 patients have been randomised in Part 1 and 
have completed the end of treatment visit (28 days). 
3. As soon as the dose is selected for Part 2, new patients will be randomised to 2 arms 
(SENS-401 selected dose and placebo). No new patients will be randomised to SENS-
401 non-selected dose.  
 
The SENS-401 dose to be tested in Part 2 will be identified by the DMC using the unblinded 
data from Part 1. The rationale will be based on the benefit/risk at each dose. PTA at 28 days 
will be considered for efficacy. This committee will be independent from the sponsor. The final 
dose and sample size will be submitted for approval to competent authorities prior to the pivotal 
part start. 


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Each part will be analysed separately. Part 1 will be fully analyzed when all patients (n= 111) 
have completed the study. Part 2 efficacy analysis will be based on data from all patients who 
have entered into Part 2 and have been randomised to either placebo or the selected active dose 
(n=190).  
 
7.3 
Independent Review Procedures  
An external data monitoring committee (DMC), consisting of two or more physicians and a 
statistician, 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, as well as the efficacy (see section 
12.8.1).  
During Part 1, two interim efficacy looks are planned. They will be performed by an 
independent statistician dedicated to the efficacy analyses according to a Group Sequential Test 
(GST) design. Each of these interim looks will lead to an automatically generated 
recommendation to the sponsor of continuing the study or of discontinuing the study for 
efficacy or futility respectively.  
The committee will review the results and will eprovide further recommendation to the sponsor 
for stopping Part 1 for efficacy, futility or continuing as planned until the next look or the final 
analysis of Part 1.. No information about these results will be communicated to investigators 
and the International Coordinating Investigators until the study is completed or discontinued. 
 
The committee will be responsible for selecting the active dose to be tested in Part 2. The 
committee will be provided with the unblinded efficacy and safety data on the primary end-
point when 111 patients randomised to Part 1 have completed the 4-week treatment. The DMC 
will review the safety information together with the efficacy data to decide on the benefit/risk 
and recommend appropriate measures if needed. The DMC may also recommend to modify the 
sample size of the Part 2 study. 
7.4 
Study diagram  
As soon as eligibility of the patient is confirmed, the investigator will dispense to the subject 
the study drug that is to be taken immediately after all baseline assessments are performed.  
Part 1 
The study diagram is presented in Erreur ! Source du renvoi introuvable.. 


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Figure 2: Part 1 and Part 2 (until dose selection) Study Diagram 
 
 
Until the dose selection, the study diagram will be similar to Part 1 (see Erreur ! Source du 
renvoi introuvable.). 
 
Part 2 
 
After the dose selection, the study diagram is as follows (see Figure 3): 
 
 
Figure 3: Part 2 (after dose selection) Study diagram 
 
7.5 
Number of subjects and duration of study participation  
It is planned to enroll a total of 301 or less  patients in the study.  
Part 1: 111 patients will be enrolled (37 in the placebo arm; 37 in SENS-401 29mg arm, 37 in 
SENS-401 43.5mg arm) 
Part 2: 190 patients will be enrolled (95 in the placebo arm; 95 in selected-dose SENS-401 arm; 
and approximately 10 in the non-selected dose SENS-401 arm) 
F OL L O W-UP
DO UBL E- B L I N D  
 
T R EA T ME NT
S E N S - 4 01  
 
4 3 , 5m g BI D 
S E N S-401  
 
2 9 mg  
 
BID
Pl a c e bo
Sc r ee n i ng 
 
V i s i t  
 
1 
D ay 
 
1
I nc l u s i o n
V i s i t  
 
2
Da y  
 
7 
V i s i t  3 
D ay  
 
1 4 
V i s i t  
 
4 
D a y 
 
2 8 
E nd  of  T r e at m e nt  
V i s i t  
 
5 
D a y  
 
8 4 
E nd  
 
o f  
 
s t u d y  
V i s i t  
 
6 
F OL L O W - U P 
D O U BL E - BL IN D  TR EA T M EN T 
SE N S - 4 0 1  
 
s el e c t ed  
 
d o s e B I D 
P l ace bo
S c r e e ni ng 
 
V i s i t  1
Day  
 
1 
In c l u s i on
V i s i t  2
Day 
 
7 
V i s i t  
 
3 
D ay  
 
14 
V i s i t  4 
D ay  
 
28
E n d  
 
o f  
 
T r e a t m ent  
 
V i s i t  5
D a y  8 4 
E nd  
 
o f  
 
st ud y 
V i si t  6 


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Each patient’s participation in the study will be 12 weeks: 
• 1 to 4 days screening 
• 28 days of double blind treatment  
• A follow up with no investigational product until 84 Days after inclusion.  
 
7.6 
Determination of end of clinical trial (all patients) 
The first part of the study will be considered complete when all patients randomised in Part 1 
have completed all the scheduled procedures as described in the flow chart (Section 4). 
Any withdrawal from treatment during the 28-day treatment period will be considered as 
treatment discontinuation. 
 
The end of trial will be considered after the last subject last visit.  
 
 


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8 INCLUSION AND EXCLUSION CRITERIA  
Patients will be included if they are presenting with unilateral sudden sensorineural hearing loss 
(noise induced or idiopathic) and have met all the following inclusion criteria and no exclusion 
criteria: 
8.1 
Inclusion criteria  
1. Male or female 
2. Aged at least 18 years old 
3. Patients 
with 
unilateral 
idiopathic 
sudden 
sensorineural 
hearing 
loss 
or 
unilateral/bilateral acute acoustic trauma leading to SSNHL defined by both: 
3.1. At least 1 hearing threshold of 50 dB or more among the 3 most affected contiguous 
frequencies on pure tone audiometric air conduction testing performed 24 hours or less 
prior to first study treatment), and 
3.2. Mean hearing loss of 30 dB or more, averaged across the 3 most affected contiguous 
frequencies on pure tone audiometric air conduction testing (PTA: Pure Tone Average) 
performed 24 hours or less prior to first study treatment), compared with the unaffected 
contralateral ear or reference values from a pre-existing audiogram (dated less than 2 
years) 
4. Patients with sudden hearing loss with onset within 96 hours prior to prior to first study 
drug intake. 
5. Females must meet 1 of the following: Postmenopausal defined as 12 consecutive 
months with no menses without an alternative medical cause or Surgically sterile or 
Abstinent or Practicing highly effective birth control (must agree to use 2 forms of 
contraception [1 of which must be a barrier method]) (Appendix 4) and willing to 
continue to use highly effective contraception for the duration of study participation and 
for 30 days after the final dose of study drug). Women of childbearing potential must 
have a negative pregnancy test at screening before the first dose of study drug is taken.  
Women of childbearing potential are defined as any female who has experienced 
menarche and who is not permanently sterile or postmenopausal. 
6. Male subjects and their female partner(s) must agree to use highly effective 
contraception (must agree to use 2 forms of contraception [1 of which must be a barrier 
method]) (Appendix 4) for the duration of study participation and for 90 days after the 
final dose of study drug. 
7. 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. Bilateral idiopathic hearing loss 
2. Fluctuating hearing loss  
3. History of asymmetric hearing (>20dB difference between ears) to the best knowledge 
of the patient  
4. Severe hearing loss (>90 dB) associated with unilateral (ipsilateral) complete vestibular 
loss.   


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5. History of Ménière’s disease, autoimmune hearing loss, radiation-induced hearing loss, 
acoustic neuroma (schwannoma) 
6. Previous SSNHL in the affected ear within the past 6 weeks 
7. History of otosclerosis, suspected perilymph fistula or membrane rupture, suspected 
retro-cochlear lesion, barotrauma  
8. Congenital or hereditary hearing loss 
9. History of severe head or neck trauma 
10.  Complete loss of peripheral vestibular function on the affected side 
11. Any drug-based therapy for inner ear hearing loss that is ongoing or was performed 
over the past 6 weeks (except oral corticosteroids) 
12. Any ongoing or planned concomitant medication for the treatment of tinnitus until 6 
weeks after administration. 
13. Any therapy known as ototoxic (e.g. aminoglycosides, cisplatin, loop diuretics, quinine 
etc.) at the current time or in the past 6 months prior to study inclusion. 
14. Air-bone gap of greater than 20 dB in 3 contiguous frequencies 
15. Acute chronic otitis media or otitis externa terminated less than 7 days prior to 
randomisation. 
16. History of chronic inflammatory or suppurative ear disease or cholesteatoma   
17. Prior ear surgery of any kind (except ventilating tubes), or cochlear implants 
18. Patients with moderate to severe renal impairment defined by a creatinine clearance ≤ 
60 ml/min (calculated with the Cockroft-Gault formula for patients <65 years old and 
with CKD-EPI creatinine equation or with MDRD equation for patients ≥65 years old) 
19. Treatment with triptans in the 24 hours before inclusion. 
20. History of drug abuse or alcoholism within the last 2 years 
21. Known or suspected ongoing active infection of HIV, Hepatitis B or C, or herpes zoster 
22. Known history of, or concomitant severe hepatic, gastrointestinal, cardiovascular, 
respiratory, neurological (except vertigo or tinnitus), hematological, renal, 
dermatological or psychiatric disease or substance abuse or any condition that, in the 
opinion of the Investigator might interfere with the evaluation of study treatment or 
warrant exclusion (see list of discontinuation criteria, section 11.3.2) 
23. Patients who, in the opinion of the investigator, have any clinically relevant findings 
that warrant exclusion.  Examples of clinically relevant problems include, but are not 
limited to, 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 
24. Neurological disorders including stroke, demyelinating disease, brain stem or 
cerebellar dysfunction within the last 3 months. (In case of possible stroke of the 
brainstem or cerebellum, or demyelinating disease the diagnosis should have been 
excluded by a MRI performed in the past 48 hours) 


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25. Known hypersensitivity, allergy or intolerance to the study medication or any history 
of severe abnormal drug reaction 
26. Pregnant or breast-feeding  
27. Mentally unable to understand the nature, objectives and possible consequences of the 
trial, or refusing its constraints 
28. Treatment with any investigational agent within 4 weeks prior to randomisation or 5 
half-lives of the investigational drug (whichever is longer) 
29. Prior participation in a clinical trial with SENS-401 or any past treatment with 
azasetron.  
30. 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. 
31. Patients with either a history of significant arrhythmia, or a history of conditions known 
to increase the proarrhythmic risk (e.g., congestive heart failure, long QT Syndrome, 
hypokalemia etc...). 
 
 
 


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9 
 TREATMENT  
9.1 
Investigational Product 
SENS-401 14.5 mg tablets (10 mg free base), with a matching placebo 
 
Doses in Part 1:  
• 
29 mg dose group: 2 tablets of 14.5 mg SENS-401 and 1 tablet of matching placebo 
twice daily (morning and evening), oral route 
• 
43.5 mg dose group: 3 tablets of 14.5 mg SENS-401 twice daily (morning and 
evening), oral route 
• 
Placebo group: 3 matching placebo tablets twice daily (morning and evening), oral 
route 
Doses in Part 2:  
• 
29 mg dose group:  2 tablets of 14.5 mg SENS-401 and 1 tablet of matching placebo, 
twice daily (morning and evening), oral route Depending upon the final dose 
selected, if this dose is the non-selected dose, it will be stopped immediately after 
the decision is taken  
• 
43.5 mg dose group or 3 tablets of 14.5 mg SENS-401, twice daily (morning and 
evening), oral route. Depending upon the final dose selected, if this dose is the non-
selected dose, it will be stopped immediately after the decision is taken  
• 
Placebo group: 3 matching placebo tablets twice daily (morning and evening), oral 
route 
Duration:  Given for 28 days.  
 
Administration Route: The tablets must be swallowed  with water 
 
9.2 
Non-Investigational Product 
There is no medical treatment recommended by the medical societies. However, all patients 
will receive concomitantly oral corticosteroids, unless contra-indicated, which is standard of 
care treatment. The type and dose will be at the discretion of the investigator and recorded in 
the e-CRF. Administration of intratympanic treatments, including corticosteroids, is not 
authorized until day 14. A rescue treatment with intratympanic corticosteroids may be proposed 
from day 14 in case of non-response. 
 
9.3 
Description of blinding methods 
The SENS-401 and placebo tablet are identical.  
 
Two lists of randomisation using a 1:1:1 randomisation ratio will be generated for the whole 
study, one for the French sites involved in the ancillary study and one for all the other sites 
globally, including French sites not participating in the ancillary study.  


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During Part 1, the 3 treatment arms will be used. During Part 2 the 3 treatment arms will 
continue to be allocated until one active dose is selected. After dose selection, only the 
placebo and the selected active dose will continue to be allocated. 
 
The lists of randomisation will be generated centrally, and the investigator, the sponsor study 
team, the CRO or subjects will be blinded to the Investigational drug administration. The lists 
of randomisation will be stratified by the duration of the disease at baseline (≥24 hours or < 24 
hours) and oral corticosteroids intake at baseline (no, yes).  
 
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 randomisation code except under special circumstances. 
In case of an emergency, when knowledge of the randomisation status is deemed necessary for 
the medical care of the patient, the randomisation code can be unblinded for a specific patient 
(see section 11.3.4).  
 
9.4 
Randomisation process 
The randomisation will be managed centrally using an interactive web response system 
(IWRS). The IWRS allocates a treatment number to the patient according to the relevant 
randomisation list (non ancillary study sites or ancillary study sites), and the further 
stratification on the duration of the disease (≥24 hours or < 24 hours), and oral corticosteroids 
intake at baseline (no, yes). During the course of the study, one of the two active treatment arms 
may be disabled (dose dropped after decision of Part 2). 
 
A patient will be considered randomised when the IWRS has given the treatment number to be 
allocated. 
 
All randomised subjects (Day 1) will receive either SENS 29 mg, or SENS 43.5 mg or Placebo 
treatment at the study site according to the IWRS allocation. 
The treatment will be then self-administered twice daily to all patients for 28 days. 
A patient cannot be randomised more than once during the study. 
9.5 
Packaging and labeling 
SENS-401 and matching placebo will be inserted in bottles with a child resistant cap. The 
bottles are packaged and labeled into a sealed clinical pack that includes 3 bottles including 30 
tablets each of the investigational product or placebo for a 14-day administration including 1 
additional day (rescue tablets). Twice daily, each patient will take 3 tablets (one tablet from 
each of the 3 bottles) included in one assigned pack. Each patient will receive 2 clinical packs 
(inserted into a final pack) according to the randomisation lists. During the 28-day treatment 
period, in exceptional case of any bottle being lost, the IWRS can allocate a replacement 
treatment number to a patient. The first dose to be administered at the study site will be taken 
out from one of the clinical packs that will be dispensed to the patient on Day 1 (visit 2), to be 
taken home. The content of the labeling is in accordance with the local regulatory specifications 
and requirements. 
 


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9.6 
Accountability and compliance 
The date and time of the first intake will be recorded on the eCRF. 
The patient will be instructed to return all used and unused investigational kits at every on-site 
visit. He/she will be provided a diary to record the intake of IP (number of tablets, date and 
time). The investigator or designee will count the returned tablets and complete the 
corresponding e-CRF. 
 
The type and dose of corticosteroids will be recorded on the eCRF. The patient will record the 
intake of corticosteroid in the diary. Corticosteroids intake will be also recorded on the e-CRF, 
based on the patient’s information. 
9.7 
Storage conditions 
SENS-401 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 regulation, and label specifications.  
Patients should be warned to store the treatment according to the labeling and out of reach of 
children. They will be warned not to take the tablets out of the bottles in advance. They will be 
requested to return the bottles with the remaining tablets at the following on site visit. 
9.8 
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.  
9.9 
Management of treatment at the end of the study 
All partially used or unused investigational product (IP) will be returned to Sensorion or 
designee 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. 
9.10 Concomitant treatment  
9.10.1  Background therapy 
Corticosteroids by oral route (including but not limited to prednisone, methyl prednisolone, 
dexamethasone) are usually considered as the standard of care (Appendix 6). The guidelines 
published by the AAO-HNS recommend prednisone for patients with SSNHL within 2 weeks 
after the diagnosis, with a recommended dose of Prednisone 1 mg/kg/day (max: 60 mg/day), or 
Methylprednisolone 48 mg/d or Dexamethasone 10 mg/d given as a single dose for 7-14 days, 
then taper over similar time period. Since there is no harmonization on this clinical practice, 


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each site will be requested to pre-specify the type and dosage regimen of oral corticosteroid 
that will be given to patients as standard of care. Unless contra-indicated, the pre-specified oral 
corticosteroids will be prescribed to all patients at a given site. The time, dose and route of 
administration will be recorded on the e-CRF. The randomisation will be stratified according 
to the corticosteroid intake. Compliance of the corticosteroids intake will be assessed by the 
investigator at every on-site visit from the patient diary. Any contra-indication will be recorded 
on the e-CRF at the sites.  
9.10.2 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 new 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 on the e-CRF. 
9.10.3 Not permitted concomitant medication 
The medications listed below are not permitted, unless in exceptional circumstances (see 
below rescue medication): 
Corticosteroids by intratympanic route (including but not limited to prednisone, methyl 
prednisolone, dexamethasone) is not permitted except from D14 where they can be given as 
rescue medication (see criteria in section 9.9.3.) 
Other intratympanic treatments  
Hyperbaric oxygen 
Antivirals, vasodilators, vasoactive substances, or antioxidants. In case of chronic treatment for 
reasons other than inner ear diseases, these agents can be continued but the dose regimen must 
not be modified until the end of the treatment period 
Any investigational drug,  
Any ototoxic treatment (e.g. aminoglycosides, cisplatin, loop diuretics, quinine etc.) 
Initiation of antidepressant treatment containing serotoninergic agents within the previous 24 
hours (see non-exhaustive list of serotoninergic agents in Appendix 7) due to the risk of 
serotoninergic syndrome.  
Substrates of BCRP and transporter (see non-exhaustive list in Appendix 8) 
5 HT3 antagonists (ondansetron, tropisetron, palonosetron, granisetron etc..) and calcineurin 
inhibitors (cyclosporine, tacrolimus, azasetron) 
Any additional medication aiming at treating SSNHL must be discussed with the monitoring 
team. 
9.10.4  Rescue medication 
Despite the absence of evidence, the American Academy of Otolaryngology- Head and neck 
surgery (AAO-HNS) recommends the use of rescue treatment to patients without hearing 
improvement. Hearing is considered improved if the change in hearing loss is 10 dB or more 
in the 3 contiguous frequencies compared to the worst hearing threshold of the affected ear as 
identified at study entry. Rescue medication consists of intratympanic administration of 
corticosteroids (Appendix 6). The type of drug and number of injections are not specified. 
Rescue medication may be proposed from Day 14 only in patients without hearing 


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improvement as defined above. The rescue medication (date, dose, indication) should be 
recorded on the e-CRF. 


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10 STUDY ASSESSMENTS 
Test equipment, test environment, and test procedures must meet all relevant national standards 
and guidelines. All audiologic testings should be conducted in a quiet testing environment 
meeting appropriate current standards. The patients should be seated in a comfortable position. 
Before each audiologic evaluation, a quiet period or lack of noise for 16 to 24 hours is required. 
For a given patient, the same certified and trained audiologist will perform the tests. Any 
exception should be justified. 
10.1 Efficacy assessments 
10.1.1 Pure Tone Audiometry 
Pure tone audiometry is considered the diagnostic gold standard for assessing SSNHL (11) (24). 
The primary purpose of pure tone audiometry is to determine the degree, type and configuration 
of hearing loss as its measurement covers the entire auditory pathway from the external ear to 
the cortex.  
 
It is a standardized subjective hearing test in which air and bone-conduction hearing thresholds 
in decibels (dB) for a set of fixed frequencies between 0.25 kHz and 8 kHz are plotted on an 
audiogram for each ear independently. 
 
Audiometry will be performed in order to determine the pure-tone air-conduction and bone-
conduction thresholds for each ear according to the recommended procedure of the British 
Society of Audiology and the guidelines of the American Speech Language Hearing 
Association (ASHA).  
 
The detailed procedures will be described in a specific manual. All materials will need to be 
calibrated before the study start and on a monthly basis, following ASHA, American 
Association of Autology (AAA), American National Standards Institute (ANSI) 
recommendations and military standards where applicable (6), (7), (8), (9). 
 
At the inclusion visit, pure-tone air-conduction testing should be immediately repeated at 1 and 
2 kHz to determine that the subject provides reliable responses. Responses are considered 
reliable if retest thresholds at both frequencies do not exceed ±5dB of the previously obtained 
threshold response.  
 
Pure tone air and bone conduction thresholds will be determined for each ear (best ear at first) 
at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz for air conduction and 0.5, 1, 2, 3, 4 kHz for bone conduction 
using the descending method of limits (modified Hughson Westlake procedure as follows: 
initial descent towards threshold is accomplished in 10-dB steps. Beginning with the first non- 
response, level is increased by 5-dB for each non- response and decreased by 10-dB after each 
correct detection response.  
 
The baseline pure tone audiometry test is the last test performed at site within 24 hours prior to 
the first study drug administration. In case of longer time or if a pure tone audiometry test  was 
performed elsewhere than at study site, the test should be repeated prior to the first study drug 
intake. If a screening test has been performed at the study site within 24 hours prior to the first 
study drug intake, there is no need to repeat it.  
 


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The hearing threshold is defined as the lowest audible level, measured twice out of three 
presentations for that patient. The thresholds at each frequency for each ear for both air and 
bone pure tone audiometry will be recorded on the e-CRF at each study visit. The information 
will be captured in case of no response because of profound hearing loss. 
 
The hearing loss will be determined as follows: Difference between the mean hearing threshold 
at the 3 most affected contiguous test frequencies (air pure tone average) and the corresponding 
mean hearing threshold of the contralateral ear or  values from a pre-existing audiogram (dated 
less than 2 years) for the same frequencies (mandatory for bilateral acute acoustic trauma). 
The Pure tone average frequencies determined at baseline will remain fixed for all evaluations. 
In case of bilateral acute acoustic trauma leading to sudden sensorineural hearing loss, the most 
affected ear according to the inclusion criteria will be considered for the analysis. If both ears 
are equally affected, the right ear will be considered. 
In case of one missing frequency in any of the post baseline measurement, the PTA will be 
determined on the 2 out of the 3 available frequencies. An absolute improvement of 10dB is 
considered clinically meaningful. 
 
10.1.2  Speech audiometry  
Speech audiometry is a diagnostic hearing test designed to test word or speech recognition. It 
has become a fundamental tool in hearing-loss assessment. In conjunction with pure-tone 
audiometry, it can aid in determining the degree and type of hearing loss. Speech audiometry 
also provides information regarding discomfort or tolerance to speech stimuli and information 
on word recognition abilities.  
Speech audiometry will be performed according to the guidelines of the American Speech 
Language Hearing Association (10). 
 
The Speech recognition threshold is the minimum hearing level at which the patient can 
correctly recognizes the speech stimuli 50 % of the presented speech material. Spondaic words 
are the usual and recommended test material for the speech recognition threshold; spondaic 
words are two-syllable words with equal stress on both syllables (e.g. birthday) 
According to the ASHA guidelines, patients will be familiarized with the spondaic words prior 
to the test. Patients will listen to the list of words and indicate if any are unfamiliar. These words 
can be eliminated from the list. The median speech reception threshold (SRT) for normal 
listeners is 20 dB SPL (0 dB HL). 
The standard amount of time given for the patient to respond is approximately four seconds. 
The list of spondees adapted to local languages will be standardized across all centers in a given 
country. 
The speech recognition threshold will be recorded on the e-CRF.  
 
The speech discrimination or word recognition is the ability to repeat correctly an open set 
of monosyllabic words at supra threshold intensity. The word recognition score (WRS) is the 
percentage of test words correctly repeated by the patient. 
The test will be administered in a quiet room without any competing noise. Word lists are 
derived from a standard list with language-specific monosyllabic words. 
Words are presented randomly to each ear separately, with contralateral masking. They are 
phonetically balanced, meaning that the speech sounds used occur with the same frequency as 
in the whole language. In order to alert the patient, patients will be instructed to repeat the word, 
as follows: “(Say the word …)”.   
At the inclusion visit (day 1) visit 2, words will be presented at 60dB and 80dB. The WRS 
(percent correct rate) will be further derived by computerization.   


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An absolute improvement of >15% is considered clinically meaningful. 
 
10.1.3  Tinnitus 
Tinnitus is often associated with SSNHL. It is defined as the hearing of sound when no external 
sound is present. While often described as a ringing, it may also sound like a clicking, hiss or 
roaring.  
If the patient presents tinnitus in both ears, only the severity of the tinnitus in the ear affected 
by SSNHL will be assessed on a numerical scale (NRS). For the Tinnitus NRS, the patients will 
be asked to rate tinnitus loudness ‘‘right now’’ on a scale scored from 0 (no tinnitus) to 10 
(extremely loud). The Tinnitus NRS score will be recorded on the e-CRF at each study visit. 
In addition, the patients will be given a diary for recording the presence and the severity of the 
tinnitus (if any) on a daily basis during the first 14 days of treatment. 
10.1.4 Vertigo 
The presence and severity (if relevant) of the vertigo will be assessed on a numerical scale. For 
the vertigo NRS, the patients reporting vertigo will be asked to assess if present and rate its 
severity ‘‘right now’’at V2, then in the past week from V3 on a scale scored from 0 (no vertigo) 
to 10 (extreme vertigo). The vertigo NRS score will be recorded on the e-CRF at each study 
visit. 
 
10.1.5  QoL 
1) EQ-5D-5L  
Hearing loss with tinnitus can affect the patient quality of life which can be assessed by various 
tools including EuroQoL (28).  
EQ-5D is a standardized measure of health status developed by the EuroQoL Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal. EuroQoL, 
consists of two parts: the health-status descriptive system (EuroQoL 5-dimension, EQ-5D) and 
the EQ visual analogue scale. 
The EQ-5D-5L version records the level of self-reported problems according to five dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).  
Each dimension is assessed based on a single question with five response levels (no problem, 
slight problems, moderate problems, severe problems and extreme problems), to indicate 
his/her health state by ticking the box next to the most appropriate statement in each of the five 
dimensions. This decision results in a 1-digit number that expresses the level selected for that 
dimension. The digits for the five dimensions can be combined into a 5-digit number that 
describes the patient’s health state. 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale ranging 
0 to 100, where the endpoints are labelled “The best health you can imagine” (100) and “The 
worst health you can imagine” (0). The VAS can be used as a quantitative measure of health 
outcome that reflect the patient’s own judgement. 
The EQ-5D-5L will be completed at every visit from visit 2. Results will be recorded on the e-
CRF (see appendix 2).  
 


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2) The tinnitus functional index (TFI)  
The impact of tinnitus on quality of life will be also assessed through a specific scale, the 
Tinnitus functional Index (TFI) (26) (see Appendix17). 
The TFI comprises 25 questions on the impact of the tinnitus on the individual behavior and 
feelings.  It includes eight subscales that address the intrusiveness of tinnitus, the sense of 
control the patient has, cognitive interference, sleep disturbance, auditory issues, relaxation 
issues, quality of life, and emotional distress.   
The TFI will be completed at every visit from visit 2. Results will be recorded on the e-CRF  
 
10.1.6 Otoacoustic emissions (optional) 
Otoacoustic emissions (OAEs) are low-intensity sounds generated by the inner ear when the 
cochlea is stimulated by a sound (functioning outer hair cells of the cochlea). When sound 
stimulates the cochlea, the outer hair cells vibrate. The vibration produces a nearly inaudible 
sound that echoes back into the middle ear. The sound can be measured with a small probe 
inserted into the ear canal. 
OAEs recording is an objective neurophysiological test reflecting the function of the inner ear 
outer hair cells (OHCs) (29).  
People with normal hearing produce emissions. Those with hearing loss greater than 25–30 
decibels (dB) do not produce these very soft sounds.  
The evoked OAEs include the transient evoked otoacoustic emissions (TEOAEs) and the 
distortion products otoacoustic emissions (DPOAEs). TEOAEs and DPOAEs are either present 
(recordable) or absent (non-recordable) in physiological conditions.  
Some authors suggested a potential role of TEOAEs and DPOAEs early evaluation in the 
prediction of the ISSNHL prognosis (48). The early detectability of TEAOAEs and DPOAEs 
preceding pure tone audiometry hearing improvement might be explained by the high 
sensitivity of those testing modalities of changing the outer hair cells activity.  
 
OAEs are measured by acoustic stimuli such as a series of very brief clicks to the ear through 
a probe that is inserted in the outer third of the ear canal. The probe contains loudspeakers that 
generate the clicks and a microphone for measuring the resulting OAEs. OAE testing requires 
no behavioral or interactive feedback by the individual being tested. 
 
Two pure tones (f1, f2) are simultaneously presented at 2 separate frequencies. DPOAEs 
originate from the cochlea when the two tones are closely related frequencies that activate the 
cochlea at a specific region of the basilar membrane corresponding to the f2 frequency. The 
DPOAEs are thought to reflect the outer hair cells activity at the supra-threshold level (31). 
For the TEOAE, a single brief click that covers a broad frequency range activates wide regions 
of the basilar membrane and reflects the OHCs activity at the threshold level (cochlear 
function). 
 
Thus, although both evoked OAEs measure the OHCs function, they reflect different ranges of 
their activity. Presence or Absence of TEOAEs and DPOAEs will be recorded on the e-CRF at 
each study visit, at sites conducting these tests. 
For each tested frequency, the results of the 2f1-f2 level and of the Signal-to-noise ratio S/N (in 
dB SPL) will be recorded in the e-CRF for DPOAE.  
For each tested frequency, the results of the Echo SPL level and of the Signal-to-noise ratio 
S/N (in dB SPL) as well as the Whole Wave reproducibility (WWR) (%) of the test for each 
ear will be recorded in the e-CRF for TEOAE. 


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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 height, weight, Body Mass Index (BMI) and evaluation of 
main body systems/regions, including: skin and mucous, eyes/nose/throat, pulmonary, cardiac, 
gastro-intestinal and neurological systems is to be conducted at the screening visit (Visit 1), 
End of treatment (Visit 5) and End of Study (Visit 6).  
A specific attention will be paid to neurological, head and neck, as well as otologic systems. 
Care should be taken to examine and assess any abnormalities that have been indicated as 
potentially present by medical history.   
 
10.2.2 Otologic and audiologic examination  
Otoscopy is to be done just before each hearing assessment at every visit to rule out possible 
outer-ear abnormality, such as otitis media, tympanic perforation. It is part of the standard of 
care. Tympanometry will follow the otoscopy in order to test the condition of the middle ear 
and mobility of the eardrum (tympanic membrane) and the conduction bones by creating 
variations of air pressure in the ear canal. There is no need to repeat the tests if it has been 
conducted within 6 hours prior to the screening visit.  
 
10.2.3 Vital signs 
Vital signs including temperature, systolic (SBP) and diastolic (DBP) blood pressures, heart 
rate will be collected after 10 minutes rest in the supine position. 
Vital signs will be measured at each study visit, if possible, prior to blood draw (when relevant). 
 
10.2.4 Electrocardiogram (ECG) 
A standard digitalized 12-lead electrocardiogram (ECG) will be performed at baseline (Visit 2) 
prior to randomisation, on Day 7 (Visit 3), Day 14 (Visit 4), and End of treatment visit Day 28 
(Visit 5).  Each ECG will be triplicated. Ideally at V4 and V5 least one of the PK samples 
MUST be collected within 15 minutes of the 3rd ECG test being performed. 
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 digitalized ECG, collected in 
triplicate, will be managed with a central reading. Corrections of the QT interval will be 
calculated using Fridericia's and Bazett's formula. Changes from the baseline QT interval will 
also be assessed. 
 
10.2.5  Laboratory safety 
A standard laboratory blood test will be performed at the screening visit (Visit1), on Day 14 
(Visit 4), and End of treatment visit Day 28 (Visit 5) also performed in case of Early termination 
between Visit 2 and Visit 5.  Routine serum hematology and chemistry samples will be 
collected in EDTA tubes and according to the study flow chart. They will be kept at the local 


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laboratory as per laboratory requirements and outlined in the investigator manual which will be 
available at each investigational site.  
 
The standard laboratory blood test comprises: 
• haematology: complete blood count (CBC) including haematocrit, haemoglobin, red blood 
cell count, white blood cell count with differential count and platelets, 
• Serum chemistry including: sodium, potassium, chloride, calcium, phosphorous, urea, 
creatinine, creatinine clearance (calculated with the Cockroft-Gault formula for patients 
<65 years old and CKD-EPI creatinine equation or with MDRD equation for patients ≥65 
years old), uric acid, total protein, albumin, lactate dehydrogenase (LDH), Alanine 
Aminotransferase (ALT), Aspartate Transaminase (ASAT), alkaline phosphatase, GGT and 
total bilirubin, fasting glycaemia (fasting is not required at baseline), creatine 
phosphokinase (CPK), triglycerides, cholesterol. 
• Glucose (no fasting is needed at screening) 
• C Reactive Protein (CRP). 
• A urine or blood pregnancy test (in females of childbearing potential) will be performed at 
the screening visit, on D14 (Visit 4), end of treatment visit (D28 visit 5) and end of study 
visit (D 84 Visit 6). 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. For practicability, urine 
samples may be replaced by blood samples.  
 
No centralized laboratory procedure for laboratory safety is planned. Only local laboratories 
will be used. 
 
10.2.6  Adverse event collection 
Adverse events will be collected throughout the study and at every visit after consent. The 
medically-qualified investigator will be available to provide clinical judgment on all trial-
related medical issues including adverse events and clinical laboratory values. 
As a precautionary measure, specific attention will be paid to any potential serotoninergic 
syndrome, particularly the following symptoms agitation, mental status changes (confusion, 
hypomania), myoclonus, shivering, tremor, hyperreflexia, ataxia, severe diarrhea or high fever 
will be checked carefully. 
10.2.7 Suicidality assessment: 
As per FDA guidelines for any neurologic investigational product, a suicidality assessment will 
be performed via the C-SSRS questionnaires (42) that will be completed at every visit from  
visit 2 until end of treatment visit (visit 5) by a trained personal. A series of questions about 
suicidal thoughts and behaviors will be asked. To most quickly and simply identify whether a 
person is at risk and needs assistance, a minimum of two and a maximum of six questions, 
depending on the answers will be asked. The patient should answer yes or no to the questions. 
The C-SSRS questions use plain and direct language, which is most effective in eliciting honest 
and clear responses. This scale has been widely used in clinical trials and is translated in many 
languages. It has been validated by most of health authorities.  
Results could trigger decisions about hospitalisation, counseling, referrals, and other actions.  
If any, an adverse event form should be completed.  


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10.3 Pharmacokinetic evaluation  
Serum samples will be collected for pharmacokinetic (PK) analysis on Day 14 (Visit 4) and 
End of treatment visit (Visit 5): for more details, please refer to the laboratory manual.  Ideally 
at least one V4 and V5 PK samples MUST be collected within 15 minutes of the 3rd ECG test 
being performed. Blood samples will be drawn, handled and stored in a secure location as per 
laboratory requirements, outlined in the laboratory manual which will be available at each 
investigational site, until shipment. The date and hour of the last drug intake and blood sampling 
will be recorded.  
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 Biomarker 
Prestin has been described as a potential prognosis biomarker (40). Serum samples will be 
collected for prestin dosage at inclusion (Visit 2), or screening (Visit 1) in case the screening 
and inclusion visits are planned to be performed within 24hrs (to prevent an additional blood 
draw for a small blood volume), on Day 14 (Visit 4), and End of treatment visit (Visit 5). Blood 
samples will be drawn, handled and stored in a secure location as per laboratory requirements, 
outlined in the laboratory manual which will be available at each investigational site, until 
shipment. The date and hour of the last drug intake and blood sampling will be recorded. 
 
 
 


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11 STUDY PROCEDURES 
11.1 Visits 
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 the follow-up visits during the defined window 
periods. 
A final follow-up visit is required for all patients. In the rare cases the End of Study Visit (V6) 
cannot occur, any attempt to contact the patient should be recorded on a special contact form, 
until/unless appropriate information is obtained which will allow completion of final follow-up 
visit in the e-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 concerned patient. 
Patients will be advised to avoid skin exposure to strong sunlight and to wear sunglasses in 
bright sunlight for the duration of the study and for 1 week after the last dose. 
 
11.1.1  Screening visit - Visit 1 (Day-4 to Day 1) 
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 the investigator or a fully 
designated person, 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 e-CRF Portal, site 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, including body weight and evaluation of main body 
systems/regions, 
• Otologic examination and tympanometry 
• Pure tone audiometry test unless performed within 24 hours prior to screening. 
• Previous Medical, surgical and otologic history 
• Concomitant medications (over the past 3 months) 
• Recording of concomitant medication including oral corticosteroid use for SSNHL 


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• Vital signs: supine blood pressure and heart rate, temperature 
• Blood collection for routine hematology, serum chemistry (section 9.2.4) 
• Pregnancy test (for WOCBP) 
 
If the patient meets all inclusion and no exclusion criteria (per history, exam and laboratory) 
the patient can be included in the study and will therefore be randomised.  
 
11.1.2 Baseline visit - Visit 2 (Day 1) 
The following tests and procedures will be performed: 
 
• Re-confirmation of eligibility by reviewing inclusion/exclusion criteria 
• Checking for Concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• Recording of concomitant medication including oral corticosteroid use for SSNHL 
• Vital signs: blood pressure and heart rate, temperature 
• 12-lead digitalised ECG 
• Otologic examination and tympanometry* 
• Audiometric tests: pure tone audiometry*, OAE tests (optional)  
• Word and speech recognition Tests 
• Serum sample for Prestin concentration (before study drug intake) 
 
The patient will be asked to complete specific questionnaires: 
 
• Tinnitus and Vertigo presence and severity (NRS)  
• QoL: EQ-5D-5L;  
• TFI 
• C-SSRS 
*Pure tone audiometry should be performed within the last 24 hours before the first study drug 
intake. In case of longer time or not performed at the study site, the Pure tone audiometry should 
be repeated. If a Pure tone audiometry was performed at the study site for screening less than 
24 hours before the first study drug intake, there is no need to repeat it. 
After all assessments have been completed, the investigator will connect to the IWRS for 
allocation of a randomised 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 3 tablets (one from each bottle 
of one clinical pack). Date and time of the intake should be recorded on the patient diary and e-
CRF. 
The patient will be given the treatment carton to be taken home and asked to complete a patient 
diary for IP and corticosteroid compliance. The patient will be instructed to return his/her 
treatment carton and diary at the following visit.  


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The patient will also be asked to record tinnitus presence and intensity in the SSNHL affected 
ear on a daily basis in the patient diary. He will be asked to return the diary at the following 
visit. 
11.1.3  Visit 3 (Day 7 ±2)  
The following tests and procedures will be performed: 
 
• Checking for concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• Checking the patient’s diary for tinnitus 
• The investigator or designee will check the IP and oral corticosteroids diary for 
compliance. 
• Vital signs: blood pressure and heart rate, temperature 
• 12-lead digitalized ECG 
• Otologic examination and tympanometry 
• Audiometric tests: Pure tone audiometry, OAE tests (optional) 
• Word and speech recognition Tests 
 
The patient will be asked to complete specific questionnaires: 
• Tinnitus and Vertigo presence and Severity (NRS)  
• QoL: EQ-5D-5L;  
• Tinnitus functional Index (TFI) 
• C-SSRS 
 
The patient will be asked to complete a new patient diary for IP and corticosteroid compliance. 
The patient will be instructed to return his/her treatment carton and diary at the following visit. 
The patient will be given back the treatment carton to be taken home. The patient will be 
reminded to record tinnitus presence and intensity in the SSNHL affected ear on a daily basis, 
and IP and corticosteroid intake. He will be asked to return the diary at the following visit, and 
to come in a fasting condition and not take the morning IP dose whenever the visit 4 is scheduled 
in the morning to allow a Pre-dose PK at Visit 4. 
 
11.1.4  Visit 4 (Day 14 ±2)  
The following tests and procedures will be performed: 
 
• Checking for concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• The investigator or designee will check the IP and oral corticosteroids diary for 
compliance  
• Checking the patient’s diary for tinnitus 
• Otologic examination and tympanometry 


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• Vital signs: blood pressure and heart rate, temperature 
• 12-lead digitalised ECG 
• Blood collection for routine hematology and serum chemistry (section 9.2.4) 
• Serum sample for prestin and plasma sample for drug concentrations 
• Audiometric tests: Pure tone audiometry and OAE tests (optional) 
• Word and speech recognition Tests  
• Pregnancy test (for WOCBP) 
In case rescue medication is administered, please report in the e-CRF 
The patient will be asked to complete specific questionnaires: 
 
• Tinnitus and Vertigo Presence and Severity (NRS)  
• QoL: EQ-5D-5L;  
• TFI 
• C-SSRS 
 
The patient will be asked to complete a new patient diary for IP and corticosteroid compliance. 
The patient will be instructed to return his/her treatment carton and diary at the following visit,  
The patient will be instructed to return all used and unused study treatment bottles at the 
following visit and to come in a fasting condition. 
 
11.1.5  Visit 5: End of Treatment Visit (Day 28±3) 
The following tests and procedures will be performed: 
 
• Checking for concomitant medication 
• Inquiring about adverse event and fill an adverse event form if any 
• The investigator or designee will count the returned IP tablets  
• The investigator or designee will check the oral corticosteroids diary 
• Otologic examination and tympanometry 
• Complete Physical examination including weight and evaluation of main body 
systems/regions, 
• Vital signs: Blood pressure and heart rate, temperature 
• 12-lead digitalized ECG 
• Audiometric tests: Pure tone audiometry and OAE tests (optional)  
• Word and Speech Recognition Tests  
• Blood collection for routine hematology and serum chemistry (section 9.2.4) 
• Serum sample for prestin and plasma sample for drug concentrations 
• Pregnancy test (for WOCBP) 


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In case rescue medication has been administered, please report in the e-CRF. 
 
The patient will be asked to complete specific questionnaires: 
 
• Tinnitus and Vertigo Severity (NRS)  
• QoL: EQ-5D-5L  
• TFI 
• C-SSRS 
 
11.1.6  Visit 6 End Study visit (Day 84±3)  
The following tests and procedures will be performed at Visit 6 and in the case of premature 
withdrawal during the study (i.e. prior to Visit 6): 
 
• Inquiring about adverse event and fill an adverse event form if any 
• Checking for concomitant medication 
• Physical examination including weight and evaluation of main body systems/regions, 
• Vital signs: supine blood pressure and heart rate, temperature 
• Otologic examination and tympanometry 
• Audiometric tests: Pure tone audiometry and OAE tests (optional) 
• Word and Speech recognition Tests  
• Pregnancy test (for WOCBP) 
 
The patient will be asked to complete specific questionnaires: 
 
• Tinnitus and Vertigo Severity (NRS)  
• QoL: EQ-5D-5L 
• TFI   
 
11.1.7 Unscheduled Visit: Visit 99 
In case of adverse event, abnormal values or dispensation of a replacement IMP kit, an 
additional visit may be needed to repeat the test or document an adverse event or to dispense a 
new IMP kit. 
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 Appendix 5. 
The results of certain investigations or assessments included on the e-CRF may be considered 
to be raw data. Direct e-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. 
 


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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 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 (V6) if discontinuation occurs after Visit 5 or the 
end of Treatment Visit (V5) if discontinuation occurs before Visit 5.   
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…). 
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. 
Subjects may be removed from the study by the investigator or the sponsor, if one or more of 
the following occurs: 
• Any serious or severe (CTCAE GRADE 3) related adverse event will lead to permanent 
treatment discontinuation   
• Adverse events of lesser grade should be evaluated in the context of concomitant clinical 
and laboratory findings and, in the judgment of the Investigator and responsible medical 
officers, may be cause for temporary or permanent discontinuation of treatment for an 
individual subject. If interruption of treatment for an individual subject is required due to 
adverse events more than once during the trial, then the subject will be withdrawn from 
further treatment.  
• Significant laboratory abnormalities  
− Confirmed ALT > 5 ULN (or > 3 times baseline value if ALT > ULN at baseline) 
or in case of confirmed ALT >3 ULN and total bilirubin >2 ULN (unless the patient 
has Gilbert’s disease documented by genetic testing)  
− Confirmed, non-rapidly reversible, increase in serum creatinine ≥ 1.7 mg/dL  
(150 μmol/L) or rapid decrease in creatinine clearance reaching < 50 ml/min-  
− Confirmed rhabdomyolysis (CPK should be controlled in case of suspicion) 
− Confirmed decline in hemoglobin of > 3 g/dL compared to baseline and hemoglobin 


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level grade 1 (< LLN - 10 g/dL) or higher of CTCAE terminology  
− Confirmed platelet count < 100,000 cells/mm3 with or without spontaneous 
bleeding   
− Confirmed decline in total white blood cell count of > 50% compared to baseline 
and white blood cell count grade 1 or higher of CTCAE terminology (< LLN - 
3000/mm3)  
− Confirmed neutrophil count < 1500/mm3 with or without signs of infection  
− Confirmed decline in lymphocyte count of > 50% compared to baseline and 
lymphocyte count grade 2 (< LLN - 500/mm3) or higher of CTCAE terminology 
− Confirmed elevated INR grade 3 (> 2.5 x ULN) or higher of CTCAE terminology   
− Confirmed QTc > 500 ms  
Note: Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of IMP for the concerned 
patient.  
• Any adverse events, per investigator judgment, that may jeopardize the patient safety   
• Any patient with a temporary discontinuation for safety reasons that is greater than or 
equal to 10 consecutive days from last IMP administration  
• Any treatment unblinded by the Investigator  
• Noncompliance with study protocol by the subject. 
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 e-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 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 (IP) that could change the current 
benefit-risk profile of the IP or that would be sufficient to require changes in the IP 
administration or in the overall conduct of the trial. 
• The total number of subjects included earlier than expected. 


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• Discontinuation recommended by the DMC after a GST interim look in case of 
futility or because of efficacy of the highest tested dose (see Statistical 
considerations) 
• Unexpected events that could jeopardize the conduct and quality of the study. These 
events could be any of the followings: Conflicts in a specific country, Major climatic 
reasons or earthquakes, Unexpected epidemics (eg. SRAS), Financial issues 
(funding does not match the incurring costs), External constraints that could prevent 
IP distribution etc.…External events not yet identified. 
 
In any case, the exact reason of termination will be specified and the ethics committee informed 
within 15 days after the decision is taken. 
 
11.3.4  Decided by the investigator 
The Investigator could stop the research if in his judgment the participating subjects are exposed 
to risks that are not ethically or scientifically justifiable and must notify in writing the Sponsor 
of this decision providing the reason thereof. 
 
In all cases IEC/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 unfavourable 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. 
Lack of efficacy unless considered serious, should not be reported as adverse event. The 
Pure tone audiometry assessment is part of the efficacy assessment, as well as the 
administration of rescue treatment.  
 
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 hospitalisation or prolongation of existing hospitalisation.  Prolongation 
of existing hospitalisation 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 hospitalisation, 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 hospitalisation; 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. 
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-401, 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 


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of vital signs, supportive care for cardiovascular function, respiratory aid in case of 
compromise, electrolyte balance and other measures as clinically indicated. 
12.3 Pregnancy 
If a female participating in the study becomes pregnant during the study (positive pregnancy 
test after 1 dose), the investigator must stop the treatment and notify it as a Serious Adverse 
event. 
The occurrence of a pregnancy of a partner of a trial subject discovered during the study (start 
pregnancy after 1st dose) or within 10 days after last administration of the IP 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. 
In all cases, the investigator will contribute to the pregnancy follow-up. 
12.4 Reporting of adverse events 
12.4.1 Adverse events 
Any AE occurring after the patient has signed the informed consent must be fully recorded on 
the patient’s e-CRF. The AE form should be supported by a complete documentation available 
in the patient’s file.  
Any abnormal laboratory test or ECG 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 test should be repeated as soon as possible for confirmation. The AE should be fully 
described along with start and stop dates, severity, relations 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 treatment 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). 
 
12.4.2  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 


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and the study 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. 
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/IRB in writing in accordance with current regulations.  
 
12.4.3 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: 
• Unrelated:  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. 
• Probable: assuming a causal relationship; 
• Possible: a causal relationship cannot be excluded  
• Unlikely: a causal relationship with another origin is more likely Unrelated; 
• 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 effect. 
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.  
 
12.5 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 medical monitor by phone or email and the monitoring 
team using the specific e-CRF form. The sponsor or designee will inform the authorities. 


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12.6 Safety follow-up 
• The Investigator should take all appropriate measures to ensure the safety of the 
subjects. All patients 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 
(V6). 
• 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. 
 
12.7 Unblinding procedure 
In case of an emergency, the Investigator can unblind the treatment for a specific patient through 
IWRS that will be available 24h/24h and 7days a week.  
Unblinded subjects must be discontinued from the study. 
 
12.8 General Safety Monitoring 
12.8.1  Data Monitoring Committee 
An external data monitoring committee (DMC), consisting of two or more physicians and a 
statistician, 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, as well as the efficacy when the last 
(Day 28) visit of Part 1 is reached or if an interim GST look recommends premature 
discontinuation of Part 1. 
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 first review is expected to be 
done after 30 patients have completed the study. 
The DMC will meet regularly to review the blinded safety information as follows: 
• The number of screened and included patients and demography (gender, age) 
• The total number of AEs and SAE per treatment groups, displayed by preferred term. 
• The ECG database provided by central reader 
• The clinically significant abnormal laboratory values 
In addition, the DMC members will receive the EDC SAE alerts by email that are automatically 
triggered when a site enters a SAE in the eCRF. The PV representative will provide each SAE 
blinded report for this study to the DMC members for their consideration within 7 days in case 
of fatal or life threatening events or within 15 days in case of other SAEs from the time Drug 
Safety has received the report.  
In case of SUSAR or any other relevant SAE, the DMC will re-evaluate the risk for the 
patients to allow or not the continuation of the study. 


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The final list of adverse events to be reviewed will be discussed and finalized by the DMC 
members during the kick off meeting prior to the start of the study and appended to the signed 
DMC charter. It will be sent upon request to European or National authorities.During Part 1, 
two interim efficacy looks are planned. They will be performed by an independent statistician 
dedicated to the Group Sequential Test (GST) (see section about Possible changes during Part 
1). Each of these interim looks will lead to an automatically generated recommendation to the 
sponsor of continuing the study for efficacy or futility respectively.  
The committee will review the results and will provide further recommendation to the sponsor 
for stopping Part 1for efficacy or futility or continuing the study as planned, until the next look 
or the final analysis of Part 1. 
No information about these results will be communicated to investigators and the International 
Coordinating Investigator until the study is completed or discontinued.  
The committee will be responsible for selecting the active dose to be tested in Part 2. The 
committee will be provided with the unblinded efficacy data on the primary end-point when 
111 patients randomised to Part 1 have completed the 4-week treatment. The DMC may also 
recommend to modify the sample size of the Part 2 study. 
 
 
 


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13 STATISTICAL CONSIDERATIONS  
The two parts of the study (Part 1 and Part 2) will be analysed separately. 
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. 
All statistical analyses will be displayed on total population and on the 2 subgroups: non-
ancillary studiy sites and ancillary study sites. 
SAS Version 9.4 or later will be used for statistical programming.  
 
13.1 Determination of sample size 
The sample size is based on the primary end-point: average change in air conduction derived 
from PTA in dB between the baseline and week 4 (Day 28±3d) on the 3 most affected 
contiguous frequencies.  
 
Part 1: A sample size of 111 patients (37 patients per treatment arm) was retained corresponding 
to following assumptions: 
• 
Each comparison to placebo performed at 5% one-sided significance level (with higher 
dose to be tested first and low dose to be tested conditionally to the high dose 
significance). 
• 
Power of each comparison to placebo set to 7575%. 
• 
Randomisation ratio 1:1:1. 
• 
Intra-group standard deviation of 30 dB is estimated based on recent publication in 
SSNHL with other pharmaceutical therapies and blinded examination of variance (a 
0.45 correlation between Day 28  and baseline). 
• 
A difference to placebo of 15 dB is expected, which would be considered clinically 
meaningful. 
• 
The corresponding fixed design sample size of 105 patients (35 patients per treatment 
arm) was then inflated to 111 patients (37 patients per treatment arm) to allow the use 
of a GST design with 3 looks (2 interim looks and a final look). 
 
This design of Part 1 was introduced in the protocol amendment leading to version 4.0. The 
revised assumption of the intra-group standard deviation (adjusted for baseline) of 30 dB was 
based on a blinded review of the variability of 63 patients, which led to an estimate of the 
adjusted standard deviation more in line with the 27 dB seen in a recent publication in SSNHL 
(52) than with the 20dB seen in the publication used at time of the protocol initiation (53). The 
choice of the power level and of the significance level, combined with the strategy of testing 
the low dose conditionally after the high dose, was guided by the unexpected low recruitment 
rate observed in the study.  The 3-look GST design (interim looks plus one final part 1 analysis) 
was introduced in order to allow an early discontinuation (for futility or for efficacy) of Part 1. 
The first GST look was performed and the outcome was a recommendation to continue Part 1 
in the absence of crossing of any boundary. 
 


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Part 2: A sample size of 190 patients (95 patients per treatment arm) was retained corresponding 
to following assumptions: 
• 
Comparison to placebo performed at 5% two-sided significance level 
• 
Power of the comparison to placebo set to 90%. 
• 
Randomisation ratio 1:1 
• 
Intra-group standard deviation of 20 dB is estimated based on recent publication in 
SSNHL with other pharmaceutical therapies. 
• 
A difference to placebo of 10 dB is expected as considered clinically meaningful 
• 
10% dropout rate 
 
The sample size of Part 2 will be re-estimated based on Part1 results when available.  
The final sample size will be submitted for approval to competent authorities prior to the pivotal 
part start 
 
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 (those who have signed an informed consent),   
• Included subjects (= randomised: those who receive a treatment number), 
• Exposed subjects (those who take at least one dose of randomised study drug), 
• Completed subjects, 
• Reasons for treatment discontinuation 
In summary tables, a breakdown by center and randomised treatment group (3 groups as defined 
in section 7.1) will be given. 
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 randomised 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 randomised 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 randomised subjects as denominator. 
 
13.2.2  Protocol deviations 
Protocol deviations will be identified and classified. These deviations will be described in the 
statistical analysis plan. 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).  
 


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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 randomised patients according to 
randomisation 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 Handling of missing data:  
The primary end-point is the absolute change in PTA (in dB) from baseline to the end of 
treatment visit (D28) based on the average on the 3 most affected contiguous audiometric test 
frequencies identified at baseline.  
The 3 most affected contiguous audiometric test frequencies are the reference and will remain 
fixed for all further calculations. They are defined according to the unaffected contralateral ear 
or values of a pre-existing audiogram dated less than 2 years.  
At baseline, if 2 or more sequences of 3 contiguous frequencies are similarly affected, the index 
sequence with the lower contiguous frequencies will be selected as the reference.  
If one of the frequency is missing for post baseline values, the PTA will be determined on 2 out 
of the 3 identified frequencies. If more than 1 is missing, the PTA will not be calculated.  
 
13.5 Statistical methods 
13.5.1  Analysis of primary efficacy endpoint 
Mean changes from baseline of the PTA at days 7, 14 and 28 will be analyzed using a restricted 
maximum likelihood (REML)-based repeated measures approach.  
Analyses will include the categorical, fixed covariates of site category (non-ancillary, 
ancillary), duration of disease and oral corticosteroids intake at baseline (stratification factors) 
and the fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well 
as the continuous, fixed covariates of baseline score and baseline score-by-visit 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 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 


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full model. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom. 
The estimations and standard errors of the contrasts of interest will be derived from this model. 
The primary comparison(s) to placebo will be the ones at week 4 ; the comparisons to placebo 
at the other visits being seen as secondary. 
The comparison(s) to placebo at week 4 in the 2 interim GST looks and the final analysis of 
Part 1 will be performed at the pre-specified significance level attached to each analysis as 
described later in this section.  
Possible changes  during Part 1 
1-Before the interim analysis a blinded examination of the variance of the primary efficacy 
endpoint will be conducted and compared to the assumption used in planning the study. If this 
comparison suggests the initial assumption was  not optimized, a change in the study sample 
size will be considered. This possible change will be decided before the first GST look is 
performed.   
2-In the absence of literature results, the pre-specified list of covariates used in the main analysis 
is not justified from clinical findings. To avoid multi-linearity between covariates, a blind 
examination of the correlation between the pre-specified covariates and the main endpoint may 
allow to remove covariates without association with the main endpoint, and simplify the model.    
3-During this same blinded examination, the distribution of the D28 primary endpoint data 
(residuals and predicted value, from a simplified model of D28 data including D0 data as one 
of the covariates) will also be graphically inspected to determine whether a logarithmic 
transformation of the data would be appropriate. If such a transformation is retained, the 
statistical analysis plan will be amended accordingly before the interim analysis.4-Two interim 
GST looks will be performed during Part 1 of the study, which may lead to early discontinuation 
of Part 1 for futility or efficacy. 
The GST design was defined with a 75% power for a standardized difference of means of 0.546 
(15/26.79), an overall 5% one-sided significance level (with a gamma function of  parameter -
2 as alpha spending function) and a binding futility procedure (with a gamma function of 
parameter -4 as beta spending function). At each GST look, the z-score statistic will be 
calculated for the estimated difference of high dose versus placebo. The GST looks are planned 
for 41 (first GST look), 55 (second GST look) and 74 (final analysis of Part 1) patients available 
for the high dose and the placebo together. The GST design can be summarized as follows: 
 
 
 


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In this GST design, the first interim look, second interim look and final analysis are planned 
when 63, 85 and 111 patients, respectively (when 41, 55, 74 patients can be expected in the 
high dose and placebo groups) have been randomized up to the date still theoretically 
compatible with reaching Day 28 and having the data centrally reviewed before he considered 
GST look. However, irrespective of the actual number of patients in high dose and placebo 
observed in the GST look, the z-score limits for futility and efficacy will be used without any 
change. 
 
Final analysis of Part 1 
If the comparison of the high dose versus placebo has been found statistically significant at the 
last (possibly interim) GST look performed, the comparison of the low dose to placebo will be 
tested at 5% one-sided significance level; otherwise the 5% one-sided p-value of the 
comparison of low dosetodose placebo will be considered exploratory. 
 
Analysis of Part 2 
The efficacy analysis of Part 2 will consider only the data of the patients enrolled in Part 2 and 
assigned to placebo or to the selected dose. The comparison of the two treatment groups 
(selected dose, placebo) will be performed at the 5% (two-sided) significance level. 
 
Combined analysis of Part 1 and Part 2 
A meta-analysis combining all data from Part 1 and Part 2 will be performed. 
 
13.5.2 Analysis of secondary efficacy endpoints 
Mean changes from baseline in pure tone audiometry (average of the hearing threshold of the 
2 most affected hearing frequencies identified at baseline) in affected ear will be analysed using 
the same modeling approach as for the primary endpoint, but reporting estimates with 
unadjusted p-values. 
Mean changes from baseline in pure tone audiometry (the most affected hearing frequencies 
identified at baseline) in affected ear will be analysed using the same modeling approach as for 
the primary endpoint, but reporting estimates with unadjusted p-values. 
Mean changes from baseline of the speech recognition threshold at Days 7, 14, 28 and 84 will 
be analysed using the same modeling approach as for the primary endpoint, but reporting 
estimates with unadjusted p-values. 
Mean changes from baseline of the severity of tinnitus (assessed numerical rating scale) at Days 
7, 14, 28 and 84 will be analysed using the same modelling approach as for the primary 
endpoint, but reporting estimates with unadjusted p-values. 
 
13.5.3 Analysis of exploratory efficacy endpoints 
The analyses planned for the exploratory efficacy endpoints will be detailed in the statistical 
analysis plan. 
 


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13.5.4 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. 
 
13.5.4.1 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 
randomised 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. 
These endpoints apply to all adverse events, regardless of relationship of the event to the study 
drug. 
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 randomised 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 randomised 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. 
 
13.5.4.2 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 test parameter. 
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 
 
13.5.4.3 Vital signs  
The same approach as for the analysis of clinical laboratory evaluations will be used. 


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13.5.4.4 ECG 
The same approach as for the analysis of clinical laboratory evaluations will be used. 
 
13.5.4.5 Columbia-Suicide Severity Rating Scale 
A descriptive analysis will be performed. 
 


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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, and the GCP 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/IEC, 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/She will be given a copy of the information 
leaflet and consent form.  
 
14.3 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The Investigator (or authorized person) 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 (or authorized person) 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. 
14.4 Regulatory Authority Approval 
Before the trial is initiated at a site, the Sponsor will obtain approval to conduct the trial from 
the appropriate regulatory authority in accordance with applicable country-specific regulatory 
requirements. 
Before starting the pivotal part of the study, the sponsor will submit a substantial amendment 
to competent authorities for approval of the dose finally selected and sample size. The 
informed consent form will be updated with the safety information gained from part 1 and the 
new dose and sample size. 
 
14.5 End of the Trial 
The end of the entire trial will be defined as the date of the  last subject last visit. This provides 
for a single and conservative definition across all trial sites. 


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STUDY MONITORING 
14.6 Responsibilities of the Investigator 
The Investigator undertakes to perform the study in accordance with this protocol, GCP, data 
protection 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.  
The Investigator agrees to complete all information requested in the e-CRF 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 central data management group 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.  
 
14.7 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, quality 
management, integrity and validity of the data recorded on the Case Report Forms. Thus, the 
main duty of the CRO/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.  
 
14.8 Source documents and Data protection 
According to the ICH guidelines on GCP, the Monitoring Team must verify the Case Report 
Form entries against the source documents, except for the pre-identified source data directly 
recorded in the Case Report Form. The patient will authorize the Sponsor’s duly authorized 
personnel or CRO, the Ethics Committee (IRB/IEC), and the regulatory authorities to access 
directly to source documents, in case of audit or specific request to verify any source data which 
justify the data captured on the Case Report Forms (e.g. subject's medical file, appointment 


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books, original laboratory records, etc.). The Informed Consent Form will include such a 
statement.  
Subject age, race and ethnicity will be collected in this study as this is required by several health 
authorities (FDA in the US on African-American, or Hispanics, PMDA: Japanese population 
in Japan). 
 
14.9 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 substantial 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. 
The Sponsor will request prior approval by the regulatory and ethics committee all amendments 
that are considered substantial and likely to have an impact on the safety of the trial subjects or 
conduct of the study unless there are overriding safety reasons. Non-substantial amendments 
will be filed in the TMF and the regulatory and ethics committee notified. 
 
 
 
 


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15 ADMINISTRATIVE RULES 
15.1 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 [with the exception 
of Germany] and Financial Disclosure Form study under an IND) will be provided to the 
Sponsor prior to the beginning of the study and after any changes and end of study. 
 
15.2 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 least 15 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. 
 
15.3 Confidentiality  
The current protocol and any unpublished document referring to SENS-401 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 and data obtained from this 
clinical trial. Personal data should be treated with the same degree of vigilance as confidential 
information and in accordance with applicable regulations, including the General Data 
Protection Regulation n ° 2016/679 ("GDPR"). 
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 and investigational staff member 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 authorize the sponsor to participate at this audit.  
 
15.4 Ownership of data and use of the study results 
The data collected in this study will be used only for the purpose of the study and to document 
the benefit/risk ratio of the investigational product. They may be further processed if they have 
been anonymized. 
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 


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any country. In no case, the investigator or his/her staff member is authorized to file patent 
application referring to the investigational product tested in this clinical trial, 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 only 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 of the abstract or the text and slides of the presentation at least 
7 days in advance prior to the deadline for submission. Sensorion may request to add the 
sponsor’s name or the name of some employees on the manuscript.  
Study results will be made public according to local law. 
15.5 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.  
An insurance certificate will be provided to the Investigator in countries requiring this 
document. 
15.6 Premature discontinuation of the study or premature close out of a center 
15.6.1  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. 
• Discontinuation recommended by the DMC after the GST looks  in case of futility or 
because 
of 
efficacy 
of 
the 
highest 
tested 
dose 
(see 
Statistical 
ConsiderationsConsiderations) 
• Unexpected events that could jeopardize the conduct and quality of the study. These 
events could be any of the followings: Conflicts in a specific country, Major climatic 
reasons or earthquakes, Unexpected epidemics (eg. SRAS), Financial issues (funding 
does not match the incurring costs), External constraints that could prevent IMP 
distribution etc.…External events not yet identified. 
In any case, the exact reason of termination will be specified and the ethics committee 
informed within 15 days after the decision is taken. The health authorities will be informed as 
soon as possible but not later than 15 days after the decision taken.  
 
15.6.2  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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17 APPENDICES  
 Appendix 1: THE TINNITUS FUNCTIONAL INDEX 
Meikle MB, Henry JA, Griest SE, Stewart BJ, Abrams HB, McArdle R, Myers PJ, Newman CW, Sandridge S, Turk 
DC, Folmer RL, Frederick EJ, House JW, Jacobson GP, Kinney SE, Martin WH, Nagler SM, Reich GE, 
Searchfield G, Sweetow R, Vernon JA. (2012) The Tinnitus Functional Index: Development of a New Clinical 
Measure for Chronic, Intrusive Tinnitus. Ear Hear 33(2):153–176. 
 
Todayʼs Date   
 
 
 
 
 
 
Your Name 
Month / Day / Year   
 
 
 
 
 
Please Print 
 
Please read each question below carefully. To answer a question, select ONE of the 
numbers that is listed for that question, and draw a CIRCLE around it like this: 10% or 1 . 
 
I Over the PAST WEEK... 
1. What percentage of your time awake were you consciously AWARE OF your tinnitus? 
Never aware   0%  10%  20%  30%  40%  50%  60%  70   80%    90%  100%   Always aware 
2. How STRONG or LOUD was your tinnitus? 
Not at all strong or loud   0   1   2   3   4   5   6   7   8   9    10    Extremely strong or loud 
3. What percentage of your time awake were you ANNOYED by your tinnitus? 
None of the time  0%  10% 20% 30% 40% 50% 60%  70%  80%  90%  100%   All of the time 
SC Over the PAST WEEK 
4. Did you feel IN CONTROL in regard to your tinnitus? 
Very much in control  0    1     2    3      4     5     6     7     8     9    10    Never in control 
5.How easy was it for you to COPE with your tinnitus? 
Very easy to cope  0    1     2    3      4     5     6     7     8     9    10    Impossible to cope 
6. How easy was it for you to IGNORE your tinnitus? 
Very easy to ignore       0    1     2    3      4     5     6     7     8     9    10    Impossible to ignore 
C Over the PAST WEEK... 
7. Your ability to CONCENTRATE? 
 Did not interfere      0    1     2    3      4     5     6     7     8     9    10    Completely interfered 
8. Your ability to THINK CLEARLY? 
 Did not interfere      0    1     2    3      4     5     6     7     8     9    10    Completely interfered 
9. Your ability to FOCUS ATTENTION on other things besides your tinnitus? 
Did not interfere      0    1     2    3      4     5     6     7     8     9    10          Completely interfered 
SL Over the PAST WEEK... 
10. How often did your tinnitus make it difficult to FALL ASLEEP or STAY ASLEEP? 
Never had difficulty   0    1     2    3      4     5     6     7     8     9    10    Always had difficulty 
11. How often did your tinnitus cause you difficulty in getting AS MUCH SLEEP as you 
needed? 
Never had difficulty   0    1     2    3      4     5     6     7     8     9    10    Always had difficulty 
12. How much of the time did your tinnitus keep you from SLEEPING as DEEPLY or as 
PEACEFULLY as you would have liked? 
 None of the time   0    1     2    3      4     5     6     7     8     9    10    All of the time 
 
A Over the PAST WEEK, how much has 
your tinnitus interfered with...  
 
 
 
Completely                                         Did not  
interfered                                            interfere 


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13. Your ability to HEAR CLEARLY ? 
14. Your ability to UNDERSTAND 
PEOPLE who are talking?                           
15. Your ability to FOLLOW 
CONVERSATIONS in a group or at 
meetings?                         
0    1     2    3      4     5     6     7     8     9    10     
 
0    1     2    3      4     5     6     7     8     9    10     
 
0    1     2    3      4     5     6     7     8     9    10     
R Over the PAST WEEK, how much has 
your tinnitus interfered with... 
 
 
 
16. Your QUIET RESTING 
ACTIVITIES?  
17. Your ability to RELAX?  
18. Your ability to enjoy “PEACE AND 
QUIET”?  
Completely                                         Did not  
interfered                                            interfere 
 
0    1     2    3      4     5     6     7     8     9    10        
0    1     2    3      4     5     6     7     8     9    10 
 
0    1     2    3      4     5     6     7     8     9    10 
Q Over the PAST WEEK, how much has 
your tinnitus interfered with... 
 
 
 
 
 
19. Your enjoyment of SOCIAL 
ACTIVITIES?  
20. Your ENJOYMENT OF LIFE?  
21. Your RELATIONSHIPS with family, 
friends and other people? 
 
Completely                                         Did not  
interfered                                            interfere 
 
0    1     2    3      4     5     6     7     8     9    10 
 
0    1     2    3      4     5     6     7     8     9    10 
 
0    1     2    3      4     5     6     7     8     9    10 
 
22. How often did your tinnitus cause you to have difficulty performing your WORK OR 
OTHER 
TASKS, such as home maintenance, school work, or caring for children or others? 
Never had difficulty  0     1     2     3     4     5     6     7     8     9     10    Always had difficulty 
 
E Over the PAST WEEK... 
23. How ANXIOUS or WORRIED has your tinnitus made you feel? 
Not at all anxious 0     1     2     3     4     5     6     7     8     9     10    Extremely anxious              
or worried                                                                                           or worried 
 
24. How BOTHERED or UPSET have you been because of your tinnitus? 
Not at all bothered    0     1     2     3     4     5     6     7     8     9     10          Extremely bothered 
     or Upset                                                                                                                 or upset 
25. How DEPRESSED were you because of your tinnitus? 
 Not at all depressed    0     1     2     3     4     5     6     7     8     9     10       Extremely depressed 
 
 
 
 
 
 
 
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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INSTRUCTIONS FOR SCORING THE TINNITUS FUNCTIONAL INDEX (TFI) 
 
1. Preparation for scoring:  
 
A. Two items to be transformed: Items #1 and #3 require a simple transformation from a percentage scale to a 
0-10 scale, achieved by dividing the values circled by the respondent by 10. The examiner should write the 
transformed value in the margin beside the relevant item, preferably using ink of a different color than that used 
by the respondent.  
B. Ambiguous items: Because respondents differ in regard to how clearly they circle or mark their answers on 
the 0-10 scale for each item, the examiner should review every item to resolve any ambiguities. It is helpful if 
examiners note their decision about each answer in the margin beside the given item, using the differently-
colored ink. Some commonly-occurring ambiguities and how to handle them are as follows:  
 
(1) More than one value marked on the 0-10 scale for a given item— 
Typically done by respondents whose tinnitus undergoes large variations over time. The clinic or the examiner 
should settle on a consistent procedure for all such responses, such as (a) averaging the multiple values indicated 
for a given item, or (b) marking the item "cannot code", thus removing that item from consideration in the 
overall TFI score. (The latter choice reduces the information available for calculating the respondent's overall 
score, and may be desirable only in extremely variable cases where the respondent's reliability is questionable.)  
(2) Respondent marks a value between the 0-10 values on the item scale—  
Again, the clinic or the examiner should settle on a consistent procedure for handling all such ambiguous 
responses in the same way, such as (a) noting a value of 3.5 in the margin, for a respondent who marked the 
scale between 3 and 4, or (b) collapsing the intermediate value either to the right (to 4) or to the left (to 3).  
(3) Respondent does not make any response to a given item— 
The clinic or examiner should decide beforehand how they will indicate missing values, and that notation (e.g. 
"NA" for "No Answer") should be entered in the margin. If the data will be entered into a computer database, a 
standard missing value such as "99" can be entered in the margin beside the relevant item. Of course, care must 
be taken to exclude "99" values if the examiner performs a manual calculation of the overall TFI score. C. 
Unambiguous items: To facilitate rapid scanning and summing of all valid answers to obtain the respondent's 
overall TFI score, all of the unambiguous values indicated by the respondent should also be noted in the margin, 
each such value beside its corresponding item. The examiner can then quickly generate a valid score for the 
overall TFI.  
 
2. Calculation of overall TFI score 
(1) Sum all valid answers from both TFI pages (maximum possible score = 250 if the respondent were 
to rate all 25 TFI items at the maximum value of 10).  
(2) Divide by the number of questions for which that respondent provided valid answers (yields the 
respondent's mean item score for all items having valid answers).  
(3) Multiply by 10 (provides that respondent's overall TFI score within 0-100 range).  
 
CAUTION—Overall TFI score is not valid if respondent omits 7 or more items. To be valid as a measure of 
tinnitus severity, the respondent must answer at least 19 items (76% of items).  
 
3. Calculation of subscale scores  
The 8 subscales address 8 important domains of negative tinnitus impact as indicated below. Each subscale has a 
brief title (in capital letters) and a 1- or 2-letter abbreviation (e.g. I for Intrusive, SC for Sense of Control):  
 
 
SUBSCALE NAME (and conceptual content) 
ITEMS IN SUBSCALE 
I: INTRUSIVE (unpleasantness, intrusiveness, persistence) 
#1, #2, #3 
SC: SENSE OF CONTROL (reduced sense of control) 
#4, #5, #6 
C: COGNITIVE (cognitive interference) 
#7, #8, #9 
SL: SLEEP (sleep disturbance) 
#10, #11, #12 
A: AUDITORY (auditory difficulties attributed to tinnitus) 
#13, #14, #15 
R: RELAXATION (interference with relaxation) 
#16, #17, #18 
Q: QUALITY OF LIFE (QOL) (quality of life reduced) 
#19, #20, #21, #22 
E: EMOTIONAL (emotional distress) 
#23, #24, #25 


STUDY: SENS 401-201 
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Each of the 8 subscales consists of 3 items except for the Quality of life subscale, which consists of 4 items (SEE 
ITEMS LIST ABOVE).  
 
For valid subscale scores, no more than 1 item should be omitted.  
 
Computation of subscale scores is as follows:  
1) Sum all of that respondent's valid answers for a given subscale.  
2) Divide by the number of valid answers that were provided by that respondent for that subscale.  
3) Multiply by 10. For the respondent in question, this procedure generates a subscale score in the range 0- 100 
for each valid subscale.  
 
CAUTION—Do not attempt to compute a respondent's overall TFI score by combining that respondent's valid 
subscale scores, as the valid subscales may encompass a total number of items that is different from the number 
of items accepted as valid for the overall TFI score. 
 
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 2: EQ-5D-5L 
 
EQ-5D-5L (UK English sample version)  
 
By placing a tick in one box in each group below, please indicate which statements best 
describe your own health state today.  
 
Mobility  
 
I have no problems in walking about                    ☐ 
I have slight problems in walking about 
☐ 
I have moderate problems in walking about 
☐ 
I have severe problems in walking about 
☐ 
I am unable to walk about 
☐ 
 
Self-Care  
 
I have no problems washing or dressing myself  
☐ 
I have slight problems washing or dressing myself 
☐ 
I have moderate problems washing or dressing myself  ☐ 
I have severe problems in washing or dressing myself 
☐ 
I am unable to wash or dress myself 
☐ 
 
Usual Activities (e.g. work, study, housework, family or leisure activities)  
 
I have no problems doing my usual activities 
☐ 
I have slight problems doing my usual activities 
☐ 
I have moderate problems doing my usual activities ☐ 
I have severe problems doing my usual activities 
☐ 
I am unable to do my usual activities  
☐ 
 
Pain/Discomfort  
I have no pain or discomfort   
☐ 
I have slight pain or discomfort   
☐ 
I have moderate pain or discomfort  ☐ 
I have severe pain or discomfort   
☐ 
I have extreme pain or discomfort  
 
☐ 
Anxiety/Depression  
I am not anxious or depressed 
☐ 
I am slightly anxious or depressed 
☐ 
I am moderately anxious or depressed ☐ 
I am severely anxious or depressed 
☐ 
I am extremely anxious or depressed  
☐ 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 3: 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 spermicide 
• Cap, diaphragm or sponge with spermicide 
 
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.  
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 4: List of commonly prescribed ototoxic treatments 
 
Class 
INN 
Class 
INN 
Antibiotics 
Cytotoxic  
Aminoglycosides –  
 
Amikacin 
Gentamycin 
Netilmycin 
Tobramycin 
Vinca alkaloid and 
etoposide 
Etoposide.  
Vinblastine  
Vincristine  
Vindesine  
Vinorelbine 
Macrolides 
Azithromycin  
Clarithromycin.  
Erythromycin 
Platinum derivatives 
Carboplatin  
Cisplatin  
Oxaliplatin 
Tetracyclines  
Minocycline 
 
 
Other antibiotics – 
 
Teicoplanin 
Vancomycin  
Streptomycin 
 
 
Antiviral 
Antimalarial drugs 
 
Ganciclovir 
 
Chloroquine 
Hydroxichloroquine 
sulphate 
Antifungal 
Diuretics 
 
Amphotericin B 
Loop diuretic 
Furosemide 
Torsemide 
 
This list is not exhaustive. In case of doubt, please refer to the labeling of the compound.  
 
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 5: List of raw data 
Study data which should be included in the source dossier: 
 
• Subject’s identity and contact detail 
• Pathology studied, date of onset of SSNHL and associated symptoms. 
• 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: blood pressure, heart rate, 
 Questionnaires scores including but not limited to TFI, QOL, C-SSRS, vertigo and 
tinnitus NRS, Tinnitus diary etc 
• Adverse events (+ follow-up). 
• Pure tone audiometry results and speech recognition threshold and WRS 
• Date of drop-out and reason. 
• Pregnancy test results 
• Laboratory test results 
• ECG 
• Dates of IP administration, IP non-administration, and rescue medication delivery and 
compliance 
• Patients diary  
 
 
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 6: AAO-HNS guidelines 
The guidelines published by the AAO-HNS* recommend prednisone for patients with SSNHL 
within 2 weeks after the diagnosis, with a recommended dose of Prednisone 1 mg/kg/day (max: 
60 mg/day), or Methylprednisolone 48 mg/d or Dexamethasone 10 mg/d given as a single 
dose for 7-14 days, then taper over similar time period. 
 
Intratympanic corticosteroids are recommended as salvage (rescue) after systemic treatment 
fails. The recommended dose regimen is Dexamethasone 24 mg/mL or 16 mg/mL 
(compounded), or 10 mg/mL (stock) Methylprednisolone 40 mg/mL or 30 mg/mL with a 0.4 
to 0.8 mL injected into middle ear space every 3 to 7 days for a total of 3 to 4 sessions  
 
 
Anti-
inflammatory 
activity 
Minéralo-
corticoïd 
Activity 
Dose 
Equivalence 
Biological 
half life 
Prednisone/Prednisolone* 
4 
0.8 
5 mg 
12-36 
Méthylprednisolone 
5 
0.5 
4 mg 
12-36 
Dexamethasone 
25 
0 
0.75 mg 
36-54 
 
 
*Reference:  Stacler and al. 2012  
 


STUDY: SENS 401-201 
VERSION DATE: 05 FEBRUARY 2021 
 
 
 
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Appendix 7: non-exhaustive list of serotoninergic agents 
• 
Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram, 
fluoxetine, fluvoxamine, paroxetine and sertraline 
• 
Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as 
trazodone, duloxetine and venlafaxin 
• 
Bupropion, an antidepressant and tobacco-addiction medication 
• 
Tricyclic antidepressants, such as amitriptyline and nortriptyline 
• 
Monoamine oxidase inhibitors (MAOIs), antidepressants such as isocarboxazid and 
phenelzine 
• 
Anti-migraine medications such as triptans, carbamazepine and valproic acid 
• 
Pain medications such as opioid pain medications including codeine, fentanyl, hydrocodone 
meperidine, oxycodone and tramadol 
• 
Lithium, a mood stabilizer 
• 
Illicit drugs, including LSD, Ecstasy, cocaine and amphetamines 
• 
Herbal supplements, including St. John's wort, ginseng and nutmeg 
• 
Over-the-counter cough and cold medications containing dextromethorphan 
• 
Anti-nausea medications such as granisetron, metoclopramide, droperidol and ondansetron 
• 
Linezolid, an antibiotic 
• 
Ritonav, an anti-retroviral medication used to treat HIV/AIDS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8: Clinical inhibitors for transporters 
Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug labeling) 
(9/26/2016) 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm093664.htm#table5-2) 
 
Transporter 
Gene 
Inhibitor 
P-gp 
ABCB1 
amiodarone, carvedilol, clarithromycin, dronedarone, 
itraconazole, lapatinib, lopinavir and ritonavir, 
propafenone, quinidine, ranolazine, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir and ritonavir, verapamil 
BCRP 
ABCG2 
curcumin, cyclosporine A, eltrombopag 
OATP1B1, 
OATP1B3 
SLCO1B1, 
SLCO1B3 
atazanavir and ritonavir, clarithromycin, cyclosporine, 
erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin 
(single dose), simeprevir 
OAT1, OAT3 
SLC22A6, 
SLC22A8 
p-aminohippuric acid (PAH), probenecid, teriflunomide 
MATE1, MATE2-K 
SLC47A1, 
SLC47A2 
cimetidine, dolutegravir, isavuconazole, ranolazine, 
trimethoprim, vandetanib 
 
 

SAP_001.pdf: 
 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 1 of 67 
 
Statistical Analysis Plan 
Title: A two-part, randomized, double-blind, placebo-controlled, parallel-group, 
efficacy and safety study of SENS-401 in subjects with severe or profound sudden 
sensorineural hearing loss 
Protocol Number: SENS 401-201 
Protocol Version: Clinical Trial Protocol v4.0 / 05-FEB-2021 
 
 
 
SAP Version 1.0 
SAP Issue Date: 06-DEC-2021 
SAP Authors:  
 
Previous SAP Versions 
Not Applicable 
 
 
 


 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 2 of 67 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 5 
2 
STUDY OBJECTIVES ....................................................................................... 5 
2.1 
Primary Objective ........................................................................................................... 5 
2.2 
Secondary Objectives...................................................................................................... 5 
3 
ENDPOINTS ....................................................................................................... 5 
3.1 
Primary Endpoint ............................................................................................................ 6 
3.2 
Secondary Endpoints ...................................................................................................... 6 
3.3 
Exploratory Efficacy Endpoints ...................................................................................... 6 
4 
SAMPLE SIZE .................................................................................................... 7 
5 
RANDOMIZATION ........................................................................................... 8 
6 
PLANNED ANALYSES ..................................................................................... 9 
6.1 
Analysis Sets ................................................................................................................... 9 
6.1.1 
Intent-To-Treat Analysis Set..................................................................................... 9 
6.1.2 
Per-Protocol Analysis Set ......................................................................................... 9 
6.1.3 
Safety Analysis Set ................................................................................................. 10 
6.2 
Derived Data ................................................................................................................. 10 
6.2.1 
Race......................................................................................................................... 10 
6.2.2 
Baseline ................................................................................................................... 10 
6.2.3 
Duration / Treatment Day / Study Day ................................................................... 10 
6.2.4 
Conventions for Missing and Partial Dates ............................................................ 11 
6.2.5 
Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications ........................................................................................................................... 11 
6.2.6 
Missing Last Dates of Study Drug Dosing ............................................................. 12 
6.2.7 
Missing Diagnosis Dates......................................................................................... 12 
6.2.8 
Exposure to Study Drug .......................................................................................... 13 
6.2.9 
Inexact Values ......................................................................................................... 13 
6.2.10 
Height/Weight/Temperature ................................................................................... 13 
6.2.11 
Electrocardiogram (ECG) Data ............................................................................... 13 
6.2.12 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 13 
6.2.13 
Laboratory data ....................................................................................................... 14 
6.2.14 
Randomization Strata .............................................................................................. 15 
6.2.15 
Change from baseline ............................................................................................. 15 


 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 3 of 67 
6.2.16 
Analysis Window .................................................................................................... 15 
6.3 
Conventions .................................................................................................................. 15 
6.3.1 
Decimal Places ........................................................................................................ 16 
6.4 
Subject Disposition ....................................................................................................... 17 
6.5 
Protocol Deviations ....................................................................................................... 17 
6.6 
Stratification factors ...................................................................................................... 17 
6.7 
Baseline Comparability ................................................................................................. 17 
6.7.1 
Demographics ......................................................................................................... 18 
6.7.2 
Disease Characteristics and Other Relevant Baseline Data .................................... 18 
6.8 
Medical/Surgical History .............................................................................................. 19 
6.9 
Prior and Concomitant Medications ............................................................................. 20 
6.10 
Exposure to Study Drug ................................................................................................ 20 
6.11 
Treatment Compliance .................................................................................................. 20 
6.12 
Efficacy Analyses ......................................................................................................... 21 
6.12.1 
Primary Endpoint .................................................................................................... 21 
6.12.2 
Primary Efficacy Analysis ...................................................................................... 21 
6.12.3 
Sensitivity Analyses ................................................................................................ 24 
6.12.4 
Secondary Endpoints .............................................................................................. 26 
6.12.5 
Exploratory Endpoints ............................................................................................ 28 
6.12.6 
Multiplicity ............................................................................................................. 32 
6.13 
Pharmacokinetic Analyses ............................................................................................ 33 
6.14 
Safety Analyses ............................................................................................................. 33 
6.14.1 
Adverse Events ....................................................................................................... 33 
6.14.2 
Laboratory Data ...................................................................................................... 35 
6.14.3 
Vital Signs ............................................................................................................... 37 
6.14.4 
Physical Examination.............................................................................................. 37 
6.14.5 
Otoscopy ................................................................................................................. 37 
6.14.6 
Tympanometry ........................................................................................................ 38 
6.14.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 38 
7 
INTERIM ANALYSIS ......................................................................................38 
8 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................39 
9 
REFERENCES ..................................................................................................41 
10 LIST OF TABLES, FIGURES AND LISTINGS .............................................42 
10.1 
Part 1 outputs ................................................................................................................ 42 


 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 4 of 67 
10.2 
Part 2 outputs ................................................................................................................ 55 
 


 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 5 of 67 
1 INTRODUCTION 
This document details the planned statistical analyses for Sensorion, protocol “SENS 401-201” 
study titled “A two-part, randomized, double-blind, placebo-controlled, parallel-group, efficacy 
and safety study of SENS-401 in subjects with severe or profound sudden sensorineural hearing 
loss”. This document covers the analyses planned for the clinical study reports; one for each part 
of the study (Part 1 and Part 2). The use of a group sequential test during part 1 is described in 
section 7 of this document and further detailed in a separate statistical analysis plan (Group 
Sequential Test SAP). The safety analyses and the efficacy analysis of Part 1 (when all patients 
have completed or prematurely discontinued the 4-week treatment period) conducted for the Data 
Monitoring Committee are detailed in a separate statistical analysis plan (Data Monitoring 
Committee SAP version 1.1 dated 26-NOV-2021). 
The proposed analyses are based on the contents of the amended version of the protocol (v4.0 
dated 05-FEB-2021). 
The study is a 2- part, multicenter, double-blind, randomized, placebo-controlled study of SENS-
401 administered orally twice daily (BID for 28 days), with an 8-week follow-up. The study will 
be conducted according to an operational seamless design. In the first part, 2 doses of SENS-401 
29 mg/day and 43.5 mg/day (respectively 20 mg and 30 mg free base) will be tested, whereas in 
the second part only the dose that demonstrated efficacy in part 1 will be tested. The selection of 
the dose will be done by the Data Monitoring Committee (DMC) when all patients have completed 
28 days of treatment in part 1. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
To confirm the efficacy of SENS-401 on hearing loss in comparison to placebo at the end of the 
4-week treatment period. 
2.2 Secondary Objectives 
• To confirm the maintenance of any early efficacy on hearing loss at 12-week 
• To evaluate the efficacy on sudden sensorineural hearing loss (SSNHL)-related tinnitus 
• To determine the dose effect on hearing loss 
• To confirm the safety of SENS-401 in the studied population/dosage regimen 
3 ENDPOINTS 


 
Sponsor: 
Sensorion 
Protocol Number: 
SENS 401-201 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 6 of 67 
3.1 Primary Endpoint 
The primary endpoint is the change in pure tone audiometry (PTA; average of the hearing threshold 
of 3 contiguous most affected hearing frequencies in decibels as identified at study entry on pure 
tone audiometric air conduction testing) in affected ear from baseline to the end of treatment visit 
(Visit D28 ± 3). 
3.2 Secondary Endpoints 
• Change in pure tone audiometry (average of the hearing threshold of the 2 most affected 
hearing frequencies identified at study entry) in affected ear from baseline to the end of 
treatment visit (Visit D28± 3) 
• Change in pure tone audiometry (the most affected hearing frequency identified at study 
entry) in affected ear from baseline to the end of treatment visit (Visit D28± 3) 
• Change in pure tone audiometry (PTA; average of the hearing threshold of 3 contiguous 
most affected hearing frequencies in decibels as identified at study entry on pure tone 
audiometric air conduction testing) in affected ear from baseline to the end of study visit 
(Visit D84 ± 3) 
• Change in speech discrimination threshold from baseline to Days 28, and 84 
• Frequency and severity of tinnitus at Days 7, 14, 28, and 84 assessed by numerical rating 
scale 
3.3 Exploratory Efficacy Endpoints 
• % of patients with complete hearing recovery defined as PTA <20 dB or hearing similar to 
the unaffected contralateral ear 
• % of patients with marked improvement defined as PTA threshold absolute improvement 
> 30 dB  
• % of patients with PTA > 35 dB and > 90 dB on Day 7, Day 14 and end of study visit (visit 
D84± 3) 
• % of responders (response is defined as an improvement of 10dB or more) in PTA  
• Word recognition score at 80 dB and 60 dB in the affected ear on Day 28 and 84 
• Relationship between time of onset of symptoms to first study drug intake and the primary 
endpoint 
• Frequency and severity of any vertigo at day 1,7,14, 28 and 84 
• Tinnitus burden based on the change in tinnitus QOL scores at day 1,7,14, 28 and 84 


 
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• Change in biomarkers 
• Change in EQ-5D-5L scores between baseline and Day 28 and 84 
• Change in Distortion Products Otoacoustic Emissions (DPOAE) at Days 7, 14, 28, and 84 
compared to baseline values 
• Change in Transient Evoked Otoacoustic Emissions (TEOAE) at Days 7, 14, 28 and 84 
compared to baseline values 
 
4 SAMPLE SIZE 
The sample size is based on the primary endpoint: average change in PTA in dB between the 
baseline and week 4 (Day 28±3d) on the 3 most affected contiguous frequencies.  
Part 1: A sample size of 111 patients (37 patients per treatment arm) was retained corresponding 
to following assumptions: 
• Each comparison to placebo performed at 5% one-sided significance level (with higher 
dose to be tested first and low dose to be tested conditionally to the high dose significance) 
• Power of each comparison to placebo set to 75%. 
• Randomization ratio 1:1:1 
• Intra-group standard deviation of 30 dB is estimated based on recent publication in SSNHL 
with other pharmaceutical therapies and blinded examination of variance (with a 0.45 
correlation between Day 28 and baseline) 
• A difference to placebo of 15 dB is expected, which would be considered clinically 
meaningful 
• The corresponding fixed design sample size of 105 patients (35 patients per treatment arm) 
was then inflated to 111 patients (37 patients per treatment arm) to allow the use of a group 
sequential test (GST) design with 3 looks (2 interim looks and a final look). 
 
This design of Part 1 was introduced in the protocol amendment leading to version 4.0. The revised 
assumption of the intra-group standard deviation (adjusted for baseline) of 30 dB was based on a 
blinded review of the variability of 63 patients, which led to an estimate of the adjusted standard 
deviation more in line with the 27 dB seen in a recent publication in SSNHL1 than with the 20dB 
seen in the publication used at time of the protocol initiation2. The choice of the power level and 
of the significance level, combined with the strategy of testing the low dose conditionally after the 
high dose, was guided by the unexpected low recruitment rate observed in the study.  The 3-look 
GST design (interim looks plus one final part 1 analysis) was introduced in order to allow an early 
discontinuation (for futility or for efficacy) of Part 1. 


 
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The first GST look was performed, and the outcome was a recommendation to continue Part 1 in 
the absence of crossing of any boundary. The second GST look was not performed because all 
amendment protocol approvals were not obtained yet at time when the sample size of the second 
GST was reached. The final look will finally not be performed as it does not have enough added 
value compared to the analysis planned in the DMC SAP section 2.6. 
 
Part 2: A sample size of 190 patients (95 patients per treatment arm) was retained corresponding 
to following assumptions: 
• Comparison to placebo performed at 5% two-sided significance level 
• Power of the comparison to placebo set to 90% 
• Randomization ratio 1:1 
• Intra-group standard deviation of 20 dB is estimated based on recent publication in SSNHL 
with other pharmaceutical therapies 
• A difference to placebo of 10 dB is expected as considered clinically meaningful 
• 10% dropout rate 
 
The sample size of Part 2 was not revised at time of the amendment for protocol version 4.0 but 
will be re-estimated based on Part 1 results when available. The final sample size will be submitted 
for approval to competent authorities prior to the pivotal part start. 
5 RANDOMIZATION 
Subjects will be randomized to receive one of the treatments (SENS 29 mg dose, SENS 43.5 mg 
dose, Placebo) according to relevant randomization list (non-ancillary study sites and ancillary 
study sites). The randomization lists will be stratified according to the duration of the hearing loss 
(≥24 hours or <24 hours) and the intake of oral corticosteroids (Yes, No). Two randomization lists 
using a 1:1:1 randomization ratio will be generated for the whole study, one for the French sites 
involved in the ancillary study and one for all the other sites globally, including French sites not 
participating in the ancillary study. These two randomization lists will cover both Parts 1 and 2 of 
the study. 
 
During Part 1, the 3 treatment arms will be allocated by the IWRS. After dose selection at the end 
of Part 1, only the placebo and the selected active dose (43.5 mg or 29 mg) will be allocated by 
the IWRS during Part 2. 
 


 
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The randomization lists will be generated centrally, and the investigator, the sponsor study team, 
the CRO and subjects will be blinded to the Investigational drug administration.  
 
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 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 11.3.4 of protocol). 
 
A patient cannot be randomized more than once during the study. 
 
A patient will be considered randomized when the IWRS has given the treatment number to be 
allocated. 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
The analysis of Part 1 will include only patients of Part 1. Meanwhile, the analysis of Part 2 will 
include only patients of Part 2.  
6.1 Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2 of the CSR. 
6.1.1 Intent-To-Treat Analysis Set 
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.  
6.1.2 Per-Protocol Analysis Set 
The Per-Protocol (PP) analysis set will comprise all patients of the ITT analysis set without major 
protocol deviation, which could affect the analysis of the primary efficacy endpoint. Selected 


 
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efficacy analyses (primary efficacy endpoint and secondary endpoints) will be repeated on the PP 
analysis set.  
All protocol deviations will be assessed and documented on a case-by-case basis before the 
database lock, and deviations considered to have a serious impact on the efficacy results will lead 
to the relevant subject being excluded from the PP analysis set. Before the soft database lock, that 
is, when all subjects have completed (or prematurely discontinued) the 4 week treatment period, 
potential subject exclusions from the PP analysis set will be reviewed by the Sponsor and 
documented in a subject evaluability document. 
6.1.3 Safety Analysis Set 
The Safety analysis set will comprise all treated patients. Subjects will be analyzed based on the 
treatment actually received. In the situation of accidental dispensation of two or three distinct 
treatments to the same patient, the patient will be counted for the whole study on the highest dose 
received. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple” in the summary tables. The listings will reflect 
the original selected categories.  
6.2.2 Baseline 
Baseline for efficacy is defined as the last non-missing value (either scheduled, unscheduled or 
repeat) up to the randomization day included but before randomization date and time. According 
to the protocol, no data are expected to be collected between the randomization and the first intake 
of study drug.  
Baseline for safety is defined as the last non-missing value (either scheduled, unscheduled or 
repeat) up to the date of first dose of study drug. 
6.2.3 Duration / Treatment Day / Study Day  


 
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Treatment day, which is to be used for safety analyses, will be calculated as the number of days 
from first dose of study drug:  
• date of event – date of first dose of study drug + 1, for events on or after first dose  
• date of event – date of first dose of study drug, for events before first dose  
Study day, which is to be used for efficacy analyses, will be calculated as the number of days from 
date of randomization:  
• date of event – date of randomization + 1, for events on or after randomization  
• date of event – date of randomization, for events before randomization  
6.2.4 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2.5 Missing / Partial Start / Stop Date of Adverse Events (AE) and 
Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the subject has stopped taking 
the concomitant medication, the stop date will be imputed as the date of the subject’s last clinic 
visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  


 
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• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the subject’s screening date or the stop date of the 
event/concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the concomitant 
medication/event corresponds to the date of the first dose of study drug. The time will be imputed 
as the same time as the first dose of study drug. In all other cases the time will not be imputed. 
6.2.6 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study drug 
will be taken for analysis purposes as the date when the subject would have run out of study drug 
assuming full compliance from the date the study drug was last dispensed or the date of subject’s 
last clinic visit in the study or early withdrawal or death whichever the earlier. 
If only the month and year of the last dose was recorded, then the date of last dosing will be taken 
for analysis purposes as the date the subject would have run out of study drug assuming full 
compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of subject’s last clinic visit in the study or early withdrawal or death 
whichever the earlier. 
6.2.7 Missing Diagnosis Dates   


 
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If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
6.2.8 Exposure to Study Drug  
Exposure to study drug will be calculated as follows from the date of last dosing minus the first 
day of dosing + 1. The exposure calculation will not take into account breaks in therapy. 
6.2.9 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
6.2.10 Height/Weight/Temperature 
When height is collected in inches (in), the measurements will be converted to centimeters (cm) 
using the following rule: 
Height (cm) = 2.54*height (in) 
When weight is collected in pounds (lbs), the measurements will be converted to kilograms (kg) 
using the following rule: 
Weight (kg) = 0.45359237*weight (lbs) 
When temperature is collected in Fahrenheit degrees (F), the measurements will be converted to 
Celsius degrees (C) using the following rule: 
Temperature (C) = (temperature (F) – 32)/1.8 
6.2.11 Electrocardiogram (ECG) Data 
The Banook Group will prepare a separate ECG SAP for the analysis of the ECG data. . 
6.2.12 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 


 
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Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behavior 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non-fatal) 
Category 10 
Suicidal Behavior (Lifetime and Past 12 Months version) / Suicide 
(Since Last Visit version) 
Suicidal Ideation at baseline – A “yes” answer at baseline to any one of the 5 suicidal ideation 
questions (categories 1-5) on the C-SSRS Lifetime or Past 12 Months version. 
Suicidal Behavior at baseline – A “yes” answer at baseline to any one of the 5 suicidal behavior 
questions (categories 6-10) on the C-SSRS Lifetime or Past 12 Months version. 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment to any 
one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS Since Last Visit version. 
Suicidal Behavior since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS Since Last Visit 
version. 
There will be no imputation of missing data for C-SSRS. 
6.2.13 Laboratory data 
The following rules will be applied for purposes of unit conversion of WBC differential 
parameters: 
Result value (10^9/L) = Result value (%) * WBC (10^9/L) 
Ref Range value (10^9/L) = Ref Range value (%) * WBC Ref Range value (10^9/L) min and 
max 


 
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6.2.14 Randomization Strata 
The randomization will be stratified according to the site category (non-ancillary, ancillary), the 
duration of the hearing loss (≥ 24hours/< 24 hours) and the intake of corticosteroids (Yes, No).  
6.2.15 Change from baseline 
Change from baseline in absolute terms is defined as the baseline value subtracted from the 
postbaseline value. 
6.2.16 Analysis Window 
For the analysis of all the efficacy and safety endpoints, the following analysis windows will be 
used to obtain the analysis visits. For each respective analysis visit, all assessments, either 
scheduled or unscheduled/repeat, will be considered. The values collected during the study will 
be mapped to protocol visits according to the windowed times indicated below. Should more 
than one value fall within the same time window, then the closest value to the planned day will 
be assigned to the visit. If the values are equidistant to the planned day, the latest value will be 
retained.   
Analysis Visit 
Window 
Day 7 
[Day 5, Day 9] (Day 7 +/- 2 days) 
Day 14 
[Day 10, Day 18] (Day 14 +/- 4 days) 
Day 28 
[Day 20, Day 36] (Day 28 +/- 8 days) 
Day 84 
[Day 60, Day 108] (Day 84 +/- 24 days) 
 
Note: Day in the table is Study Day for efficacy endpoints, Treatment Day for safety endpoints 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.4 or higher3. 
Summaries will be presented by treatment group and/or overall. Treatment group labels will be 
displayed as follows for Part 1:  
SENS 29mg 
SENS 43.5mg 
Placebo 
For Part 2, treatment group labels will be displayed as follows: 
SENS XXmg 
Placebo 


 
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Overall columns are to be included within the table shells as follows: 
Data 
Columns labels 
Demography 
Treatment groups and overall 
Baseline 
Treatment groups and overall 
Disposition 
Treatment groups and overall 
Efficacy 
Treatment groups 
Pharmacokinetic (PK) 
Treatment groups 
PD 
Treatment groups 
AEs 
Treatment groups and overall 
Other safety 
Treatment groups 
 
Listings will be sorted in the following order: treatment group, subject, parameter, and visit, unless 
otherwise stated. All data will be listed, subjects who were not randomized will be displayed after 
the randomized treatment groups.  
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. For all tabulations of changes from 
baseline data, the lower and upper 95% confidence limits for the mean for the individual treatments 
will be given.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 Decimal Places 
Decimal places for derived data described in Section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places.  


 
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Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place.  
P- Values will be quoted to 4 decimal places. P-values < 0.0001 will be presented as p<0.0001.  
6.4 Subject Disposition 
For each part of the study, subject disposition will be summarized by center and overall (i.e. across 
centers) as follows:  
• 
The number of subjects who failed screening and the reasons for failure will be tabulated 
for all screened subjects. 
• 
The number of subjects randomized, and number of subjects in each analysis set will be 
summarized by treatment group and overall based on the ITT set. 
• The number of early withdrawals and the reason for withdrawals will be tabulated by 
treatment group and overall based on the ITT set. 
6.5 Protocol Deviations 
Protocol deviations will be classified as Major, Minor, or Critical. Additionally, any COVID-19-
related protocol deviations will be identified. A tabulation of the number of protocol deviations 
within each classification will be presented by treatment group and overall for the ITT analysis 
set. A listing of protocol deviations will be provided within Appendix 16.2 of the CSR. 
6.6 Stratification factors 
For each part of the study, the distribution of the subjects across the categories of each of the 3 
stratification factors (site category (non-ancillary, ancillary), duration of disease (< 24 hours, ≥24 
hours), and oral corticosteroids intake at baseline (yes, no)), will be summarized by randomized 
treatment group and overall based on the ITT analysis set. 
6.7 Baseline Comparability 
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 


 
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For each part of the study, standard continuous or categorical variable summaries will be presented 
by randomized treatment group and overall based on the ITT analysis set. 
All baseline data will also be listed. 
6.7.1 Demographics 
The following variables will be summarized: 
o age at informed consent (years) 
o gender 
o fertility status (female subjects) 
o ethnicity 
o race 
o height (cm) 
o weight (kg) 
o BMI (kg/m2) 
6.7.2 Disease Characteristics and Other Relevant Baseline Data 
The following variables will be summarized: 
• Duration of current hearing loss episode at time of randomisation (in hours): randomisation 
date/time-SSNHL onset date/time, continuous and by class (<24 hours, [24; 48[, [48; 72[, 
>72 hours) 
• Cause of current hearing loss/SSNHL: idiopathic, trauma (including noise induced), 
infectious, otologic disease, ototoxic drug intake, vascular/hematologic, neoplastic 
• Oral Corticosteroids (CM.CMCAT = “ORAL STEROID”) for SSNHL (CM.CMINDC = 
“SSNHL”) at baseline (ongoing or started the day of first study treatment intake): yes/no 
and type (prednisone/prednisolone, methylprednisolone, dexamethasone or other) 
• Otologic history: ear used for telephone and recent switch, professional exposure to very 
loud noise, recreational exposure to very loud noise, history of severe ear problems 
(previous SSNHL, frequent otitis media, past history of ear surgery, wearing hearing aids, 
past history of tinnitus in each ear), ear/head/neck/nose/throat problems (infection, 
respiratory tract infection, ear pain, ear pressure, otorhea, severe headache or migraine, 
recent head or neck trauma, recent baro trauma, exposure to loud noise, past otologic 
evaluation) 


 
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• Baseline Pure Tone Audiometry air conduction average of the hearing threshold of 3 
contiguous most affected hearing frequencies in decibels as identified at study entry (PTA) 
for the current hearing loss episode: 
o Initial frequency range (≤ 2000 Hz, > 2000 Hz) derived as the mean between the 
lowest and the highest of the most affected frequencies 
o Affected ear side (right, left) 
o Affected ear PTA continuous (in decibels) 
o Affected ear PTA by class (<20 dB, ≥20 dB to ≤35 dB, >35 dB to ≤50dB, >50 to 
≤70 dB, >70 to ≤90 dB, >90 dB) 
o Reference type (contralateral ear, previous PTA, reference frequency) 
o Reference PTA continuous 
o Reference PTA by class 
o Hearing loss (difference between the PTA on affected ear and the reference PTA 
for the identified frequencies) continuous (in decibels) 
o Hearing loss by class according to American Speech-Language-Hearing 
Association criteria (ASHA) (<16, 16 to <26dB, 26 to <41dB, 41 to <56dB, 56 to 
<71dB, 71 to <91dB, ≥91dB) 
• Tinnitus numeric rating scale (NRS) as recorded in the eCRF (XT.XTCAT= 
“Questionaire”): score (from 0 to 10)  
• Vertigo NRS: score (from 0 to 10) 
• Speech recognition threshold (SRT) on affected ear: minimum hearing level at which the 
patient can correctly recognizes 50 % of the presented speech material 
• Word recognition score (WRS) also called Speech discrimination score on affected ear: 
percentage of words correctly repeated at 60dB and 80dB  
• Tinnitus functional index (TFI) Total Score (from 0 to 250) 
6.8 Medical/Surgical History 
For each part of the study, separate tabulations of previous and ongoing medical and surgical 
conditions at screening will be presented by randomized treatment group and overall, for the ITT 
analysis set. Conditions will be presented by Medical Dictionary for Regulatory Activities 
(MedDRA) primary system organ class and preferred term, using the most recent MedDRA 
version available at the time of database lock. 
All data will be listed. 


 
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6.9 Prior and Concomitant Medications 
For each part of the study, separate tabulations will be produced for prior and concomitant 
medications presented by randomized treatment group and overall, for the Safety analysis set. Prior 
medications are defined as all medications that started and stopped before the date of first dose of 
study drug. Concomitant medications are defined as medications that started prior to, on or after 
the date of first dose of study drug and ended on or after the date of first dose of study drug or are 
ongoing at end of study. Prior and concomitant medications will be summarized using Anatomic 
Therapeutic Chemical (ATC) Level 2. All medications will be coded using the most recent version 
of the WHO Drug Dictionary available at the time of database lock. 
A separate tabulation for study treatment concomitant medications, defined as medications that 
started before date of the first dose of study drug and continued while on study drug or medications 
that started between the day of the first dose of study drug (included) and the date of the last dose 
of study drug (included) will be displayed by randomized treatment group and overall, for the 
Safety analysis set. 
A separate tabulation for prior and concomitant use of oral corticosteroids (excluding use as rescue 
medication) will be displayed by randomized treatment group and overall, for the Safety analysis 
set. 
A separate tabulation for concomitant corticosteroid as rescue treatment will be tabulated. 
Supporting dosing information will be listed, along with the other prior and concomitant 
medications. 
6.10 Exposure to Study Drug 
Extent of exposure (number of days of exposure to study drug) will be presented by randomized 
treatment group for the Safety analysis set.   
6.11 Treatment Compliance 
Overall percent compliance to study drug dosage regimen, calculated as percent doses taken 
relative to doses scheduled to be taken, that is, 
(Total Dispensed –  Total Returned) × 100
3 ∗2 ∗𝐸𝑥𝑡𝑒𝑛𝑡 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑡𝑜 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 


 
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where the “Total Dispensed” is 180 and “Total Returned” is the sum of the Blue label, Yellow 
label, and Green label tablets returned by patient. Subject compliance will be summarized by 
treatment group for the Safety analysis set. 
6.12  Efficacy Analyses 
For Part 1 all statistical tests will be performed using a one-tailed 5% significance level. All 
comparisons between treatments, where high dose vs. placebo will be tested first, and then testing 
conditionally low dose vs. placebo, will be reported with 90% confidence intervals for the 
difference.  
For Part 2, all statistical tests will be performed using a two-tailed 5% significance level. All 
comparisons between treatments will be reported with 95% confidence intervals for the difference.  
6.12.1 Primary Endpoint 
The primary endpoint is the change in pure tone audiometry (PTA: average of the hearing threshold 
of 3 contiguous most affected hearing frequencies in decibels as identified at study entry) on pure 
tone audiometric air conduction testing in the affected ear from baseline to the end of treatment 
visit (Visit D28 ± 3).  
The 3 most affected contiguous audiometric test frequencies are defined with respect to the 
unaffected contralateral ear and will be fixed for all further calculations. In case of a pre-existing 
contralateral hearing loss, the corresponding values of a pre-existing audiogram of the affected 
ear, if dating back less than 2 years, will be considered as the reference. For all other scenarios 
(e.g. pre-existing contralateral hearing loss with no audiogram in the past 2 years) the reference 
frequencies will be set using the ISO 7029;2017 norm values. In case of bilateral acute acoustic 
trauma leading to sudden sensorineural hearing loss, the most affected ear according to the 
inclusion criteria will be considered. If both ears are equally affected, the right ear will be 
considered. 
At baseline, if 2 or more sequences of 3 contiguous frequencies are similarly affected, the index 
sequence with the lower contiguous frequencies will be selected as the reference. Pure tone average 
frequencies determined at baseline will remain fixed for all evaluations.   
If one of the frequencies is missing for post baseline values the PTA will be averaged on 2 out of 
the 3 identified frequencies. If more than 1 is missing, the PTA will not be calculated. 
6.12.2 Primary Efficacy Analysis 


 
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The null and alternative hypotheses for part 1 of the study are as follows, where μH, μL and μP are 
defined as the mean change in PTA of the high dose, low dose, and placebo respectively: 
H0H: μH - μP = 0, HAH: μH - μP < 0 (greater decrease on high dose)  
H0L: μL - μP = 0, HAL: μL - μP < 0 (greater decrease on low dose) 
 
Analysis of Part 1 
To preserve type I error rate during part 1, the above hypotheses will be tested according to a fixed-
sequence testing strategy: the comparison of the high dose versus placebo will be tested first at 5% 
one-sided significance level; then the comparison of the low dose versus placebo will tested at 5% 
one-sided significance level conditionally to the significance of the high dose. This procedure is 
compliant with the principle of the closed test procedure (Marcus4 et al., 1976, Koch5 1996). In 
the event that the null hypothesis H0H cannot be rejected for the high dose, the p-value associated 
with H0L will still be provided but considered exploratory. The comparison of the high dose versus 
the low dose will be considered exploratory. 
 
Analysis of Part 2 
After completion of Part 1, one dose will be dropped and the other will be carried over to part 2. 
Hence at the end of part 2 only one null hypothesis will be tested: 
H0: μT - μP = 0, HA: μT - μP ≠ 0 
 
Where μT is the change from baseline in PTA for the active treatment arm of part 2. This 
hypothesis will be tested at the 5% two-sided significance level. 
 
Analysis details 
Descriptive statistics (n, mean, SD, median, Q1, Q3, min, max) of observed data by visit (Day 7, 
14, 28) and treatment group (placebo, SENS401 29 mg, SENS401 43.5 mg) displaying baseline, 
post-baseline, change will be provided. 
Mean changes from baseline of the hearing loss at days 7, 14, and 28 will be analyzed using a 
restricted maximum likelihood (REML)-based repeated measures approach under the assumption 
of data missing at random (MAR). Analyses will include the categorical, fixed covariates of site 
category (non-ancillary, ancillary), duration of disease (≥24 hours or < 24 hours), and oral 


 
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Page 23 of 67 
corticosteroids intake at baseline (yes or no) as entered in the IWRS and the fixed, categorical 
effects of treatment, visit (Day 7, Day 14, Day 28), and treatment-by-visit interaction, as well as 
the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. An 
unstructured (UN) covariance structure will be used to model the within-patient errors. If this 
analysis fails to converge, simpler structures such as first-order ante-dependent ANTE(1), first- 
order autoregressive AR(1), or compound symmetry (CS) will be tested in a model without 
treatment effect. The covariance structure converging to the best fit, that is, with the lowest 
Akaike’s information criterion (AIC), will be used in the full model. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. The estimations and 
standard errors of the contrasts of interest will be derived from this model. For each timepoint the 
marginal predicted means (Least Squares Means) and corresponding standard error and confidence 
interval (consistent with the significance level applied for the study part considered) will be 
displayed (and also graphically illustrated with mean changes on y-axis and time on the x-axis by 
treatment groups). The p-value of the visit by treatment interaction will be provided. For each 
timepoint, one-sided p-values for the comparisons with Placebo and for the comparison of high 
dose versus low dose will also be displayed with comparisons with Placebo at Day 28 being the 
comparisons of primary interest while the other comparisons are secondary. 
SAS code to perform the analysis described above for part 1 (i.e. when 3 treatment arms are 
available) is provided below wherein TRT01PN is the treatment group, AVISITN is the analysis 
visit (Day 7, 14, and 28) as defined in Section 6.2.15, ANCIL is the site category (non-ancillary, 
ancillary), DHR is the duration of the hearing loss (≥24 hours or <24 hours) strata, and CORT is 
the intake of oral corticosteroids at baseline (Yes, No) strata. Note that the ordering of the 
coefficients for the ESTIMATE statements may need to be updated depending on the entry order 
in the CLASS statement and will be different for the analysis of part 2 (where only 2 treatment 
arms will be present). Moreover, ‘TYPE=UN’ may need to be replaced with ‘TYPE=ANTE(1)’, 
'TYPE = AR(1), or ‘TYPE=CS’ if the model with ‘TYPE=UN’ failed to converge. 
 
proc mixed data = <dataset>; 
  class subjid trt01pn avisitn ANCIL DHR CORT; 
  model chg = trt01pn avisitn trt01pn*avisitn base base*avisitn ANCIL DHR 
CORT / ddfm = kr; 
  repeated avisitn / type = un subject=subjid(trt01pn); 
  lsmeans trt01pn*avisitn / cl e alpha = 0.10; 
  estimate 'High vs Placebo, day 28'  
            trt01pn -1 0 1  
            trt01pn*avisitn 0 0 -1 0 0 0 0 0 1 / alpha = 0.10 cl; 
  estimate 'Low vs Placebo, day 28'  


 
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            trt01pn -1 1 0  
            trt01pn*avisitn 0 0 -1 0 0 1 0 0 0 / alpha = 0.10 cl; 
  estimate 'Low vs High, day 28'  
            trt01pn 0 1 -1  
            trt01pn*avisitn 0 0 0 0 0 1 0 0 -1 / alpha = 0.10 cl; 
run; 
A similar code (with 2 groups only and alpha = 0.05, two-sided p-value) will be used for the 
analysis of Part 2.  
The number of subjects, the affected ear and the type of reference (unaffected contralateral ear, 
reference values from a pre-existing audiogram, ISO 2017) will be tabulated by treatment group, 
stratification groups, and overall. 
All PTA data will also be listed. 
6.12.3 Sensitivity Analyses 
A first sensitivity analysis will assess the impact of major protocol violations to study results, by 
repeating the primary analysis on the Per Protocol population. 
A second sensitivity analysis will further assess the impact of the MAR assumption of the main 
analysis by imputing missing data at Day 7, Day 14 or Day 28 under control-based multiple 
imputation framework under the assumption that data are missing not at random (MNAR) and 
using the Copy Reference (CR) approach (Carpenter6 2013). Thus, instead of imputing a single 
value for each missing observation, a set of values will be generated from the model resulting in 
as many distinct complete datasets without missing data. The imputation model will include the 
PTA baseline, the three stratification factors (site category, hearing loss duration and intake of 
corticosteroids at baseline) and the Day 7, Day 14, Day 28 PTA data. Missing data at Day 7, Day 
14, and Day 28 for subjects from all three treatment groups will be imputed using data observed 
in the placebo group. This approach assumes that patients with missing data in the active treatment 
groups have outcomes trending towards outcomes observed in the placebo group, i.e., the 
imputations result in a treatment effect that gradually diminishes towards the placebo group. In a 
first step "intermittent" missing data (a post-baseline is missing but one or more later assessments 
are available) will be first imputed by a Markov Chain Monte-Carlo (MCMC) method using a non-
informative Jeffrey's prior, thus creating multiple partially imputed "monotone" datasets; then, the 
remaining missing data will be imputed once in each of the "monotone" imputed datasets using 
the CR approach leading finally to multiple complete imputed datasets. An analysis of covariance 
(ANCOVA) will then be used to analyze the change from baseline to Day 28 on each complete 


 
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imputed dataset. The following terms will be included in the ANCOVA model: the PTA baseline, 
the three stratification factors (site category, hearing loss duration and intake of corticosteroids at 
baseline), and the treatment group. Uncertainty in the imputations will be reflected appropriately 
in the analysis by combining the results on each imputed dataset using Rubin's methodology. 
More specifically, the imputations will be performed in two steps: “intermittent” missing data (a 
result is missing but one or more results are available at following visits) will be first imputed by 
a MCMC method using a non-informative Jeffrey’s prior, thus creating 500 partially imputed 
“monotone” datasets; then, the remaining missing data will be imputed once in each of these 500 
“monotone” imputed datasets using the CR approach leading finally to 500 complete imputed 
datasets. 
The two-step MI procedure will be implemented by the following SAS code: 
proc mi data=<dataset> nimpute=500 seed=32767 min = . . . . . -10 -10 -10  
max = . . . . . 120 120 120 minmaxiter = 1000000 out=h2; 
 where base ne .; 
 mcmc impute = monotone; 
 var trt01pn ANCIL DHR CORT base Day07 Day14 Day28; 
run; 
 
proc mi data=h2 nimpute=1 seed=32767 min = . . . . . -10 -10 -10  max = . . . 
. . 120 120 120 minmaxiter = 1000000 out=h3; 
 by _imputation_; 
 class trt01pn ANCIL DHR CORT; 
 var ANCIL DHR CORT base Day07 Day14 Day28; 
 mnar model (Day07 Day14 Day28 / modelobs=(trt01pn = "1"));*"1" = placebo; 
 monotone regression; 
run; 
 
data h3; 
 set h3; 
 chg = Day28 - baseline; 
run; 
An analysis of covariance (ANCOVA) model will then be used to analyze this endpoint on each 
imputed dataset using the following SAS code for Part 1: 
proc mixed data=h3; 
by _imputation_; 
 class trt01pn ANCIL DHR CORT; 
 model chg = ANCIL DHR CORT base trt01pn / solution; 
 lsmeans trt01pn / diff=control("3") cl;*"1" = placebo; 
 ods output lsmeans =lsm diffs=lsmdiffs ; 
run; 


 
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Uncertainty in the imputations will be reflected appropriately in the analysis by combining the 
results on each imputed dataset using Rubin’s methodology (Rubin7 1987). The final estimate is 
the mean of the estimates from the 500 imputed datasets, and the final variance is the sum of the 
average within-imputation variance and (1 + 1 / 500) times the between-imputation variance. From 
the final point estimate and variance, the 90% CI will be determined. The results aggregation of 
the MI procedure after analysis of the 500 imputed datasets will be implemented by the following 
SAS code: 
proc mianalyze data=lsm alpha=0.10; 
 by trt01pn; 
 modeleffects Estimate; 
 stderr StdErr ; 
run; 
 
proc mianalyze data=lsmdiffs alpha=0.10; 
 modeleffects Estimate; 
 stderr StdErr ; 
run; 
 
A similar code (with 2 groups only and alpha = 0.05) will be used for the analysis of part 2 
A third sensitivity analysis will assess the impact of the use of rescue therapy by repeating the 
primary analysis after having set to missing all PTA assessments performed after initiation of a 
rescue therapy and then imputing each missing Day 28 of a subject having received rescue therapy 
by the subject baseline. 
6.12.4 Secondary Endpoints 
6.12.4.1 Change in pure tone audiometry (average of the hearing threshold of the 2 most 
affected hearing frequencies identified at study entry) in affected ear from baseline to 
the end of treatment visit (Visit D28± 3) 
Mean changes from baseline in pure tone audiometry (average of the hearing threshold of the 2 
most affected hearing frequencies identified at baseline) on pure tone audiometric air conduction 
testing in affected ear will be analyzed using the same modeling approach as for the primary 
endpoint for both study parts. The 2 most affected hearing frequencies will be defined as the first 
2 frequencies within the 3 most affected hearing frequencies identified at baseline sorted by 
descending order of the hearing losses observed at baseline and by increasing order of the 
frequencies. 


 
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Values at each timepoint and their changes from baseline will also be summarized descriptively 
by treatment group and a line plot of the model estimates of the mean changes from baseline over 
time by treatment group will be presented. 
6.12.4.2 Change in pure tone audiometry (the most affected hearing frequency identified at 
study entry) in affected ear from baseline to the end of treatment visit (Visit D28± 3) 
Mean changes from baseline in pure tone audiometry (the most affected hearing frequency 
identified at baseline) on pure tone audiometric air conduction testing in affected ear will be 
analyzed using the same modeling approach as for the primary endpoint for both study parts but 
without imputation for missing Day 28 results. The most affected hearing frequency will be 
defined as the first frequency within the 3 most affected hearing frequencies identified at baseline 
sorted by descending order of the hearing losses observed at baseline and by increasing order of 
the frequencies. 
Values at each timepoint and their changes from baseline will also be summarized descriptively 
by treatment group and a line plot of the model estimates of the mean changes from baseline over 
time by treatment group will be presented. 
6.12.4.3 Change in pure tone audiometry (PTA; average of the hearing threshold of 3 
contiguous most affected hearing frequencies in decibels as identified at study entry on 
pure tone audiometric air conduction testing) in affected ear from baseline to the end 
of study visit (Visit D84 ± 3) 
Mean changes from baseline in pure tone audiometry (average of the hearing threshold of the 3 
contiguous most affected hearing frequencies identified at baseline) on pure tone audiometric air 
conduction testing in affected ear will be analyzed using the same modeling approach as for the 
primary endpoint for both study parts and expanded by including the Day 84 data in the model.  
Values at each timepoint and their changes from baseline will also be summarized descriptively 
by treatment group and a line plot of the model estimates of the mean changes from baseline.  
6.12.4.4 Change in speech discrimination threshold from baseline to Day 28, and 84. 
The Speech recognition threshold is the minimum hearing level at which the patient can correctly 
recognizes the speech stimuli 50% of the presented speech material. Assessments with missing 
value with "Reason not performed" = "No response due to hearing loss" will be assigned with the 
maximum observed value in the database. 


 
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Mean changes from baseline of the speech recognition threshold at Days 7, 14, 28 and 84 will be 
analyzed using the same modeling approach as for the primary endpoint for both study parts. A 
line plot will be produced to show the discrimination threshold by timepoint for each treatment 
group for all individual subjects.  
6.12.4.5 Frequency and severity of tinnitus at Days 7, 14, 28, and 84 assessed by numerical 
rating scale 
Mean changes from baseline of the severity of tinnitus (assessed numerical rating scale) at Days 
7, 14, 28 and 84 will be analyzed using the same modeling approach as for the primary endpoint. 
For Days 7 and 14 the patients diary log data (PM measurements) will be used. 
For each relevant timepoint the number and percentage of patients experiencing tinnitus will be 
tabulated. Severity of reported tinnitus will be summarized as counts and percentages as well on a 
scale from 0 (no tinnitus) to 10 (extreme tinnitus). 
All data on reported tinnitus occurrences and severity will also be listed. 
6.12.5 Exploratory Endpoints 
All the following endpoints will only be analyzed based on the ITT population. The results will 
be presented descriptively (with confidence intervals where indicated, 90% confidence intervals 
for Part 1 data, 95% confidence intervals for Part 2 data). 
6.12.5.1 % of patients with complete hearing recovery defined as PTA <20 dB or hearing similar 
to the unaffected contralateral ear 
The proportion of patients with a complete hearing recovery or hearing similar to the unaffected 
ear will be summarized at Day 28 and Day 84 alongside an exact confidence interval. Hearing in 
the affected ear will be considered similar to the unaffected one if the absolute difference in  pure 
tone audiometric air conduction testing (average of the hearing threshold of 3 contiguous most 
affected hearing frequencies in decibels as identified at study entry) is < 5dB, and this rule will 
also be applied to cases where either an old audiogram was used or normative values were 
considered as reference (e.g. pre-existing contralateral hearing loss with no audiogram in the past 
2 years). Patients with complete hearing recovery are those that have pure tone audiometric air 
conduction testing (average of the hearing threshold of 3 contiguous most affected hearing 
frequencies in decibels as identified at study entry) of < 20dB. 


 
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6.12.5.2 % of patients with marked improvement defined as PTA threshold absolute 
improvement > 30 dB  
The proportion of patients with marked improvement in pure tone audiometric air conduction 
testing (average of the hearing threshold of 3 contiguous most affected hearing frequencies in 
decibels as identified at study entry), that is, PTA at post-baseline minus baseline PTA is > 30dB, 
will be summarized by treatment group for Day 28 and Day 84 along with an exact confidence 
interval.  
6.12.5.3 % of patients with PTA > 35 dB and > 90 dB on Day 7, Day 14 and end of study visit 
(visit D84± 3) 
The proportion of patients with PTA >35 dB and >90 dB on pure tone audiometric air conduction 
testing at the given timepoints (Day 7, 14, and 84) will be summarized by treatment group 
alongside an exact confidence interval. The PTA that will be utilized here is the average of the 
hearing threshold of 3 contiguous most affected hearing frequencies in decibels as identified at 
study entry. 
6.12.5.4 % of responders (response is defined as an improvement of 10dB or more) in PTA  
For this endpoint, a subject will be classified as “responder”, that is, if the subject has an 
improvement of 10dB or more in PTA (pure tone audiometric air conduction testing) from 
baseline, or “non-responder” otherwise for each timepoint (Day 7, 14, 28, and 84). The PTA that 
will be utilized here is the average of the hearing threshold of 3 contiguous most affected hearing 
frequencies in decibels as identified at study entry. The % of responders will be summarized by 
treatment group at each timepoint alongside an exact confidence interval. In addition, the 
proportion of responders at each timepoint for each treatment arm will also be graphically 
represented. 
6.12.5.5 Word recognition score at 80 dB and 60 dB in the affected ear on Day 28 and 84 
The word recognition score (that is, percent of words correctly repeated) at 80 and 60 dB in the 
affected ear and its changes from baseline to post-baseline timepoints will be summarized by 
treatment group using descriptive statistics for continuous variables. In addition, the following 
graphical displays will be presented: 


 
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• Percent change from baseline in Word Recognition Score in the affected ear by dB level 
over time, with a reference line at 15% to identify the clinically relevant improvement 
threshold.  
• Word Recognition Score for the affected ear over time, by treatment group and dB level 
• Difference in Word Recognition Scores between the affected and reference ear over time, 
by treatment group and dB level 
All word recognition data on both ears will be listed. 
6.12.5.6 Relationship between time of onset of symptoms to first study drug intake and the 
primary endpoint 
The time of onset of symptoms to first study drug intake (in days) will be obtained as follows: 
date of first dose of study drug – date of the onset of SSNHL symptoms and will be summarized 
descriptively by treatment group. 
The relationship between time of onset of symptoms to first study drug intake and the change in 
PTA at Day 28 from baseline will be explored through a scatter plot along with the Pearson 
correlation coefficient. 
6.12.5.7 Frequency and severity of any vertigo at day 1,7,14, 28 and 84 
For each relevant timepoint the number and percentage of patients reporting vertigo will be 
summarized by treatment group. Severity of reported vertigo episodes will be summarized as 
counts and percentages as well on a scale from 0 (no vertigo) to 10 (extreme vertigo). The 
frequency of patients experiencing vertigo will also be displayed graphically for each treatment 
group and timepoint via a bar chart. 
All data on reported vertigo episodes will also be listed. 
6.12.5.8 Tinnitus burden based on the change in tinnitus QOL scores at day 1,7,14, 28 and 84 
The Tinnitus Functional Index (TFI) comprise of 25 questions on the impact of the tinnitus on the 
individual behavior and feelings in which items 1 and 3 are in percentage scale, that is, from 0 to 
100 with increment of 10 while all the other items are in 0 to 10 scale with an increment of 1. Thus, 
items 1 and 3 need to be transformed into a 0 to 10 scale by dividing the value by 10 before 
obtaining the subscale score to which the items belong, as well as the total TFI score. The 
questionnaire has eight subscales that address the intrusiveness of tinnitus (items 1, 2, 3), the sense 
of control the patient has (items 4, 5, 6), cognitive interference (items 7, 8 , 9), sleep disturbance 


 
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(items 10, 11, 12), auditory issues (items 13, 14, 15), relaxation issues (items 16, 17, 18), quality 
of life (items 19, 20, 21, 22), and emotional distress (items 23, 24, 25). In obtaining the subscale 
score, the response to all the items that belong to the corresponding subscale score will be added 
then divided by the number of items that have responses, and eventually multiplied by 10. Thus, 
the subscale score would range from 0 to 100. For a valid subscale score, no more than 1 item 
should have missing response. Otherwise, the subscale score will be set to missing. The TFI total 
score is obtained by adding the values of all the items that have responses then dividing by the 
number of items that have responses, and eventually multiplying by 100. TFI total score will range 
from 0 to 100. For a valid TFI total score, there should be at least 19 items that have non-missing 
responses. Otherwise, the TFI total score will be set to missing.  
The TFI subscale scores and total score, along with the corresponding changes from baseline will 
be summarized for all the relevant timepoints by treatment group. All responses to TFI items, as 
well as derived TFI data (total and subscale scores) will be listed. 
6.12.5.9 Change in biomarkers 
Prestin results and its change from baseline will be summarized descriptively at baseline, Day 14, 
and Day 28 (EoT). 
All biomarker data will be listed. 
6.12.5.10 
Change in EQ-5D-5L scores between baseline and Day 28 and 84 
EQ-5D is a standardize measure of health status that consists of two parts: health-status descriptive 
system questionnaire which provides a simple descriptive profile of the responder’s health, and 
EQ visual analogue scale (VAS) which is a quantitative measure of the responder’s overall health 
based on his/her own judgement. The descriptive system comprises five dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression) with five response levels (no 
problems, slight problems, moderate problems, severe problems, unable to/extreme problems). 
Meanwhile, VAS ranges from 0 to 100 which corresponds to ‘worst health you can imagine’ to 
‘best health you can imagine’ respectively.  
The number of patients reporting each response level for each of the five dimensions will be 
summarized by treatment group for each baseline and post-baseline visits. Shift tables from 
baseline to post-baseline visits will also be presented for each dimension. In addition, a summary 
of dichotomize response, that is, ‘no problem’ when the response is level 1 (“no problems” or “no 
pain or discomfort” or “not anxious or depressed”) and ‘any problems’ when the response is level 


 
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2 to 5 (any other responses), will be presented by treatment group for the baseline and post-baseline 
visits. 
The EQ Visual Analogue Scale (VAS) and its change from baseline to Day 28 (EoT) and Day 84 
(EoS/Follow-up) will be summarized by treatment group. 
All EQ-5D-5L data will also be listed. 
6.12.5.11 
Change in DPOAE at Days 7, 14, 28, and 84 compared to baseline values 
The corresponding assessments were optional in the protocol leading to data available in only a 
small subset of subjects. For each collected variable, descriptive statistics by treatment group and 
visit will be presented for the affected ear. 
6.12.5.12 
Change in TEOAE at Days 7, 14, 28 and 84 compared to baseline values 
The corresponding assessments were optional in the protocol leading to data available in only a 
small subset of subjects. For each collected variable, descriptive statistics by treatment group and 
visit will be presented for the affected ear. 
6.12.6 Multiplicity 
Multiplicity adjustment for comparing treatment groups in part 1 (3 treatment groups) for a given 
endpoint is addressed by testing first the high dose versus placebo and then testing the low dose 
versus placebo conditionally to the significance of the high dose as described in Section 6.12.2. 
As for the secondary endpoints, analyses will be carried out after the primary endpoint following 
a sequential testing procedure. The order of testing will be as follows: 
1. Change in pure tone audiometry (PTA; average of the hearing threshold of 3 contiguous 
most affected hearing frequencies in decibels as identified at study entry) in affected ear 
from baseline to the end of treatment visit (Visit D28± 3) [primary endpoint] 
2. Change in pure tone audiometry (average of the hearing threshold of the 2 most affected 
hearing frequencies identified at study entry) in affected ear from baseline to the end of 
treatment visit (Visit D28± 3) 
3. Change in pure tone audiometry (the most affected hearing frequency identified at study 
entry) in affected ear from baseline to the end of treatment visit (Visit D28± 3). 
4. Change in pure tone audiometry (PTA; average of the hearing threshold of 3 contiguous 
most affected hearing frequencies in decibels as identified at study entry on pure tone 


 
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audiometric air conduction testing) in affected ear from baseline to the end of study visit 
(Visit D84 ± 3) 
5. Change in speech discrimination threshold from baseline to  
a. Days 28,  
b. and 84 
6. Frequency and severity of tinnitus at Days 7, 14, 28, and 84 assessed by numerical rating 
scale 
a. severity at Day 28 
b. severity at Day14 
c. severity at Day 7 
d. severity at Day 84 
Thus, if significance is not achieved on the higher-ranking endpoint, analysis of lower-ranking 
endpoints will still be conducted but will be purely exploratory. For example, if significance 
is not achieved in 2, analysis of 3-6 will still be conducted but will be declared as non-
significant and thus purely exploratory. For the Part 1, the high dose will be tested, first, within 
each secondary endpoint (i.e. 2, 3, 4, 5), then followed by testing the low dose conditionally to 
the significance of the high dose. 
6.13 Pharmacokinetic Analyses 
Serum samples will be collected for pharmacokinetic (PK) analysis at pre- and post-dose on Day 
14 (V4) and on Day 28 (EoT). Plasma concentration values will be summarized at each relevant 
timepoint by treatment group using number of non-missing observations, geometric mean, 
geometric coefficient of variation (CV), defined as 100 ∗√(𝑒𝑠2 −1) where s is the SD of the data 
on a log scale, minimum and maximum.  
All PK data will also be listed. 
6.14 Safety Analyses 
The safety analyses will be presented by the treatment actually received for the Safety analysis set. 
In the situation of accidental dispensation of two or three distinct treatments to the same patient, 
the patient will be counted for the whole study on the highest dose received. 
6.14.1 Adverse Events 


 
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A treatment emergent adverse event (TEAE) is defined as any AE that has an onset on or after 
the first dose of study drug (without limitation after end of treatment). 
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. 
Late AE is defined as any AE that has an onset on or later than 3 days after the last study treatment 
intake. 
A treatment-related AE is defined as an AE as being possibly or probably related to the study drug. 
If an AE has missing or not assessable relationship it is assumed to be related to the study drug for 
analysis purposes. 
Maximum severity will be assumed for an AE with missing severity.  
All AEs will be coded using the most recent MedDRA version available at time of database lock. 
Summaries over system organ class (SOC) and preferred term (PT) by treatment groups, and 
listings of all TEAEs, Serious Adverse Events (SAEs), AEs leading to withdrawal, and AEs 
leading to death will be presented. The following tables will be presented for AEs: 
• Overall incidence and the number of TEAEs, treatment-related TEAEs, SAEs, TEAEs 
leading to withdrawal, and TEAEs leading to death. 
• TEAE by system organ class and preferred term, incidence and number of events 
• Treatment-related TEAE by system organ class and preferred term, incidence and number 
of events 
• Serious TEAE by system organ class and preferred term, incidence and number of events 
• Severe TEAE by system organ class and preferred term, incidence and number of events 
• TEAE by system organ class, preferred term and maximum severity, incidence 
• Treatment-related TEAE by system organ class, preferred term and maximum severity, 
incidence  
• TEAE leading to early withdrawal by system organ class and preferred term, incidence and 
number of events 
• Listing of serious AEs (presented in the Table section of the appendices). 
• Listing of AEs leading to withdrawal (presented in the Table section of the appendices) 
• Listing of AEs leading to deaths (presented in the Table section of the appendices). 


 
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In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by the 
same subject will be counted as multiple events. 
A late TEAE is defined as a TEAE that has an onset date 3 days or more after the last intake of 
study drug.  
The outputs listed above will be repeated on the late TEAEs only. 
All AEs will be listed (with flags identifying TEAEs and late TEAEs). 
SAEs not classified as treatment-emergent will be displayed in a separate listing. 
6.14.2 Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology, serum chemistry, and C-reactive 
protein parameter. For categorical laboratory parameters, subject counts within each category will 
be summarized. Shift tables from baseline to each post-baseline visit will also be presented, as 
applicable.  
Each measurement (continuous data) will be classified as below, within, or above normal range, 
based on ranges supplied by the laboratory used. This study utilizes local laboratories only and 
therefore each local laboratory will provide its reference ranges. Shift tables in relation to the 
normal range from baseline to each follow-up visit will be presented. 
Moreover, the number and percentage of subjects with treatment-emergent marked laboratory 
abnormalities will be tabulated for each laboratory parameter for which marked abnormalities are 
defined in the table below. For a given parameter, percentages will be based on the number of 
subjects at risk: those not meeting the criterion at baseline (or having a missing baseline value) 
and having at least one post-baseline value (including post-baseline value after last intake of study 
drug). The marked laboratory date abnormalities are defined as follows: 
 
 


 
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Category 
Lab Test/ 
Examination 
Name 
Unit 
Marked Abnormalities 
LL 
LLL 
HH 
HHH 
HHHH 
CHEMISTRY 
Alanine 
Aminotransferase 
U/L 
  
  
>3ULN 
>5ULN 
>8ULN 
CHEMISTRY 
Albumin 
g/L 
<30 
<20 
  
  
  
CHEMISTRY 
Alkaline 
Phosphatase 
U/L 
  
  
>2.5ULN 
>5ULN 
  
CHEMISTRY 
Aspartate 
Aminotransferase 
U/L 
  
  
>3ULN 
>5ULN 
>8ULN 
CHEMISTRY 
Bilirubin 
umol/L 
  
  
>2ULN 
>5ULN 
  
CHEMISTRY 
Calcium 
mmol/L 
<2.0 
<1.75 
>2.9 
>3.1 
  
CHEMISTRY 
Creatine Kinase 
U/L 
  
  
>5ULN 
>10ULN 
  
CHEMISTRY 
Creatinine 
mmol/L 
  
  
>1.5ULN or 
(>1.5baseline if 
baseline > ULN) 
>3ULN or 
(>3baseline if 
baseline>ULN) 
  
CHEMISTRY 
Creatinine 
Clearance 
mL/min/
1.73m2 
<60 
<30 
  
  
  
CHEMISTRY 
Gamma Glutamyl 
Transferase 
U/L 
  
  
>2.5ULN 
>5ULN 
  
CHEMISTRY 
Glucose 
mmol/L 
<3.0 
<2.2 
>8.9 
>13.9 
  
CHEMISTRY 
Phosphate 
mmol/L 
<0.8 
<0.6 
  
  
  
CHEMISTRY 
Potassium 
mmol/L 
<3.2 
<3.0 
>5.5 
>6.0 
  
CHEMISTRY 
Sodium 
mmol/L 
<130 
  
>150 
>155 
  
CHEMISTRY 
Triglycerides 
mmol/L 
  
  
  
  
  
CHEMISTRY 
Urate 
umol/L 
  
  
>590 
>720 
  
CHEMISTRY 
Urea 
mmol/L 
  
  
>2.5ULN 
>5ULN 
  
HEMATOLOGY 
Eosinophils 
10^9/L 
  
  
>5.0 
  
  
HEMATOLOGY 
Hematocrit 
Ratio 
<0.32(men), 
<0.28(women) 
<0.20 
>0.60(men),  
>0.55 (women) 
>0.65 
  
HEMATOLOGY 
Hemoglobin 
g/L 
<100 
<80 
>ULN+20 (or 
>baseline+20 if 
baseline>ULN) 
>ULN+40 (or 
>baseline+40 if 
baseline>ULN) 
  
HEMATOLOGY 
Leukocytes 
10^9/L 
<3.0 
<2.0 
>20 
>100 
  
HEMATOLOGY 
Lymphocytes 
10^9/L 
<0.8 
<0.5 
>4.0 
>20 
  
HEMATOLOGY 
Neutrophils 
10^9/L 
<1.5 
<1.0 
  
  
  
HEMATOLOGY 
Platelets 
10^9/L 
<75 
<50 
>600 
>999 
  
 
A listing of any clinically significant laboratory measurements recorded throughout the study will 
be presented. For lab parameters that have defined marked abnormalities, the most extreme 


 
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abnormality will be listed. All laboratory assessments, including urine and serum pregnancy tests, 
will also be listed. 
6.14.3 Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm)  
• Body temperature (degrees Celsius) 
• Body weight (kg) 
Moreover, the number and percentage of subjects with treatment-emergent marked abnormality 
will be tabulated for each parameter. Percentages will be based on the number of subjects at risk 
for the parameter: those having a baseline value and at least one post-baseline value (including 
post-baseline value after last intake of study drug). The marked vital sign abnormalities are defined 
as follows: 
Parameter 
Abnormality 
SBP (mmHg) 
≤ 95 mmHg and decrease from baseline ≥ 20 mmHg,   
≥ 160 mmHg and increase from baseline ≥ 20 mmHg 
DBP (mmHg) 
≤ 45 mmHg and decrease from baseline ≥ 10 mmHg, 
≥ 110 mmHg and increase from baseline ≥ 10 mmHg 
HR (bpm) 
≤ 50 bpm and decrease from baseline ≥ 20 bpm, 
≥ 120 bpm and increase from baseline ≥ 20 bpm 
 
6.14.4 Physical Examination 
The body systems within the physical examination data will be summarized by treatment and visit. 
In addition, shift tables in terms of findings (Normal, Abnormal NCS, Abnormal CS) from baseline 
to Day 28 (EoT) and Day 84 (EoS/Follow-up) for each body system will be presented. Details of 
clinically significant findings will be listed.  
6.14.5 Otoscopy 
Otoscopy is to be done just before each hearing assessment at every visit to rule out possible outer-
ear abnormality, such as otitis media, tympanic perforation. It is part of the standard of care.  
Findings (Normal, Abnormal NCS and Abnormal CS) will be summarized for each ear by 


 
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treatment group and visit. In addition, shift tables from baseline to all post-baseline visits will be 
presented for each ear by treatment group.  
All otoscopy data will be listed. 
6.14.6 Tympanometry 
Tympanometry will follow the otoscopy in order to test the condition of the middle ear and 
mobility of the eardrum (tympanic membrane) and the conduction bones by creating variations of 
air pressure in the ear canal. 
Findings (Normal, Abnormal NCS, Abnormal CS) will be summarized for each ear by treatment 
group and visit. Shift tables from baseline to each post-baseline visit will be presented for each ear 
by treatment group. 
All tympanometry data will be listed. 
6.14.7 Columbia-Suicide Severity Rating Scale (C-SSRS) 
C-SSRS will be used to assess suicidal ideations and behaviors. Number of subjects that responded 
‘yes’ to any of the C-SSRS Suicidal Ideation Items, as described in Section 6.2.12, will be 
presented by treatment group, and will be tabulated separately for baseline and post-baseline 
assessments. Similarly, number of subjects that responded ‘yes’ to any of the C-SSRS Suicidal 
Behavioral Items, as described in Section 6.2.12, will be presented by treatment group, and will 
be tabulated separately at baseline and post-baseline assessments. 
Derived C-SSRS data as described in Section 6.2.12 will be listed for baseline and post-baseline 
assessments for all subjects.  
7 INTERIM ANALYSIS 
Protocol version 4.0 introduced two interim GST looks to be performed during Part 1 of the study, 
which may lead to early discontinuation of Part 1 for futility or efficacy. 
The GST design was defined with a 75% power for a standardized difference of means of 0.546 
(15/26.79), an overall 5% one-sided significance level (with a gamma function of parameter -2 as 
Hwang-Shih-DeCani alpha spending function) and a binding futility procedure (with a gamma 
function of parameter -4 as Hwang-Shih-DeCani beta spending function). At each GST look, the 
z-score statistic was to be calculated for the estimated difference of high dose versus placebo. The 
GST looks were planned for 41 (first GST look), 55 (second GST look) and 74 (final analysis of 


 
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Part 1) patients available for the high dose and the placebo together. The GST design can be 
summarized as follows: 
 
In this GST design, the first interim look, second interim look and final analysis were planned 
when 63, 85 and 111 patients, respectively (when 41, 55, 74 patients could be expected in the high 
dose and placebo groups) have been randomized up to the date still theoretically compatible with 
reaching Day 28 and having the data centrally reviewed before he considered GST look. However, 
irrespective of the actual number of patients in high dose and placebo observed in the GST look, 
the z-score limits for futility and efficacy were to be used without any change. 
Further details of the GST analyses are described in a separate SAP. The GST analyses were to 
be undertaken by a separate statistical group contracted by the sponsor.  
The first GST look was performed, and the outcome was a recommendation to continue Part 1 in 
the absence of crossing of any boundary. The second GST look was not performed because all 
amendment protocol approvals were not obtained yet at time when the sample size of the second 
GST was reached. The final look will finally not be performed as it does not have enough added 
value compared to the analysis planned in the DMC SAP section 2.6 (same boundary p-value of 
0.0500 one-sided for both analyses). 
8 CHANGES TO PLANNED PROTOCOL ANALYSIS 
1. Clarified the primary efficacy endpoint, that is, added “on pure tone audiometric air 
conduction testing” since there are two PTAs – bone and air conduction. Inclusion criteria 
#3.1-3.2 of the protocol implies the primary efficacy endpoint is based on the pure tone 
audiometric air conduction testing only and that the audiometric bone conduction testing 
is useful only at study entry to check the exclusion criterion #14. Moreover, the definition 
of hearing loss in in Section 10.1.1 of the protocol indicated the use of air pure tone average.  


 
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2. Clarified the secondary efficacy endpoint “Change in pure tone audiometry (the most 
affected hearing frequencies identified at study entry) in affected ear from baseline to the 
end of treatment visit (Visit D28± 3)”, that is, “frequencies” was changed to “frequency” 
since the endpoint pertains only to a single most affected frequency.  
3. Added “Change in pure tone audiometry (PTA; average of the hearing threshold of 3 
contiguous most affected hearing frequencies in decibels as identified at study entry on 
pure tone audiometric air conduction testing) in affected ear from baseline to the end of 
study visit (Visit D84 ± 3)” as a secondary endpoint to cover the first secondary objective 
“To confirm the maintenance of any early efficacy on hearing loss at 12-week”. 
4. Removed the exploratory efficacy endpoint “Change in PTA from baseline to Day 7, Day 
14 and end of study visit (Visit D84±3)” since this is already covered by the added 
secondary efficacy endpoint (see above item). 
5. Multiplicity adjustment for Part 1 and Part 2 of the study was specified. 
6. The combined analysis of all primary endpoint data from Part 1 and Part 2 in a meta-
analysis was not further detailed and finally removed. 
7. The first-order autoregressive covariance structure was added as an additional possible 
choice in case of absence of convergence of the unstructured covariance in the model for 
repeated measurements. 
8. The second GST look was not performed because all amendment protocol approvals were 
not obtained yet at time when the sample size of the second GST was reached. The final 
look will finally not be performed as it does not have enough added value compared to the 
analysis planned in the DMC SAP section 2.6 (same boundary p-value of 0.0500 one-sided 
for both analyses). 
9. Definition of treatment-emergent adverse events was modified to have no limitation in time 
after the last dose intake of study drug (instead of excluding events occurring later than 
five half-lives after the last lost dose). Late TEAEs were defined as TEAEs with onset date 
on 3 days or more after the last study drug intake. 
10. Number and percentage of subjects with treatment-emergent abnormality was added in the 
analysis of laboratory data and vital signs. 
 
 


 
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9 REFERENCES 
1. Staecker et al., Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral 
Sudden Deafness-A Double-blind, Randomized, Placebo-controlled Phase 3 Study, Otol 
Neurotol 2019;40(5):584-594. 
2. Suckfuell et al., Efficacy and safety of AM-111 in the treatment of acute sensorineural 
hearing loss: a double-blind, randomized, placebo-controlled phase II study, Otol 
Neurotol 2014;35(8):1317-26. 
3. SAS Institute Inc., Cary, NC, 27513, USA 
4.  Marcus R; Peritz E; Gabriel KR, On closed testing procedures with special reference to 
ordered analysis of variance, Biometrika. 1976; 63: 655–660. 
5. Koch GG, Gansky SASA, Statistical Considerations for Multiplicity in Confirmatory 
Protocols, Drug Information Journal 1996, Vol. 30. pp. 523-534. 
6. Carpenter JR, Roger JH, Kenward MG., Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat. 2013;23(6):1352–71. 
7. Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY, USA: John 
Wiley & Sons; 1987. 
 
 
 


 
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10 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods maybe 
used:  
• Independent programming of numbers and manual review of format (IP) 
• Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
• Manual review (MR) 
• Code review (CR) 
Furthermore, separate set of outputs will be produced for the Part 1 and Part 2 of the study: 
 
10.1 Part 1 outputs 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1a 
Subject Disposition 
Part 1 – All Screened Subjects 
IP 
 
14.1.1.2a 
Analysis Sets  
Part 1 – All Randomized Subjects 
IP 
 
14.1.1.3.1a 
Protocol Deviations 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.1.3.2a 
COVID-19-related Protocol Deviations 
Part 1 – Intent-to-Treat Analysis Set 
IP 
14.1.1.3.1a 
14.1.1.4a 
Stratification factors 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.1.5a 
Possible Discrepancies in Stratification Factors Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.2  
Demographics 
 
 
14.1.2.1a 
Demographics 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1a 
Medical and Surgical History Prior to Screening  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 


 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.1.3.2a 
Medical and Surgical History Ongoing at Screening  
Part 1– Intent-to-Treat Analysis Set 
IP 
14.1.3.1a 
14.1.3.3a 
Hearing Loss - Current Episode at Time of 
Randomization 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.4a 
Otologic History 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.5a 
Air Conduction PTA at Baseline 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.6a 
Other Relevant Baseline Characteristics 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1a 
Primary Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.1.2a 
Sensitivity Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1a 
14.2.1.3a 
Sensitivity Analysis: ANCOVA of Change in Pure 
Tone Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment (MNAR: Copy Reference 
Imputation) 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.1.4a 
Sensitivity Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment (Assessments after rescue therapy 
set to missing and each Day 28 assessment after rescue 
therapy imputed by subject baseline) 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.1.1a 


 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.1.5a 
Summary of Pure Tone Audiometry (3 contiguous 
most affected hearing frequencies) in the Affected Ear 
from Baseline to the End of Treatment – Descriptive 
Statistics 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1.1a 
MMRM of Change in Pure Tone Audiometry (2 Most 
Affected Frequencies) in Affected Ear from Baseline 
to the End of Treatment 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.1.1a 
14.2.2.1.2a 
MMRM of Change in Pure Tone Audiometry (2 Most 
Affected Frequencies) in Affected Ear from Baseline 
to the End of Treatment 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1a 
14.2.2.2.1a 
MMRM of Change in Pure Tone Audiometry (Most 
Affected Frequency) in Affected Ear from Baseline to 
the End of Treatment 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.1.1a 
14.2.2.2.2a 
MMRM of Change in Pure Tone Audiometry (Most 
Affected Frequency) in Affected Ear from Baseline to 
the End of Treatment 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1a 
14.2.2.3a 
MMRM of Change in Pure Tone Audiometry (3 
contiguous most affected hearing frequencies) in the 
Affected Ear from Baseline to the End of Study 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.2.4a 
MMRM of Change in Pure Tone Audiometry (3 
contiguous most affected hearing frequencies) in the 
Affected Ear from Baseline to the End of Study 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3a 
14.2.2.4.1a 
MMRM of Change in Speech Discrimination 
Threshold from Baseline to Post-baseline Visits 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.2.3a 
14.2.2.4.2a 
MMRM of Change in Speech Discrimination 
Threshold from Baseline to Post-baseline Visits 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3a 


 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.2.5.1a 
MMRM of Change in Severity of Tinnitus (Numerical 
Rating Scale) from Baseline to Post-baseline Visits 
Part 1 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.2.3a 
14.2.2.5.2a 
MMRM of Change in Severity of Tinnitus (Numerical 
Rating Scale) from Baseline to Post-baseline Visits 
Part 1 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3a 
14.2.2.5.3a 
Frequency and Severity of Tinnitus (Numerical Rating 
Scale) at Day 7, 14, 28 and 84 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.2.5.4a 
Frequency and Severity of Tinnitus (Numerical Rating 
Scale) at Day 7, 14, 28 and 84 
Part 1 – Per-Protocol Analysis Set 
IP 
14.2.2.5.3a 
14.2.3 
Exploratory Endpoints 
 
 
14.2.3.1a 
Proportion of Patients with Complete Hearing 
Recovery or Hearing Similar to Unaffected 
Contralateral Ear 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.2a 
Proportion of Patients with Marked Improvement  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.3a 
Proportion of Patients with Air Pure Tone Audiometry 
Threshold of >35dB and >90dB on Day 7, Day 14, and 
End of Study 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.4a 
Proportion of Responders (Improvement of 10 dB or 
more) in Pure Tone Audiometry Threshold  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.5a 
Word Recognition Score at 80 dB and 60 dB in the 
Affected Ear 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.6a 
Time of Onset of Symptoms to First Study Drug 
Intake  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.7a 
Frequency and Severity of any Vertigo at Day 1, 7, 14, 
28 and 84 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 


 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.3.8a 
Tinnitus Burden Based on the Change in Tinnitus QoL 
Scores at Day 1, 7, 14, 28 and 84 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.9a 
Change in Biomarkers from Baseline to Post-baseline 
Visits 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.1a Summary of EQ-5D-5L Responses at Baseline and 
Post-baseline Visits 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.2a EQ-5D-5L Responses, Shifts from Baseline to Day 28 
and 84 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.3a Summary of EQ-5D-5L Dichotomized Responses at 
Baseline and Post-baseline Visits 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.4a Change in EQ Visual Analogue Scale from Baseline to 
Day 28 and 84 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.11a 
Change in DPOAE at Days 7, 14, 28, and 84 
Compared to Baseline 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.12a 
Change in TEOAE at Days 7, 14, 28 and 84 Compared 
to Baseline 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1.1a 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAEs)  
Part 1 – Safety Analysis Set 
IP 
 
14.3.1.1.2a 
Overall Summary of Late Adverse Events  
Part 1 – Safety Analysis Set 
IP 
 
14.3.1.2.1a 
TEAEs by Primary System Organ Class and Preferred 
Term  
Part 1 – Safety Analysis Set 
IP 
 


 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.1.2.2a 
Late AEs by Primary System Organ Class and 
Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.3.1a 
Treatment-Related TEAEs by Primary System Organ 
Class and Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.3.2a 
Treatment-Related Late AEs by Primary System 
Organ Class and Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.4.1a 
Serious TEAEs by Primary System Organ Class and 
Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.4.2a 
Serious Late AEs by Primary System Organ Class and 
Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.5.1a 
Severe TEAEs by Primary System Organ Class and 
Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.5.2a 
Severe Late AEs by Primary System Organ Class and 
Preferred Term  
Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.1.6.1a 
TEAEs by Primary System Organ Class Preferred 
Term, and Severity  
Part 1 – Safety Analysis Set 
IP 
 
14.3.1.6.2a 
Late AEs by Primary System Organ Class Preferred 
Term, and Severity  
Part 1 – Safety Analysis Set 
IP 
14.3.1.6.1a 
14.3.1.7.1a 
Treatment-Related TEAEs by Primary System Organ 
Class, Preferred Term, and Severity 
Part 1 – Safety Analysis Set 
IP 
14.3.1.6.1a 
14.3.1.7.2a 
Treatment-Related Late AEs by Primary System 
Organ Class, Preferred Term, and Severity 
Part 1 – Safety Analysis Set 
IP 
14.3.1.6.1a 
14.3.1.8.1a 
TEAEs Leading to Early Withdrawal by Primary 
System Organ Class and Preferred Term  
 Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 


 
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Page 48 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.1.8.2a 
Late AEs Leading to Early Withdrawal by Primary 
System Organ Class and Preferred Term  
 Part 1 – Safety Analysis Set 
IP 
14.3.1.2.1a 
14.3.2  
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
 
14.3.2.1a 
Listing of Serious Adverse Events 
Part 1 – Safety Analysis Set 
IP 
 
14.3.2.2a 
Listing of Adverse Events Leading to Early 
Withdrawal 
Part 1 – Safety Analysis Set 
IP 
 
14.3.2.3a 
Listing of Adverse Events Leading to Deaths 
Part 1 – Safety Analysis Set 
IP 
 
14.3.3  
Narratives of Deaths, Other Serious and Certain 
Other Significant Adverse Events  
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1a 
Listing of Clinically Significant Laboratory Values  
Part 1 – Safety Analysis Set  
IP 
 
14.3.5  
Extent of Exposure, Dosage Information, and 
Compliance 
 
 
14.3.5.1a 
Extent of Exposure to Study Drug  
Part 1 – Safety Analysis Set 
IP 
 
14.3.5.2a 
Treatment Compliance 
Part 1 – Safety Analysis Set 
IP 
 
14.3.6  
Vital Signs and Physical Examination 
 
 
14.3.6.1a 
Vital Signs, Descriptive Statistics and Changes from 
Baseline to Post-baseline Assessments 
Part 1 – Safety Analysis Set 
IP 
 
14.3.6.2a 
Vital Signs, Treatment-Emergent Marked 
Abnormalities 
Part 1 – Safety Analysis Set 
IP 
 
14.3.6.3a 
Physical Examination, Descriptive Statistics of Post-
baseline Assessments 
Part 1 – Safety Analysis Set 
IP 
 
14.3.6.4a 
Physical Examination, Shifts from Baseline to Post-
baseline Assessments 
Part 1 – Safety Analysis Set 
IP 
 


 
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Page 49 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.7  
Other Safety 
 
 
14.3.7.1a 
Hematology, Change from Baseline to Post-baseline 
Assessments  
Part 1 – Safety Analysis Set 
IP 
 
14.3.7.2a 
Hematology, Normal Range Shifts  
Part 1 – Safety Analysis Set 
IP 
 
14.3.7.3a 
Hematology, Treatment-Emergent Marked 
Abnormalities 
IP 
 
14.3.7.4a 
Serum Chemistry, Change from Baseline to Post-
baseline Assessments  
Part 1 – Safety Analysis Set 
IP 
14.3.7.1a 
14.3.7.5a 
Serum Chemistry, Normal Range Shifts  
Part 1 – Safety Analysis Set 
IP 
14.3.7.2a 
14.3.7.6a 
Serum Chemistry, Treatment-Emergent Marked 
Abnormalities 
IP 
 
14.3.7.7a 
Otoscopy, Descriptive Statistics 
Part 1 – Safety Analysis Set 
IP 
14.3.6.2a 
14.3.7.8a 
Otoscopy, Shift from Baseline to Post-baseline 
Assessments, Findings 
Part 1 – Safety Analysis Set 
IP 
14.3.6.3a 
14.3.7.9a 
Tympanometry, Descriptive Statistics 
Part 1 – Safety Analysis Set 
IP 
14.3.6.2a 
14.3.7.10a 
Tympanometry, Shift from Baseline to Post-baseline 
Assessments, Findings 
Part 1 – Safety Analysis Set 
IP 
14.3.6.3a 
14.3.7.11.1a Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Ideation Item at Baseline  
Part 1 – Safety Analysis Set 
IP 
 
14.3.7.11.2a Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Ideation Item at Any Time Post-
baseline  
Part 1 – Safety Analysis Set 
IP 
 


 
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Page 50 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.7.11.3a Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Behavioral Item at Baseline 
Part 1 – Safety Analysis Set 
IP 
 
14.3.7.11.4a Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Behavioral Item at Any Time Post-
baseline 
Part 1 – Safety Analysis Set 
IP 
 
14.3.8  
Concomitant Medication 
 
 
14.3.8.1a 
Prior Medication  
Part 1 – Safety Analysis Set 
IP 
 
14.3.8.2a 
Concomitant Medication  
Part 1 – Safety Analysis Set 
IP 
14.3.8.1a 
14.3.8.3a 
Study Treatment Concomitant Medication  
Part 1 – Safety Analysis Set 
IP 
14.3.8.1a 
14.3.8.4a 
Prior Oral Corticosteroids 
Part 1 – Safety Analysis Set 
IP 
14.3.8.1a 
14.3.8.5a 
Concomitant Oral Corticosteroids 
Part 1 – Safety Analysis Set 
IP 
14.3.8.1a 
14.3.8.6a 
Corticosteroids as Rescue Treatment 
Part 1 – Safety Analysis Set 
IP 
 
14.4  
PK Tables 
 
 
14.4.1a 
Serum Concentration, Descriptive Statistics 
Part 1 – Safety Analysis Set 
IP 
 
14.6  
Other Data 
 
 
 
 


 
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Page 51 of 67 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.2.1.1a 
Line plot of Change in Pure Tone Audiometry (3 most 
affected frequencies) in the Affected Ear Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.2a 
Line plot of Change in Pure Tone Audiometry (2 most 
affected frequencies) in the Affected Ear Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
14.2.1.1a 
14.2.1.3a 
Line plot of Change in Pure Tone Audiometry (most 
affected frequency) in the Affected Ear Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
14.2.1.1a 
14.2.1.4a 
Line plot of Change in Speech Recognition Threshold 
Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.5a 
Line Plot of Speech Discrimination Threshold Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.6a 
Bar Chart of the Frequency of Tinnitus at Each Timepoint 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.7a 
Proportion of Responders (Improvement of 10 dB or more) 
in Pure Tone Audiometry Threshold 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.1a Percent Change in Word Recognition Score at 80 dB and 
60 dB in the Affected Ear Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.2a Word Recognition Score at 80 and 60 dB in the Affected 
Ear Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.3a Absolute Difference in Word Recognition Score between 
the Affected and Reference Ear at 80 and 60 dB Over Time 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.9a 
Relationship of Time of Onset of Symptoms to First Study 
Drug Intake and the Primary Endpoint 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.10a 
Bar Chart of the Frequency of Vertigo at Each Timepoint  
Part 1 – Intent-to-Treat Analysis Set 
IP 
14.2.1.6a 
 
 


 
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Page 52 of 67 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1a  
Screen Failures  
Part 1 – All Screened Subjects 
IP 
 
16.2.1.2a 
Early Withdrawals  
Part 1 – All Randomized Subjects 
IP 
 
16.2.1.3a 
Inclusion and Exclusion Criteria – Screen Failures  
Part 1 – All Screened Subjects 
IP 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1a 
Protocol Deviations  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.3 
Subjects Excluded from the Efficacy Analyses 
 
 
16.2.3.1a  
Analysis Sets  
Part 1 – All Randomized Subjects 
IP 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1a  
Demographics Data  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.2a 
Baseline Characteristics and Other Relevant Data  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.3a 
Medical History  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.4a 
Otologic History  
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.5a 
Ear, Neck, Nose and Throat Problems 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.6a 
Baseline Pure Tone Audiometry 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.7a 
Raw Data on Pure Tone Audiometry 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.5  
Compliance and/or Drug Concentration Data 
 
 
16.2.5.1a  
Prior, Study Concomitant and Study Treatment 
Concomitant Medications  
Part 1 – Safety Analysis Set 
IP 
 
16.2.5.2a 
Prior and Concomitant Oral Corticosteroids 
IP 
 


 
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Page 53 of 67 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
Part 1 – Safety Analysis Set 
16.2.5.3a 
Study Treatment Exposure  
Part 1 – Safety Analysis Set 
IP 
 
16.2.5.4a 
PK Sample Collection Data 
Part 1 – Pharmacokinetic Analysis Set 
IP 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1a 
PTA Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.2a 
Speech Discrimination Threshold 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.3a 
Vertigo Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.4a 
Tinnitus Severity Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.5a 
Tinnitus Questionnaire Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.6a 
DPOAE Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.7a 
TEOAE Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.8a 
EQ-5D-5L Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.9a 
Word Recognition Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.10a 
Biomarkers Data 
Part 1 – Intent-to-Treat Analysis Set 
IP 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1a 
Adverse Events 
Part 1 – Safety Analysis Set 
IP 
 
16.2.7.2a 
Late Adverse Events 
Part 1 – Safety Analysis Set 
 
 
16.2.8  
Individual Laboratory Measurements and Other 
Safety 
 
 
16.2.8.1a 
Hematology Data  
Part 1 – Safety Analysis Set 
IP 
 


 
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Page 54 of 67 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.8.2a 
Serum Chemistry Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.3a 
C-Reactive Protein Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.4a 
Pregnancy Test Data  
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.5a 
Physical Examination Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.6a 
Vital Signs Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.7a 
Otoscopy Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.8a 
Tympanometry Data 
Part 1 – Safety Analysis Set 
IP 
 
16.2.8.9a 
Suicidality Assessment (C-SSRS) 
Part 1 – Safety Analysis Set 
IP 
 
 
 
 


 
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Page 55 of 67 
 
10.2 Part 2 outputs 
Part 2 outputs the same as for Part 1 but for 2 treatment arms. 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Items in bold are not table titles but references to the section headings within 
eCTD. 
 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1b 
Subject Disposition 
Part 2 – All Screened Subjects 
IP 
 
14.1.1.2b 
Analysis Sets  
Part 2 – All Randomized Subjects 
IP 
 
14.1.1.3.1
b 
Protocol Deviations 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.1.3.2
b 
COVID-19-related Protocol Deviations 
Part 2 – Intent-to-Treat Analysis Set 
IP 
14.1.1.3.1b 
14.1.1.4b 
Stratification factors 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.1.5b 
Possible Discrepancies in Stratification Factors Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.2  
Demographics 
 
 
14.1.2.1b 
Demographics 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1b 
Medical and Surgical History Prior to Screening  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.2b 
Medical and Surgical History Ongoing at Screening  
Part 2– Intent-to-Treat Analysis Set 
IP 
14.1.3.1b 
14.1.3.3b 
Hearing Loss - Current Episode at Time of 
Randomization 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.4b 
Otologic History 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.1.3.5b 
Air Conduction PTA at Baseline 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 


 
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Page 56 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.1.3.6b 
Other Relevant Baseline Characteristics 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1b 
Primary Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.1.2b 
Sensitivity Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1b 
14.2.1.3b 
Sensitivity Analysis: ANCOVA of Change in Pure 
Tone Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment (MNAR: Copy Reference 
Imputation) 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.1.4b 
Sensitivity Analysis: MMRM of Change in Pure Tone 
Audiometry (3 contiguous most affected hearing 
frequencies) in the Affected Ear from Baseline to the 
End of Treatment (Assessments after rescue therapy 
set to missing and each Day 28 assessment after rescue 
therapy imputed by subject baseline) 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.1.1b 
14.2.1.5b 
Summary of Pure Tone Audiometry (3 contiguous 
most affected hearing frequencies) in the Affected Ear 
from Baseline to the End of Treatment – Descriptive 
Statistics 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1.1
b 
MMRM of Change in Pure Tone Audiometry (2 Most 
Affected Frequencies) in Affected Ear from Baseline 
to the End of Treatment 
Stat IP 
14.2.1.1b 


 
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Page 57 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Part 2 – Intent-to-Treat Analysis Set 
14.2.2.1.2
b 
MMRM of Change in Pure Tone Audiometry (2 Most 
Affected Frequencies) in Affected Ear from Baseline 
to the End of Treatment 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1b 
14.2.2.2.1
b 
MMRM of Change in Pure Tone Audiometry (Most 
Affected Frequency) in Affected Ear from Baseline to 
the End of Treatment 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.1.1b 
14.2.2.2.2
b 
MMRM of Change in Pure Tone Audiometry (Most 
Affected Frequency) in Affected Ear from Baseline to 
the End of Treatment 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.1.1b 
14.2.2.3b 
MMRM of Change in Pure Tone Audiometry (3 
contiguous most affected hearing frequencies) in the 
Affected Ear from Baseline to the End of Study 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
 
14.2.2.4b 
MMRM of Change in Pure Tone Audiometry (3 
contiguous most affected hearing frequencies) in the 
Affected Ear from Baseline to the End of Study 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3b 
14.2.2.4.1
b 
MMRM of Change in Speech Discrimination 
Threshold from Baseline to Post-baseline Visits 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.2.3b 
14.2.2.4.2
b 
MMRM of Change in Speech Discrimination 
Threshold from Baseline to Post-baseline Visits 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3b 
14.2.2.5.1
b 
MMRM of Change in Severity of Tinnitus (Numerical 
Rating Scale) from Baseline to Post-baseline Visits 
Part 2 – Intent-to-Treat Analysis Set 
Stat IP 
14.2.2.3b 
14.2.2.5.2
b 
MMRM of Change in Severity of Tinnitus (Numerical 
Rating Scale) from Baseline to Post-baseline Visits 
Part 2 – Per-Protocol Analysis Set 
Stat IP 
14.2.2.3b 
14.2.2.5.3
b 
Frequency and Severity of Tinnitus (Numerical Rating 
Scale) at Day 7, 14, 28 and 84 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 


 
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Page 58 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.2.5.4
b 
Frequency and Severity of Tinnitus (Numerical Rating 
Scale) at Day 7, 14, 28 and 84 
Part 2 – Per-Protocol Analysis Set 
IP 
14.2.2.5.3b 
14.2.3 
Exploratory Endpoints 
 
 
14.2.3.1b 
Proportion of Patients with Complete Hearing 
Recovery or Hearing Similar to Unaffected 
Contralateral Ear 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.2b 
Proportion of Patients with Marked Improvement  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.3b 
Proportion of Patients with Air Pure Tone Audiometry 
Threshold of >35dB and >90dB on Day 7, Day 14, 
and End of Study 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.4b 
Proportion of Responders (Improvement of 10 dB or 
more) in Pure Tone Audiometry Threshold  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.5b 
Word Recognition Score at 80 dB and 60 dB in the 
Affected Ear 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.6b 
Time of Onset of Symptoms to First Study Drug 
Intake  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.7b 
Frequency and Severity of any Vertigo at Day 1, 7, 14, 
28 and 84 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.8b 
Tinnitus Burden Based on the Change in Tinnitus QoL 
Scores at Day 1, 7, 14, 28 and 84 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.9b 
Change in Biomarkers from Baseline to Post-baseline 
Visits 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.
1b 
Summary of EQ-5D-5L Responses at Baseline and 
Post-baseline Visits 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 


 
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Page 59 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.3.10.
2b 
EQ-5D-5L Responses, Shifts from Baseline to Day 28 
and 84 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.
3b 
Summary of EQ-5D-5L Dichotomized Responses at 
Baseline and Post-baseline Visits 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.10.
4b 
Change in EQ Visual Analogue Scale from Baseline to 
Day 28 and 84 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.11b 
Change in DPOAE at Days 7, 14, 28, and 84 
Compared to Baseline 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.3.12b 
Change in TEOAE at Days 7, 14, 28 and 84 Compared 
to Baseline 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1.1
b 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAEs)  
Part 2 – Safety Analysis Set 
IP 
 
14.3.1.1.2
b 
Overall Summary of Late Adverse Events  
Part 2 – Safety Analysis Set 
IP 
 
14.3.1.2.1
b 
TEAEs by Primary System Organ Class and Preferred 
Term  
Part 2 – Safety Analysis Set 
IP 
 
14.3.1.2.2
b 
Late AEs by Primary System Organ Class and 
Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.3.1
b 
Treatment-Related TEAEs by Primary System Organ 
Class and Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.3.2
b 
Treatment-Related Late AEs by Primary System 
Organ Class and Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 


 
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Page 60 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.1.4.1
b 
Serious TEAEs by Primary System Organ Class and 
Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.4.2
b 
Serious Late AEs by Primary System Organ Class and 
Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.5.1
b 
Severe TEAEs by Primary System Organ Class and 
Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.5.2
b 
Severe Late AEs by Primary System Organ Class and 
Preferred Term  
Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.6.1
b 
TEAEs by Primary System Organ Class Preferred 
Term, and Severity  
Part 2 – Safety Analysis Set 
IP 
 
14.3.1.6.2
b 
Late AEs by Primary System Organ Class Preferred 
Term, and Severity  
Part 2 – Safety Analysis Set 
IP 
14.3.1.6.1b 
14.3.1.7.1
b 
Treatment-Related TEAEs by Primary System Organ 
Class, Preferred Term, and Severity 
Part 2 – Safety Analysis Set 
IP 
14.3.1.6.1b 
14.3.1.7.2
b 
Treatment-Related Late AEs by Primary System 
Organ Class, Preferred Term, and Severity 
Part 2 – Safety Analysis Set 
IP 
14.3.1.6.1b 
14.3.1.8.1
b 
TEAEs Leading to Early Withdrawal by Primary 
System Organ Class and Preferred Term  
 Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.1.8.2
b 
Late AEs Leading to Early Withdrawal by Primary 
System Organ Class and Preferred Term  
 Part 2 – Safety Analysis Set 
IP 
14.3.1.2.1b 
14.3.2  
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
 
14.3.2.1b 
Listing of Serious Adverse Events 
Part 2 – Safety Analysis Set 
IP 
 
14.3.2.2b 
Listing of Adverse Events Leading to Early 
Withdrawal 
IP 
 


 
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Page 61 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
Part 2 – Safety Analysis Set 
14.3.2.3b 
Listing of Adverse Events Leading to Deaths 
Part 2 – Safety Analysis Set 
IP 
 
14.3.3  
Narratives of Deaths, Other Serious and Certain 
Other Significant Adverse Events  
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1b 
Listing of Clinically Significant Laboratory Values  
Part 2 – Safety Analysis Set  
IP 
 
14.3.5  
Extent of Exposure, Dosage Information, and 
Compliance 
 
 
14.3.5.1b 
Extent of Exposure to Study Drug  
Part 2 – Safety Analysis Set 
IP 
 
14.3.5.2b 
Treatment Compliance 
Part 2 – Safety Analysis Set 
IP 
 
14.3.6  
Vital Signs and Physical Examination 
 
 
14.3.6.1b 
Vital Signs, Descriptive Statistics and Changes from 
Baseline to Post-baseline Assessments 
Part 2 – Safety Analysis Set 
IP 
 
14.3.6.2b 
Vital Signs, Treatment-Emergent Marked 
Abnormalities 
Part 2 – Safety Analysis Set 
IP 
 
14.3.6.3b 
Physical Examination, Descriptive Statistics of Post-
baseline Assessments 
Part 2 – Safety Analysis Set 
IP 
 
14.3.6.4b 
Physical Examination, Shifts from Baseline to Post-
baseline Assessments 
Part 2 – Safety Analysis Set 
IP 
 
14.3.7  
Other Safety 
 
 
14.3.7.1b 
Hematology, Change from Baseline to Post-baseline 
Assessments  
Part 2 – Safety Analysis Set 
IP 
 
14.3.7.2b 
Hematology, Normal Range Shifts  
Part 2 – Safety Analysis Set 
IP 
 
14.3.7.3b 
Hematology, Treatment-Emergent Marked 
Abnormalities 
IP 
 


 
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Page 62 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.7.4b 
Serum Chemistry, Change from Baseline to Post-
baseline Assessments  
Part 2 – Safety Analysis Set 
IP 
14.3.7.1b 
14.3.7.5b 
Serum Chemistry, Normal Range Shifts  
Part 2 – Safety Analysis Set 
IP 
14.3.7.2b 
14.3.7.6b 
Serum Chemistry, Treatment-Emergent Marked 
Abnormalities 
IP 
 
14.3.7.7b 
Otoscopy, Descriptive Statistics 
Part 2 – Safety Analysis Set 
IP 
14.3.6.2b 
14.3.7.8b 
Otoscopy, Shift from Baseline to Post-baseline 
Assessments, Findings 
Part 2 – Safety Analysis Set 
IP 
14.3.6.3b 
14.3.7.9b 
Tympanometry, Descriptive Statistics 
Part 2 – Safety Analysis Set 
IP 
14.3.6.2b 
14.3.7.10b 
Tympanometry, Shift from Baseline to Post-baseline 
Assessments, Findings 
Part 2 – Safety Analysis Set 
IP 
14.3.6.3b 
14.3.7.11.
1b 
Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Ideation Item at Baseline  
Part 2 – Safety Analysis Set 
IP 
 
14.3.7.11.
2b 
Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Ideation Item at Any Time Post-
baseline  
Part 2 – Safety Analysis Set 
IP 
 
14.3.7.11.
3b 
Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Behavioral Item at Baseline 
Part 2 – Safety Analysis Set 
IP 
 
14.3.7.11.
4b 
Number and Percentage of Subjects with a Response 
of Yes to Any Columbia Suicide Severity Rating Scale 
(C-SSRS) Suicidal Behavioral Item at Any Time Post-
baseline 
Part 2 – Safety Analysis Set 
IP 
 
14.3.8  
Concomitant Medication 
 
 


 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 63 of 67 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.8.1b 
Prior Medication  
Part 2 – Safety Analysis Set 
IP 
 
14.3.8.2b 
Concomitant Medication  
Part 2 – Safety Analysis Set 
IP 
14.3.8.1b 
14.3.8.3b 
Study Treatment Concomitant Medication  
Part 2 – Safety Analysis Set 
IP 
14.3.8.1b 
14.3.8.4b 
Prior Oral Corticosteroids 
Part 2 – Safety Analysis Set 
IP 
14.3.8.1b 
14.3.8.5b 
Concomitant Oral Corticosteroids 
Part 2 – Safety Analysis Set 
IP 
14.3.8.1b 
14.3.8.6b 
Corticosteroids as Rescue Treatment 
Part 2 – Safety Analysis Set 
IP 
 
14.4  
PK Tables 
 
 
14.4.1b 
Serum Concentration, Descriptive Statistics 
Part 2 – Safety Analysis Set 
IP 
 
14.6  
Other Data 
 
 
 
 
 


 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 64 of 67 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.2.1.1b 
Line plot of Change in Pure Tone Audiometry (3 most 
affected frequencies) in the Affected Ear Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.2b 
Line plot of Change in Pure Tone Audiometry (2 most 
affected frequencies) in the Affected Ear Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.3b 
Line plot of Change in Pure Tone Audiometry (most 
affected frequency) in the Affected Ear Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.4b 
Line plot of Change in Speech Recognition Threshold 
Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.5b 
Line Plot of Speech Discrimination Threshold Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.6b 
Bar Chart of the Frequency of Tinnitus at Each Timepoint 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.7b 
Proportion of Responders (Improvement of 10 dB or more) 
in Pure Tone Audiometry Threshold 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.1b Percent Change in Word Recognition Score at 80 dB and 
60 dB in the Affected Ear Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.2b Word Recognition Score at 80 and 60 dB in the Affected 
Ear Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.8.3b Absolute Difference in Word Recognition Score between 
the Affected and Reference Ear at 80 and 60 dB Over Time 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.9b 
Relationship of Time of  Onset of Symptoms to First Study 
Drug Intake and the Primary Endpoint 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
14.2.1.10b 
Bar Chart of the Frequency of Vertigo at Each Timepoint  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
 
 


 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 65 of 67 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1b 
Screen Failures  
Part 2 – All Screened Subjects 
IP 
 
16.2.1.2b 
Early Withdrawals  
Part 2 – All Randomized Subjects 
IP 
 
16.2.1.3b 
Inclusion and Exclusion Criteria – Screen Failures  
Part 2 – All Screened Subjects 
IP 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1b 
Protocol Deviations  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.3 
Subjects Excluded from the Efficacy Analyses 
 
 
16.2.3.1b 
Analysis Sets  
Part 2 – All Randomized Subjects 
IP 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1b 
Demographics Data  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.2b 
Baseline Characteristics and Other Relevant Data  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.3b 
Medical History  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.4b 
Otologic History  
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.5b 
Ear, Neck, Nose and Throat Problems 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.6b 
Baseline Pure Tone Audiometry 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.4.7b 
Raw Data on Pure Tone Audiometry 
Part 1 – Intent-to-Treat Analysis Set 
 
 
16.2.5  
Compliance and/or Drug Concentration Data 
 
 
16.2.5.1b 
Prior, Study Concomitant and Study Treatment 
Concomitant Medications  
Part 1 – Safety Analysis Set 
IP 
 
16.2.5.2b 
Prior and Concomitant Oral Corticosteroids 
IP 
 


 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 66 of 67 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
Part 2 – Safety Analysis Set 
16.2.5.3b 
Study Treatment Exposure  
Part 2 – Safety Analysis Set 
IP 
 
16.2.5.4b 
PK Sample Collection Data 
Part 2 – Pharmacokinetic Analysis Set 
IP 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1b 
PTA Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.2b 
Speech Discrimination Threshold 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.3b 
Vertigo Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.4b 
Tinnitus Severity Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.5b 
Tinnitus Questionnaire Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.6b 
DPOAE Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.7b 
TEOAE Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.8b 
EQ-5D-5L Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.9b 
Word Recognition Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.6.10b Biomarkers Data 
Part 2 – Intent-to-Treat Analysis Set 
IP 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1b 
Adverse Events 
Part 2 – Safety Analysis Set 
IP 
 
16.2.7.2b 
Late Adverse Events 
Part 2 – Safety Analysis Set 
 
 
16.2.8  
Individual Laboratory Measurements and Other Safety 
 
 
16.2.8.1b 
Hematology Data  
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.2b 
Serum Chemistry Data 
IP 
 


 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
Page 67 of 67 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
Part 2 – Safety Analysis Set 
16.2.8.3b 
C-Reactive Protein Data 
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.4b 
Pregnancy Test Data  
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.5b 
Physical Examination Data 
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.6b 
Vital Signs Data 
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.7b 
Otoscopy Data 
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.8b 
Tympanometry Data 
Part 2 – Safety Analysis Set 
IP 
 
16.2.8.9b 
Suicidality Assessment (C-SSRS) 
Part 2 – Safety Analysis Set 
IP