Conditions: Meniere's Disease
Keywords: Meniere's Disease Vertigo
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 166
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effectiveness of OTO-104 for the treatment of Meniere's disease.

Detailed description:

Arms:
arm 1: 12 mg dexamethasone arm 2: None

Interventions: intervention 1: OTO-104 intervention 2: Placebo
Intervention descriptions: intervention 1: Single intratympanic injection of 12 mg OTO-104 intervention 2: Single intratympanic injection of placebo

Protocol document:
Prot_SAP_000.pdf: 
 
                                                              1  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
 
 
CLINICAL STUDY PROTOCOL 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, 
MULTICENTER, PHASE 3 EFFICACY AND SAFETY STUDY OF OTO-104 GIVEN AS 
A SINGLE INTRATYMPANIC INJECTION IN SUBJECTS WITH UNILATERAL 
MENIERE’S DISEASE 
 
Protocol Number:  104-201506 
 
 
 
Sponsor Contact: 
 
 
Otonomy, Inc. 
6275 Nancy Ridge Drive, Suite 100 
San Diego, CA 92121, USA 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
Version: 
2.0 
Date of Protocol: 
22 February 2016 
Proprietary Notice 
The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in 
whole or in part without the expressed, written consent of Otonomy, 
Inc. 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In any 
event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you which is indicated as privileged or confidential. 
 




 
                                                              3  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL AMENDMENT, VERSION 2.0 ................................................................................6 
SPONSOR CONTACT INFORMATION.......................................................................................7 
INVESTIGATOR AGREEMENT...................................................................................................8 
ABBREVIATIONS .........................................................................................................................9 
1. 
BACKGROUND ........................................................................................................17 
1.1. 
Rationale for Study .....................................................................................................17 
2. 
OBJECTIVES .............................................................................................................18 
2.1. 
Primary Objective .......................................................................................................18 
2.2. 
Secondary Objective ...................................................................................................18 
3. 
OVERVIEW OF STUDY DESIGN ...........................................................................18 
4. 
STUDY POPULATION .............................................................................................19 
4.1. 
General Considerations...............................................................................................19 
4.2. 
Inclusion Criteria ........................................................................................................19 
4.3. 
Exclusion Criteria .......................................................................................................20 
5. 
RANDOMIZATION AND BLINDING ....................................................................21 
5.1. 
Overview.....................................................................................................................21 
5.2. 
Enrollment Procedures................................................................................................21 
5.3. 
Blinding ......................................................................................................................22 
6. 
DOSAGE AND ADMINISTRATION .......................................................................22 
6.1. 
Study Drug Administration.........................................................................................22 
6.2. 
Compliance .................................................................................................................23 
7. 
PRIOR, CONCOMITANT AND SUBSEQUENT THERAPY .................................23 
7.1. 
Proscribed Therapy During the Study Period .............................................................23 
7.2. 
Symptomatic Relief Medications ...............................................................................24 
8. 
STUDY EVALUATIONS ..........................................................................................24 
8.1. 
Study Procedures by Visit ..........................................................................................24 
8.2. 
Efficacy Evaluations ...................................................................................................26 
8.3. 
Safety Evaluations ......................................................................................................27 
9. 
ADVERSE EVENT REPORTING ............................................................................29 
9.1. 
Adverse Event Classification Definitions...................................................................30 


 
                                                              4  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
9.2. 
Monitoring of Adverse Events....................................................................................32 
9.3. 
Contacting Sponsor Regarding Safety ........................................................................33 
10. 
SUBJECT COMPLETION.........................................................................................34 
10.1. 
Completion .................................................................................................................34 
10.2. 
Withdrawal .................................................................................................................34 
11. 
STATISTICAL METHODS.......................................................................................35 
11.1. 
Sample Size ................................................................................................................35 
11.2. 
Analysis Sets...............................................................................................................35 
11.3. 
Description of Subgroups to be Analyzed ..................................................................36 
11.4. 
Subject Demographics, Baseline Disease Status, and Disposition .............................36 
11.5. 
Efficacy Evaluations ...................................................................................................36 
11.6. 
Safety Evaluations ......................................................................................................39 
11.7. 
Handling of Missing Data, Subject Withdrawals, and Treatment Failures ................42 
11.8. 
Interim Analyses .........................................................................................................42 
12. 
STUDY DRUG INFORMATION..............................................................................42 
12.1. 
Physical Description of Study Drug(s) .......................................................................42 
12.2. 
Directions for Use .......................................................................................................42 
12.3. 
Packaging and Labeling..............................................................................................43 
12.4. 
Management of Clinical Supplies...............................................................................43 
12.5. 
Drug Accountability ...................................................................................................43 
13. 
ETHICAL ASPECTS .................................................................................................44 
13.1. 
Investigator Responsibilities.......................................................................................44 
13.2. 
Institutional Review Board (IRB)...............................................................................44 
13.3. 
Informed Consent .......................................................................................................44 
14. 
ADMINISTRATIVE REQUIREMENTS ..................................................................45 
14.1. 
Protocol Modifications ...............................................................................................45 
14.2. 
Regulatory Documentation .........................................................................................45 
14.3. 
Subject Identification Register ...................................................................................46 
14.4. 
Record Retention ........................................................................................................46 
14.5. 
Electronic Case Report Form......................................................................................46 
14.6. 
Termination.................................................................................................................47 
14.7. 
Data and Safety Monitoring Plan ...............................................................................47 
14.8. 
Monitoring ..................................................................................................................47 


 
                                                              5  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
14.9. 
Data Quality Assurance ..............................................................................................48 
14.10. 
On-Site Audits ............................................................................................................48 
14.11. 
Use of Information and Publication............................................................................48 
15. 
REFERENCES ...........................................................................................................50 
 
 


 
                                                              6  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
PROTOCOL AMENDMENT, VERSION 2.0 
This protocol amendment serves to make the following changes. 
Item 
No. 
Change 
Section and Page Number 
1 
Updated date and version of protocol. 
Title page, pg. 1 
Footer, every page 
2 
Safety reporting changed to ProPharma from 
Rho. 
Sponsor Contact Information, pg. 7 
Section 9.3 Contacting Sponsor Regarding 
Safety, pg. 28 
3 
Added additional exclusion criteria to 
hypersensitivity to dexamethasone or any of 
the OTO-104 excipients. 
Synopsis, pg. 12 
Section 4.3 Exclusion Criteria, pg. 20 
 
4 
Corrected spelling in document 
Synopsis, pg. 12 
Section 15 References, pg. 50 
5 
Added weight measurements to Visit 5. 
Time and Events Table, pg. 15 
Section 8.1.5 Visit 5: Week 12, pg. 26 
6 
Included rationale for dose selection. 
Section 1.1 Rationale for Study, pg. 18 
7 
Modified statement regarding contacting the 
medical monitor if an unblinding has occurred. 
Section 5.3 Blinding, pg. 22 
8 
Included statement that 250 and 3000 Hz 
frequencies should be conducted at the 
screening visit audiometry if a subjects does 
not present with a recent audiogram 
demonstrating asymmetrical hearing loss. 
Section 8.1.1 Visit 1: Up to 14 days prior to 
initiation of lead-in period, pg. 24 


 
                                                              7  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
SPONSOR CONTACT INFORMATION 
Medical Monitor: 
 
Name 
Title 
Office Phone Number 
Mobile Phone Number 
E-Mail 
 
 
Other Appropriate Trial Contact Personnel: 
Name 
 
Title 
 
Office Phone Number 
 
Mobile Phone Number 
 
E-Mail 
 
 
 
Safety Email: 
 
 
If any sponsor contact information needs to be changed during the course of the study, this will 
be done by the sponsor, with written notification to the investigator, and will not require a 
protocol amendment. 


 
                                                              8  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated and will abide by all obligations stated on the Form FDA 1572 and other local 
regulatory authority required document(s). 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by the sponsor or its representative and 
approved by the Institutional Review Board (IRB) responsible for this study and will fulfill all 
responsibilities for submitting pertinent information to the IRB responsible for this study.  I will 
assure that each subject enrolled into the trial, or legally authorized representative, reads, 
understands, and signs the appropriate version of the informed consent. I agree that the sponsor 
or its representatives shall have access to any original source documents to verify data captured 
for this clinical trial. 
I further agree not to originate or use the name of the Otonomy, Inc. and/or OTO-104, or any of 
its employees, in any publicity, news release or other public announcement, written or oral, 
whether to the public, press or otherwise, relating to this protocol, to any amendment hereto, or 
to the performance hereunder, without the prior written consent of Otonomy, Inc. 
 
 
 
 
 
Investigator's Signature 
 
Date 
Name of Investigator (typed or printed) 


 
                                                              9  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AAO-HNS  
American Academy of Otolaryngology - Head and Neck Surgery  
C 
Celsius 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DVD 
Definitive Vertigo Day 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
FAX 
Full Analysis Set 
Facsimile 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Randomization System 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
N 
Number 
OTO-104 
Investigational Product (Study Drug) 
PP 
Per Protocol 
QMP 
SAE 
Qualified Medical Professional 
Serious Adverse Event 
SOC 
Standard of Care  
VF 
WHO Drug 
Vertigo Frequency 
World Health Organization Drug Dictionary 
 


 
                                                              10  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
SYNOPSIS 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-104 
 
Dexamethasone 
 
Protocol No.: 104-201506 
Title of Study: A prospective, randomized, double blind, placebo-controlled, multicenter, Phase 3 efficacy 
and safety study of OTO-104 given as a single intratympanic injection in subjects with unilateral Meniere’s 
disease. 
Study Center(s):  This study will be conducted at approximately 60-70 sites in the United States. 
Study Period: 1-1.5 years 
Phase of Development: 3 
Study Design: 
This is a randomized, double blind, placebo-controlled, multicenter 16-week Phase 3 study.  Following an 
initial 4-week lead-in period, eligible subjects will be randomly assigned to either 12 mg OTO-104 or placebo 
using a 1:1 allocation ratio stratified by gender.  Subjects will be observed for 12 weeks following a single 
intratympanic injection of either 12 mg OTO-104 or placebo. 
Study Objectives: 
Primary: To confirm the efficacy of OTO-104 in subjects with Meniere’s disease, as measured by the number 
of definitive vertigo days (DVD) at Week 12 (the 4-week interval from Week 9 through Week 12). 
  
Secondary:  To describe the safety profile of OTO-104 in subjects with Meniere’s disease. 
Methods: 
The duration of the study for each subject will be a maximum of approximately 16 weeks, including a 4-week 
lead-in period before dosing (a single injection), followed by a 12-week follow-up period. 
After screening (Visit 1), all eligible subjects will enter into a 4-week lead-in period.  During the lead-in 
period, subjects will record their daily vertigo experience to allow for a baseline assessment of these events.  
Any day with a recorded definitive vertigo episode, an episode lasting at least 20 minutes (corresponding to a 
Vertigo Severity Score of 2 or more), will be defined as a definitive vertigo day (DVD).  Following the lead-in 
period, eligible subjects will be randomized to 12 mg OTO-104 or placebo using a 1:1 allocation ratio.   The 
randomization is stratified by gender. 
After a single intratympanic injection with OTO-104 or placebo on Day 1, subjects will continue to record 
their daily vertigo experience during the 12-week follow-up period. Subjects will visit the study site at Weeks 
4 and 8 for additional efficacy and safety assessments. Efficacy and safety assessments will also be completed 
at the end of study (Week 12) or upon early discontinuation from the study. 
Number of Subjects: 
The planned sample size for this study is 160 subjects (80 assigned to 12 mg OTO-104 and 80 to placebo). 
Diagnosis and Main Criteria for Inclusion: 
Subjects enrolled in the study will have unilateral Meniere’s disease as outlined by the American Academy of 
Otolaryngology - Head and Neck Surgery (AAO-HNS) Committee on Hearing and Equilibrium in 1995 
(Committee on Hearing and Equilibrium, 1995). 
To be eligible for this study, each of the following criteria must be satisfied with a “YES” answer (unless not 
applicable): 
1. 
Subject is a male or female aged 18 to 85 years, inclusive. 


 
                                                              11  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-104 
 
Dexamethasone 
 
2. 
Subject has a diagnosis of definite unilateral Meniere’s disease by 1995 AAO-HNS criteria. 
3. 
Subject self-reports active, definitive vertigo episodes for the 2 months prior to the study lead-in 
period. 
4. 
Subject has documented asymmetric sensorineural hearing loss at screening or within the past 12 
months according to AAO-HNS 1995 criteria defined as one of the following:  
a. 
The arithmetic mean of hearing thresholds (pure tone average, PTA) at 250, 500 and 
1000 Hz of 15 dB or more higher than the PTA of 1000, 2000, and 3000 Hz, 
b. The arithmetic mean of  PTA at 500, 1000, 2000 and 3000 Hz is 20 dB or more poorer in the 
ear in question than on the opposite side, 
c. 
It is the judgment of the investigator that the subject’s hearing loss meets reasonable 
audiometric criteria for hearing loss characteristic of Meniere’s disease, and if so, it should 
be justified and documented. 
5. 
Subject agrees to maintain their current treatments for Meniere’s disease while on-study. 
6. 
Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-menopausal 
(≥12 months since last menstrual period and 45 years of age or older)] must have a negative urine 
pregnancy test before enrollment. Women of childbearing potential who are not abstinent from sex 
with male partners may be entered into the study if they are using and willing to continue to use 
highly effective or “double barrier” contraceptive precautions for the duration of the study (e.g., oral 
contraceptives, contraceptive implant or injection, intrauterine device, or “double barrier” methods 
including condom with diaphragm, male condom with cervical cap, male condom with spermicide, or 
diaphragm and spermicide).  
7. 
Subject is willing to comply with the protocol and attend all study visits. 
8. 
Subject is able to use the telephone to complete their daily diary. 
9. 
Subject is able to provide written informed consent, including agreement to privacy language either 
within the informed consent or in ancillary documents compliant with Health Insurance Portability 
and Accountability Act (HIPAA) before the initiation of any study-related procedures. 
At the completion of the first 28 days of the lead-in period: 
10. Subject has experienced and recorded at least 4 and a maximum of 22 definitive vertigo days during 
the 4-week lead-in period. 
11. Subject completed at least 22 of 28 diary entries during the 4-week lead-in period. 
 
Diagnosis and Main Criteria for Exclusion: 
To be eligible for this study, each of the following criteria must be satisfied with a “NO” answer: (unless not 
applicable): 
1. 
Subject has an infection in the ear, sinuses, or upper respiratory system at the time of randomization. 
2. 
Subject is pregnant or lactating. 
3. 
Subject has a history of immunodeficiency disease. 
4. 
Subject has active or recent (<1 month prior to screening) middle ear disease, including but not 
limited to:  chronic otitis media, acute otitis media, middle ear effusions, middle ear atelectasis, or 
cholesteatoma. 
5. 
Subject has an abnormality of the tympanic membrane in the affected ear that would increase the risk 
associated with intratympanic injection including but not limited to monomeric tympanic membrane. 


 
                                                              12  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-104 
 
Dexamethasone 
 
6. 
Subject has a history of previous endolymphatic sac surgery. 
7. 
Subject has a history of previous use of intratympanic gentamicin in the affected ear. 
8. 
Subject has a history of tympanostomy tubes with evidence of perforation or lack of closure. 
9. 
Subject has used systemic steroids within 1 month prior to entering the lead-in period. 
10. Subject has had intratympanic steroids within 1 month prior to entering the lead-in period. 
11. Subject has experienced an adverse reaction to intratympanic injection of steroids. 
12. Subject has a hypersensitivity to dexamethasone or any of the excipients in OTO-104. 
13. Subject has history of migrainous vertigo. 
14. Subject has history of drop attacks. 
15. Subject is not able to accurately identify and report episodes of vertigo. 
16. Subject has any other clinically significant illness, medical condition or medical history that, in the 
investigator’s or the medical monitor’s opinion, would prohibit the subject from participating in the 
study at screening or at the time of randomization. 
17. Subject has used an investigational drug or device in the 3 months prior to screening.  
18. Subject has a history of substance abuse within the preceding 6 months prior to screening. 
19. Subject has previously been randomized to a trial of OTO-104. 
Test Product, Dose and Mode of Administration: 
12 mg OTO-104, single 0.2 mL intratympanic injection to the affected ear 
Duration of Treatment:   
Single 0.2 mL intratympanic injection to the affected ear  
Reference Therapy, Dose and Mode of Administration: 
OTO-104 Diluent (placebo), single 0.2 mL intratympanic injection to the affected ear 
Outcome Measures for Evaluation: 
Primary Efficacy Endpoint:  
The primary efficacy endpoint is the number of definitive vertigo days (DVD) at Week 12 [the 4-week 
(28-day) interval from Week 9 through Week 12].  A DVD is defined as a day where the subject recorded at 
least one vertigo episode lasting at least 20 minutes and corresponds to a Vertigo Severity Score of 2 or more.  
If multiple episodes occur on a given day, subjects will be instructed to record the Vertigo Severity Score for 
the worst episode experienced during the day. 
Secondary Efficacy Endpoints: 
 
The number of definitive vertigo days (DVD) at Week 8 [the 4-week (28-day) interval from Week 5 
through Week 8] 
 
The number of definitive vertigo days (DVD) at Week 4 [the 4-week (28-day) interval from Week 1 
through Week 4] 
 
The change from baseline in vertigo frequency (VF) during the 4-week study interval (Week 9 
through Week 12), where vertigo frequency is defined as the proportion of days during the 4-week 
interval where a definitive vertigo episode was recorded divided by the number of non-missing diary 
entries for the relevant interval 


 
                                                              13  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-104 
 
Dexamethasone 
 
 
The change from baseline with respect to severity of vertigo episodes as measured by the mean 
Vertigo Score during the 4-week study interval (Week 9 through Week 12) 
 
The change from baseline in average daily count of vertigo episodes, during the 4-week study interval 
(Week 9 through Week 12) 
 
Occurrence of Normal activity, Slight limitation, Moderate limitation, Sick at home, and Bed ridden 
events as a consequence of vertigo at Week 12  
 
SF-36 at Week 12 
o 
Physical Health Summary Measure 
o 
Mental Health Summary Measure 
o 
8 Scales 
Exploratory Efficacy Endpoints: 
 
The change from baseline in vertigo frequency (VF) during the 4-week study interval (Week 1 
through Week 4) and (Week 5 through Week 8), where vertigo frequency is defined as the proportion 
of days during the 4-week interval where a definitive vertigo episode was recorded divided by the 
number of non-missing diary entries for the relevant interval 
 
The change from baseline with respect to severity of vertigo episodes as measured by the mean 
Vertigo Score during each 4-week study interval (Week 1 through Week 4) and (Week 5 through 8).  
 
The change from baseline in average daily count of vertigo episodes, during each 4-week study 
interval (Week 1 through Week 4) and (Week 5 through Week 8) 
 
Occurrence of Normal activity, Slight limitation, Moderate limitation, Sick at home, and Bed ridden 
events as a consequence of vertigo at Week 4 and 8 
 
SF-36 at Weeks 4 and 8 
o 
Physical Health Summary Measure 
o 
Mental Health Summary Measure 
o 
8 Scales 
 
Tinnitus Functional Index (TFI) at Weeks 4, 8, and 12 
 
Safety Assessments: 
Safety assessments include: 
 
Adverse events 
 
Audiometry assessments 
 
Tympanometry 
 
Local tolerability (otoscopic examinations) 
 
Clinical laboratory measurements 
 
Vital sign measurements 
 
Columbia-Suicide Severity Rating Scale (C-SSRS): Baseline and Since Last Visit versions 


 
                                                              14  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-104 
 
Dexamethasone 
 
 Statistical Methods: 
The primary efficacy endpoint is the number of DVD at Week 12 [the 4-week (28-day) interval from Week 9 
through Week 12].  The target total sample size for the study is 160 randomized with1:1 allocation, 80 in each 
treatment group, stratified by gender.  The sample size estimate was chosen to achieve more than 90% power 
with significance level of 0.05 two-sided to reject the null hypothesis of no treatment difference for the 
primary endpoint of DVD. 
The power estimate was based on the estimated treatment group means for DVD at Week 12 [the 4-week 
(28-day) interval from Week 9 through Week 12] from the recently completed Phase 2b trial in this indication.  
The OTO-104 and placebo treatment groups in that study received a single dose of the study drug at Day 1.  
The OTO-104 treatment group received the same dose as will be evaluated in this Phase 3 study.   A Poisson 
generalized linear regression model was used to estimate the mean number of DVDs for the OTO-104 and 
placebo groups during the primary endpoint 4-week study interval.  The model included treatment group as a 
factor (categorical), and the lead-in period as a covariate.  An offset for the number of diary entries recorded 
for that 4-week interval (interval from Week 9 through 12) was included for each subject to account for 
missing diary entries.  The number of lead-in period DVD was adjusted to 28 days.  The model was also 
adjusted for over-dispersion using Pearson residuals as the scale factor.  The estimated mean number of DVD 
for the OTO-104 and placebo groups were 4.5 and 2.1, respectively with an estimated mean difference of 
(active – placebo) -2.4 days, adjusted for lead-in period number of DVD.  The model residual variance was 
4.79.   For the purpose of the sample size calculation the residual variance and true mean difference was 
considered as 5.0 and 2.2, respectively. 
The Poisson regression model will be used to analyze the primary endpoint in this study.   The primary 
analysis population for this study is full analysis set (FAS). The full analysis set will include all subjects who 
are randomized, receive study drug, have a baseline DVD measurement for the 4-week lead-in period, and 
have at least one 4-week DVD measurement post-baseline.    
In the primary efficacy analysis if a subject misses all diary data for the primary endpoint then an imputation 
method which will be specified in the Statistical Analysis Plan (SAP) will used. 
Subjects will be included in the treatment group to which they were randomized regardless of the actual study 
drug received.  
If the primary endpoint comparison between the two treatment groups is statistically significant in favor of 
OTO-104 then a closed testing, gate-keeping procedure, will be used to compare the following secondary 
efficacy endpoints sequentially:  
1. 
The number of DVD at Week 8 [the 4-week (28-day) interval from Week 5 through Week 8] 
2. 
The number of DVD at Week 4 [the 4-week (28-day) interval from Week 1 through Week 4] 
In this procedure if the first secondary endpoint comparison between the two treatment groups is statistically 
significant in favor of OTO-104 then the second secondary endpoint will be compared and tested.  If the 
comparison of the first secondary endpoint is not statistically significant in favor of OTO-104 then the reported 
p-value for the second secondary endpoint will be considered as a nominal p-value. 
The remaining secondary endpoints comparison will not go through the gate keeping procedure and therefore 
the reported p-values will be reported as nominal p-values.  This procedure controls the study-wise Type I 
error.  Since the study-wise error is maintained with the above procedure, there is no α penalty associated with 
it.  All efficacy hypothesis tests will be 2-sided and performed at α = 0.05 significance level. 
Time and Events Schedule: See Table 1. 


 
                                                                                                                          15  
Otonomy 104-201506 Protocol V2.0: 22 February 2016
Table 1: 
Time and Events Schedule 
Procedure 
Screening 
Lead-In 
Baseline
1/ 
Treatment 
Visit 
Follow-up 
Visit 
Follow-up 
Visit 
End-of-Study/  
Early 
Termination 
Unscheduled 
Visit 
Visit 1 
– 
Visit 2 
Visit 3 
Visit 4 
Visit 5
2 
Unscheduled 
– 
– 
– 
Week 4 
Week 8 
Week 12 
N/A 
Up to 14 days 
prior to start 
of lead-in 
Day -28 to -1 
(+3 days) 
Day 1 
Day 28 
(±2 days) 
Day 56 
(±2 days) 
Day 84 
(+4 days) 
N/A 
Informed consent (including 
privacy language/documents) 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
X
3 
X 
 
 
 
 
Medical history
4 
X 
 
X 
 
 
 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
Vital sign measurements
5 
X 
 
X 
X 
X 
X 
X 
Height and weight measurements 
X 
 
 
 
 
X
6 
 
Pregnancy test
7 
X 
 
X 
 
 
X 
 
Clinical laboratory test
8 
X 
 
X 
 
 
X 
X as indicated 
Tympanometry 
X 
 
X 
X 
X 
X 
X as indicated 
Audiometry 
X 
 
X 
X 
X 
X 
X as indicated 
Otoscopy 
X 
 
X 
X 
X 
X 
X 
TFI-25 
 
 
X 
X 
X 
X 
 
SF-36 assessment 
 
 
X 
X 
X 
X 
 
C-SSRS assessment
9 
X 
 
X 
X 
X 
X 
X 
Review subject IVRS diary 
compliance and instruct subject 
on IVRS diary use
10 
X 
 
X 
X 
X 
 
 
Randomization
1112 
 
 
X 
 
 
 
 
Administer study drug 
 
 
X 
 
 
 
 
Adverse event monitoring 
 
 
X 
X 
X 
X 
X 


 
                                                                                                                          16  
Otonomy 104-201506 Protocol V2.0: 22 February 2016
1 Baseline assessments on Day 1 are to be performed before administration of study drug shown. Review eligibility criteria at the baseline visit to ensure subjects 
remain eligible following the lead-in period. 
2 Procedures scheduled for Visit 5 will be performed at the end of the follow-up period (+4 days) or upon early discontinuation from the study. 
3 Once the subject has met the inclusion/exclusion criteria as appropriate at screening, the subject will enter a 4-week lead-in period.  During the lead-in, the 
subject will record their daily vertigo experience.  A determination of whether the subject meets Inclusion Criteria No. 10 and 11 will be determined 28 days 
after subjects enter the lead-in period. 
4 Medical history to include information on demographics. 
5 Vital sign measurements include blood pressure and pulse rate.  
6 Only weight is to be measured at Visit 5. 
7 Female subjects of childbearing potential will have a serum pregnancy test at screening and a urine pregnancy test at baselin e, prior to randomization. If the 
screening or baseline pregnancy test result is positive, the subject is not eligible for enrollment into the study. If a subject is found to be pregnant after dosing 
with study drug, they will complete the follow-up period. All serum pregnancy tests will be analyzed by a central laboratory. Serum pregnancy test results from 
Visit 1 as well as the urine pregnancy test at baseline prior to randomization must be included in eligibility assessment at Visit 2. 
8 Clinical laboratory tests include hematology, clinical chemistry, and urinalysis and will be analyzed by a central laboratory . 
9 Columbia-Suicide Severity Rating Scale: The Baseline version will be used at the Screening visit and the Since Last Visit version will be used at all subsequent 
visits. 
10Subjects will be instructed and trained how to record daily vertigo experience using the IVRS diary. 
11A subject is considered randomized when a randomization number has been assigned by IWRS.  Randomization must occur prior to administration of study 
drug. Study sites log in to the IWRS to execute each randomization after a subject has met all prerequisites for randomization and has completed all scheduled 
procedures for Day 1. 
12Subjects will be randomized using laboratory results from Visit 1; laboratory results from Visit 2 are not required for randomization. 
 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
1. 
BACKGROUND 
Meniere’s disease is an idiopathic syndrome of endolymphatic hydrops (Committee on Hearing 
and Equilibrium, 1995).  It is associated with a distinct pattern of clinical symptoms comprised 
of vertigo, hearing loss, tinnitus and aural fullness. It is more frequently unilateral than bilateral.  
Episodic vertigo is considered the most prominent symptom, with episodes typically lasting at 
least 20 minutes and resulting in significant patient morbidity.  The diagnosis is primarily a 
clinical one, since there are no specific diagnostic tests for Meniere’s disease.  The disease is 
known to wax and wane, but eventually results in irreversible sensorineural hearing loss at all 
frequencies in the affected ear.  While the pathogenesis of Meniere’s disease has not been 
elucidated, one well-accepted mechanism involves the dysregulation of labyrinth fluid 
volume/ion balance resulting in endolymphatic hydrops (Shea, 1993).  The increase in fluid 
volume and consequent increased labyrinth pressure may then be expressed as the Meniere’s 
spectrum of symptoms. 
There is no cure for Meniere’s disease.  Treatment tends to focus on relieving the vertigo 
symptoms, where it is hypothesized that reducing inner ear fluid volume will relieve the hydrops 
and associated clinical picture.  It is for this reason that many subjects are initially started on low 
salt diets and diuretics (Barritt, 2008).  A number of medical systemic treatments are also used to 
relieve Meniere’s disease symptoms, including but not limited to antihistamines, 
anticholinergics, phenothiazines, benzodiazepines, and corticosteroids; however, these 
interventions are often inadequate in relieving the symptoms of Meniere’s disease.  A device that 
generates low-pressure pulses, the Meniett® device, is indicated for the symptomatic treatment 
of Meniere’s disease.  However, the device is not widely used and is not currently considered 
standard of care (Kim et al, 2005).  Surgical decompression may be attempted in severe cases 
unresponsive to medical intervention, but surgical outcomes are frequently unsatisfactory.  
Finally, patients with unresponsive disease may undergo chemical or surgical neuroablation, 
resulting in symptom relief at the cost of destruction of the 8th cranial nerve. Thus, there 
continues to be an unmet medical need for therapies to address this debilitating disease. 
 
 
  
 
 
 
 Single and repeat-dose nonclinical 
safety studies in guinea pigs, rats and cats have been conducted to support clinical development.  
Special emphasis in the toxicology studies has been placed on the effects of OTO-104 and 
poloxamer 407 vehicle control on middle and inner ear compartments, where both functional and 
histological assessments have been conducted.  Additionally, pharmacokinetic assessments have 
been conducted in guinea pigs, rats, cats, and sheep that provide a complete profile of exposure 
of OTO-104 to the inner ear compartment, as well as systemic exposure. 
1.1. 
Rationale for Study 
Otonomy has completed 2 placebo-controlled, double-blind, multi-center clinical studies with 
OTO-104 in Meniere’s disease: a Phase 1b study, 104-200901, and a Phase 2b study, 104-


 
                                                              18  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
201102.  The Phase 1b study demonstrated that a single intratympanic injection of OTO-104 at 
doses of 3 mg or 12 mg was safe and well tolerated in subjects with Meniere’s disease.  In the 
exploratory Phase 1b study, the trends in the data suggest treatment with 12 mg OTO-104 is 
associated with a clinically meaningful reduction in vertigo frequency at 3 months after 
treatment compared to 3 mg OTO-104 or placebo.  The Phase 2b study therefore randomized 154 
subjects with unilateral Meniere’s disease to treatment with 12 mg OTO-104 or placebo.  This 
study demonstrated improvement in number of definitive vertigo days compared to the lead-in 
period with a single IT injection of OTO-104 compared to placebo during the Week 12 interval 
with a smaller improvement observed at Week 16.  Therefore, the final dose selected and 
primary observation point for this study is 12 mg OTO-104 and the Week 12 interval.   
2. 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to confirm the efficacy of OTO-104 in subjects with Meniere’s disease, 
as measured by the number of definitive vertigo days (DVD) at Week 12 (the 4-week interval 
from Week 9 through Week 12). 
2.2. 
Secondary Objective 
The secondary objective is to describe the safety profile of OTO-104 in subjects with Meniere’s 
disease. 
3. 
OVERVIEW OF STUDY DESIGN 
This is a randomized, double blind, placebo-controlled, multicenter 16-week Phase 3 study.  
Following an initial 4-week lead-in period, eligible subjects will be randomly assigned to either 
12 mg OTO-104 or placebo using a 1:1 allocation ratio stratified by gender.  Subjects will be 
observed for 12 weeks following a single intratympanic injection of either 12 mg OTO-104 or 
placebo. 
The duration of the study for each subject will be a maximum of approximately 16 weeks, 
including a 4-week lead-in period before dosing (a single injection), followed by a 12-week 
follow-up period. 
After screening (Visit 1), all eligible subjects will enter into a 4-week lead-in period.  During the 
lead-in period, subjects will record their daily vertigo experience to allow for a baseline 
assessment of these events.  Any day with a recorded definitive vertigo episode, an episode 
lasting at least 20 minutes (corresponding to a Vertigo Severity Score of 2 or more), will be 
defined as a definitive vertigo day (DVD).  Following the lead-in period, eligible subjects will be 
randomized to 12 mg OTO-104 or placebo using a 1:1 allocation ratio.   
After a single intratympanic injection with OTO-104 or placebo on Day 1, subjects will continue 
to record their daily vertigo experience during the 12-week follow-up period. Subjects will visit 
the study site at Weeks 4 and 8 for additional efficacy and safety assessments. Efficacy and 


 
                                                              19  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
safety assessments will also be completed at the end of study (Week 12) or upon early 
discontinuation from the study. 
4. 
STUDY POPULATION 
4.1. 
General Considerations 
Approximately 160 subjects will be enrolled at 60-70 study sites in the United States.  Subjects 
will be randomized only if they meet all of the inclusion criteria and none of the exclusion 
criteria. 
4.2. 
Inclusion Criteria 
Subjects enrolled in the study will have unilateral Meniere’s disease as outlined by the American 
Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) Committee on Hearing and 
Equilibrium in 1995 (Committee on Hearing and Equilibrium, 1995). 
To be eligible for this study, each of the following criteria must be satisfied with a “YES” answer 
(unless not applicable): 
1. Subject is a male or female aged 18 to 85 years, inclusive. 
2. Subject has a diagnosis of definite unilateral Meniere's disease by 1995 AAO-HNS 
criteria. 
3. Subject self-reports active, definitive vertigo episodes for the 2 months prior to the study 
lead-in period. 
4. Subject has documented asymmetric sensorineural hearing loss at screening or within the 
past 12 months according to AAO-HNS 1995 criteria defined as one of the following:  
a. The arithmetic mean of hearing thresholds (pure tone average, PTA) at 250, 500 and 
1000 Hz of 15 dB or more higher than the PTA of 1000, 2000, and 3000 Hz, 
b. The arithmetic mean of  PTA at 500, 1000, 2000 and 3000 Hz is 20 dB or more 
poorer in the ear in question than on the opposite side, 
c. It is the judgment of the investigator that the subject's hearing loss meets reasonable 
audiometric criteria for hearing loss characteristic of Meniere's disease, and if so, it 
should be justified and documented. 
5. Subject agrees to maintain their current treatments for Meniere's disease while on-study. 
6. Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-
menopausal (≥12 months since last menstrual period and 45 years of age or older)] must 
have a negative urine pregnancy test before randomization. Women of childbearing 
potential who are not abstinent from sex with male partners may be entered into the study 
if they are using and willing to continue to use highly effective or “double barrier” 
contraceptive precautions for the duration of the study (e.g., oral contraceptives, 
contraceptive implant or injection, intrauterine device, “double barrier” methods 
including male condom with diaphragm, male condom with cervical cap, male condom 
with spermicide, or diaphragm and spermicide).  


 
                                                              20  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
7. Subject is willing to comply with the protocol and attend all study visits. 
8. Subject is able to use the telephone to complete their daily diary. 
9. Subject is able to provide written informed consent, including agreement to privacy 
language either within the informed consent or in ancillary documents compliant with 
Health Insurance Portability and Accountability Act (HIPAA) before the initiation of any 
study-related procedures. 
At the completion of the first 28 days of the lead-in period: 
10. Subject has experienced and recorded at least 4 and a maximum of 22 definitive vertigo 
days during the 4-week lead-in period. 
11. Subject completed at least 22 of 28 diary entries during the 4-week lead-in period. 
4.3. 
Exclusion Criteria 
To be eligible for this study, each of the following criteria must be satisfied with a “NO” answer: 
(unless not applicable): 
1. Subject has an infection in the ear, sinuses, or upper respiratory system at the time of 
randomization. 
2. Subject is pregnant or lactating. 
3. Subject has a history of immunodeficiency disease. 
4. Subject has active or recent (<1 month prior to screening) middle ear disease, including 
but not limited to:  chronic otitis media, acute otitis media, middle ear effusions, middle 
ear atelectasis, or cholesteatoma. 
5. Subject has an abnormality of the tympanic membrane in the affected ear that would 
increase the risk associated with intratympanic injection including but not limited to 
monomeric tympanic membrane. 
6. Subject has a history of previous endolymphatic sac surgery. 
7. Subject has a history of previous use of intratympanic gentamicin in the affected ear. 
8. Subject has a history of tympanostomy tubes with evidence of perforation or lack of 
closure. 
9. Subject has used systemic steroids within 1 month prior to entering the lead-in period. 
10. Subject has had intratympanic steroids within 1 month prior to entering the lead-in 
period. 
11. Subject has experienced an adverse reaction to intratympanic injection of steroids. 
12. Subject has a hypersensitivity to dexamethasone or any of the excipients in OTO-104. 
13. Subject has history of migrainous vertigo. 
14. Subject has history of drop attacks. 
15. Subject is not able to accurately identify and report episodes of vertigo. 


 
                                                              21  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
16. Subject has any other clinically significant illness, medical condition, or medical history 
that, in the investigator’s or the medical monitor’s opinion, would prohibit the subject 
from participating in the study at screening or at the time of randomization. 
17. Subject has used an investigational drug or device in the 3 months prior to screening.  
18. Subject has a history of substance abuse within the preceding 6 months prior to 
screening. 
19. Subject has previously been randomized to a trial of OTO-104. 
5. 
RANDOMIZATION AND BLINDING 
5.1. 
Overview 
At the conclusion of the screening/lead-in period, eligible subjects will be randomly assigned to 
either OTO-104 or placebo in a 1:1 allocation ratio, stratified by gender, based on a computer-
generated randomization schedule.   
• 
12 mg OTO-104; single, intratympanic injection 
• 
Placebo; single, intratympanic injection  
5.2. 
Enrollment Procedures 
5.2.1. 
Assignment of Subject Identification Numbers 
At the screening visit, Visit 1, subjects signing the informed consent will be assigned a unique 
subject identification number via the Electronic Data Capture system (EDC).  Once assigned, the 
subject identification number will not be re-assigned and should not be changed.  This number 
will be used to identify the subject throughout the study, including the screening and lead-in 
periods. 
5.2.2. 
Treatment Assignment 
Study sites will log in to the IWRS to execute each randomization after a subject has met all 
prerequisites for randomization and has completed all scheduled procedures for Day 1 (Visit 2).   
Study site personnel, who are blinded to treatment assignment, will receive a randomization 
notification indicating the kit number (packaged study drug), and the date and time of 
randomization for each subject.  Once assigned, kit numbers cannot be re-assigned.  Subjects 
will be considered enrolled into the study once they are randomized and assigned a unique 
randomization number. 
Study sites will provide the information contained in the IWRS randomization notification to the 
unblinded qualified medical professional (QMP) responsible for preparation of the syringe 
containing study drug.  The unique kit number provided by the IWRS will correspond to a kit of 
packaged study drug labeled with the identical kit number.  The QMP will prepare the syringe 
from the contents of the study drug package corresponding to the IWRS kit number according to 
the instructions in the study Pharmacy Binder.  The subject identification number and kit number 
must both be recorded in the subject’s record. 


 
                                                              22  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
5.2.3. 
Randomization Algorithm 
Subjects will randomized in a 1:1 ratio treatment groups stratifying by gender using a permuted 
block randomization algorithm.  The randomization process will be deployed via an internet-
based IWRS which is accessible 24 hours a day to authorized users.  The subject’s randomization 
number will determine the randomized treatment assignment.  Numbered kits will be dispensed 
by the qualified medical professional based on the treatment assignment.  Study drug kits will be 
labeled with a unique kit number using a separate and independent randomization algorithm. 
5.3. 
Blinding 
The study will be double-blinded.  To maintain the blind for site personnel involved in study 
assessments, the following procedures will be followed: 
Treatment syringes will be pre-loaded by an unblinded QMP.  Each syringe will be prepared 
according to the detailed instructions in the Pharmacy Binder in a manner that prevents 
visualization of syringe contents by all other study staff through the use of a syringe overlabel.  
In addition, any interaction with subjects with regard to the collection, review or discussion of 
study assessments, with the exception of otoscopic exams, will be done by the study coordinator, 
audiologist or someone other than the QMP who prepared the syringe and the physician who 
administered the intratympanic injection of study drug.  Every effort should be made to ensure 
that otoscopic exams are conducted by the physician who administered the study drug or another 
physician involved in the study, but not responsible for other assessments for the specific subject.  
Physicians administering study drug and conducting the otoscopic exams will be instructed not 
to discuss any potential visual differences observed in study material with subjects or study staff. 
The blind should be broken only if knowing the subject’s treatment allocation would facilitate 
specific emergency treatment.  The physician who administered the study drug is unblinded at 
the time of injection.  If the physician who administered the study drug is not available or does 
not recollect the treatment administered, the investigator can access the unblinded drug 
accountability records completed and retained by the QMP when preparing OTO-104 or placebo.  
In all cases, the investigator must contact the medical monitor as soon as it is practical after 
unblinding has occurred and treatment initiated. 
If the blind is broken, the subject will continue to be followed and evaluated per-protocol.  The 
date, time, and reason for the unblinding must be documented on the appropriate page of the 
eCRF.  
The randomization schedule or blocking factor(s) will not be revealed to study subjects, 
investigators, clinical staff, site managers or Sponsor representatives until all subjects have 
completed the trial and the database has been finalized by Otonomy. 
6. 
DOSAGE AND ADMINISTRATION 
6.1. 
Study Drug Administration 
OTO-104 12 mg will be administered as a single, 0.2 mL intratympanic injection of 60 mg/mL 
OTO-104. The recommended injection procedure for intratympanic administration of OTO-104 
in Meniere’s disease subjects is as follows:   


 
                                                              23  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
1. Place the subject in a recumbent position with the treated ear upwards.  Anesthetize the 
tympanic membrane by covering the external surface of the posterior inferior quadrant 
with topical lidocaine/prilocaine cream (
 
) until the tympanic 
membrane is numb.  If applicable, suction away the topical lidocaine/prilocaine cream.  
2. Using the 1 mL syringe pre-loaded with OTO-104 and equipped with a 25 or 26 gauge 
needle, insert the needle through the tympanic membrane with the bevel facing in an 
inferoposterior direction to a depth of approximately 2-3 mm just inferior to the round 
window niche, and with firm but gentle pressure, inject 0.2 mL taking care not to insert 
the needle further than necessary.  Use of this technique will minimize the possibility of 
OTO-104 adhering to the underside of the tympanic membrane.  Do not incise the 
tympanic membrane to form a ventilation hole as this is not needed due to the small 
injection volume. 
6.2. 
Compliance 
OTO-104 will be administered by site medical professionals as a single, intratympanic injection 
at Visit 2.  Any deviations in administration will be documented in the source documents and the 
eCRF. 
The site will maintain a log of all study drug dispensed and returned. Drug supplies for each 
subject will be inventoried and accounted for throughout the trial. 
7. 
PRIOR, CONCOMITANT AND SUBSEQUENT THERAPY 
Use of all concomitant medications will be recorded in the subject’s eCRF.  This will include all 
symptomatic relief medications for Meniere’s disease symptoms, prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications taken within 30 days before 
randomization, which will be considered prior therapy.  Any concomitant medication deemed 
necessary for the welfare of the subject during the study may be given at the discretion of the 
Investigator except for those listed in Section 7.1.  Any changes in concomitant medications will 
be recorded in the subject’s eCRF. 
7.1. 
Proscribed Therapy During the Study Period 
The following therapies are prohibited during the study: 
 Systemic corticosteroids 
 Immunosuppressive medications 
 Intratympanic injection other than that outlined in the current study 
 Surgery for treatment of Meniere’s disease 
 Other investigational drug(s) or device(s)  
Use of any of these proscribed therapies will be considered a protocol deviation. 


 
                                                              24  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
7.2. 
Symptomatic Relief Medications 
It is recognized that subjects may at times use certain medications for relief of symptoms related 
to Meniere’s disease during the course of the study.  Use of vestibular suppressants and anti-
emetics is allowed as symptomatic relief medications.  The use of gentamicin or ear surgery at 
any time during the study will be considered a protocol deviation.  Any changes reported by the 
subjects in concomitant medications should be recorded in the subject’s eCRF. 
8. 
STUDY EVALUATIONS 
8.1. 
Study Procedures by Visit 
8.1.1. 
Visit 1: Up to 14 days prior to initiation of lead-in period (Screening) 
Because audiology, tympanometry and otoscopic exams are considered routine for this patient 
population, data obtained from assessments performed prior to documentation of informed 
consent can be used as screening data.  In these cases, the data should have been collected within 
14 days of initiation of the lead-in period. 
The following assessments will be performed at Visit 1. 
 Informed consent 
 Confirm eligibility criteria 
 Medical history 
 Concomitant medications 
 Vital signs 
 Height and weight measurements 
 Serum pregnancy test (for female subjects of childbearing potential only) 
 Clinical laboratory test 
 Tympanometry 
 Audiometry  
 For subjects that present without documented audiograms showing asymmetrical 
hearing loss to meet eligibility criteria, audiometry at the screening visit should be 
conducted including the 250 and 3000 Hz frequencies. 
 Otoscopy 
 C-SSRS assessment: Baseline version  
 Review IVRS diary instructions with subject 
8.1.2. 
Lead-In Period (Day -28 through -1 (+3 days)) 
The subject will record their daily vertigo experience during the entire lead-in period until 
randomization, ineligibility or withdrawal of consent.  The determination of whether subjects 


 
                                                              25  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
meet Inclusion Criteria No. 10 and 11 will be conducted 28 days after initiation of the lead-in 
period. 
8.1.3. 
Visit 2: Day 1 (Baseline/Dose Administration) 
The following assessments will be performed at Visit 2. 
 Confirm eligibility criteria 
 Medical history 
 Concomitant medications 
 Vital signs 
 Urine pregnancy test (for female subjects of childbearing potential only) 
 Clinical laboratory test 
 Tympanometry 
 Audiometry 
 Otoscopy 
 TFI-25 
 SF-36 Health Survey 
 C-SSRS assessment, Since Last Visit version 
 Randomize and administer OTO-104 or placebo (all assessments in the above list 
must be conducted prior to OTO-104 or placebo administration) 
 Review subject IVRS diary instructions 
 Adverse events (to be collected during or after OTO-104 administration) 
8.1.4. 
Visit 3, 4: Week 4 and 8 (± 2 days) (Follow Up) 
The following assessments will be performed at Visit 3 and 4. 
 Concomitant medications 
 Vital signs 
 Tympanometry 
 Audiometry  
 Otoscopy 
 TFI-25 
 SF-36 Health Survey 
 C-SSRS assessment, Since Last Visit version 
 Review subject IVRS diary instructions 


 
                                                              26  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
 Adverse events  
8.1.5. 
Visit 5: Week 12 (± 4 days) (End of Study/Early Termination) 
The following assessments will be performed at Visit 5. 
 Concomitant medications 
 Vital signs 
 Weight measurements 
 Urine pregnancy test (for female subjects of childbearing potential only) 
 Clinical laboratory test 
 Tympanometry 
 Audiometry 
 Otoscopy 
 TFI-25 
 SF-36 Health Survey 
 C-SSRS assessment, Since Last Visit version 
 Adverse events 
8.2. 
Efficacy Evaluations 
Efficacy assessments include: 
 Characterization of Daily Vertigo Experience  
 TFI-25 (exploratory endpoint) 
 Short Form 36 Health Survey (SF-36) (exploratory endpoint) 
To maintain the double-blind of the study, it is required that any interaction with subjects in the 
collection, review, or discussion of these assessments be done by the study coordinator or 
someone other than the investigator who administered the intratympanic injection of study drug.  
An exception may be made only if it involves the safety of the subject. 
8.2.1. 
Daily Diary – Vertigo Experience 
Subjects will record their daily vertigo experience via an IVRS daily diary by recording the 
severity of the worst vertigo episode experienced during the day, the effect of vertigo on their 
daily activities, and the number of vertigo episodes experienced during the day.  Subjects eligible 
at screening will begin using the IVRS daily diary at the start of the lead-in period, and if 
randomized, will continue to record their daily vertigo experience throughout the remainder of 
the study.  Subjects will be able to record missed diary entries for 1 day after a missed entry.  
Compliance with the IVRS vertigo diary will be monitored.   
Using the daily vertigo scales developed by Gates (Gates, 2000; Gates, 2004; Gates 2005; Gates, 
2006) and adapted to an IVRS, subjects are instructed to record the score that best corresponds to 


 
                                                              27  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
the worst vertigo episode experienced each day and the effect on their daily activities of their 
total vertigo experience that day using a 5-point scoring system: 
Vertigo Severity Score 
0 = Vertigo-free day 
1 = Mild - an attack lasting less than 20 minutes  
2 = Moderate - an attack lasting more than 20 minutes 
3 = Severe - an attack lasting more than 20 minutes and accompanied by nausea and/or 
vomiting 
4 = The worst attack experienced to date 
Effect of Vertigo on Activity Level 
0 = Normal Activity 
1 = Slight limitation 
2 = Moderate limitation 
3 = Sick at home 
4 = Bed ridden 
The occurrence of a definitive vertigo episode for a given day is defined as a recorded Vertigo 
Severity Score of 2 or more for that day.  If multiple attacks occur on the same day, only the 
worst attack should be scored. 
8.2.2. 
Tinnitus Functional Index (TFI-25) 
The TFI-25 is a validated, 25-item questionnaire that can be used to quantify treatment-related 
change in tinnitus (Meikle et al., 2013; Henry et al., 2015).  The total TFI score is a sum of the 
25 items with a maximum score of 250, with higher scores representing greater perceived 
handicap.  The 25 items can also be grouped into 8 subscales: 1) Intrusive, 2) Sense of Control, 
3) Cognitive, 4) Sleep, 5) Auditory, 6) Relaxation, 7) Quality of Life, and 8) Emotional.   
The TFI-25 will be administered to subjects at Visits 2, 3, 4, and 5. 
8.2.3. 
Short Form 36 (SF-36) Health Survey 
SF-36 is a validated, 36-item, multi-purpose, short-form health survey (Ware et al., 1993; Ware 
et al., 1994).  It consists of 8 subscales: 1) Physical Functioning, 2) Role-Physical, 3) Bodily 
Pain, 4) General Health, 5) Vitality, 6) Social Functioning, 7) Role-Emotional, and 8) Mental 
Health. 
The SF-36 health survey will be administered to subjects at Visits 2, 3, 4, and 5. 
8.3. 
Safety Evaluations 
Safety assessments include: 
 Vital Signs, Height and Weight Measurements 


 
                                                              28  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
 Clinical Laboratory Test 
 Tympanometry 
 Audiometry 
 Otoscopy  
 C-SSRS Assessment 
 Concomitant Medications 
 Adverse events (see Section 9) 
8.3.1. 
Vital Sign, Height and Weight Measurements 
Vital sign measurements (including systolic and diastolic blood pressure and pulse rate) will be 
collected at all study visits.  Vital signs will be measured after subjects have been seated for 5 
minutes and while subjects are in a sitting position.  Height and weight will be measured at Visit 
1 and weight will be measured again at Visit 5. 
8.3.2. 
Clinical Laboratory Test 
All clinical laboratory tests will be processed by a Central Laboratory. 
Blood and urine samples for hematology, serum chemistry, urinalysis, and pregnancy tests will 
be prepared using standard procedures.  Clinical laboratory testing will be completed at Visits 1, 
2 and 5.  In addition, female subjects of childbearing potential will have serum pregnancy test at 
Visit 1 and a urine pregnancy test at Visits 2 and 5. 
The blood and urine samples will be used for the following tests: 
Hematology: white blood cell count with differential, hemoglobin, hematocrit, platelet count, 
red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration. 
Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen, carbon dioxide, calcium, chloride, creatinine, 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total bilirubin, total protein. 
Urinalysis: appearance, color, glucose, ketones, nitrite, pH, protein, specific gravity, occult 
blood, leukocyte esterase, and urobilinogen. 
8.3.3. 
Tympanometry 
Tympanometry assessments will be used to assess the mobility and compliance of the tympanic 
membrane, pressure and volume in the middle ear, and function of the tympanic membrane, 
ossicles and eustachian tube.  Tympanograms will be completed in both ears at all study visits.  
Subjects wearing hearing aids should be instructed not to wear their hearing aids during the 
tympanometry assessment. 
8.3.4. 
Audiometry 
Audiometric assessments will be used to assess hearing function in both ears.  Audiograms must 
be conducted at 500, 1000, 2000, 4000 and 8000 Hz for both air and bone conduction at all study 


 
                                                              29  
Otonomy 104-201506 Protocol V2.0: 22 February 2016 
visits.  Both air and bone conduction thresholds will be assessed.  Pure tone averaging bone and 
air conduction testing will be done at 500, 1000, and 2000 Hz frequencies.  Subjects wearing 
hearing aids should be instructed not to wear their hearing aids during the audiogram. 
Audiometric assessments must be conducted in accordance with American-Speech-Language-
Hearing Association Guidelines (ASHA, 2005).  Equipment calibration must be current and 
documented.  The audiometric assessments must be conducted by a licensed audiologist or a 
qualified assistant with appropriate training under the direct supervision of a licensed 
audiologist. 
8.3.5. 
Otoscopy 
Otoscopic exams will be used to assess the auditory canal, the appearance of the tympanic 
membrane, and the healing of the intratympanic injection site.  Otoscopic examinations will be 
performed in both ears at all study visits during the study by the physician.  Presence and size of 
tympanic membrane perforations will be recorded.  Perforations of the tympanic membrane will 
be captured as AEs only if the perforation increases in size and does not resolve by the end of the 
study.  Subjects wearing hearing aids should be instructed not to wear their hearing aids during 
the otoscopic exam. 
8.3.6. 
C-SSRS Assessment 
The C-SSRS assessment will be administered at all study visits.  The Baseline version will be 
used at Visit 1 for all subjects.  For Visits 2 through 5, the Since Last Visit version will be used.  
Any subject with a positive score at on the Baseline version or an appearance of any new suicidal 
ideation or suicide behavior since the Baseline version should be referred to their primary care 
provider for follow-up. 
If a subject has any post-Screening C-SSRS score of 1-3 for Ideation (i.e., a “yes” answer to 
Questions 1, 2, or 3) or a “yes” response to the Non-Suicidal Self-Injurious Behavior question) 
and the score is higher than the Screening C-SSRS score, then this assessment should be 
recorded as an AE.  This information is reported as indicated in Section 9. (Possible AE terms: 
Suicidal plans, Suicidal ideation, Suicidal tendency, Suicidal behavior, Suicidal intention, 
Suicidal depression, Active suicidal ideation, Passive suicidal ideation, Self-injurious behavior 
without suicidal intent). 
If a subject has any post-Screening C-SSRS score of 4 or 5 for Ideation (i.e., a “yes” answer to 
question 4 or 5) and/or any questions answered yes for Suicidal Behavior (with the exception of 
a “yes” response to the Non-Suicidal Self-Injurious Behavior question), and this was not 
observed at Screening, then this assessment should be recorded as a Serious Adverse Event 
(SAE).  This information is reported as indicated in Section 9.2.2. 
9. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials 
will be conducted in accordance with Good Clinical Practice. 
All AEs, including serious adverse events (SAEs) reported or observed during or after dosing 
with the study drug will be recorded on the AE page of the eCRF for all enrolled subjects.  


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
Information to be collected includes description of event, date of onset, investigator-specified 
assessment of the severity and relationship to study drug, date of resolution of the event, 
seriousness, any required treatment or evaluations, and outcome.  Adverse events resulting from 
concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or 
progression of disease states must also be reported.  Perforations of the tympanic membrane will 
be captured as AEs only if the perforation increases in size and does not resolve by the end of the 
study. 
If the existing medical condition worsens at any time after application of study drug, it should be 
recorded as an AE. 
9.1. 
Adverse Event Classification Definitions 
Adverse Event: 
An AE is any unfavorable and unintended diagnosis, symptom, sign, syndrome or disease which 
occurs during the study, having been absent at baseline, or, if present at baseline, appears to 
worsen. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, including abnormal results of diagnostic procedures and/or laboratory test 
abnormalities, which are considered AEs if they: 
 result in discontinuation from the study 
 require treatment or any other therapeutic intervention 
 require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality) 
 are associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact 
Serious Adverse Event (SAE): 
An SAE is defined as any untoward medical occurrence that: 
 results in death, 
 is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event rather than to an event which 
hypothetically might have caused death if it were more severe.), 
 requires in-patient hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/incapacity, or 
 is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the above definition.  These events 
should be considered serious. 


 
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9.1.1. 
Assessment of Severity 
The investigator will assess the intensity of the AE and rate the AE as mild, moderate, or severe 
using the following criteria: 
Grade 1 – Mild: These events are easily tolerated, require minimal or no treatment, and do 
not interfere with the subject’s daily activities. 
Grade 2 – Moderate: These events cause sufficient discomfort to interfere with daily 
activity and/or require a simple dose of medication, e.g., analgesics or anti-emetics. 
Grade 3 – Severe: These events incapacitate and prevent usual activity or require complex 
medication/treatment or hospitalization. 
Grade 4 – Life Threatening: These events are those for which the subject was at risk of 
death at the time of the event rather than an event which hypothetically might have caused 
death if it were more severe. 
Grade 5 – Death: The event resulted in the death of the subject. 
Changes in the severity of an AE should be documented to allow for an assessment of the 
duration of the event at each level of intensity to be performed.  
9.1.2. 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug will be part of the 
documentation process, but will not be a factor in determining what is or is not reported in the 
study.   
The investigator will assess the relationship or association of the study drug in causing or 
contributing to the AE, which will be characterized using the following classification and 
criteria: 
Definite: Adverse events that, after careful medical evaluation, are considered definitely 
related to the study drug; other conditions (concurrent illness, progression/expression of 
disease state, or concurrent medication reaction) do not appear to explain the event. 
Probable: Adverse events that, after careful medical evaluation, are considered with a high 
degree of certainty to be related to the study drug.  The following characteristics will apply: 
 a reasonable temporal relationship exists between the event and exposure to the study 
drug, and 
 the event is a known reaction to the study drug that cannot be explained by an 
alternative cause commonly occurring in the population/individual, or 
 the event is not a known reaction to the study drug but cannot be reasonably 
explained by an alternative cause. 
Possible: Adverse events that, after careful medical evaluation, do not meet the criteria for a 
definite or probable relationship to the study drug, but for which a connection cannot be ruled 
out with certainty.  The following characteristics will apply: 
 the event occurs after exposure to the study drug, and 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
 there is a reasonable temporal relationship to the application, but the event is not a 
known reaction to the study drug and could be explained by a commonly occurring 
alternative cause, or 
 in the absence of a reasonable temporal relationship, the event cannot be explained by 
an alternative cause. 
Not related: Adverse events in this category will have either of the following characteristics: 
 the event does not have a reasonable temporal relationship to study drug 
administration and/or can be explained by a commonly occurring alternative cause. 
9.1.3. 
Follow up of Adverse Events 
The investigator will follow a non-serious AE until resolution, stabilization, or the End of Study 
Visit.  The investigator will follow an SAE (regardless of relationship to study drug) until the 
event resolves, stabilizes, or becomes non-serious.  All AEs identified on the last scheduled 
contact must be recorded on the AE page of the eCRF and the current status (ongoing or 
resolved) will be noted.  In addition, SAEs will be reported to Product Safety according to the 
reporting guidelines identified in Section 9.2.2. 
9.2. 
Monitoring of Adverse Events 
9.2.1. 
All Adverse Events 
All AEs will be analyzed for safety.  Those meeting the definition of SAE must be reported using 
the SAE Form.  Subjects should voluntarily report any AEs or report AEs in response to general, 
non-directed questioning (e.g., "How has your health been since the last visit?").  For each AE 
volunteered by the subject, the investigator should obtain all the information required to 
complete the AE page of the eCRF, in accordance with the guidelines that accompany it. 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology in the source document and on the eCRF.  Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection").  Investigators must record on the eCRF their opinion concerning the 
relationship of the AE to study therapy.  All measures required for AE management must be 
recorded in the source document and reported according to sponsor instructions. 
Any non-serious AE that occurs after the dose of study drug must be reported in detail on the 
appropriate eCRF page and followed until resolution, stabilization, or the End of Study Visit.  
The description of the AE will include description of event, date of onset, date of resolution, 
investigator assessment of severity and relationship to study drug, seriousness, any required 
treatment or evaluations, and outcome.  
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.  
The sponsor will also report to the investigators all serious AEs that are unlisted and associated 
with the use of the drug.  The investigators must report these events to the appropriate 
Institutional Review Board (IRB) in accordance with local regulations. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
9.2.2. 
Serious Adverse Events 
All SAEs occurring during clinical trials must be reported within 24 hours to Product Safety. 
The cause of death of a subject in a clinical trial, whether the event is expected or associated with 
the investigational agent, is an SAE. 
The initial report of an SAE may be made by telephone, e-mail or facsimile (fax).  The 
investigator must provide the minimal information: i.e., protocol number, subject's initials and 
date of birth, subject number or medication code number, nature of the AE and investigator's 
attribution. 
All oral reports of an SAE must be confirmed within 24 hours by a written, more detailed report 
and signed by the investigator.  For this purpose, the sponsor will provide the investigator with 
the Serious Adverse Event Form for Clinical Trials. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until either: 
 the event resolves, 
 the event stabilizes, or 
 the event becomes non-serious 
The investigator should report any follow-up information as it becomes available. 
9.2.3. 
Pregnancies 
Pregnancies occurring after the first dose of investigational product and during participation of 
the study are considered immediately reportable events.  While not considered a SAE unless a 
serious criterion is met, pregnancies occurring in subjects enrolled on the study must be reported 
and followed to outcome.  The investigator should complete the pregnancy report eCRF within 
one working day of knowledge of the pregnancy.  Following delivery or termination of 
pregnancy, the follow-up pregnancy report form should be completed on the pregnancy CRF.  
Spontaneous abortions should always be reported as SAEs.  Follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant will be required.  
9.3. 
Contacting Sponsor Regarding Safety 
Any AE considered serious by the investigator, or that meets the SAE criteria stated in this 
protocol, must be reported to Product Safety within 24 hours from the time that study site 
personnel first learns of the event.  The study site must enter the SAE into the EDC system.  
  
 
 
Source documents will be requested from the study sites for SAEs and should be provided to 
Product Safety.  If the subject is hospitalized during the study, a copy of the hospital discharge 
summary should be provided to the Product Safety as soon as it becomes available. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
10. 
SUBJECT COMPLETION 
10.1. 
Completion 
Study subject participation is complete after Visit 5.  Subjects who withdraw their consent to be 
followed or are lost-to-follow-up before completion of Visit 5 (Week 12) will not be considered 
to have completed the study. 
10.2. 
Withdrawal 
All subjects have the right to withdraw from study evaluations at any time, for any reason, 
without prejudice; nonetheless, investigators should attempt to encourage subjects to complete 
the protocol so that continued observation and follow-up measurements may be obtained.  The 
investigator may discontinue a subject’s participation in the study at his/her discretion for 
reasons including, but not limited to, the following: 
1. Subject experiences a serious or intolerable AE that, in the opinion of the investigator, 
requires withdrawal from the study. 
2. Subject is in violation of the protocol. 
3. Subject develops a condition during the course of the study that makes it unwise to 
continue with the trial. 
4. Subject requires a medication that is prohibited by the protocol. 
5. Subject requests an early discontinuation for any reason. 
At any point, the investigator may discontinue the subject’s study participation at his/her 
discretion and ensure the subject receives appropriate medical care; the investigator may also 
consult the medical monitor to discuss out-of-range test results. 
10.2.1. 
Handling of Withdrawals 
Subjects will be free to withdraw from study drug administration and further follow-up the study 
at any time.  Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
Whenever possible, all subjects who withdraw from study drug administration should be 
encouraged to remain on-study for further follow-up through the subject last scheduled visit.  
However, should a request for early withdrawal from the study with no further follow-up be 
made, the subject should be encouraged to return to the study site for a last follow up visit and 
undergo all end of study/early termination assessments.  
When a subject withdraws from administration of study drug or the study prior to completing 
Visit 5 (Week 12), the reason for withdrawal is to be documented on the eCRFs and in the source 
document.   
10.2.2. 
Replacements 
Subjects who discontinue participation in the study for any reason after dosing will not be 
replaced. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
11. 
STATISTICAL METHODS 
The primary objective of this Phase 3 study is to test the hypothesis that subjects randomized to 
OTO-104 will demonstrate fewer definitive vertigo days (DVD) than subjects randomized to 
placebo at Week 12 (the 4-week (28-day) interval from Week 9 through Week 12).  The 
secondary objective of the study is to describe the safety profile of a 12 mg dose of OTO-104 
compared to placebo when administered as a single intratympanic injection in subjects with 
Meniere’s disease. 
The following statistical sections describe the general analytic methods to be implemented to 
assess the overall study objectives.  More detailed descriptions of the methodology will be 
provided in the Statistical Analysis Plan (SAP).  The SAP will be prepared and finalized before 
unblinding the subjects’ randomized treatment assignments. 
11.1. 
Sample Size 
The target total sample size for the study is 160 randomized with 1:1 allocation, 80 in each 
treatment group stratified by gender.  The sample size estimate was chosen to achieve more than 
90% power with significance level of 0.05 two-sided to reject the null hypothesis of no treatment 
difference for the primary endpoint of DVD. 
The power estimate was based on the estimated treatment means for DVD at Week 12 (the 4-
week (28-day) interval from Week 9 through Week 12) from the recently completed Phase 2b 
trial in this indication.  The OTO-104 and placebo treatment groups received a single dose of the 
study drug at Day 1.  In the 2b trial, the OTO-104 treatment group received the same dose as will 
be evaluated in this Phase 3 study.   A Poisson generalized linear regression model was used to 
estimate the mean number of DVD for the OTO-104 and placebo groups during the primary 
endpoint 4-week study interval.  The model included treatment group as a factor (categorical), 
and the lead-in period as a covariate.  An offset for the number of diary entries recorded for that 
4-week interval (interval from Week 9 through 12) was included for each subject to account for 
missing diary entries.  The number of lead-in period DVD was adjusted to 28 days.  The model 
was also adjusted for over-dispersion using the Pearson residuals as the scale factor.  The 
estimated mean number of DVD for the OTO-104 and placebo groups were 4.5 and 2.1, 
respectively with an estimated mean difference of (active – placebo) -2.4 days, adjusted for lead-
in period number of DVD.  The model residual variance was 4.79.  For the purpose of the sample 
size calculation the residual variance and true mean difference was considered as 5.0 and 2.2, 
respectively. 
11.2. 
Analysis Sets 
The following definitions will be used to derive the analysis sets for this study.    
Full Analysis Set (FAS):  The full analysis set will include all subjects who are randomized, 
receive study drug, have a baseline definitive vertigo measurement for the 4-week lead-in 
period and at least one 4-week definitive vertigo measurement post-baseline.   The primary 
analysis for the primary endpoint of DVD will be conducted using the FAS.  Subjects will be 
included in the treatment group to which they were randomized regardless of the actual study 
drug received. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
Completers Analysis Set:  The completers analysis set will include all subjects who are 
randomized, receive study drug, and have all baseline and post-baseline definitive vertigo 
measurements for each 4-week study interval.  Subjects will be included in the treatment 
group to which they were randomized regardless of the actual study drug received. 
Per Protocol Analysis Set:  The per protocol analysis set will include all subjects who are 
randomized, receive study drug, meet eligibility criteria, have no major protocol deviations,  
and have a baseline and at least one 4-week definitive vertigo measurement post-baseline.  
Subjects will be included in the treatment group of the actual study drug received. 
Intent-to-Treat Analysis Set (ITT):  The ITT analysis set will include all randomized 
subjects who receive study drug.  Subjects will be included in the treatment group to which 
they were randomized regardless of the actual study drug received. 
Safety Analysis Set:  The safety analysis set will include all subjects who receive study 
drug.  Subjects will be included in the treatment group according to the actual treatment 
received regardless of their randomized assignment.  When the ear is the unit of analysis, the 
safety analysis will categorize an ear by whether it was a treated or an untreated ear, 
irrespective of whether it was the affected ear. 
11.3. 
Description of Subgroups to be Analyzed 
Descriptive analyses will be performed for the primary efficacy endpoint for the following 
subgroups using the FAS with details provided in the Statistical Analysis Plan (SAP): 
 Subject Demographics 
 Gender 
 Race/Ethnicity 
 Age (categories:  18-30, 31-40, 41-60, > 61yrs.) 
 Baseline Disease Characteristics 
 Duration of Meniere’s Disease  
 Previous intratympanic steroid injection for Meniere’s Disease 
 Degree of hearing loss  
11.4. 
Subject Demographics, Baseline Disease Status, and Disposition 
Descriptive statistics for subject demographics, baseline disease status, and subject disposition 
will be provided.   
11.5. 
Efficacy Evaluations  
11.5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the number of definitive vertigo days (DVD) at Week 12 (the 4-
week (28-day) interval from Week 9 through Week 12).  A DVD is defined as each day the 
subject recorded a vertigo episode lasting at least 20 minutes and corresponds to a Vertigo Score 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
of 2 or more.  If multiple episodes occur on a given day, only the worst episode in terms of score 
should be recorded.   
11.5.2. 
Secondary Efficacy Endpoints 
Secondary Efficacy Endpoint: 
 The number of definitive vertigo days (DVD) at Week 8 [the 4-week (28-day) interval 
from Week 5 through Week 8] 
 The number of definitive vertigo days (DVD) at Week 4 [the 4-week (28-day) interval 
from Week 1 through Week 4] 
 The change from baseline in vertigo frequency (VF) during the 4-week study interval 
(Week 9 through Week 12), where vertigo frequency is defined as the proportion of days 
during the 4-week interval where a definitive vertigo episode was recorded divided by the 
number of non-missing diary entries for the relevant interval 
 The change from baseline with respect to severity of vertigo episodes as measured by the 
mean Vertigo Score during the 4-week study interval (Week 9 through Week 12 ) 
 The change from baseline in average daily count of vertigo episodes, during the 4-week 
study interval (Week 9 through Week 12) 
 Occurrence of Normal activity, Slight limitation, Moderate limitation, Sick at home, and 
Bed ridden events as a consequence of vertigo at Week 12  
 SF-36 at Week 12 
o Physical Health Summary Measure 
o Mental Health Summary Measure 
o 8 Scales 
11.5.3. 
Exploratory Efficacy Endpoints 
Exploratory Efficacy Endpoints are: 
 The change from baseline in vertigo frequency (VF) during each 4-week study interval 
(Week 1 through Week 4) and (Week 5 through Week 8), where vertigo frequency is 
defined as the proportion of days during the 4-week interval where a definitive vertigo 
episode was recorded divided by the number of non-missing diary entries for the relevant 
interval 
 The change from baseline with respect to severity of vertigo episodes as measured by the 
mean Vertigo Score during each 4-week study interval (Week 1 through Week 4) and 
(Week 5 through 8)  
 The change from baseline in average daily count of vertigo episodes, during each 4-week 
study interval (Week 1 through Week 4) and (Week 5 through Week 8) 
 Occurrence of Normal activity, Slight limitation, Moderate limitation, Sick at home, and 
Bed ridden events as a consequence of vertigo at Week 4 and Week 8 
 SF-36 at Weeks 4 and 8 
o Physical Health Summary Measure 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
o Mental Health Summary Measure 
o 8 Scales 
 Tinnitus Functional Index (TFI) at Weeks 4, 8, and 12 
Details regarding imputation of missing data, including items for questionnaires, will be 
provided in the Statistical Analysis Plan (SAP). 
11.5.4. 
Analytic Methods for Efficacy 
The primary efficacy endpoint is the number of DVD at Week 12 (the 4-week (28-day) interval 
from Week 9 through Week 12).  Poisson regression model will be used to estimate and compare 
the mean number of DVD for OTO-104 and placebo groups during the primary endpoint 4-week 
study interval.  The model will include treatment group (OTO-104 vs. placebo) and gender as 
factors (categorical), and the lead-in period as a covariate.  An offset for the number of diary 
entries recorded for that 4-week interval (interval from Week 9 through 12) will be included for 
each subject.  The number of lead-in period DVD will be adjusted to 28 days.  The model will 
also adjust for over-dispersion using Pearson residuals as the scale factor. 
The primary analysis population for the comparison of the primary endpoint between the 
treatment groups in this study is full analysis set (FAS).   Subjects will be included in the 
treatment group to which they were randomized regardless of the actual study drug received. 
The primary endpoint analysis also will be conducted using per-protocol, ITT, and completers 
analysis sets as sensitivity analyses.   
If a subject has no recorded diary data for the Vertigo Severity Score during Week 12 interval 
then an imputation method which will be specified in the SAP will be used. 
The secondary efficacy endpoints of number of DVD during 4-week study interval (Week 1 
through Week 4) and (Week 5 through Week 8) will be compared between the treatment groups 
separately using the same Poisson regression model specified for the primary endpoint. 
The secondary efficacy endpoint of change from baseline in vertigo frequency (VF) at Week 12 
(the 4-week interval from Week 9 through Week 12), will be compared between the treatment 
groups using analysis of covariance (ANCOVA).  The model will contain treatment group 
(OTO-104 vs. placebo) and gender as factors (categorical) and baseline vertigo frequency as a 
covariate.   
The secondary efficacy endpoint of change from baseline in severity of vertigo during 4-week 
study interval (Week 9 through Week 12) will be compared between the treatment groups using 
ANCOVA including treatment groups, gender, and severity score at baseline as a covariate. 
The secondary efficacy endpoint of change from baseline in average daily count of vertigo 
episodes, during 4-week study interval (Week 9 through Week 12) will be compared between the 
treatment groups using ANCOVA including treatment groups, gender, and average daily count of vertigo 
episode at baseline as a covariate.  
The secondary endpoint of occurrence of Normal activity, Slight limitation, Moderate limitation, 
Sick at home, and Bed ridden events as a consequence of vertigo at Week 12 will be compared 
between the treatment groups using Mantel-Haenszel Row Mean Scores stratified by gender. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
Alternative models will be pre-specified in the SAP should certain assumptions regarding data 
and models do not hold.  In addition, the SAP will include pre-specified data transformations 
should evaluation of the residuals suggest a data transformation is more suitable. 
If the primary endpoint comparison between the two treatment groups is statistically significant 
in favor of OTO-104 then a closed testing, gate-keeping procedure will be used to compare the 
following secondary efficacy endpoints sequentially:  
1. The number of DVD at Week 8 [the 4-week (28-day) interval from Week 5 through 
Week 8] 
2. The number of DVD at Week 4 [the 4-week (28-day) interval from Week 1 through 
Week 4] 
In this procedure if the first secondary endpoint comparison between the two treatment groups is 
statistically significant in favor of OTO-104 then the second secondary endpoint will be 
compared and tested.  If the comparison of the first secondary endpoint is not statistically 
significant in favor of OTO-104 then the reported p-value for the second secondary endpoint will 
be considered as a nominal p-value. 
The remaining secondary endpoints comparison will not follow the gate keeping procedure and 
therefore the reported p-values will be reported as nominal p-values.  This procedure controls the 
study-wise Type I error.  Since the study-wise error is maintained with the above procedure, 
there is no α penalty associated with it.  All efficacy hypothesis tests will be 2-sided and 
performed at α = 0.05 significance level. 
11.6. 
Safety Evaluations 
Safety endpoints to be examined include: 
 Vital Signs, Height and Weight Measurements 
 Clinical Laboratory Test 
 Tympanometry 
 Audiometry 
 Otoscopy  
 C-SSRS Assessment 
 Concomitant Medications 
 Adverse events  
Descriptive statistical tabulations will be presented for all subjects included in the Safety 
Analysis Set. 
11.6.1. 
Adverse Events 
The current version of Medical Dictionary for Regulatory Activities (MedDRA), as indicated in 
the Data Management Plan, will be used to code all AEs. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
The primary analysis of AEs will consider only treatment-emergent AEs, events occurring for 
the first time, or worsening during or after the first dose of study drug.  Subject incidence of 
TEAEs and SAEs will be tabulated by preferred terms and system organ class.  Severity and 
relationship to study drug will also be presented.  For summary tables, a subject who experiences 
the same coded event more than once is counted only one time for that coded event at the highest 
severity level.  AEs will be presented by descending order of frequency in MedDRA system 
organ class and preferred term. 
Subgroup analyses for age, race, and gender will also be examined provided a reasonable number 
of subjects in each subgroup are available for analysis.  Listings of all SAEs, AEs leading to 
study withdrawal, and deaths on-study will also be included.  Duration and outcome of each AE 
will be reported in subject listings.   
Adverse events occurring during the lead-in period prior to exposure to study drug will be 
reported in data listings.  Further details will be provided in the SAP. 
11.6.2. 
Vital Signs and Laboratory Parameters 
The analysis of vital signs and laboratory parameters will include descriptive statistics for the 
change from baseline to the endpoint visit, change from baseline for each visit (vital signs only).  
Where appropriate, analyses will also include shifts from baseline to the endpoint visit.  For 
laboratory values, the normal ranges will be used to determine the classifications. Values below 
the normal range will be classified as low, values above the normal range will be classified as 
high, and values within the normal range will be classified as normal. 
11.6.3. 
Otoscopic Examinations 
Observations recorded during the conduct of otoscopic exams will be descriptive in nature.  The 
number and percent of subjects presenting with each Otoscopic classification will be provided by 
treatment group and study visit.  Where relevant, the number and proportion of subjects with 
changes in their otoscopic classification from baseline to the endpoint visit will also be provided 
for each treatment group.   
11.6.4. 
Audiometry Assessments 
Descriptive summary statistics for audiometric assessments of air and bone conduction 
thresholds at each frequency will be provided by treatment group and study visit.  In addition, the 
PTA computed as the average air conduction threshold for the 500, 1000, and 2000 Hz will also 
be calculated.  
Air-Bone Gap assessments at each frequency for treatment group and study visit will be 
tabulated as the proportion of subjects with air minus bone conduction thresholds of:   
1. ≤ 10 dB or  
2. > 10 dB. 
All audiometry assessments will be tabulated separately for the treated and untreated ear. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
11.6.5. 
Tympanometry 
Shift tables representing the proportion of subjects with changes in their tympanogram from 
baseline to each post-baseline study visit will be calculated for each treatment group.  
Tympanogram changes will include both the type of tympanogram (A, B-small volume and/or 
normal, B-large volume, or C), as well as, whether the tympanogram was judged to be normal or 
abnormal. 
11.6.6. 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be administered at each visit using the appropriate version i.e. Baseline or 
Since Last Visit. Analysis of this scale will be performed on the Safety Analysis Set. 
11.6.6.1. Baseline Version 
The Baseline version of the C-SSRS will be administered at the Screening visit (Visit 1). This 
version of the scale captures both suicide ideation and suicide behavior (lifetime). There are 5 
suicidal ideation questions, each captured as yes/no for the subject’s lifetime. Additionally a 
sixth suicidal ideation variable will be created to indicate if there was any ideation, regardless of 
type. There are 4 suicidal behavior questions, each captured as yes/no for the subject’s lifetime. 
A fifth suicidal behavior variable will be created to capture if there was any suicidal behavior 
regardless of type. An additional question asks if suicidal behavior is present during the visit. All 
suicidal ideation and behavioral variables as outlined here will be tabulated overall and by 
treatment group. All C-SSRS data will be included in data listings. There is no inclusion or 
exclusion criterion associated with the Baseline C-SSRS score.  Subjects with a positive score 
should be referred to their primary care provider for follow-up. 
11.6.6.2. Since Last Visit Version 
The Since Last Visit version of the C-SSRS will be administered at each study visit after the 
Screening visit (Visit 1). The same overall individual variables for suicidal ideation and behavior 
will be assessed as in the Baseline version. In addition, overall suicidality (yes/no) will be 
defined as any subject having any suicidal ideation or behavior since the last visit. All suicidal 
ideation and behavior variables will be tabulated overall and by treatment group for each study 
visit. All C-SSRS data will be included in data listings. 
Any subject with an appearance of any new suicidal ideation or suicide behavior since Screening 
should be referred to their primary care provider for follow-up. 
If a subject has any post-Screening C-SSRS score of 1-3 for Ideation (i.e., a “yes” answer to 
Questions 1, 2, or 3) or a “yes” response to the Non-Suicidal Self-Injurious Behavior question) 
and the score is higher than the Screening C-SSRS score, then this assessment should be 
recorded as an AE. This information is reported as indicated in Section 9.2.1.  (Possible AE 
terms: Suicidal plans, Suicidal ideation, Suicidal tendency, Suicidal behavior, Suicidal intention, 
Suicidal depression, Active suicidal ideation, Passive suicidal ideation, Self-injurious behavior 
without suicidal intent). 
If a subject has any post-Screening C-SSRS score of 4 or 5 for Ideation (i.e., a “yes” answer to 
question 4 or 5) and/or any questions answered yes for Suicidal Behavior (with the exception of 
a “yes” response to the Non-Suicidal Self-Injurious Behavior question), and this was not 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
observed at Screening, then this assessment should be recorded as a Serious Adverse Event.  
This information is reported as indicated in Section 9.2.2. 
11.7. 
Handling of Missing Data, Subject Withdrawals, and Treatment 
Failures 
In addition to the primary analysis of the primary endpoint, if needed several sensitivity analyses 
will also be evaluated.  These analyses will be included in the SAP with appropriate details prior 
to unblinding the database. 
The SAP will include greater detail regarding the handling of missing data as well as the 
algorithms for scoring the SF-36, including the handling of missing questionnaire items. 
Every effort will be made to follow subjects for study observation and encourage compliance 
with study measurements to minimize the amount of missing data. 
Except for partial dates, safety data will not be imputed.  The imputation algorithm for partial 
dates will be defined in the SAP. 
11.8. 
Interim Analyses 
There are no formal interim analyses planned.  Blinded reviews of safety data will be conducted 
as described in Section 14.7; however, the review of such data is not intended to impact the study 
conduct unless there are safety concerns.  As such, it is expected that the trial will continue to its 
scheduled completion barring any unexpected safety issues. 
12. 
STUDY DRUG INFORMATION 
12.1. 
Physical Description of Study Drug(s) 
The investigational drug product administered to subjects in this study will be OTO-104 and 
placebo.  The OTO-104 final product suspension for dosing will be prepared from two separate 
components, OTO-104 Diluent (one vial needed) and OTO-104 Active (one vial needed). An 
appropriate volume of OTO-104 Diluent will be withdrawn and delivered into the OTO-104 
Active vial to achieve a visually homogeneous suspension of a target drug concentration of 60 
mg/mL.  Placebo will consist of the vehicle used to formulate OTO-104 and will be supplied 
from one vial (OTO-104 Diluent). 
The following drug supplies will be used in the study: 
Product 
Supplied as: 
OTO-104 
A kit containing: one vial of OTO-104 Active and one vial of OTO-104 
Diluent.  
Placebo  
A kit containing: one vial of OTO-104 Diluent.  
12.2. 
Directions for Use 
OTO-104 and placebo will be prepared by an unblinded QMP in a clean, secure location with a 
room temperature preferably at or below 23°C (73°F). The location will not be accessed by the 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
blinded personnel during study drug preparation.  Please refer to the Pharmacy Manual for 
detailed study drug preparation instructions. 
12.3. 
Packaging and Labeling 
12.3.1. 
Packaging 
All study drug kits will be labeled with information that will meet the applicable regulatory 
requirements.  
12.3.2. 
Labels and Labeling Instructions 
A label will be affixed to each kit box indicating kit number and storage instructions.  A label 
will be affixed to the OTO-104 Active and Diluent vials indicating contents and storage 
instructions.  A syringe blinding label will be provided to mask the syringe contents for injection. 
12.4. 
Management of Clinical Supplies  
The clinical supplies will be managed by the IWRS.  The IWRS will create shipment requests 
that will be generated based on inventory thresholds that are set for each site.  A shipment 
request will be generated by the IWRS system and sent to the clinical supplies vendor.  Upon 
shipment and receipt of the clinical trial material, the site personnel (e.g., pharmacy) will 
acknowledge the shipment using the IWRS and identify any damaged, missing, or unusable kits 
so they will not be dispensed. 
12.4.1. 
Storage of Kits 
All kits will be stored at -20°C (±5C), with allowable temperature excursions as high as 25°C 
for up to 72 hours.  All temperature excursions of the study drug must be documented in the 
study drug accountability log.  Any excursions within the allowable temperature range and 
conditions should be documented, but the study drug is still acceptable for use and dispensing to 
subjects.  If any excursions are outside of these conditions, the study drug should not be used to 
treat subjects.  If this occurs, the QMP preparing the study drug should immediately quarantine 
the product and report the kit(s) as unacceptable for dispensing to the IWRS to remove it from 
inventory. 
12.5. 
Drug Accountability 
It is the responsibility of the clinical investigator to ensure that all study drug received at the site 
will be inventoried and accounted for throughout the study and the result recorded on the drug 
accountability form maintained in the Pharmacy Manual.  The QMP will be instructed to return 
all original containers, whether empty or containing study drug, when instructed by the study 
monitor to return.  Study drug returned by the clinical site staff will be stored and disposed of 
according to the sponsor's instructions.  Drug accountability will be verified by the sponsor's 
unblinded study monitor during the course of the study.  Study drug will be stored in a limited 
access area or in a locked freezer under appropriate environmental conditions.  
The investigator agrees not to supply the study drug to any person other than sub-investigators, 
designated staff and the subjects participating in the study.  Study drug may not be relabeled or 
reassigned for use by other subjects except under special circumstances approved by Otonomy. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
The investigator will retain and store all original containers returned by the clinical site staff until 
these containers are inventoried by the study monitor.  Unless otherwise instructed by the 
sponsor, the investigator agrees at the end of the study to return all original containers, whether 
empty or containing study drug, to the sponsor as instructed by the study manager.  The 
investigator agrees to neither dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor. 
The sponsor will ensure proper disposition of original containers empty or full with returned or 
unused study drug.  Appropriate documentation will be maintained.  Permission may be granted 
for local disposition, with supporting documentation. 
13. 
ETHICAL ASPECTS 
13.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, the Declaration of Helsinki, as well as with the Note for Guidance on Good 
Clinical Practice (ICH/135/95), and applicable regulatory requirements.  These documents set 
forth that the informed consent of the subjects is an essential precondition for participation in the 
clinical study. 
13.2. 
Institutional Review Board (IRB) 
This trial will be undertaken only after full approval of the protocol and addenda has been 
obtained from a designated IRB and the sponsor has received a copy of this approval. 
The IRB must be informed of all subsequent protocol amendments issued by the sponsor. 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines. 
13.3. 
Informed Consent 
Each subject must give written consent (and sign other locally required documents) according to 
local requirements after the nature of the study has been fully explained.  The consent form must 
be signed prior to performance of any study-related activity.  The consent form that is used must 
be approved both by the sponsor and by the reviewing IRB.  The informed consent should be in 
accordance with the current revision of the Declaration of Helsinki, current International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and Otonomy 
policy. 
The investigator must explain to potential subjects the aims, methods, reasonably anticipated 
benefits and potential hazards of the trial and any discomfort it may entail.  Subjects will be 
informed that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time.  They will be told which alternative treatments are available if they refuse 
to take part, and that such refusal will not prejudice future treatment.  Finally, they will be told 
that their records may be examined by competent authorities and authorized persons, but that 
personal information will be treated as strictly confidential and will not be publicly available.  
Subjects must be given the opportunity to ask questions.  After this explanation and before entry 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
into the trial, consent should be appropriately recorded by means of the subject's dated signature.  
If a subject is unable to read, an impartial witness must be present during the entire informed 
consent discussion.  The signature of the impartial witness will certify the subject's consent.  The 
subject should receive a signed and dated copy of the informed consent form. 
14. 
ADMINISTRATIVE REQUIREMENTS 
14.1. 
Protocol Modifications 
All protocol amendments must be issued by the sponsor, signed and dated by the investigator, 
and should not be implemented without prior IRB approval, except where necessary to eliminate 
immediate hazards to the subjects or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g., change in monitor, change of telephone number).  
Responsibilities for reporting protocol amendments to any Regulatory Authority (if applicable) 
and/or IRB are further described in the Ethical Aspects section of the protocol. 
In situations requiring a departure from the protocol, the investigator or other physician in 
attendance will contact the site manager, Medical Monitor, or other appropriate sponsor 
representative by fax, email or telephone (see Sponsor Contact Information page).  If possible, 
this contact will be made before implementing any departure from protocol.  In all cases, contact 
with the sponsor must be made as soon as possible in order to discuss the situation and agree on 
an appropriate course of action.  The eCRF and source document will describe any departure 
from the protocol and the circumstances requiring it. 
14.2. 
Regulatory Documentation 
Documents that must be provided to the sponsor prior to study drug shipment are as follows: 
 Up-to-date curriculum vitae for each investigator and sub-investigator. 
 Signed and dated Investigator Agreement. 
 Applicable local regulatory documentation 
 A copy of the formal written notification to the investigator regarding approval of the 
protocol by an IRB that is in compliance with regulatory guidelines.  The written 
notification is to be signed by the chairman or authorized designee and must identify 
the specific protocol.  In cases where an IRB member has a known conflict of 
interest, abstention of that individual from voting should be documented; an 
investigator (or sub-investigator) may be a member of the IRB, but may not vote on 
any research in which he or she is involved. 
 Financial disclosure documentation for each investigator and sub-investigator. 
 Name and address of the IRB with a statement that it is organized and operates 
according to GCP and the applicable laws and regulations, and a current list of the 
IRB members.  The IRB Attestation form can be used to capture this information. 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
 A copy of the IRB approved informed consent form and other adjunctive materials 
(e.g., advertising) to be used in the study, including written documentation of IRB 
approval of these items. 
 Required financial agreement. 
In addition to the documents required prior to the study, other documentation may be required 
during the course of the study. 
14.3. 
Subject Identification Register 
The investigator agrees to complete a subject identification register, which will be used for the 
purpose of long-term follow-up, if needed.  This form will be treated as confidential, and will be 
filed by the investigator in the Trial Site File.  Otherwise, all reports and communications 
relating to the study will identify subjects by initials and assigned number only. 
14.4. 
Record Retention 
In compliance with the ICH/GCP guidelines the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, and all trial 
documents as specified in Essential Documents for the Conduct of a Clinical Trial and as 
specified by the applicable regulatory requirement(s).  The investigator/institution will take 
measures to prevent accidental or premature destruction of these documents.  Essential 
documents must be retained until at least two years after the last approval of a marketing 
application in an ICH region or at least two years have elapsed since the formal discontinuation 
of clinical development of the investigational product.  These documents will be retained for a 
longer period if required by the applicable regulatory requirements or by an agreement with the 
sponsor.  It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  If the responsible investigator retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person who will accept the responsibility.  The sponsor must be notified in 
writing of the name and address of the new custodian. 
14.5. 
Electronic Case Report Form  
Electronic Case Report Forms (eCRFs) will be completed for each subject.  Access for data entry 
will be provided to appropriate site staff members.  All data must be entered into the eCRFs in 
English and signed and dated electronically by the investigator.   
The eCRFs should be completed by investigator site staff at the time of the subject's visit, with 
the exception of results of tests performed outside the investigator's office, so that they always 
reflect the latest observations on the subjects participating in the trial.  
As the site staff enters data, discrepancies will be automatically generated within the Electronic 
Data Capture (EDC) system for the site staff to resolve immediately.  In addition, as a result of 
data review by the Sponsor or designee, manual queries will be raised electronically in the EDC 
system.  Queries may also be raised as a result of source data verification by the clinical monitor.  
All corrections will be made within the EDC system by the investigator or other authorized study 
site personnel.  The clinical monitor and data management teams will ensure appropriate 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
resolution of queries.  The investigator must authorize changes to the recorded safety and 
efficacy data.  
14.6. 
Termination 
An initiative for center closure or trial termination can be taken at any time either by the sponsor 
or by the investigator, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination.  Reasons for such action taken by the sponsor include, but 
are not limited to: 
 Successful completion of the trial at the center 
 The maximum number of eligible subjects for the trial has been enrolled 
 Failure of the investigator to comply with the protocol, the sponsor's procedures, or 
GCP guidelines 
 Safety concerns 
 Inadequate recruitment of subjects by the investigator 
 Business reasons 
14.7. 
Data and Safety Monitoring Plan 
The sponsor shall promptly review all information relevant to the safety of the drug obtained or 
otherwise received from foreign or domestic sources, including information derived from this 
clinical study and any other clinical study conducted with OTO-104.  In order to comply with 
this, the sponsor and CRO medical personnel will have the ability to review blinded safety 
information as it is entered and verified in the electronic data capture system (Section 14.5).  
Depending on the enrollment rate, all AEs in the ear and labyrinth disorders SOC will be 
reviewed at least every other month.  In addition, reasons for study discontinuation will be 
reviewed to see if any trends in study discontinuation are identified. 
Investigators are instructed to contact the Product Safety within 24 hours following the 
identification of a SAE (Section 9.2.2).  All SAEs will be reviewed by the sponsor and CRO 
medical personnel within 1-2 days after receipt whether or not the event was considered 
associated with study drug. The sponsor assumes responsibility for appropriate reporting to the 
regulatory authorities. The investigator assumes responsibility for reporting events to the IRB in 
accordance with the IRB requirements.  All SAE’s will be part of the CRO medical 
personnel/sponsor safety review. 
If, through this ongoing review, the sponsor determines that OTO-104 presents an unreasonable 
and significant risk to subjects, the sponsor shall take appropriate steps to suspend or discontinue 
the study and notify regulatory authorities, investigators and IRBs as appropriate. 
14.8. 
Monitoring 
The sponsor or its representatives will perform on-site monitoring visits as frequently as 
necessary based on site activity to review protocol compliance, compare eCRFs with individual 
subject’s medical records and clinic charts, and ensure that the study is being conducted 
according to pertinent regulatory requirements.  The dates of the visits will be recorded by the 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
monitor in a trial center visit log to be kept at the site.  The first post-initiation visit will usually 
be made as soon as possible after enrollment has begun.  At these visits, the monitor will 
compare the data entered onto the eCRFs with the hospital or clinic records (source documents).  
The review of medical records will be performed in a manner that ensures subject confidentiality 
is maintained.  At a minimum, source documentation must be available to substantiate proper 
informed consent procedures, adherence to protocol procedures, adequate reporting and follow-
up of AEs, administration of concomitant medication, drug receipt/dispensing/return records, and 
study drug administration information.  Specific items required as source documents will be 
reviewed with the investigator prior to the study.  Findings from this review of eCRFs and source 
documents will be discussed with the investigator.  The sponsor expects that, during monitoring 
visits, the investigator (and as appropriate, the study coordinator) will be available, the source 
documentation will be available, and a suitable environment will be provided for review of 
study-related documents. 
14.9. 
Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigator 
and associated personnel prior to study initiation, and periodic monitoring visits by the sponsor 
or its representatives.  Case report forms will be reviewed for accuracy and completeness in the 
EDC system database by the sponsor or its representatives during and after on-site monitoring 
visits, and any discrepancies will be resolved with the investigator or designees, as appropriate, 
and documented in the EDC system. 
14.10. 
On-Site Audits 
Representatives of the sponsor's Quality Assurance department may visit the site to carry out an 
audit of the study in compliance with regulatory guidelines and company policy.  Such audits 
will require access to all study records, including source documents, for inspection and 
comparison with the eCRFs. Subject privacy must, however, be respected.  Sufficient prior 
notice will be provided to allow the investigator to prepare properly for the audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing 
the results of this study in support of a Licensing Application.  The investigator should 
immediately notify the sponsor if they have been contacted by a regulatory agency concerning an 
upcoming inspection. 
14.11. 
Use of Information and Publication 
All information concerning OTO-104, Otonomy operations, patent application, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied by the 
sponsor to the investigator and not previously published, is considered confidential and remains 
the sole property of Otonomy.  The investigator agrees to use this information only to 
accomplish this study and will not use it for other purposes without the sponsor's written consent. 
The investigator understands that the information developed in the clinical study will be used by 
Otonomy in connection with the continued development of OTO-104, and thus may be disclosed 
as required to other clinical investigators or government regulatory agencies.  To permit the 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study. 
Any publication or other public presentation of results from this study requires prior review and 
written approval of Otonomy.  Draft abstracts, manuscripts, and materials for presentation at 
scientific meetings should be provided to the sponsor at least 30 working days prior to abstract or 
other relevant submission deadlines.  Authorship of publications resulting from this study will be 
based on generally accepted criteria for major medical journals. 
 


 
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Otonomy 104-201506 Protocol V2.0: 22 February 2016 
15. 
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Gates, GA, AM Verrall, JD Green, DL Tucci, and SA Telian. "Meniett Clinical Trial: Long-term 
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Gates, George A. "Clinimetrics of Meniere's Disease." The Laryngoscope, 2000: 8-11. 
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Meikle, MB, et al. "The Tinnitus Functional Index: Development of a New Clinical Measure for 
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Shea, John. "Classification of Meniere's Disease." The American Journal of Otology 14, no. 3 
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Thornton, A, and M Raffin. "Speech Discrimination Scores Modeled as a Binomial Variable." 
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Ware, JE, KK Snow, B Kosinski, and B Gandek. SF-36 Health Survey: Manual and 
Interpretation Guide. The Health Institute, New England Medical Center, 1993. 
Ware, John E. SF-36 Physical & Mental Health Summary Scales: A User's Manual. Quality 
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