Conditions: Subjective Tinnitus
Keywords: intratympanic injection IT injection gacyclidine tinnitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 153
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy of OTO-313 in subjects with unilateral tinnitus and to determine the safety and tolerability of OTO-313 in subjects with unilateral tinnitus.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: OTO-313 intervention 2: Placebo
Intervention descriptions: intervention 1: Single intratympanic injection intervention 2: Single intratympanic injection

Protocol document:
Prot_SAP_000.pdf: 
 
                                                    1 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 STUDY OF 
OTO-313 GIVEN AS A SINGLE INTRATYMPANIC INJECTION IN SUBJECTS WITH 
UNILATERAL SUBJECTIVE TINNITUS 
 
Protocol Number: OTO-313-201 
IND Number: 123556   
EudraCT Number: 2021-000229-28 
 
 
 
Sponsor Contact: 
 
 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
Version: 
3.0 
 
Date of Protocol: 
20 July 2021 
 
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, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
PROTOCOL AMENDMENT, VERSION 3.0 ................................................................................6 
CONTACT INFORMATION ..........................................................................................................7 
INVESTIGATOR AGREEMENT...................................................................................................8 
ABBREVIATIONS .........................................................................................................................9 
SYNOPSIS 10 
1. 
BACKGROUND ........................................................................................................17 
1.1. 
Intratympanic formulation of gacyclidine (OTO-313) ...............................................17 
1.2. 
Clinical studies with OTO-313 ...................................................................................18 
1.3. 
Rationale for current study .........................................................................................18 
2. 
OBJECTIVES .............................................................................................................19 
2.1. 
Primary objective ........................................................................................................19 
2.2. 
Secondary objectives ..................................................................................................19 
3. 
OVERVIEW OF STUDY DESIGN ...........................................................................19 
4. 
STUDY POPULATION .............................................................................................20 
4.1. 
General Considerations ...............................................................................................20 
4.2. 
Inclusion Criteria ........................................................................................................20 
4.3. 
Exclusion Criteria .......................................................................................................21 
5. 
RANDOMIZATION AND BLINDING ....................................................................23 
5.1. 
Overview .....................................................................................................................23 
5.2. 
Enrollment Procedures ................................................................................................23 
5.3. 
Blinding ......................................................................................................................24 
6. 
DOSAGE AND ADMINISTRATION .......................................................................24 
6.1. 
Investigational Product Administration ......................................................................24 
6.2. 
Compliance .................................................................................................................25 
7. 
PRIOR, CONCOMITANT AND SUBSEQUENT THERAPY .................................25 
7.1. 
Prohibited Therapy During the Study Period .............................................................25 
7.2. 
Other Medications and Therapies ...............................................................................26 
8. 
STUDY EVALUATIONS ..........................................................................................27 


 
                                                    4 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
8.1. 
Study Procedures by Visit ..........................................................................................27 
8.2. 
Medical History and Demographics ...........................................................................29 
8.3. 
Video for Subjects on Clinical Research Participation ...............................................29 
8.4. 
Efficacy Evaluations ...................................................................................................29 
8.5. 
Safety Evaluations ......................................................................................................31 
9. 
ADVERSE EVENT REPORTING ............................................................................34 
9.1. 
Adverse Event Classification Definitions ...................................................................35 
9.2. 
Monitoring of Adverse Events ....................................................................................37 
10. 
SUBJECT COMPLETION .........................................................................................39 
10.1. 
Completion .................................................................................................................39 
10.2. 
Study Discontinuation ................................................................................................39 
11. 
STATISTICAL METHODS .......................................................................................40 
11.1. 
Introduction .................................................................................................................40 
11.2. 
Analysis Sets ...............................................................................................................40 
11.3. 
Study Endpoints ..........................................................................................................40 
11.4. 
Statistical Analyses .....................................................................................................41 
11.5. 
Sample Size ................................................................................................................44 
12. 
INVESTIGATIONAL PRODUCT INFORMATION ...............................................44 
12.1. 
Physical Description of Investigational Product .........................................................44 
12.2. 
Directions for Use .......................................................................................................45 
12.3. 
Packaging and Labeling ..............................................................................................45 
12.4. 
Management of Clinical Supplies ...............................................................................45 
12.5. 
Investigational Product Accountability ......................................................................45 
13. 
ETHICAL ASPECTS .................................................................................................46 
13.1. 
Investigator Responsibilities .......................................................................................46 
13.2. 
Institutional Review Board (IRB) and Ethics Committee (EC) .................................46 
13.3. 
Informed Consent .......................................................................................................46 
14. 
ADMINISTRATIVE REQUIREMENTS ..................................................................47 
14.1. 
Protocol Modifications ...............................................................................................47 
14.2. 
Regulatory Documentation .........................................................................................47 
14.3. 
Record Retention ........................................................................................................48 
14.4. 
Electronic Case Report Form (eCRF) .........................................................................48 


 
                                                    5 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
14.5. 
Termination .................................................................................................................48 
14.6. 
Data and Safety Monitoring Plan ...............................................................................49 
14.7. 
Monitoring ..................................................................................................................50 
14.8. 
Data Quality Assurance ..............................................................................................50 
14.9. 
On-Site Audits ............................................................................................................50 
14.10. 
Publication Policy .......................................................................................................50 
15. 
REFERENCES ...........................................................................................................51 
 
LIST OF TABLES 
Table 1.  Time and Events Schedule ..............................................................................................15 
 
LIST OF FIGURES 
Figure 1.  Study Design Schematic ................................................................................................20 
 
 
 
 
 


 
                                                    6 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
PROTOCOL AMENDMENT, VERSION 3.0 
 
This protocol amendment serves to make the following change: 
 
Item No. 
Change 
Section 
1 
Added ongoing independent 
Safety Data Reviews to 
ensure appropriate safety and 
tolerability of OTO-313 and 
placebo. 
Synopsis 
Section 3 
Section 14.6.1 
 
 


 
                                                    7 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
CONTACT INFORMATION 
Study Medical Monitor: 
Name 
 
 
Title 
 
 
Mobile Phone Number 
 
 
E-Mail 
 
 
 
Back-up Medical Monitor: 
Name 
 
 
Title 
 
Mobile Phone Number 
 
 
Email 
 
 
 
Sponsor’s Trial Contact Personnel: 
Name 
 
 
 
Title 
 
 
 
 
Office Phone Number 
 
 
E-Mail 
 
 
 
Safety: 
 
 
USA 
 
 
Telephone 
 
 
Email 
 
 
Europe 
 
 
Email 
 
Telephone 
 
 
 
 
 
If any contact information needs to be changed during the study, this will be done by the 
Sponsor, with written notification to the Investigator, and will not require a protocol amendment. 


 
                                                    8 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
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 applicable local and national regulatory obligations. 
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 Otonomy, Inc. (hereafter, “the Sponsor”) 
or its representative and approved by the Institutional Review Board (IRB) or Ethics Committee 
(EC) responsible for this study and will fulfill all responsibilities for submitting pertinent 
information to the IRB or EC responsible for this study.  I will assure that each subject enrolled 
into the study, 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 study. 
I further agree not to originate or use the name of the Sponsor and/or OTO-313, 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 the Sponsor. 
 
 
 
 
 
 
 
Investigator's Signature 
 
Date 
Name of Investigator (typed or printed) 
 
 
 
 
 
 
 


 
                                                    9 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
ABBREVIATIONS 
AE 
Adverse Event 
ASHA 
American Speech and Language Hearing Association 
CRO 
Clinical Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP2B6 
Cytochrome P450 Isoform 2B6 
dB 
Decibel 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
Hz 
Hertz 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
N 
Number 
NMDA 
N-Methyl-D-Aspartic Acid 
NRS 
Numeric Rating Scale 
OTO-311 
Otonomy Investigational Product in poloxamer, Gacyclidine (Active Ingredient) 
OTO-313 
Otonomy Investigational Product in medium-chain triglycerides, Gacyclidine (Active 
Ingredient) 
PGIC 
Patient Global Impression of Change 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-12 
Short Form 12 Health Survey 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFI 
Tinnitus Functional Index 
TSCHQ 
Tinnitus Sample Case History Questionnaire 
 


 
                                                    10 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
SYNOPSIS 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-313 
 
Gacyclidine 
 
Protocol No.: OTO-313-201 
Title of Study: A randomized, double-blind, placebo-controlled Phase 2 study of OTO-313 given as a single 
intratympanic injection in subjects with unilateral subjective tinnitus 
Study Center(s):  Study will be conducted at approximately 55 sites globally 
Study Period: Approximately 20 months 
Phase of Development: 2 
Study Design: 
This is a randomized, double-blind, placebo-controlled Phase 2 study to evaluate the efficacy and safety of 
intratympanic OTO-313.  Approximately 140 eligible subjects with unilateral tinnitus will be randomly 
assigned 1:1 to either 0.32 mg OTO-313 or placebo for intratympanic injection to the affected (study) ear.  
Randomization is stratified by study site, duration of tinnitus (≥2 to ≤6 months and >6 to ≤ 12 months since 
onset) and by the average of the Tinnitus Functional Index (TFI) score at Screening and Baseline (≥32 to ≤53 
points, ≥54 to ≤100 points).  Subjects will be observed for efficacy and safety for 16 weeks following dosing.  
An independent Safety Review Committee will review accumulated individual subject safety data to ensure 
appropriate safety and tolerability of OTO-313 and placebo. 
Study Objectives: 
Primary: 
• 
To determine the efficacy of OTO-313 in subjects with unilateral tinnitus by comparing the 
proportion of subjects achieving response using the TFI relative to placebo. 
Secondary:  
• 
To determine the effect of OTO-313 across additional secondary measures of efficacy (tinnitus 
loudness and annoyance NRS, PGIC, SF-12) relative to placebo. 
• 
To determine the safety and tolerability of OTO-313 in subjects with unilateral tinnitus. 
Methods: 
This study will be conducted at approximately 55 sites globally.   
The duration for each subject will be approximately 18-22 weeks, including an up-to 4-week Screening period, 
a 2-week Lead-in assessment period, and a 16-week Follow-up period.   
After signing informed consent, subjects will complete the TFI at the Screening visit.  Subjects must have an 
overall TFI score of ≥ 32 at both Screening and Baseline visits for eligibility.  After Screening, potential 
subjects will begin a 2-week Lead-in assessment period.  During this time, subjects will enter daily tinnitus 
annoyance and tinnitus loudness severity into a diary using the appropriate Numeric Rating Scales (NRS) for 
each symptom.  Subjects must have completed the tinnitus diary on 5 of the last 7 days of the 14-day Lead-in 
period for eligibility. 
At the Baseline (Day 1) visit, approximately 140 eligible subjects will be randomized to OTO-313 or placebo 
using a 1:1 allocation ratio.  Randomization is stratified by study site, duration of tinnitus (≥2 to ≤6 months and 
>6 to ≤ 12 months since onset) and by the average of the TFI score at Screening and Baseline (≥32 to ≤53 points, 
≥54 to ≤100 points).    
After a single intratympanic injection with 0.32 mg OTO-313 or placebo to the affected (study) ear on Day 1, 
subjects will continue to record their tinnitus annoyance and tinnitus loudness on a daily basis using the diary 
during the 16-week Follow-up period.  Subjects will complete the TFI at study visits at Week 4, Week 8, Week 


 
                                                    11 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-313 
 
Gacyclidine 
 
12, and Week 16.  Additional efficacy and/or safety assessments will also be completed at Baseline (Day 1), 
Week 4, Week 8, Week 12, and Week 16 or upon early termination from the study.   
Safety Data Review 
An independent Safety Review Committee will review accumulated individual safety data for the first 25% (35 
subjects), 50% (70 subjects), and 75% (105 subjects) of subjects randomized and who have post-administration 
safety data.  Blinded safety data including adverse events, concomitant medications, medical history, clinical 
safety laboratory measurements, audiometry, otoscopy, tympanometry, and C-SSRS data will be reviewed.  The 
treatment assignment for an individual subject may be unblinded, if deemed necessary to enable medical care or 
study decision-making by the Safety Review Committee.  The decision to continue with the study will be based 
on recommendations from the Safety Review Committee on the clinical significance of any adverse events or 
suspected investigational product-related or procedure-related findings.  Additional information on the Safety 
Data Review and composition of the independent Safety Review Committee is provided in the Safety Review 
Committee Charter.   
Number of Subjects: 
The planned sample size for this study is approximately 140 subjects. 
Diagnosis and Main Criteria for Inclusion: 
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 75 years, inclusive. 
2. Subject has subjective unilateral tinnitus and is consistently aware of their tinnitus throughout much 
of the waking day. 
3. Subject’s tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing loss; acute 
hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast 
trauma, middle ear surgery, inner ear barotrauma); age-related hearing loss; resolved otitis media; 
ototoxic drug exposure.  
4. Subject’s self-reported duration of tinnitus is between 2 months and 12 months (≥60 to ≤365 days) 
prior to signing informed consent. 
5. Subject has an overall score of ≥ 32 on the TFI at both Screening and Baseline visits. 
6. Subject has audiometrically-defined normal hearing or up to moderately severe hearing impairment in 
the affected ear (study ear) as characterized by pure tone average of ≤ 70 dB at 1000, 2000, and 4000 
Hz at Screening. 
7. Subject is able to use the diary to complete their daily tinnitus ratings and has completed at least 5 of 
the last 7 days of diary entries during the 14-day Lead-in period.  
8. Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-menopausal 
(≥12 months since last menstrual period without an alternative medical cause)] must have a negative 
urine pregnancy test at Baseline.  Women of childbearing potential who are not abstinent from sex 
with male partners must use highly effective methods of contraception for the duration of the study 
including: established use of oral, injected, or implanted hormonal methods of contraception; or 
placement of an intrauterine device or intrauterine system.  Female subjects of childbearing potential 
must also refrain from egg donation or retrieval for the duration of the study.  
9. Male subjects (unless surgically sterile) who are not abstinent from sex with female partners of 
childbearing potential must agree to use an effective contraceptive method (as detailed for Inclusion 
Criteria 8) for the duration of the study.  Male subjects must refrain from sperm donation for the 


 
                                                    12 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-313 
 
Gacyclidine 
 
duration of the study. 
Note:  Abstinence (male or female subjects) is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.  Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable. 
10. Subject is willing to comply with the protocol and attend all study visits. 
11. Subject is able to provide written informed consent, including agreement to privacy language 
compliant with country and/or local requirements, after the scope and nature of the investigation have 
been explained, and before the initiation of any study-related procedures. 
 
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 pulsatile tinnitus, temporomandibular joint disease associated with tinnitus perception, 
tinnitus resulting from traumatic head or neck injury, or tinnitus resulting from a tumor or stroke. 
2. Subject has active middle ear disease (including but not limited to: chronic otitis media, acute otitis 
media, middle ear effusions, middle ear atelectasis, otosclerosis, Eustachian tube dysfunction, or 
cholesteatoma), Meniere’s disease as outlined by the American Academy of Otolaryngology-Head 
and Neck Surgery Equilibrium Committee in 2015 (Goebel 2016), concurrent vestibular pathology, or 
vestibular schwannoma. 
3. Subject has recently (< 1 month of Screening) initiated new treatment for tinnitus (e.g., noise or sound 
generators, hearing aids, behavioral therapy, non-conventional therapy, medications or over-the-
counter supplements, transcranial magnetic stimulation); only stable tinnitus treatments (i.e., initiated 
at least 1 month prior to Screening) are allowed during the study and no new treatments should be 
introduced during the course of the Study.  
4. Subject is not able to accurately localize, identify, and report their tinnitus per Investigator’s opinion. 
5. Subject has an abnormality of the tympanic membrane in the affected (study) ear that would increase 
the risk associated with intratympanic injection, including but not limited to monomeric tympanic 
membrane. 
6. Subject has evidence of perforation or lack of closure of the tympanic membrane, or a myringotomy 
tube in affected ear at Screening or Baseline visits. 
7. Subject is receiving any ongoing therapy known as potentially tinnitus-inducing (e.g., 
aminoglycosides, ototoxic chemotherapeutic drugs, high doses of intravenous loop diuretics, quinine, 
high doses of aspirin or other nonsteroidal anti-inflammatory drugs).  Usage of low doses of aspirin 
(e.g., daily doses of 81 mg) or low doses of other non-steroidal anti-inflammatory drugs for 
intermittent pain relief may be permitted at the Investigator’s discretion (see Section 7.1).  
8. Subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation on the C-SSRS 
administered at Screening or Baseline visits.  In addition, subjects deemed by the Investigator to be at 
significant risk of suicidal behavior should be excluded. 
9. Subject has severe or untreated depression or anxiety that, in the Investigator’s opinion, would likely 
reduce the safety of study participation.  Antidepressant and anti-anxiety medications are allowed 
only if administered at stable doses and frequency for ≥ 1 month prior to Screening with the 
expectation that the stable daily dose will continue for the duration of the study.    
10. Subject is pregnant, lactating, or undergoing fertility treatment. 


 
                                                    13 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-313 
 
Gacyclidine 
 
11. Subject has a history of serious substance abuse (e.g., cocaine, heroin) within 6 months prior to 
Screening.  
12. Subject has received or is receiving concomitant treatment with any other NMDA receptor antagonist 
(e.g., memantine, dextromethorphan) within 30 days prior to the Baseline visit.  Note, occasional use 
of dextromethorphan for cough suppression is allowed except between 7 days prior to Baseline and 7 
days after injection of the investigational product. 
13. Subject has a history of any use of intratympanic gentamicin in the affected ear. 
14. Subject has received systemic or intratympanic steroids (including dexamethasone) within 6 weeks 
prior to the Screening visit. 
15. Subject has previously participated in a clinical study with OTO-313 or OTO-311. 
16. Subject has used moderate or strong inducers of CYP2B6 (e.g., carbamazepine, efavirenz, rifampin, 
or ritonavir) within 30 days prior to Baseline visit.  
17. Subject has used an investigational drug or device within 30 days prior to Screening. 
18. Subject has other clinically significant illness, medical condition or medical history at Screening or 
Baseline that, in the Investigator’s opinion, would likely reduce the safety of study participation or 
compliance with study procedures. 
Test Product, Dose, and Mode of Administration: 
0.32 mg OTO-313 (solution of gacyclidine in medium-chain triglycerides), single (0.2 mL volume) 
intratympanic injection to the affected (study) ear 
Reference Product, Dose, and Mode of Administration: 
Placebo (100% medium-chain triglycerides), single (0.2 mL volume) intratympanic injection to the affected 
(study) ear  
Duration of Treatment:   
Single (0.2 mL volume) intratympanic injection to the affected (study) ear  
Endpoints for Evaluation: 
Primary Efficacy Endpoint: 
• 
Percentage of responders with response defined as a ≥13-point reduction from baseline on the TFI 
total score at both Weeks 4 and 8 
Secondary Efficacy Endpoints: 
• 
Change from Baseline in the NRS ratings of tinnitus annoyance 
• 
Change from Baseline in the NRS ratings of tinnitus loudness 
• 
Change from Baseline in TFI total score 
• 
Change from Baseline in TFI subscale scores (Intrusiveness, Sense of Control, Cognitive, Sleep, 
Auditory, Relaxation, Quality of Life, Emotional) 
• 
PGIC score 
• 
Change from Baseline in SF-12 scores 
Safety Endpoints: 
• 
Incidence of treatment-emergent adverse events 
• 
Change from Baseline in tympanometry 


 
                                                    14 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
NAME OF SPONSOR/COMPANY: 
 
Otonomy, Inc. 
 
NAME OF FINISHED PRODUCT: 
 
NAME OF ACTIVE INGREDIENT(S):     
 
OTO-313 
 
Gacyclidine 
 
• 
Change from Baseline in otoscopy 
• 
Change from Baseline in audiometry 
• 
Change from Baseline in suicidal ideation or behavior 
• 
Incidence of concomitant medications 
• 
Change from baseline in vital signs and weight 
Statistical Methods: 
Sample Size Justification: 
The primary endpoint is the percentage of responders, where response is defined as achieving at least a 
13-point reduction from baseline in the TFI total score at both Weeks 4 and 8.  It was observed from the 
previous study that the response rate for OTO-313 (0.32 mg) was 43%, and 13% for placebo.  Based on these 
results, the assumed rate of response for OTO-313 is 43% and 18% for placebo, which is the 13% observed 
response rate in previous study plus 5% inflation for potential placebo response.  
Assuming a 2-sided test and level of significance of 0.05, 60 subjects in the placebo group and 60 subjects in 
the OTO-313 group will provide approximately 85% power to detect a treatment difference in favor of 
OTO-313.  It is also assumed that an observed discontinuation rate of 15% will be observed, hence the total 
sample size for this 2-arm study is planned to be 140 subjects, 70 subjects per arm.  These sample size 
calculations were conducted using EASTv6.5 software with a test for a difference in proportions between two 
groups. 
Analyses: 
The primary endpoint, analyzed using the common risk difference between treatment groups, will be tested 
using a Mantel-Haenszel test controlling for duration of tinnitus and baseline TFI score at Week 8. The 95% 
confidence intervals (CI) around the common risk difference will be provided. The risk difference in responses 
rates will also be compared between treatment groups at Weeks 12 and 16 as secondary analyses. 
The change from baseline in NRS Loudness, NRS Annoyance, TFI total score, each TFI subscale score, and 
SF-12 will each be analyzed using a linear mixed-effects model with treatment, study day, treatment-by-study 
day interaction, gender, and tinnitus duration as fixed effects.  The unstructured covariance model will be used. 
Least-square adjusted means, the estimated difference in adjusted means between treatment groups and 
associated 95% CIs will be provided.  Comparisons between treatment groups will be conducted at each post-
baseline visit as secondary analyses. 
The results of the PGIC will be analyzed using a Cochrane-Mantel-Haenszel mean score test controlling for 
baseline TFI score and duration of tinnitus.  This will be done to compare OTO-313 with placebo. 
Adverse events, audiometry, tympanometry, otoscopic, and C-SSRS safety endpoints will be summarized 
descriptively.  Changes in vital signs and laboratory parameters will be summarized descriptively. 
 


 
                                                                                                              15 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
Table 1.  Time and Events Schedule 
Procedure 
Screening 
Lead-In 
Baseline1 / 
IP Dose 
Follow Up Period 
Visit 1 
- 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / ET2 
- 
- 
- 
Week 4 
Week 8 
Week 12 
Week 16 
Up to 28 days 
prior to Lead-In 
Day -14 to Day -1 
 (+5 days)3 
Day 11 
Day 29  
(±2 days) 
Day 57  
(± 3 days) 
Day 85  
(± 4 days) 
Day 113  
(± 4 days) 
Informed consent  
X 
  
  
  
  
  
  
Clinical study participation video4 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
  
X 
  
  
  
  
Medical history5 
X 
  
X 
  
  
  
  
Prior/concomitant medications  
X 
  
  
Adverse event monitoring 
  
 
  
Vital signs measurements6 
X 
 
X 
X 
X 
X 
X 
Height and weight7 
X 
 
  
  
  
  
X 
Pregnancy test8 
X 
 
X 
  
  
  
X 
Clinical laboratory tests9 
X 
 
X 
  
X 
  
  
TFI 
X 
 
X 
X 
X 
X 
X 
PGIC 
 
 
  
X 
X 
X 
X 
SF-12 
 
 
X 
  
X 
  
X 
Otoscopy  
X 
 
X 
X 
X 
X 
X 
Tympanometry 
X 
 
X 
X 
X 
X 
X 
Audiometry  
X 
 
X 
X 
X 
X 
X 
C-SSRS assessment10 
X 
 
X 
X 
X 
X 
X 
NRS compliance review11 
 
X 
X 
X 
X 
X 
X 
Randomization12 
 
 
X 
  
  
  
  
Administer investigational product13 
 
 
X 
  
  
  
  
 


 
                                                                                                              16 
 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
1 Baseline assessments on Day 1 are to be performed before administration of investigational product.  Results from the concomitant medications review, urine 
pregnancy test (for females of childbearing potential), and C-SSRS (“Since Last Visit” version) must be available and reviewed by the Investigator to confirm 
the subject’s eligibility before randomization. 
2 End-of-study procedures will be performed at Visit 6 (Week 16) or upon early termination (ET) from the study.  If a subject terminates early prior to Week 8, a 
clinical laboratory test should be performed. 
3 The +5 days window is allowed for purposes of scheduling the Baseline visit and is not included in determination of NRS diary compliance. 
4 Subjects view a short educational video on clinical research participation entitled “What it Means to Take Part in Clinical Research Studies”.  Viewing of the 
video will be completed after informed consent but prior to any efficacy assessments (e.g., TFI) during the screening visit. 
5 Medical history to include information on demographics and completion of the modified Tinnitus Sample Case History Questionnaire (TSCHQ) to capture 
tinnitus and related medical history information.  Changes in medical history since the Screening visit will be recorded at the Baseline visit.  In addition, if 
subject has any untoward medical occurrences that would meet the definition of a serious event (see Section 9.1 Serious Adverse Event) prior to investigational 
product administration, this information is to be recorded in medical history and immediately discussed with the Medical Monitor to evaluate whether the 
subject should be excluded from randomization/treatment.  Serious medical events that occur prior to investigational product administration should be recorded 
on the Pre-Dose Serious Medical Occurrences report form.  Medical history, conditions, and procedures that occurred prior to Screening, including COVID-19 
infection, may be added throughout the study (if identified later). 
6 Vital signs measurements include systolic and diastolic blood pressure, body temperature, respiratory rate, and pulse rate.  
7 Only weight is to be measured at Week 16. 
8 Female subjects of childbearing potential will have a serum pregnancy test at Screening, a urine pregnancy test at Baseline (prior to randomization), and a urine 
pregnancy test at Week 16.  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 based on urine test after dosing with investigational product, a confirmatory serum pregnancy test will be performed locally, and the 
subject should complete the 16-week follow-up period (See Section 9.2.3).  Only the Screening serum pregnancy tests will be analyzed by a central laboratory. 
Urine pregnancy tests and confirmatory serum pregnancy test during follow up, is to be conducted locally.  Serum pregnancy test results from Screening, as 
well as the urine pregnancy test at Baseline prior to randomization, must be included in eligibility assessment. 
9 Clinical laboratory tests include hematology, clinical chemistry, and urinalysis and will be analyzed by a central laboratory.  Subjects will be randomized using 
laboratory results from Screening.  Laboratory results from the Baseline visit are not required for randomization. 
10 Columbia-Suicide Severity Rating Scale “Baseline” version will be used at the Screening visit and the “Since Last Visit version” will be used at all subsequent 
visits. 
11 Once the subject has met the inclusion/exclusion criteria at Screening, the subject will enter a 2-week Lead-in assessment period.  Subjects may be entered into 
the Lead-in period before laboratory results from Screening are available.  During this period, the subject will record their tinnitus annoyance and tinnitus 
loudness each day using the NRS diary.  Subjects must complete their tinnitus ratings for at least 5 of the last 7 days of the 14-day Lead-in testing to be eligible 
for randomization.  Subjects will be able to record missed diary entries for 1 day after a missed entry.  Reminder alerts to subjects and site staff will help to 
ensure compliance.  After randomization, subjects will continue to record their tinnitus annoyance and tinnitus loudness for the 16-week Follow-up period.  
Review of diary compliance will be conducted throughout the Lead-in and Follow-up periods and additional instructions and training will be provided to ensure 
compliance.   
12 Randomization must occur prior to administration of investigational product.  Study sites will execute each randomization after a subject has met all 
prerequisites for randomization. 
13Investigational product (OTO-313 or placebo) is administered by intratympanic injection to the affected (study) ear.  The subject should remain recumbent for 
at least 15 minutes after the injection. 
 
 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
1. 
BACKGROUND 
Tinnitus or “ringing in the ears”, is defined as a perception of sounds without a correlated 
external auditory stimulus.  Tinnitus is a common disorder with prevalence estimates ranging 
from 11.9% to 30.3% across various countries with prevalence generally increasing with age 
(McCormack et al 2016).  Exposure to recreational, firearm, and occupational noise increases the 
odds of experiencing tinnitus (Shargorodsky et al 2010), and tinnitus is the leading service-
related cause of disability among US military veterans (US Veterans Benefits Administration).  
Tinnitus is often a long-term and persistent condition with recent survey results finding that 56% 
of individuals with tinnitus had symptoms longer than 5 years and 36% had nearly constant 
symptoms (Bhatt et al 2016).   
Tinnitus can be distressful, negatively impacting quality of life (Nondahl et al 2007) as affected 
patients report associated symptoms of insomnia, anxiety, depression, and cognitive difficulties 
(Schecklmann et al 2015; Zeman et al 2014; Bhatt et al 2017; Tegg-Quinn et al 2016).  While 
some habituate to the sound, approximately 1 in 4 people with tinnitus believe it to be a moderate 
to severe problem and nearly half will seek medical treatment (Bhatt et al 2016).  At present, 
however, there is no cure or approved medication.  Current management of tinnitus largely 
focuses on modulation of the patient’s attention and responses to the sensation.  Approaches 
include education and counseling, sound therapy, use of hearing aids, and cognitive behavioral 
therapy (Tunkel et al 2014).    
Causes and conditions associated with tinnitus include sensorineural hearing loss, acute hearing 
loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast 
trauma, middle ear surgery, inner ear barotrauma), age-related hearing loss, Meniere’s disease, 
otitis media, ototoxic drug use, and head and neck injuries (Langguth et al 2013).  In many cases, 
tinnitus arises as a consequence of cochlear insults and therefore one pharmacotherapy approach 
to the treatment of tinnitus is directed at normalizing altered neural activity within the cochlea.  
Excessive activation of NMDA receptors at the level of the inner hair cell synapses with 
subsequent deafferentation may be a key mechanism of abnormal sensory signaling in tinnitus 
(Bing et al. 2015).  Intratympanic administration of NMDA receptor antagonists in animal 
models of acute tinnitus was shown to reduce deafferentation and the decline of auditory 
brainstem response Wave I amplitude (Bing et al. 2015) and to reduce “tinnitus-like” behavior 
(Guitton et al. 2003).  These findings suggest that activation of cochlear NMDA receptors may 
be an important mechanism for generating tinnitus and that intratympanic NMDA receptor 
antagonists may have potential as a local cochlear treatment for tinnitus.  
1.1. 
Intratympanic formulation of gacyclidine (OTO-313)  
Intratympanic administration permits deposition of drugs over the round window membrane.  
This enables access to the inner ear for more localized delivery to the cochlea and less systemic 
drug exposure (Bird et al. 2007).  Gacyclidine, the active agent in OTO-313, is a noncompetitive 
NMDA-receptor antagonist that is considered to have greater potency, faster on-rate, and slower 
off-receptor rate than other NMDA-receptor antagonists (Mitha and Maynard 2001; Piu et al 
2018).  Gacyclidine was originally formulated as OTO-311, 
 
 to provide sustained exposure of 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
gacyclidine to cochlear tissues following a single intratympanic administration.  Additional 
preclinical studies showed that gacyclidine formulated 
 (OTO-313) provided greater and longer lasting inner ear exposures of 
gacyclidine compared to OTO-311 when injected intratympanically.      
1.2. 
Clinical studies with OTO-313 
Gacyclidine was originally studied using intravenous administration in clinical studies in spinal 
cord and brain trauma patients and no concerning safety issues were identified.  Gacyclidine has 
also been administered to the otic compartment in an open label study in patients with chronic 
tinnitus.  The drug was generally safe and well-tolerated and reduced subjective tinnitus ratings 
in 4 of the 6 subjects evaluated (Wenzel, et al. 2010).  In a completed Phase 1 study in healthy 
subjects (Study 311-201501), OTO-311 (the earlier formulation of gacyclidine), placebo or sham 
was administered as a single intratympanic injection.  All OTO-311 dose levels tested (0.15 mg, 
0.3 mg, and 0.6 mg) were well-tolerated and no safety concerns were identified.   
Study 313-201901 was a randomized, double-blind, placebo-controlled Phase 1/2 study which 
evaluated the safety and exploratory efficacy of a single intratympanic administration of 
OTO-313 in subjects with subjective tinnitus.  An initial safety and plasma PK cohort of 8 
subjects dosed with 0.11 mg OTO-313 or placebo (3:1) demonstrated that this dose level was 
well-tolerated with no safety concerns.  An exploratory efficacy cohort of 35 subjects with 
unilateral tinnitus of moderate to severe intensity (score of ≥ 25 on the Tinnitus Functional Index 
[TFI]) and a duration of tinnitus of 1 to 6 months received a single intratympanic injection of 
0.32 mg OTO-313 or placebo (1:1).  0.32 mg OTO-313 was well-tolerated with a lower 
incidence of adverse events than placebo.   
In the exploratory efficacy cohort, the mean TFI reduction from baseline trended in favor of 
OTO-313 at each timepoint (Day 15: -9.3 points OTO-313 vs -4.1 points Placebo; Day 29: -9.4 
points OTO-313 vs -6.6 points Placebo; Day 57: -12.9 points OTO-313 vs -4.3 points Placebo).  
A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of 
OTO-313 subjects at both Day 29 (Week 4) and Day 57 (Week 8) versus 13% (2/16) of Placebo 
subjects (ad hoc 1-sided p-value < 0.05).  The higher responder rate for OTO-313 versus Placebo 
was maintained for all TFI improvement levels of 15, 20, 25 and 30 points.  Treatment with 
OTO-313 also led to reduction in the daily ratings of tinnitus loudness and annoyance, as well as 
improved PGIC scores.  Among responders, strong correlation was observed between the various 
endpoints in favor of OTO-313.  As anticipated, plasma concentrations of gacyclidine were 
below the limit of assay quantitation (≤ 0.1 ng/mL) confirming limited systemic exposure.  These 
results suggest that a single intratympanic injection of 0.32 mg OTO-313 was well-tolerated and 
exhibited preliminary efficacy in subjects with unilateral tinnitus.  
1.3. 
Rationale for current study 
 
The purpose of this Phase 2 study, Study OTO-313-201, is to investigate the efficacy and safety 
of 0.32 mg OTO-313 administered by intratympanic injection in subjects with unilateral tinnitus. 
The 0.32 mg OTO-313 dose level is expected to be safe and well-tolerated, based on Study 313-
201901 in subjects with unilateral tinnitus.  In addition, preclinical data suggest that this dose 
level of OTO-313 will produce sufficient inner ear exposures of gacyclidine in humans.  The 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
lipid formulation of OTO-313 is expected to maintain sustained exposures to the cochlea over 
time (at least 7 to 14 days in preclinical testing).  Taken together, the preclinical and clinical data 
support the evaluation of 0.32 mg OTO-313 in this Phase 2 study in subjects with unilateral 
tinnitus. 
The preclinical and clinical data obtained to date are described in more detail in the 
Investigator’s Brochure. 
2. 
OBJECTIVES 
2.1. 
Primary objective 
 
• To determine the efficacy of OTO-313 in subjects with unilateral tinnitus by comparing 
the proportion of subjects achieving response using the TFI relative to placebo. 
2.2. 
Secondary objectives  
 
• To determine the effect of OTO-313 across additional secondary measures of efficacy 
(tinnitus loudness and annoyance NRS, PGIC, SF-12) relative to placebo. 
• To determine the safety and tolerability of OTO-313 in subjects with unilateral tinnitus. 
3. 
OVERVIEW OF STUDY DESIGN 
This study will be conducted at approximately 55 sites globally. 
The duration for each subject will be approximately 18-22 weeks, including an up-to 4-week 
Screening period, a 2-week Lead-in assessment period, and a 16-week Follow-up period.   
After signing informed consent, subjects will complete the TFI at the Screening visit.  Subjects 
must have an overall score of ≥ 32 on the TFI at both Screening and Baseline.  After Screening, 
potential subjects will begin a 2-week Lead-in assessment period.  During this time, subjects will 
enter daily tinnitus annoyance and tinnitus loudness severity into a diary using the appropriate 
Numeric Rating Scales (NRS) for each symptom.  Subjects must have completed the tinnitus 
diary on at least 5 of the last 7 days of the 14-day Lead-in period for eligibility.  The additional 
+5 days of the Lead-in period will not be used for eligibility. 
At the Baseline (Day 1) visit, approximately 140 eligible subjects will be randomized to OTO-
313 or placebo using a 1:1 allocation ratio.  Randomization is stratified by study site, duration of 
tinnitus (≥2 to ≤6 months and >6 to ≤ 12 months since onset) and by the average of the TFI score 
at Screening and Baseline (≥32 to ≤53 points, ≥54 to ≤100 points).    
After a single intratympanic injection with 0.32 mg OTO-313 or placebo to the affected (study) 
ear on Day 1, subjects will continue to record their tinnitus annoyance and tinnitus loudness on a 
daily basis using the diary during the 16-week Follow-up period.  Subjects will complete the TFI 
at study visits at Week 4, Week 8, Week 12, and Week 16.  Additional efficacy and/or safety 
assessments will also be completed at Baseline (Day 1), Week 4, Week 8, Week 12, and Week 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
16 or upon early termination from the study.  An independent Safety Review Committee will 
review accumulated individual subject safety data to ensure appropriate safety and tolerability of 
OTO-313 or placebo. 
 
Figure 1.  Study Design Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
STUDY POPULATION 
4.1. 
General Considerations 
Approximately 140 subjects will be enrolled at approximately 55 sites globally.  Subjects will be 
eligible if they meet all of the following inclusion criteria and none of the exclusion criteria. 
4.2. 
Inclusion Criteria 
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 75 years, inclusive. 
2. Subject has subjective unilateral tinnitus and is consistently aware of their tinnitus 
throughout much of the waking day. 
3. Subject’s tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing 
loss; acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury 
(acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma); age-
related hearing loss; resolved otitis media; ototoxic drug exposure.  
SCREENING  
Up to 28 days prior to Lead-in 
LEAD-IN PERIOD 
2 weeks 
Day -14 to Day -1 
BASELINE / IP ADMINISTRATION 
Day 1 
FOLLOW-UP EVALUATIONS  
Week 4, Week 8, and Week 12 
FOLLOW-UP AND END-OF-STUDY EVALUATIONS 
Week 16 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
4. Subject’s self-reported duration of tinnitus is between 2 months and 12 months (≥60 to 
≤365 days) prior to signing informed consent. 
5. Subject has an overall score of ≥ 32 on the TFI at both Screening and Baseline visits. 
6. Subject has audiometrically-defined normal hearing or up to moderately severe hearing 
impairment in the affected ear (study ear) as characterized by pure tone average of ≤ 70 
dB at 1000, 2000, and 4000 Hz at Screening. 
7. Subject is able to use the diary to complete their daily tinnitus ratings and has completed 
at least 5 of the last 7 days of diary entries during the 14-day Lead-in period.  
8. Female subjects of childbearing potential [i.e., not surgically sterile and/or not post-
menopausal (≥12 months since last menstrual period without an alternative medical 
cause)] must have a negative urine pregnancy test at Baseline.  Women of childbearing 
potential who are not abstinent from sex with male partners must use highly effective 
methods of contraception for the duration of the study including: established use of oral, 
injected, or implanted hormonal methods of contraception; or placement of an 
intrauterine device or intrauterine system.  Female subjects of childbearing potential must 
also refrain from egg donation or retrieval for the duration of the study.  
9. Male subjects (unless surgically sterile) who are not abstinent from sex with female 
partners of childbearing potential must agree to use an effective contraceptive method (as 
detailed for Inclusion Criteria 8) for the duration of the study.  Male subjects must refrain 
from sperm donation for the duration of the study. 
Note:  Abstinence (male or female subjects) is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.  Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable. 
10. Subject is willing to comply with the protocol and attend all study visits. 
11. Subject is able to provide written informed consent, including agreement to privacy 
language compliant with country and/or local requirements, after the scope and nature of 
the investigation have been explained, and before the initiation of any study-related 
procedures. 
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 pulsatile tinnitus, temporomandibular joint disease associated with tinnitus 
perception, tinnitus resulting from traumatic head or neck injury, or tinnitus resulting 
from a tumor or stroke. 
2. Subject has active middle ear disease (including but not limited to: chronic otitis media, 
acute otitis media, middle ear effusions, middle ear atelectasis, otosclerosis, Eustachian 
tube dysfunction, or cholesteatoma), Meniere’s disease as outlined by the American 
Academy of Otolaryngology-Head and Neck Surgery Equilibrium Committee in 2015 
(Goebel 2016), concurrent vestibular pathology, or vestibular schwannoma. 
3. Subject has recently (< 1 month of Screening) initiated new treatment for tinnitus (e.g., 
noise or sound generators, hearing aids, behavioral therapy, non-conventional therapy, 
medications or over-the-counter supplements, transcranial magnetic stimulation); only 
stable tinnitus treatments (i.e., initiated at least 1 month prior to Screening) are allowed 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
during the study and no new treatments should be introduced during the course of the 
Study.  
4. Subject is not able to accurately localize, identify, and report their tinnitus per 
Investigator’s opinion. 
5. Subject has an abnormality of the tympanic membrane in the affected (study) ear that 
would increase the risk associated with intratympanic injection, including but not limited 
to monomeric tympanic membrane. 
6. Subject has evidence of perforation or lack of closure of the tympanic membrane, or a 
myringotomy tube in affected ear at Screening or Baseline visits. 
7. Subject is receiving any ongoing therapy known as potentially tinnitus-inducing (e.g., 
aminoglycosides, ototoxic chemotherapeutic drugs, high doses of intravenous loop 
diuretics, quinine, high doses of aspirin or other nonsteroidal anti-inflammatory drugs).  
Usage of low doses of aspirin (e.g., daily doses of 81 mg) or low doses of other non-
steroidal anti-inflammatory drugs for intermittent pain relief may be permitted at the 
Investigator’s discretion (see Section 7.1).  
8. Subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation on the  
C-SSRS administered at Screening or Baseline visits.  In addition, subjects deemed by 
the Investigator to be at significant risk of suicidal behavior should be excluded. 
9. Subject has severe or untreated depression or anxiety that, in the Investigator’s opinion, 
would likely reduce the safety of study participation.  Antidepressant and anti-anxiety 
medications are allowed only if administered at stable doses and frequency for ≥ 1 month 
prior to Screening with the expectation that the stable daily dose will continue for the 
duration of the study.    
10. Subject is pregnant, lactating, or undergoing fertility treatment. 
11. Subject has a history of serious substance abuse (e.g., cocaine, heroin) within 6 months 
prior to Screening.  
12. Subject has received or is receiving concomitant treatment with any other NMDA 
receptor antagonist (e.g., memantine, dextromethorphan) within 30 days prior to the 
Baseline visit.  Note, occasional use of dextromethorphan for cough suppression is 
allowed except between 7 days prior to Baseline and 7 days after injection of the 
investigational product. 
13. Subject has a history of any use of intratympanic gentamicin in the affected ear. 
14. Subject has received systemic or intratympanic steroids (including dexamethasone) 
within 6 weeks prior to the Screening visit. 
15. Subject has previously participated in a clinical study with OTO-313 or OTO-311. 
16. Subject has used moderate or strong inducers of CYP2B6 (e.g., carbamazepine, 
efavirenz, rifampin, or ritonavir) within 30 days prior to Baseline visit.  
17. Subject has used an investigational drug or device within 30 days prior to Screening. 
18. Subject has other clinically significant illness, medical condition or medical history at 
Screening or Baseline that, in the Investigator’s opinion, would likely reduce the safety of 
study participation or compliance with study procedures. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
5. 
RANDOMIZATION AND BLINDING 
5.1. 
Overview 
Approximately 140 eligible subjects will be assigned randomly to 0.32 mg OTO-313 or placebo 
using a 1:1 allocation ratio, based on a computer-generated randomization schedule. 
• 0.32 mg OTO-313; single (0.2 mL volume) intratympanic injection to the affected (study) 
ear 
• Placebo (vehicle); single (0.2 mL volume) intratympanic injection to the affected (study) 
ear 
OTO-313 and placebo solutions are identical in appearance. 
5.2. 
Enrollment Procedures 
5.2.1. 
Assignment of Subject Identification Numbers 
At the Screening visit (Visit 1), subjects who have signed the informed consent will be assigned 
a sequential subject identification number by the site.  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.  Any subject that 
is re-screened will be assigned a new subject identification number.  Subjects will be considered 
enrolled into the study once they complete the informed consent process. 
The subject identification number will consist of 9 digits separated by 2 hyphens (e.g., 201-
XXX-YYY).  The first 3 digits are the study number (201) followed by a hyphen.  The second 3 
digits are the site number followed by a hyphen.  The final 3 digits are the subject number. 
5.2.2. 
Treatment Assignment 
After a subject has met all prerequisites for randomization on Day 1 (Baseline/Visit 2), study 
sites will execute each randomization via the Interactive Response Technology (IRT) 
randomization system.  All study site personnel are blinded to treatment assignment.  Study sites 
will receive a randomization notification indicating the kit number (packaged investigational 
product), and the date and time of randomization for each subject.  Once assigned, kit numbers 
cannot be re-assigned. 
Study sites will provide the information contained in the IRT randomization notification to the 
person responsible for preparation of the syringe containing investigational product (OTO-313 or 
placebo).  The unique kit number provided by IRT will correspond to a kit of packaged 
investigational product labeled with the identical kit number.  The syringe will be prepared from 
the contents of the investigational product package corresponding to the IRT kit number 
according to the instructions in the study Pharmacy Manual.  The subject identification number 
and kit number both must be recorded in the subject’s record. 
5.2.3. 
Randomization Algorithm 
Subjects will be randomized in a 1:1 ratio (OTO-313:placebo) of treatment groups using a 
permuted block randomization algorithm.  Randomization is stratified by study site, duration of 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
tinnitus (≥2 to ≤6 months and >6 to ≤ 12 months since onset) and by the average of the TFI score 
at Screening and Baseline (≥32 to ≤53 points, ≥54 to ≤100 points).   
The randomization process will be deployed via IRT which is accessible 24 hours a day to 
authorized users.  The subject’s randomization number will determine the randomized treatment 
assignment.  Investigational product kits will be labeled with a unique kit number using a 
separate and independent randomization algorithm.  Numbered kits will be dispensed based on 
the treatment assignment.   
5.3. 
Blinding 
The study will be double-blinded.  Each treatment syringe will be prepared according to the 
detailed instructions in the Pharmacy Manual.   
In case of emergency, the blind should be broken for site personnel only if knowing the subject’s 
treatment allocation would facilitate specific medical treatment.  In all cases, the Investigator 
should consult with the medical monitor prior to unblinding, and if not possible 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 the Sponsor until all subjects have completed the 
study and the database has been finalized by the Sponsor. 
6. 
DOSAGE AND ADMINISTRATION 
6.1. 
Investigational Product Administration 
OTO-313 or placebo is provided in individual Investigational Product kits.  All kits must be 
stored at 2-8°C until use.   
Syringes containing OTO-313 or placebo are prepared in a clean location at room temperature.  
Refer to the Pharmacy Manual for instructions on OTO-313 and placebo preparation 
instructions.   
OTO-313 or placebo will be administered as a single (0.2 mL volume) intratympanic injection to 
an affected (study) ear.  Only a physician may perform the intratympanic injection.   
OTO-313 or placebo should be prepared with a 1 mL luer-lock sterile syringe only.  Luer slip tip 
syringes are not acceptable for use due to the viscosity of OTO-313.  Recommended needles are 
25, 26, or 27 gauge and typically range from 1.5 to 3.5 inches in length. 
The recommended injection procedure for intratympanic administration of OTO-313 or placebo 
in subjects is as follows.  A ventilation hole in the tympanic membrane is not needed due to the 
small injection volume.   
1. Place the subject in a recumbent position with the affected (study) ear upwards.   


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
2. Prior to OTO-313 or placebo administration, confirm the ear to be treated is the affected 
(study) ear. 
3. Anesthetize the tympanic membrane by covering the external surface of the inferior-
posterior quadrant with topical lidocaine or lidocaine/prilocaine cream (e.g., 
 
 or lidocaine spray or solution) until the tympanic membrane is numb.  If 
applicable, suction away any excess topical preparation.  Use of phenol is prohibited for 
anesthetizing the tympanic membrane (Section 7.1).  
4. Using the prepared syringe, insert the needle (bevel facing) into the inferior-posterior 
quadrant of the tympanic membrane at the level of the round window, taking care not to 
insert the needle further than necessary.   
5. With the needle bevel facing in the inferior-posterior direction, inject 0.2 mL of OTO-
313 or placebo towards the round window. 
6. Have the subject remain recumbent for 15 minutes following the injection. 
6.2. 
Compliance 
OTO-313 or placebo will be administered by a physician as a single, intratympanic injection at 
Day 1.   
The site will maintain a log of all investigational product received, dispensed, and returned.  
Investigational product supplies for each subject will be inventoried and accounted for in the 
study. 
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 tinnitus symptoms, prescription drugs, herbal products, 
vitamins, minerals, and over-the-counter medications taken within 30 days before Screening, 
which will be considered prior therapy.  COVID-19 vaccination at any time prior to Screening or 
during the study will also be recorded.   
At the discretion of the Investigator, any medication deemed necessary for the welfare of the 
subject may be continued at stable doses during the study, except for those medications listed in 
Section 7.1.  Any changes in concomitant medications will be recorded in the subject’s eCRF. 
7.1. 
Prohibited Therapy During the Study Period 
The following therapies are prohibited during the study: 
• Phenol for use in anesthetizing the tympanic membrane 
• Intratympanic injection other than that outlined in the current study 
• Systemic corticosteroids (inhaled and nasal steroids are permitted) 
• Other investigational drug(s) or device(s) 
• Other NMDA receptor antagonists (e.g., memantine, dextromethorphan).  Note, 
occasional use of dextromethorphan for cough suppression is allowed except during 


 
 
26 
Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
the period 7 days prior to Baseline and 7 days after the injection of the investigational 
product. 
• Medications known as potentially tinnitus-inducing (e.g., aminoglycosides, ototoxic 
chemotherapeutic drugs, high doses of intravenous loop diuretics, quinine, high doses 
of aspirin or other non-steroidal anti-inflammatory drugs).  Usage of low doses of 
aspirin (e.g., daily doses of 81 mg) or low doses of other non-steroidal anti-
inflammatory drugs for intermittent pain relief may be permitted at the Investigator’s 
discretion. 
• Medications that are considered moderate or strong inducers of CYP2B6 (e.g., 
carbamazepine, efavirenz, rifampin, and ritonavir)  
Use of any of these prohibited therapies will be considered a protocol deviation. 
7.2. 
Other Medications and Therapies 
It is recognized that during the study subjects may require use of certain medications for relief of 
symptoms related to tinnitus or other disease (e.g., worsening depression).  Use of the following 
medication and therapies are permitted during the study: 
• Stable doses (taken for ≥ 1 month prior to Screening) of antidepressant and anti-anxiety 
medications are allowed during the study, and   
• Stable prior use (≥ 1 month prior to Screening) of over-the-counter supplements, 
medications for tinnitus (e.g., Gingko biloba, melatonin), nonconventional therapy, and 
transcranial magnetic stimulation for tinnitus.   
No new medications, over-the-counter supplements, or other therapies for tinnitus may be 
introduced during the study.   
Any changes reported by the subjects in concomitant medications, including changes in dose or 
frequency of dosing, while not considered a protocol deviation, should be recorded in the 
subject’s eCRF.   
No new hearing aids, sound/noise therapy devices, or behavioral therapy for tinnitus may be 
introduced during the study.  However, patients using devices or behavioral therapy pre-study 
are permitted to continue stable use. 
• Stable prior use (≥ 1 month prior to Screening) of hearing aids, noise generators, and/or 
sound therapy devices is allowed and, if utilized, these devices should be used 
consistently throughout the duration of study.   
• Similarly, any behavioral therapy for tinnitus should also be stable (≥ 1 month prior to 
Screening) and continue throughout the duration of the study.   
Any changes in the concurrent use of these devices or behavioral therapy for tinnitus, while not 
considered a protocol deviation, should be recorded in the subject’s eCRF. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
8. 
STUDY EVALUATIONS 
8.1. 
Study Procedures by Visit 
8.1.1. 
Screening Period: Up to 28 days prior to Lead-In 
The following assessments, as listed in the Time and Events Schedule (Table 1), will be 
performed during the screening period: obtain documented informed consent, review and 
confirm eligibility criteria, medical history, demographics, prior and concomitant medications, 
vital signs, height and weight measurements, serum pregnancy test (for female subjects of 
childbearing potential only), clinical laboratory tests, TFI assessment, otoscopy, tympanometry, 
audiometry, and C-SSRS assessment: Baseline version.  The modified Tinnitus Sample Case 
History Questionnaire (TSCHQ) will be completed at Screening as part of medical history to 
capture tinnitus-specific medical history.  Each subject will also view a short educational video 
on clinical research participation entitled “What It Means to Take Part in Clinical Research 
Studies”.  Viewing of the video will be completed after informed consent but prior to the TFI at 
the screening visit. 
8.1.2. 
Lead-In Period: Day -14 to Day -1 (+ 5 days) 
The subject will record their tinnitus loudness and tinnitus annoyance each day, using the NRS 
for each symptom, in a diary during the 14-day Lead-In assessment period.  Subjects must have 
completed the tinnitus diary on at least 5 of the last 7 days of the 14-day Lead-in period for 
eligibility.  The additional +5 days of the Lead-in period will not be used for eligibility. 
8.1.3. 
Baseline/Investigational Product Administration: Day 1 
The purpose of the Day 1 Baseline visit is to confirm subject eligibility, capture baseline efficacy 
and safety data, and administer the investigational product.   
Once the Lead-in period is complete and the subject has met the eligibility criteria for tinnitus 
diary compliance, the Day 1 Baseline assessments are performed.  Results from the prior and 
concomitant medications review, urine pregnancy test (for female subjects of childbearing 
potential), and C-SSRS (“Since Last Visit” version) must be available and reviewed by the 
Investigator to confirm the subject’s eligibility before randomization. 
In addition, the following assessments are to be performed on all subjects prior to dosing to 
establish Baseline status: medical history (with particular attention to any untoward medical 
occurrences that would meet the definition of a serious outcome – See Section 9.1 Serious 
Adverse Event), vital signs, clinical laboratory tests, TFI (overall score of ≥ 32 on the TFI at 
Screening and Baseline visits is required for eligibility), SF-12, otoscopy, tympanometry, and 
audiometry.  Once eligibility status is confirmed and the subject is randomized, the 
investigational product is administered and the remaining Day 1 assessments (i.e., AE 
monitoring) are completed. 
If the subject is no longer eligible, the subject will not be randomized and should be recorded as 
a screen failure (documentation for screen failures will be limited specifically to end of study 
reason, demographic information, TSCHQ, reason for screen failure, and inclusion/exclusion 
criteria).  Re-screening of subjects may be permitted after discussion with the medical monitor 
and sponsor.   


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
All assessments as listed in the Time and Events Schedule (Table 1) are to be performed at this 
visit. 
8.1.4. 
Week 4 (Day 29 ± 2 days): Follow Up 
The primary purpose of the Week 4 visit is to capture efficacy and safety data.  Efficacy 
assessments include the TFI and PGIC.  Safety assessments include concomitant medications, 
vital signs, otoscopy, tympanometry, audiometry, C-SSRS, and AE monitoring.  Compliance for 
completing the daily NRS diary will be reviewed with the subject.     
All Week 4 efficacy and safety assessments as listed in the Time and Events Schedule (Table 1) 
are to be performed. 
8.1.5. 
Week 8 (Day 57 ± 3 days): Follow Up 
The primary purpose of the Week 8 visit is to capture efficacy and safety data.  Efficacy 
assessments include the TFI, PGIC, and SF-12.  Safety assessments include concomitant 
medications, vital signs, clinical laboratory tests, otoscopy, tympanometry, audiometry, C-SSRS, 
and AE monitoring.  Compliance for completing the daily NRS diary will be reviewed with the 
subject.     
All Week 8 efficacy and safety assessments as listed in the Time and Events Schedule (Table 1) 
are to be performed.  In the event that a subject terminates early prior to Week 8, a clinical 
laboratory test should be conducted. 
8.1.6. 
Week 12 (Day 85 ± 4 days): Follow Up 
The primary purpose of the Week 12 visit is to capture efficacy and safety data.  Efficacy 
assessments include the TFI and PGIC.  Safety assessments include concomitant medications, 
vital signs, C-SSRS, and AE monitoring.  Compliance for completing the daily NRS diary will 
be reviewed with the subject.     
All Week 12 efficacy and safety assessments as listed in the Time and Events Schedule (Table 1) 
are to be performed. 
8.1.7. 
Week 16 (Day 113 ± 4 days): End of Study/Early Termination 
The primary purpose of the Week 16 visit is to capture final efficacy and safety data.  Efficacy 
assessments include the TFI, PGIC, and SF-12.  Safety assessments include concomitant 
medications, weight, vital signs, urine pregnancy test for women of childbearing potential, 
otoscopy, tympanometry, audiometry, C-SSRS, and AE monitoring.   
All Week 16 efficacy and safety assessments as listed in the Time and Events Schedule (Table 1) 
are to be performed.  In the event that a subject terminates prior to Week 8, a clinical laboratory 
test should be conducted. 
8.1.8. 
Unscheduled Visit 
Unscheduled Visits may occur in the event of safety-related issues.  Appropriate safety 
assessments (e.g., otoscopy, vital signs, clinical laboratory tests) may be conducted at the 
Investigator’s discretion at Unscheduled Visits. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
8.2. 
Medical History and Demographics 
The medical history will be obtained from medical records and/or via subject interview at the 
Screening visit, and includes general medical history, medication history, reproductive history, 
and history of COVID-19 infection.  In addition, if subject has any untoward medical 
occurrences that would meet the definition of a serious event (see Section 9.1 Serious Adverse 
Event) prior to investigational product administration, this information is to be recorded in 
medical history and immediately discussed with the Medical Monitor to evaluate whether the 
subject should be excluded from randomization/treatment.  Serious medical events that occur 
prior to investigational product administration should be recorded on the Pre-Dose Serious 
Medical Occurrences report form.   
Tinnitus-specific medical history information is also obtained by having potential subjects 
complete the modified TSCHQ at Screening.  Medical history, conditions, and procedures that 
occurred prior to Screening may be added throughout the study (if identified later). 
Demographic information will also be obtained at the Screening visit and will include age; sex; 
race; ethnicity; height, without shoes; weight, without shoes.  Weight will also be obtained at 
Week 16. 
8.3. 
Video for Subjects on Clinical Research Participation 
Subjects will view an educational video on clinical research participation entitled “What It 
Means to Take Part in Clinical Research Studies”.  This 7-minute video provides general 
information, in lay terms, on the purpose of blinded, controlled clinical research studies and the 
roles and responsibilities of a subject in a clinical research study.  Viewing of the video will be 
completed after informed consent but prior to any efficacy assessments (e.g., TFI) at the 
screening visit. 
8.4. 
Efficacy Evaluations 
Efficacy assessments include: 
• Tinnitus Functional Index (TFI) 
• Daily Tinnitus Annoyance NRS 
• Daily Tinnitus Loudness NRS 
• Patient Global Impression of Change (PGIC) 
• Short Form 12 (SF-12) Health Survey 
Subjects who use hearing aids, noise generators, and/or sound therapy devices should continue to 
do so during the study and should complete the tinnitus assessments and ratings (i.e., TFI, daily 
tinnitus annoyance NRS, daily tinnitus loudness NRS, PGIC, and SF-12) based on their tinnitus 
experience with the devices in use.  Only stable tinnitus treatments (i.e., started at least 1 month 
prior to Screening) are allowed during the study and no new treatments should be introduced. 
The TFI should be completed at the beginning of each visit prior to other study assessments.  The 
recommended order in which study questionnaire assessments are conducted is: TFI, PGIC, 
SF-12, and C-SSRS (the C-SSRS is administered after all efficacy questionnaires have been 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
completed).  The daily tinnitus loudness and annoyance NRS should be completed at home on 
the study visit days. 
8.4.1. 
Tinnitus Functional Index (TFI) 
The TFI is a validated, 25-item questionnaire that can be used to scale overall severity of tinnitus 
and to assess treatment-related change in tinnitus (Meikle et al., 2012; Henry et al., 2015).  The 
25 items of the TFI represent 8 subscales covering multiple domains of tinnitus severity: 1) 
Intrusive, 2) Sense of Control, 3) Cognitive, 4) Sleep, 5) Auditory, 6) Relaxation, 7) Quality of 
Life, and 8) Emotional.  Subjects answer each TFI question by rating their experience over the 
past week.   
Completing the TFI provides an index score from 0 to 100, with higher scores representing a 
greater problem with tinnitus.  A reduction in the TFI index score of 13 points or more is 
considered clinically meaningful improvement in tinnitus (Meikle et al., 2012).    
Subjects will complete the TFI at Screening, Baseline (pre-dose), and Weeks 4, 8, 12 and 16. 
The TFI should completed at the beginning of each study visit.  
8.4.2. 
Daily Tinnitus Annoyance Numeric Rating Scale (NRS)  
Subjects will record their tinnitus annoyance using a tinnitus NRS diary.  Numeric rating scales 
have been widely used to assess tinnitus severity and have demonstrated good test-retest 
reliability and concordance with other subjective measures of tinnitus (Meikle et al. 2008).  
Subjects rate their tinnitus annoyance over the past 24 hours.  Subjects respond to the following 
question by selecting the box on the NRS scale corresponding to their degree of tinnitus 
annoyance on a scale of 0 (Not annoying) to 10 (Extremely annoying):  “In the past 24 hours, 
how annoying was your tinnitus?”. 
Subjects eligible at screening will begin using the tinnitus NRS diary at the start of the 14-day 
Lead-in period to record their tinnitus annoyance every day and will continue to record their 
tinnitus annoyance once per day through the 16-week Follow Up period.  Subjects will be able to 
record missed diary entries for 1 day after a missed entry.  Compliance with the tinnitus NRS 
diary will be monitored throughout the study with re-training, as necessary. 
8.4.3. 
Daily Tinnitus Loudness Numeric Rating Scale (NRS) 
Subjects will record their tinnitus loudness using a tinnitus NRS diary.   
Subjects rate their tinnitus loudness over the past 24 hours.  Subjects respond to the following 
question by selecting the box on the NRS scale corresponding to the degree of tinnitus loudness 
on a scale of 0 (No tinnitus) to 10 (Extremely loud tinnitus):  “In the past 24 hours, how would 
you rate the loudness of your tinnitus at its worst?”. 
Subjects eligible at screening will begin using the tinnitus NRS diary at the start of the 14-day 
Lead-in period to record their tinnitus loudness every day and will continue to record their 
tinnitus loudness once per day through the 16-week Follow Up period.  Subjects will be able to 
record missed diary entries for 1 day after a missed entry.  Compliance with the tinnitus NRS 
diary will be monitored throughout the study with re-training, as necessary. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
8.4.4. 
Patient Global Impression of Change (PGIC) 
The PGIC is a patient-reported outcome that evaluates the change in overall “global” tinnitus 
status as perceived by the subject (Adamchic et al. 2012; van de Heyning et al. 2014).  The 
subject is asked: “Since the beginning of the clinical study, how would you rate your tinnitus?”.  
The beginning of the clinical study in this context is the time prior to investigational product 
administration.  The 7 response categories (and point scores) for the PGIC are:  
• Very much improved = 3 
• Much improved = 2 
• Minimally improved = 1 
• Unchanged = 0 
• Minimally worse = -1 
• Much worse = -2 
• Very much worse = -3 
Subjects will complete the PGIC at Weeks 4, 8, 12 and 16.  
8.4.5. 
Short Form 12 (SF-12) Health Survey 
The SF-12 is a validated, multipurpose short form survey of 12 questions, all selected from the 
SF-36 Health Survey (Ware et al. 1996).  The questions are weighted and scored to create two 
subscales, physical and mental health composite scores, as well as an overall health-related 
quality of life score. 
Subjects will complete the SF-12 at Baseline (pre-dose), Week 8, and Week 16. 
8.5. 
Safety Evaluations 
Safety assessments include: 
• Adverse events (see Section 9) 
• Concomitant Medications 
• Vital Signs  
• Clinical Laboratory Tests (Hematology, Serum Chemistry, and Urinalysis)  
• Otoscopy  
• Audiometry 
• Tympanometry 
• C-SSRS Assessment 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
8.5.1. 
Vital Signs and Height/Weight Measurements 
Vital signs measurements (including systolic and diastolic blood pressure, pulse rate, body 
temperature, and respiratory rate) will be collected at Screening, Baseline (pre-dose), Week 4, 
Week 8, Week 12, and Week 16. 
Vital signs will be measured after subjects have been seated for 5 minutes and while subjects are 
in a sitting position.   
8.5.2. 
Clinical Laboratory Tests 
All clinical laboratory tests (except for urine pregnancy) will be processed by a Central 
Laboratory. 
Non-fasting blood samples and urine samples for hematology, serum chemistry, urinalysis, and 
pregnancy tests will be prepared using standard procedures.  
Clinical laboratory testing will be completed at Screening, Baseline (pre-dose) and Week 8.  In 
addition, female subjects of childbearing potential will have serum pregnancy test for human 
chorionic gonadotropin (hCG) at Screening and a urine pregnancy test (hCG) at Baseline (pre-
dose) and Week 16.  The urine pregnancy tests will be performed locally at the site, so results are 
available that day. 
The blood and urine samples will be used for the following tests: 
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and platelet count. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyl-transpeptidase, bicarbonate, blood urea nitrogen, 
calcium, chloride, creatinine, glucose, lactate dehydrogenase, phosphorus, potassium, 
sodium, total bilirubin, and total protein. 
Urinalysis: appearance, color, pH, specific gravity, protein, glucose, ketones, nitrite, 
leukocyte esterase, urobilinogen, and microscopic sediment examination.  
8.5.3. 
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.  Presence and size of tympanic 
membrane perforations will be recorded.  Perforations of the tympanic membrane will be 
captured as AEs if the perforation does not resolve by the end of the study or increases in size.     
Otoscopic examinations will be performed by the physician or qualified healthcare professional 
in both ears at Screening and Baseline (pre-dose) and in study ear only at Weeks 4, 8, 12 and 16.  
8.5.4. 
Tympanometry 
Tympanometry assessments will be used to assess the mobility and compliance of the tympanic 
membrane, pressure and volume in the outer ear canal, and function of the tympanic membrane, 
ossicles and Eustachian tube.   


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
Tympanograms will be completed in both ears at Screening and Baseline (pre-dose) and in study 
ear only at Weeks 4, 8, 12 and 16, unless the examiner determines there is a contraindication to 
performing the procedure.   
8.5.5. 
Audiometry 
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 or certified 
audiologist or a qualified assistant with appropriate training under the direct supervision of a 
licensed or certified audiologist. 
Audiograms are conducted at 250, 500, 1000, 2000, 4000, 6000, and 8000 Hz for air conduction 
and at 1000, 2000, and 4000 Hz for bone conduction at all study visits.  Both air and bone 
conduction thresholds will be assessed.  Subjects wearing hearing aids should be instructed not 
to wear their hearing aids during the audiogram. 
Audiometry will be used to assess hearing function in both ears at Screening and Baseline (pre-
dose) and in study ear only at Weeks 4, 8, 12 and 16.   
8.5.6. 
C-SSRS Assessment 
The rater-administered Columbia Suicide Severity Rating Scale (C-SSRS) is a scale that captures 
the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the 
assessment period (Posner 2011).  Otologic conditions are sometimes associated with anxiety or 
depression, requiring prospective assessment of suicidal ideation to ensure patient safety.  This is 
true whether or not a particular product is known or suspected to be associated with treatment-
emergent suicidal ideation and/or behavior.   
The C-SSRS scale includes questions to solicit the type of information needed to determine if a 
suicide-related thought or behavior occurred.  The C-SSRS must be administered by 
appropriately trained and certified personnel.   
The C-SSRS assessment will be administered at Screening, Baseline (pre-dose) and Weeks 4, 8, 
12, and 16.   
• The “Baseline” version of the C-SSRS will be used at Screening.   
• The “Since Last Visit” version will be used at Baseline (pre-dose), and Weeks 4, 8, 12 
and 16 or premature termination.   
At Screening or Baseline (Day 1) visits, subjects are to be excluded (per Exclusion Criterion 8) 
if: 
• subject answered “Yes” to Question 4 or 5 regarding active suicidal ideation,  
• subject was deemed by the Investigator to be at significant risk of suicidal behavior, or  
• subject had a positive score or report of new suicidal ideation or suicidal behavior on the 
“Since Last Visit” version.  
The Investigator should record medical history of suicidal ideation or non-suicidal self-injurious 
behavior at Screening or Baseline (Day 1) visits if: 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
• subject has a post-Screening score of 1-3 for Ideation (i.e., a “yes” answer to Questions 
1, 2, or 3), or  
• subject has responded “yes” to the Non-Suicidal Self-Injurious Behavior question and 
the score is higher than the Screening C-SSRS score. 
At post-dose visits (Weeks 4, 8, 12, and 16), the Investigator is to record an AE and assess use 
and dose of concomitant antidepressant medication (Section 7.2) if: 
• subject has a positive score or report of new suicidal ideation or suicidal behavior, 
• subject has a C-SSRS score of 1-3 for Ideation (i.e., a “yes” answer to Questions 1, 2, or 
3), 
• subject has a “yes” response to the Non-Suicidal Self-Injurious Behavior question and the 
score is higher than the “Baseline” C-SSRS score. 
At post-dose visits (Weeks 4, 8, 12, and 16) the Investigator is to record a Serious Adverse Event 
(SAE) and assess use and dose of concomitant antidepressant medication (Section 7.2) if: 
• subject has any post-Baseline 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 pre-
dose testing. 
SAE information is reported as indicated in Section 9.2.2.   
Subjects reporting new suicidal ideation or behavior can be managed by concomitant 
antidepressants and may continue in the study or may be discontinued, at the discretion of the 
Investigator.  It is advised that subjects be referred to trained specialists for the treatment of 
depression, at the discretion of the Investigator.   
Suicidality information is to be reported using the following 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. 
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. 
Adverse events will be monitored and documented starting during and after administration of 
investigational product until study participation is complete. 
All AEs and serious adverse events (SAEs) that are reported or observed during or after dosing 
with the investigational product will be recorded on the AE page of the eCRF for all enrolled 
subjects.   
Information to be collected includes description of event, affected ear (for ear-related events 
only), date of onset, Investigator-specified assessment of the severity and relationship to 
investigational product, relationship to the intratympanic injection, date of resolution of the 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
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 if the perforation does not resolve by the end of the study or increases in 
size. 
If the existing medical condition worsens at any time after the injection (e.g., requires 
intervention or treatment), it should be recorded as an AE (e.g., worsening tinnitus [identify L, R, 
or both ears]). 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF using medical 
terminology.  However, if an observed or reported sign or symptom is not considered a 
component of a specific disease or syndrome by the Investigator, it should be recorded as a 
separate adverse event on the eCRF.  Additionally, the condition that led to a medical or surgical 
procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be recorded as an 
adverse event, not the procedure. 
Laboratory abnormalities are not considered AEs unless they are associated with clinical signs, 
symptoms or require medical intervention.  Laboratory values considered to be clinically 
significant may be more extreme than values that are simply outside normal ranges.  A clinically 
significant finding on an examination (e.g., vital signs) or laboratory abnormality (e.g. detected 
on clinical chemistry or hematology), present at screening and significantly worsens, and 
requires medical or surgical intervention, or leads to study drug interruption or discontinuation - 
should be reported as an AE.  Any abnormal test that is determined to be an error does not 
require reporting as an adverse event. 
9.1. 
Adverse Event Classification Definitions 
Adverse Event: 
An AE is any unfavorable and unintended diagnosis, symptom, sign, syndrome, or disease which 
occurs after administration of investigational product, 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): 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
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. 
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 will assess the relationship or association of the investigational product and the 
study procedure (intratympanic injection) in causing or contributing to the AE, which will be 
characterized using the following classification and criteria: 
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event.  Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
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 investigational product 
or study procedure) 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 
current status (ongoing or resolved) will be noted.  In addition, SAEs will be reported to 
Medpace Clinical Safety (email: medpace-safetynotification@medpace.com) 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 within the electronic data capture system eCRF.  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 investigational product 
or to study procedure, 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 investigational therapy and to study procedure.  
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 administration of investigational product 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 investigational product and to 
study procedure (with rationale), seriousness (with rationale), any required treatment or 
evaluations, and outcome (e.g., fatal, not resolved, resolved, resolved with sequelae, unknown).  
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities.  The Sponsor will also report to the Investigators all SAEs that are unlisted in the 
Investigator’s Brochure and associated with the use of the investigational product.  The 
Investigators must report these events to the appropriate Institutional Review Board (IRB) or 
Ethics Committee (EC) in accordance with local regulations. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
9.2.2. 
Serious Adverse Events 
All SAEs occurring after administration of investigational product must be reported to Medpace 
Clinical Safety within 24 hours. 
The initial report of an SAE should be made via the electronic data capture system SAE eCRF.  
The system will alert the Safety team and appropriate action will commence.  If a SAE occurs 
and access to EDC is not practical within the 24-hour time frame, 
 can 
be notified via email or telephone.   
 
  
 
 
  
 
 
 
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. 
The cause of death of a subject in a clinical study, whether the event is expected or associated 
with the investigational product, is an SAE. 
All oral reports of an SAE must be confirmed within 24 hours by a written, more detailed report 
and signed by the Investigator.  Source documents will be requested from the study sites for the 
SAE.  If the subject is hospitalized during the study, a copy of the hospital discharge summary 
should be provided as soon as it becomes available.  
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
subject dies.  Within 24 hours of receipt of follow-up information, the Investigator must update 
the SAE form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., subject discharge summary) to Medpace Clinical Safety via Fax or email.  
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
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. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
9.2.3. 
Pregnancies 
Pregnancies occurring after administration of the investigational product and during participation 
of the study are considered immediately reportable events.  While not considered an 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 Exposure In Utero 
form within one (1) working day of knowledge of the pregnancy.  The pregnancy will be 
followed until information of the final outcome becomes available and a follow-up Exposure in 
Utero form is completed.  Spontaneous abortions should always be reported as SAEs.   
10. 
SUBJECT COMPLETION 
10.1. 
Completion 
Study subject participation is complete after Week 16 (Visit 6).  Subjects who discontinue the 
study before completion of Week 16 (Visit 6) will not be considered to have completed the 
study. 
10.2. 
Study Discontinuation 
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.   
Subjects may be discontinued from the study for any of the following: 
• Withdrawal of consent 
• Lost to Follow-up 
• Adverse Event 
• Principal Investigator decision 
• Sponsor decision 
• Protocol deviation 
• Other 
At any point, the Investigator may discontinue the subject’s study participation at the discretion 
of the Investigator or at the request of the subject, 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 the study, including discontinuing investigational product 
administration, and further follow-up of the study at any time.   
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.  


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
When a subject withdraws from the study prior to completing the End-of-Study Visit, 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.  The sample size was estimated to account for an assumed discontinuation rate of 15% 
by Week 8. 
11. 
STATISTICAL METHODS 
11.1. 
Introduction 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP).  The SAP may appropriately modify the 
analyses specified in the protocol, as necessary. 
11.2. 
Analysis Sets 
The all enrolled set will include all subjects who sign an informed consent form. 
The full analysis set (FAS) includes all randomized subjects, and they will be included in the 
group to which they were randomized. 
The per-protocol analysis set (PP) includes all subjects in the full analysis set that provide TFI 
data at Weeks 4 and 8, and do not have any protocol deviations that may impact the outcome of 
the TFI overall score. 
The safety analysis set includes all subjects who receive study treatment, and they will be 
included in the treatment group based on the treatment received. 
The FAS and PP sets will be used for efficacy analyses. The safety analysis set will be used for 
all safety analyses. 
11.3. 
Study Endpoints 
11.3.1. 
Efficacy Endpoints 
The primary endpoint for this study is the percentage of subjects achieving response, where 
response is defined as achieving at least a 13-point reduction from baseline in the TFI overall 
score at both Weeks 4 and 8. 
Secondary endpoints include the following: 
• Change from Baseline in the NRS ratings of tinnitus annoyance  
• Change from Baseline in the NRS ratings of tinnitus loudness 
• Change from Baseline in TFI total score 
• Change from baseline in TFI subscale scores (Intrusiveness, Sense of Control, Cognitive, 
Sleep, Auditory, Relaxation, Quality of Life, Emotional) 
• PGIC score 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
• Change from Baseline in SF-12 scores 
11.3.2. 
Safety Endpoints 
The safety endpoints include: 
• Incidence of treatment-emergent adverse events 
• Change from Baseline in tympanometry 
• Change from Baseline in otoscopy  
• Change from Baseline in audiometry  
• Change from Baseline in suicidal ideation or behavior 
• Incidence of concomitant medications 
• Change from Baseline in vital signs and weight 
11.4. 
Statistical Analyses 
11.4.1. 
General  
There will be two sets of analyses.  The Primary analyses will be conducted after all subjects 
complete Week 8 of the study, with all planned analyses to be conducted with all data collected 
in the database at time of database freeze.  There will be a final analysis conducted once all 
subjects complete Week 16 of the study, to include all data collected from all subjects across all 
time points. 
All data collected will be summarized descriptively.  Descriptive statistics for continuous data 
are number of subjects, mean, standard deviation, median, minimum, and maximum values. 
Descriptive statistics for categorical variables will include number of observations and 
percentages. 
11.4.2. 
Efficacy Analyses 
All efficacy endpoints will be summarized descriptively and analyzed using FAS. The primary 
endpoint will also be summarized descriptively and analyzed using PP.  
11.4.2.1. Primary Analyses 
The primary endpoint is the percent of responders at Week 8, where subjects will be classified as 
responders if they achieve at least a 13-point reduction from baseline in the TFI overall score at 
both Weeks 4 and 8.  The primary endpoint will be summarized descriptively by treatment 
group.  The percentage of responders will be analyzed using the common risk difference between 
treatment groups and will be tested using a Mantel-Haenszel test controlling for study site, 
duration of tinnitus, and baseline TFI overall score.  Specifically, comparison between OTO-313 
and placebo will be made by testing the following hypothesis: 
H0: POTO-313 = PPlacebo  vs HA: POTO-313 ≠ PPlacebo  


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
The primary analysis will be conducted for the comparison of OTO-313 and placebo, using a 
2-sided test and an alpha level of 5%.  The 95% confidence intervals (CI) around the common 
risk difference will also be provided.  
Missing data for the primary endpoint will be imputed using a multiple imputation technique that 
will be described in detail in the SAP. 
11.4.2.2. Secondary Analyses 
Secondary endpoints of the change from baseline in NRS Annoyance score, NRS Loudness 
score, TFI overall score, TFI subscale scores, PGIC, and SF-12 will be summarized descriptively 
by treatment group and visit.  
There will be no adjustment of multiplicity across secondary endpoints. 
11.4.2.2.1. Additional Responder Analyses 
The following additional responder definitions will also be derived for Weeks 12 and 16: 
• Week 12 responder #1: achieving at least a 13-point reduction from baseline in the TFI 
overall score at Weeks 8 and 12 
• Week 12 responder #2: achieving at least a 13-point reduction from baseline in the TFI 
overall score at Weeks 4, 8, and 12 
• Week 16 responder #1: achieving at least a 13-point reduction from baseline in the TFI 
overall score at Weeks 12 and 16 
• Week 16 responder #2: achieving at least a 13-point reduction from baseline in the TFI 
overall score at Weeks 8, 12, and 16 
• Week 16 responder #3: achieving at least a 13-point reduction from baseline in the TFI 
overall score at Weeks 4, 8, 12 and 16 
These additional responder secondary endpoints will be analyzed in the same manner as the 
primary analysis as described in Section 11.4.2.1. 
11.4.2.2.2. Continuous Endpoint Analyses 
The change from baseline in NRS Loudness, NRS Annoyance, TFI Total score, each TFI 
subscale score, and SF-12 will each be analyzed using a linear mixed-effects model with 
treatment, study day, treatment-by-study day interaction, study site, baseline TFI overall score, 
and duration of tinnitus as fixed effects. The unstructured covariance model will be used. Least-
square adjusted means, the estimated difference in adjusted means between treatment groups and 
associated 95% CIs will be provided. 
11.4.2.2.3. Categorical Endpoint Analyses  
The results of the PGIC will be analyzed using a Cochrane-Mantel-Haenszel mean score test 
controlling for study site, baseline TFI score, and duration of tinnitus. This will be done to compare 
OTO-313 with placebo. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
11.4.3. 
Safety Analyses 
All safety endpoints will be summarized descriptively using the safety analysis set. If descriptive 
summaries warrant further exploration of comparisons between treatment groups, then additional 
safety analyses may be conducted in an ad hoc manner. 
11.4.3.1. Adverse Events 
The primary analysis of AEs will consider only treatment-emergent adverse events (TEAEs), 
events occurring for the first time, or worsening during or after the first dose of investigational 
product.  Subject incidence of TEAEs and SAEs will be tabulated by Preferred Terms (PTs) and 
System Organ Class (SOC).  Severity and relationship to investigational product 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 SOC and PT. 
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.   
11.4.3.2. Tympanometry, Otoscopic, and Audiometry 
The tympanometry category (A, B-small volume and/or normal, B-large volume, or C) will be 
summarized by treatment group and study visit. 
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.  Presence and absence of tympanic membrane perforations will be 
summarized by treatment group and study visit; the size of any tympanic membrane perforation 
will be classified as follows: pinhole; ≤25% of tympanic membrane; 25% to ≤50% of tympanic 
membrane; >50% of tympanic membrane.   
Descriptive summary statistics for audiometric assessments of air and bone conduction 
thresholds at each frequency will be provided by treatment group and study visit. All audiometry 
assessments will be tabulated separately for the treated and untreated ear. 
11.4.3.3. 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”.   
The “Baseline” version of the C-SSRS captures both suicidal ideation and suicide behavior 
(lifetime).  There are 5 suicidal ideation questions, each captured as yes/no for the subject’s 
lifetime.  There are 4 suicidal behavior questions, each captured as yes/no for the subject’s 
lifetime.  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. 
The C-SSRS version used at visits subsequent to the Baseline Visit will be a modified version of 
the “Baseline” C-SSRS.  This “Since Last Visit” version uses the same individual variables for 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
suicidal ideation and behavior assessed at Baseline to capture changes, if any, from previous 
assessments.  In addition, overall suicidality (yes/no) will be defined as any suicidal ideation or 
behavior since the last visit.   
All suicidal ideation and behavior variables will be tabulated overall and by treatment group 
using a shift table for interpretation of changes in C-SSRS results between baseline and 
post-baseline assessments.  All C-SSRS data will be included in data listings. 
11.4.4. 
Concomitant Medications 
Incidence of concomitant medications of interest will be provided for each treatment group. The 
list of concomitant medications of interest will be provided in the SAP.  
11.4.5. 
Laboratory Parameters, Vital Signs and Weight 
The analysis of laboratory parameters and vital signs 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. 
11.5. 
Sample Size 
The primary endpoint is the percentage of responders, where response is defined as achieving at 
least a 13-point reduction from baseline in the TFI total score at both Weeks 4 and 8.  It was 
observed from the previous study (Study 313-201901) that the response rate for OTO-313 (0.32 
mg) was 43% and 13% for placebo.  Based on these results, the assumed rate of response for 
OTO-313 is 43% and 18% for placebo, which is the 13% observed response rate in previous 
study plus 5% inflation for potential placebo response.  
Assuming a 2-sided test and level of significance of 0.05, 60 subjects in the placebo arm and 60 
subjects in each of the OTO-313 arms will provide approximately 85% power to detect a 
treatment difference in favor of OTO-313.  It is also assumed that an observed discontinuation 
rate of 15% will be observed, hence the total sample size is planned to be 140 subjects, 70 
subjects per arm.  These sample size calculations were conducted using EASTv6.5 software with 
a test for a difference in proportions between two groups. 
12. 
INVESTIGATIONAL PRODUCT INFORMATION 
12.1. 
Physical Description of Investigational Product 
The investigational product administered to subjects will be OTO-313 and placebo.  OTO-313 is 
supplied as a 1 mL sterile solution (1.6 mg/mL [0.16%] gacyclidine in medium-chain 
triglycerides) in a vial.  Placebo is provided as a 1 mL sterile solution of 100% medium-chain 
triglycerides in a vial.  The vials are provided as kits, and all kits must be stored at 2-8°C until 
use. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
12.2. 
Directions for Use 
OTO-313 and placebo syringes will be prepared in a clean, secure location at room temperature.  
Please refer to the Pharmacy Manual for detailed investigational product preparation instructions. 
12.3. 
Packaging and Labeling 
12.3.1. 
Packaging 
All investigational product 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-313 and placebo vials indicating contents and storage instructions.   
12.4. 
Management of Clinical Supplies  
The clinical supplies will be managed by the IRT system; instructions will be provided to all 
sites.  The IRT 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 IRT and sent to the clinical 
supply vendor.  Upon shipment and receipt of the clinical study material, the site personnel will 
acknowledge the shipment 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 in accordance with instructions on the investigational product label.  All 
temperature excursions of the investigational product must be documented in the investigational 
product accountability log.  Any excursions within the allowable temperature range and 
conditions should be documented, but the investigational product is still acceptable for use and 
dispensing to subjects.  If any excursions are outside of these conditions, the investigational 
product should not be used to treat subjects.  If this occurs, the individual preparing the 
investigational product should immediately quarantine the product and report the kit(s) as 
unacceptable for dispensing to IRT to remove it from inventory. 
12.5. 
Investigational Product Accountability 
It is the responsibility of the Investigator to ensure that all investigational product 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 person responsible for 
preparing the syringe containing the investigational product will be instructed to return all 
original containers, whether empty or containing investigational product, when instructed by the 
study monitor to return.  Investigational product returned by the clinical site staff will be stored 
and disposed of according to the Sponsor's instructions.  Investigational product accountability 
will be verified by the study monitor during the study.  Investigational product will be stored in a 
limited access area or in a locked refrigerator under appropriate environmental conditions.  


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
The Investigator agrees not to supply the investigational product to any person other than sub-
Investigators, designated staff and the subjects participating in the study.  Investigational product 
may not be relabeled or reassigned for use by other subjects except under special circumstances 
approved by the Sponsor. 
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 investigational product, to the Sponsor as instructed.  The Investigator 
agrees to neither dispense the investigational product from, nor store it at, any site other than the 
study sites agreed upon with the Sponsor. 
The Sponsor will ensure proper disposal of original containers empty or full of returned or 
unused investigational product.  Appropriate documentation will be maintained.  Permission may 
be granted for local disposal, 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.  Activities assigned to the Investigator may be delegated by the Investigator to 
staff qualified by education, training, and experience.  Delegation should be documented in the 
delegation log. 
13.2. 
Institutional Review Board (IRB) and Ethics Committee (EC) 
This study will be undertaken only after full approval of the protocol and addenda has been 
obtained from a designated IRB or EC and the Sponsor has received a copy of this approval. 
The IRB or EC must be informed of all subsequent protocol amendments issued by the Sponsor. 
Reports on, and reviews of, the study and its progress will be submitted to the IRB or EC 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 after the nature 
of the study has been fully explained.  The consent form is typically signed at the Screening Visit 
(Visit 1) and must be completed 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 or EC.  The 
informed consent is in accordance with the Declaration of Helsinki, current International 
Conference for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and Sponsor 
policy. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
The Investigator must explain to potential subjects the aims and methods of the study.  The 
Investigator must also explain potential discomfort, benefits, and risks of study participation.  
Subjects will be informed that they are free not to participate in the study and that they may 
withdraw consent to participate at any time.  They will be told which alternative treatments are 
available if they decline to participate in the study.  Subjects will also be told that declining to 
participate in the study 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 into the 
study, consent should be appropriately recorded by means of the subject's dated signature of the 
informed consent form.  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 on the 
informed consent form 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 or EC approval, except where necessary to 
eliminate immediate hazards to the subjects or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor, change of telephone number).  
Responsibilities for reporting protocol amendments to any Regulatory Authority (if applicable) 
and/or IRB or EC are further described in the Ethical Aspects section of the protocol. 
In situations requiring a departure from procedures defined in the protocol, the Investigator or 
other physician in attendance will contact the site manager, Medical Monitor, or other 
appropriate Sponsor representative by 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 to discuss the situation 
and agree on an appropriate course of action.  The eCRF and source document will describe any 
deviations from procedures defined in the protocol and the circumstances requiring such 
deviations. 
14.2. 
Regulatory Documentation 
There are essential documents that must be provided to the Sponsor at the beginning of the study 
that will enable the site to be initiated and to receive investigational product.  In some cases, 
there may be new documents required or the initial essential documents will be updated during 
the course of the study.   
Essential documents include but are not limited to curriculum vitae for each Investigator and 
sub-Investigator, documentation of IRB or EC protocol approval and associated subject consent 
documents, signed clinical trial agreement, and signed protocol.  The Sponsor or its 
representatives will work with the sites to identify, collect, review, and approve the appropriate 
documentation package. 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
14.3. 
Record Retention 
In compliance with the ICH/GCP guidelines, the Investigator or institution will maintain all 
eCRFs and all source documents that support the data collected from each subject.  All study 
documents specified in Essential Documents for the Conduct of a Clinical Trial (ICH E6) and the 
applicable regulatory requirement(s) will also be collected from each subject.  The Investigator 
or institution will take measures to prevent accidental or premature destruction of these 
documents.  Essential documents must be retained until at least two (2) years after the last 
approval of a marketing application in an ICH region or after at least two (2) 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 or 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 qualified person 
who will accept the responsibility.  The Sponsor must be notified in writing of the name, address, 
and qualifications of the new custodian. 
14.4. 
Electronic Case Report Form (eCRF) 
eCRFs will be completed by site staff for each subject.  Access for data entry will be provided to 
designated site staff.  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 the eCRFs 
always reflect the latest observations on the subjects participating in the study.  
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 
resolution of queries.  The Investigator must authorize changes to the efficacy and safety data 
recorded in the EDC system.  
14.5. 
Termination 
Closure of a center or study termination can be initiated at any time by the Sponsor, provided 
that reasonable cause and sufficient notice are 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 study at the center 
• The maximum number of eligible subjects for the study (study-wide or specific to a 
center) 
• Failure of the Investigator to comply with the protocol, the Sponsor's procedures, or 
GCP guidelines 


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
• Safety concerns 
• Inadequate recruitment of subjects by the Investigator 
• Business reasons 
14.6. 
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-313.   
The medical personnel of the Sponsor and clinical research organization (CRO) will have the 
ability to review blinded safety information as it is entered and verified in the EDC system 
(Section 14.4).  All AEs coded to the System Organ Class of ear and labyrinth disorders in the 
Medical Dictionary for Regulatory Activities (MedDRA) will be reviewed for significant safety 
trends at least every other month.  Reasons for study discontinuation will be reviewed to 
determine if any trends in study discontinuation, such as the occurrence of specific SAEs or 
worsening of symptoms, are identified. 
Investigators are instructed to contact Drug 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 
investigational product.  The Sponsor assumes responsibility for appropriate reporting to the 
regulatory authorities.  The Investigator assumes responsibility for reporting events to the IRB or 
EC in accordance with the IRB or EC requirements, respectively.  All SAEs and non-serious 
AEs will be reviewed by the medical personnel of the CRO and Sponsor during the conduct of 
the study. 
If, during ongoing data review, the Sponsor determines that OTO-313 presents a significant risk 
to subjects, the Sponsor shall take appropriate steps to suspend or discontinue the study and 
notify regulatory authorities, Investigators, IRBs, ECs as appropriate. 
14.6.1. 
Safety Review Committee 
An independent Safety Review Committee will review accumulated individual safety data for the 
first 25% (35 subjects), 50% (70 subjects), and 75% (105 subjects) of subjects randomized and 
who have post-administration safety data.  Blinded safety data including adverse events, 
concomitant medications, medical history, clinical safety laboratory measurements, audiometry, 
otoscopy, tympanometry, and C-SSRS data will be reviewed.  The treatment assignment for an 
individual subject may be unblinded, if deemed necessary to enable medical care or study 
decision-making by the Safety Review Committee.  The decision to continue with the study will 
be based recommendations from the Safety Review Committee on the clinical significance of 
any adverse events or suspected investigational product-related or procedure-related findings.  
Additional information on the Safety Data Review and composition of the independent Safety 
Review Committee is provided in the Safety Review Committee Charter.   


 
 
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Otonomy, Inc. OTO-313-201 Protocol V3.0: 20 July 2021 
14.7. 
Monitoring 
The Sponsor or its representatives will perform monitoring visits (on-site and/or remote as 
permitted by local regulations) 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 monitor in a study center visit log to be kept at the site.  
Monitoring visits will be made according to the Clinical Monitoring Plan.   
Prior to site screening of the initial subject, site-specific source documents will be compared to 
the eCRF, and any findings will be discussed with the Investigator. 
At all visits, the monitor will compare the data entered onto the eCRFs with the hospital or clinic 
records (source documents) in accordance with the Clinical Monitoring Plan.  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 
investigational product administration information.  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. 
14.8. 
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.  eCRFs 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. 
14.9. 
On-Site Audits 
Representatives of the Sponsor's Quality Assurance department or designee 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. 
14.10. 
Publication Policy 
Publication of study results is addressed in the clinical trial agreement. 


 
 
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15. 
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