Clinical trial NCT03325790
Conditions: Meniere's Disease
Keywords: Meniere's disease Hearing Loss Vertigo Tinnitus Ebselen Pharmacokinetics Safety Efficacy Speech
Sponsor: Sound Pharmaceuticals, Incorporated
Start date: 2017-09-28; Completion date: 2019-04-30
Enrollment: 149 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, efficacy, and Pharmacokinetics (PK) of two dose levels of SPI-1005 administered for 28 days compared to placebo in patients with Meniere's disease.

Detailed description:
Study participants will be randomized to SPI-1005 or placebo in this double-blind study to evaluate both safety and efficacy of the investigational treatment. Participants, aged 18-75 years, with probable or definite Meniere's disease will undergo baseline testing to assess severity of sensorineural hearing loss, tinnitus and vertigo. During the study, and 28 days after completion of treatment, participants will be evaluated for safety (adverse events, physical examinations, vital signs and clinical laboratory testing (CBC,serum chemistry). Trough plasma levels of ebselen and its major metabolite will be determined using liquid chromatography-mass spectrometry (LCMS) at specified visits. Additionally, plasma will be analyzed for selenium at the corresponding visits. The effect of SPI-1005 on hearing and balance will be evaluated. Tinnitus (TFI) and vertigo (VSS) will be evaluated at baseline, during and study treatment.

Arms: arm 1: Placebo arm 2: 200mg SPI-1005 BID arm 3: 400mg SPI-1005 BID
Interventions: intervention 1: 200mg SPI-1005 BID intervention 2: 400mg SPI-1005 BID intervention 3: Placebo
Intervention descriptions: intervention 1: Active: low dose intervention 2: Active: high dose intervention 3: Placebo Comparator

Protocol documents:
Prot_000.pdf: 
Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
CLINICAL RESEARCH PROTOCOL 
DRUG: 
SPI‑1005 
STUDY NUMBER(S): 
SPI‑1005‑251 
PROTOCOL(S) TITLE: 
A PHASE 2b, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
SPI-1005 IN MENIERE’S DISEASE 
IND NUMBER: 
127540 
SPONSOR: 
Sound Pharmaceuticals, Inc. 
4010 Stone Way N., Suite 220 
Seattle WA, 98103 
Phone: 206-634-2559 
FAX: 206-691-8262 
ORIGINAL PROTOCOL DATE: 
21 August 2017 
VERSION NUMBER: 
1.00 
VERSION DATE: 
21 August 2017 
CHEMICAL NAME:  2-phenyl-1,2-benzisoselenazol-3 (2H) -one 
Lead Investigator: 
Company Contact: 
Paul R Lambert, MD, FACS 
 
Jonathan Kil, MD 
Dept. of Otolaryngology-HNS.  
Sound Pharmaceuticals, Inc. 
135 Rutledge Ave 10th Floor 
 
4010 Stone Way North 
Medical University of South Carolina 
Suite 120  
Charleston, SC 29425  
Seattle, WA 98103 
NCT Number:  03325790 


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
1 PROTOCOL SUMMARY 
1.1 
Synopsis 
SPI-1005-251: CLINICAL TRIAL SYNOPSIS 
Title 
A PHASE 2b, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF SPI-1005 IN MENIERE’S DISEASE  
Study 
Objective(s) 
The primary objective of this Phase 2 study is to determine the: 
•
Safety of SPI-1005 treatment in adults with Meniere’s disease.
•
Efficacy of SPI-1005 will be determined by the following
clinically significant methods and measures (responder
analysis):

Pure tone audiometry (>30 dBHL at 250, 500 or 1000 Hz)
>10 dB improvement from baseline
Words in Noise Test (0-35)
>10 % increase from baseline
Tinnitus Functional Index (TFI) (0-100)
>10 pt. reduction from baseline
Tinnitus Loudness: Q#2 of TFI (0-10)
>2 pt. reduction from baseline
Vertigo Symptom Scale (0-60)
>6 pt. reduction from baseline
The responder analysis from each method and measure will be 
compared between treatment groups for significance. 
•
Efficacy of SPI-1005 treatment in adults with Meniere’s
disease based on
o
Improvement in sensorineural hearing loss using pure
tone audiometry at 250, 500, or 1000 Hz; or
o
Word recognition score using WIN testing at 24, 20,
16, 12, 8, 4 and 0 SNR; or
o
Improvement in the Tinnitus Functional Index (TFI); or
o
Improvement in Tinnitus Loudness (TL); or
o
Improvement in the Vertigo Symptoms Scale (VSS).
The secondary objectives of this study are to determine the: 
•
Pharmacokinetics of SPI-1005.
Study Design 
Randomized Double Blind Placebo Controlled Study of SPI-1005 in 
adult volunteers with Meniere’s Disease (probable or definitive 


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
SPI-1005-251: CLINICAL TRIAL SYNOPSIS 
diagnosis) with active symptoms in the months preceding study 
enrollment. All subjects will undergo baseline audiometric testing and 
have their severity of sensorineural hearing loss, tinnitus and vertigo 
determined before initiating treatment. Subjects will be randomized to 
treatment, either placebo or two different doses of SPI-1005 (1:1:1) 
and treated for 28 days. Subjects will return to clinic 2 weeks after the 
start of study drug to have safety assessments and to receive additional 
study drug. Subjects will return to clinic at week 4 to have their 
hearing loss, tinnitus and vertigo re-assessed, and again 4 weeks after 
the end of study drug treatment. Therefore, 4 scheduled clinic visits 
will be performed over an 8 week period. Audiometry will be 
performed at baseline, at the end of the 4 week treatment period, and 4 
weeks after treatment has stopped. The TFI and VSS will be 
performed at all scheduled clinic visits. Subjects are allowed to 
continue with their existing maintenance therapies (i.e. low salt diet, 
thiazide diuretic, or other PRN medications) except for the use of oral 
or locally injected steroids. New treatments should be avoided while 
on study.  
Study Centers 
Approximately 12 U.S. sites will participate in this study 
Subjects 
120 male and female adults with probable or definitive Meniere’s 
disease.  
Inclusion 
Criteria 
•
Adult male and female patients, 18-75 years of age at the time
of enrollment.
•
Diagnosis of probable or definitive Meniere’s disease by AAO-
HNS 1995 criteria (Section 12.1, APPENDIX I).
•
Two of three active symptoms including vertigo or
disequilibrium, fluctuating hearing loss, or tinnitus within the 3
months prior to study enrollment.
•
Hearing loss of >30 dBHL at either 250, 500 or 1000 Hz.
•
Voluntary consent to participate in the study.
•
Male subjects that are willing to use condoms throughout the
study period and 90-days following study completion even if
not fertile.
•
Females of childbearing potential should either be sexually
inactive (abstinent) for 14 days prior to screening and
throughout the study or be using one of the following acceptable
birth control methods:
o
IUD in place for at least 3 months prior to study; or
o
Barrier method (condom or diaphragm) with spermicide
for at least 14 days prior to screening through study
completion; or
o
Stable hormonal contraceptive for at least 3 months prior


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
SPI-1005-251: CLINICAL TRIAL SYNOPSIS 
to study and through study completion; or 
o
Surgical sterilization (vasectomy) of partner at least 6
months prior to study enrollment.
•
Females of non-childbearing potential should be surgically
sterile (bilateral tubal ligation with surgery at least 6 months
prior to study enrollment, hysterectomy, or bilateral
oophorectomy at least 2 months prior to study) or be at least 1
year since last menses.
Exclusion 
Criteria 
•
Current use of or within 60 days prior to study IV ototoxic
medications such as chemotherapy including cisplatin,
carboplatinum, or oxaliplatin; aminoglycoside antibiotics
including gentamicin, amikacin, tobramycin, kanamycin, or
streptomycin; or loop diuretics including furosemide.
•
History of otosclerosis or vestibular schwannoma.
•
History of significant middle ear or inner ear surgery.
•
Current conductive hearing loss, otitis media, or mixed hearing loss.
•
Significant cardiovascular, pulmonary, hepatic, renal, hematologic,
gastrointestinal, endocrine, immunologic, or psychiatric disease.
•
Current use or within 30 days prior to study enrollment systemic
steroids or drugs known to be strong inhibitors or inducers of
cytochrome P450 enzymes.
•
Hypersensitivity or idiosyncratic reaction to compounds related to
ebselen or selenium.
•
Female patients who are pregnant or breastfeeding.
•
Participation in another interventional drug or device study within
30 days prior to study consent.
Study Duration Estimated duration of 12 months 
Participant 
Duration 
Participation for each study participants will be approximately 8 to 12 
weeks across 4 clinic visits. 
Dose & 
Regimen 
Subjects will receive either SPI-1005 or matching placebo for 28 days. 
Treatment will be taken orally BID. Doses include 200 mg or 400 mg 
of ebselen or matching placebo in capsule form. Two week supplies 
will be provided on Clinic Visit 1 and 2. 


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
SPI-1005-251: CLINICAL TRIAL SYNOPSIS 
Safety & 
Tolerability 
Assessments 
Physical examinations, vital signs, adverse events, hematology (CBC) 
and serum chemistries will encompass safety assessments. 
Adverse events will be coded using MedDRA (Version 18.1 or 
higher) and summarized by treatment group for the number of adverse 
events and compared. 
Vital signs and clinical laboratory results will be summarized for each 
treatment group and compared. 
PK 
Assessments 
The trough plasma levels of ebselen and its major metabolite (2-
glucuronyl selenobenzanilide) will be determined using LC-MS/MS. 
The corresponding selenium plasma levels will be determined by ICP-
MS. 
PK results will be summarized by treatment group. 
Lead 
Investigator (s) 
Paul R. Lambert, MD 


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
1.2 
Schema 
Screen for 
Eligibility 
Day -28 to 1 
Day 14 
Day 28 
Day 56 
Screen participants (n=168 estimate) by inclusion and exclusion criteria 
including history and review of systems 
Clinic Visit 1 
Informed consent process, perform baseline assessments, confirm 
eligibility, randomize, complete enrollment by providing study drug. 
Refer to Section 1.3, Schedule of Assessments 
Clinic Visit 3 
Perform protocol required assessments. 
Refer to Section 1.3, Schedule of Assessments 
Clinic Visit 4 
Final Assessments 
Refer to Section 1.3, Schedule 
of Assessments 
Clinic Visit 2 
Perform protocol required assessments. 
Refer to Section 1.3, Schedule of Assessments 
Estimated Excluded (n=48) 
• Did not meet I/E criteria (n=25)
• Declined to participate (n=13)
• Other reasons (n=10)


Sound Pharmaceuticals, Inc. 
IND 127540 
SPI-1005 
Submission 0003 
1.3 
Schedule of Assessments 
Clinic Visit 
CV1 
(Screening/Baseline) 
CV2 
CV3 
CV4 
Study Day 
-28 to 1 
14 (+/- 3) 
28 (+/- 3) 
56 (+/-3) 
Informed 
Consent 
X 
Demographics 
X 
Medical 
History 
X 
Physical Exam  
X 
X 
X 
X 
Hight 
X 
Weight 
X 
X 
X 
X 
BMI 
X 
Vital Signs 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
Serum 
Chemistry 
X 
X 
X 
X 
Urine 
Pregnancy (1) 
X 
Otoscopy 
X 
X 
X 
Tympanometry 
X 
TFI 
X 
X 
X 
X 
VSS 
X 
X 
X 
X 
PTA 
X 
X 
X 
WINT 
X 
X 
X 
Concomitant 
Medication 
Review  
X 
X 
X 
X 
Randomization 
X 
SPI-1005 
Treatment (2) 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
PK 
X 
X 
X 
X 
(1) Urine pregnancy test on CV1 screening visit only. 
(2) SPI-1005 treatment begins after safety labs (CBC, serum chemistry) are reviewed and all inclusion/exclusion
criteria are met.

SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization.
STATISTICAL ANALYSIS PLAN 
Study Title:s 
A Phase 2b, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of SPI-1005 in Meniere’s disease 
Sponsor Identification: 
Sound Pharmaceuticals, Inc. 
Phase: 
Phase 2b 
Sponsor Study Number: 
SPI‑1005‑251 
EA Study Number: 
SPI‑1005‑251 
Responsible Biostatistician: 
Prabhu S  
Lead Biostatistician 
Ecron Acunova Limited 
Mobius Towers,SJR i-Park 
EPIP,Whitefield, 
Bangalore – 560 066 
E-mail : Prabhu.Siva@navitaslifesciences.com
Date of SAP: 
30MAY2019 
Version: 
Final 1.0 
Scope: 
Final 
ECRON ACUNOVA 
3
NCT Number:  03325790 


Statistical Analysis Plan 
Version No.: Final l.0 
I NLS Study Code: SP! -/005 251 
SIGNATURES 
Prepared by: 
RiyaGoel 
Associate Biostatistics 
Biostatistics & Programming 
Ecron Acunova Ltd. 
Bangalore, India 
Reviewed by: 
Prabhu S 
Lead Biostatistician 
Biostatistics & Programming 
Ecron Acunova Ltd. 
Bangalore, India 
Approved by: 
Jonathan Kil, MD 
Chief Medical Officer 
Sound Pharmaceuticals, Inc. 
4010 Stone Way North 
Suite 120 
Seattle, WA 98103 
Jonathan Kil, MD 
ECRON ACUNOVA 
Sponsor Study No: SPJ- l 005- 251 
Page 2 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
I Short Title of Study: SPJ -1005-2.H (Sound Pharmace11/!ca!s, Inc) 
3 0 H Alf 2.019 
Signature 
Date (DD/J\1MM/YYYY) 
Signature 
Date (DD/Mtv1M/YYYY) 
30May2019 
Signature 
Date (DD/NfMM/YYYY) 
Confidentiality Statement 
This document is confidential and propr.ietary to Sponsor and EA and for restricted circulation and act,;ess 
only. No part of it may be transmitted, reproduced, published or used by any person/s 
without prior written authorization. 
4


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 3 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
TABLE OF CONTENTS 
2 
SIGNATURES 
TABLE OF CONTENTS 
3 
 
5 
 
6 
 
8 
 
8 
 
8 
8 
9 
 
9 
9 
DOCUMENT HISTORY 
ABBREVIATIONS 
DOCUMENTS 
INTRODUCTION 
STUDY OBJECTIVES 
5.1 Primary Objectives 
5.2 Secondary Objectives 
STUDY DESIGN 
6.1 Overview 
6.2 Parameters 
11 
6.2.1 
Primary Parameter ..................................................................................................... 11 
6.2.2 
Secondary Parameters ................................................................................................ 12 
6.2.3 
Safety Parameters ....................................................................................................... 12 
6.2.4 
Exploratory Parameters .............................................................................................. 12 
 
12 
12 
13 
GENERAL STATISTICAL CONSIDERATIONS 
7.1 Descriptive Statistics 
7.2 Randomization and Blinding Process 
7.3 Analysis Population 
14 
7.3.1 
Randomized Population .......................................................................................... 14 
7.3.2 
Intent-to-Treat  (ITT) Analysis Population ........................................................... 14 
7.3.3 
Safety Analysis Population ...................................................................................... 14 
7.3.4 
Per-Protocol Population .......................................................................................... 14 
7.3.5 
PK Analysis Population ........................................................................................... 15 
7.4 Protocol Violation 
7.5 Data Handling
15 
15 
7.5.1
Imputation of Missing data ........................................................................................ 15 
15 
15 
16 
17 
 
7.6 Sample Size Calculation 
7.7 Interim Analysis 
7.8 Definitions and Derived Variables 
7.9 Statistical Software 
STATISTICAL ANALYSES 
17 
8.1.1 
Subject Disposition .................................................................................................... 17 
8.1.2 
Inclusion/Exclusion Criteria ...................................................................................... 17 
8.1.3 
Demographic Data and Baseline Characteristics ....................................................... 18 
8.1.4 
Medical History ......................................................................................................... 18 
8.1.5 
Prior and Concomitant Medication ............................................................................ 18 
8.2 Extent of Exposure and Compliance 
19 
8.2.1 
Treatment Exposure ................................................................................................ 19 
1 
2 
3 
4 
5 
6 
7 
8 
ECRON ACUNOVA 
5


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 4 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
8.2.2 
Treatment Compliance ............................................................................................ 19 
8.3 Efficacy Analysis 
19 
8.3.1 
Analysis of Primary Endpoint .................................................................................... 19 
8.4 Safety Analysis 
23 
8.4.1 
Adverse Events .......................................................................................................... 23 
8.4.2 
Clinical Laboratory Evaluations ................................................................................ 24 
8.4.3 
Vital Signs .................................................................................................................. 25 
8.4.4 
Physical examination ................................................................................................. 25 
25 
26 
26 
 
8.5 Pharmacokinetic Analysis 
8.6 Multicentre Studies 
8.7 Subgroup Analyses 
DEVIATION FROM THE STUDY PROTOCOL 
27 
9.1.1 
Exploratory Analysis ................................................................................................. 28 
 
29 
 
29 
 
30 
 
31 
 
36 
 
SOPS FOR ANALYSIS AND REPORTING 
DATABASE LOCK AND UNBLINDING 
REFERENCES 
LIST OF REPORTED TABLES 
LIST OF REPORTED FIGURES 
LIST OF REPORTED SUBJECT DATA LISTINGS 
38 
9 
10 
11 
12 
13 
14 
15 
ECRON ACUNOVA 
6


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 5 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
DOCUMENT HISTORY 
Version 
Date 
Change to previous version 
Final 1.0 
30MAY2019 
Nil 
ECRON ACUNOVA 
1 
7


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 6 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 ABBREVIATIONS 
ABBREVIATIONS DEFINITION 
AE 
Adverse Event 
AE(DAE) 
Discontinuation of the study due to Adverse Events 
ATC 
Anatomical Therapeutic Chemical Classification 
AUC0-t 
Area under the curve time 0 to time t 
Bid 
Twice-daily dosing 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
dB 
decibel, 1/10th of a Bel—measure of ratios on a logscale 
dBHL 
dB Hearing Level 
EXP 
Exponential 
GCP 
 Good Clinical Practice 
G.Mean
Geometric Mean 
Hz 
Hertz—unit of measure for frequency 
IQR 
Inter Quartile Range 
ICH 
International Conference on Harmonization 
LCMS 
Liquid Chromatography-Mass Spectrometry 
mg 
 milligram 
MD 
Meniere’s disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
Max 
Maximum 
Min 
Minimum 
NA 
Not Applicable 
PI 
Principal Investigator 
PK 
 Pharmacokinetics 
ECRON ACUNOVA 
2 
8


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 7 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
Po 
 By mouth 
PTA 
 Pure-Tone Audiometry 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE  
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SIC  
Subject Identification Code 
SNR 
 Signal-to-Noise Ratio 
SPI  
Sound Pharmaceuticals, Inc. 
SQRT 
Square Root 
TFI  
Tinnitus Functional Index 
TL  
Tinnitus Loudness 
TTS  
Temporary Threshold Shift 
VSS 
Vertigo Symptoms Scale 
WINT 
Words-in-Noise Test 
 
 
 
 
ECRON ACUNOVA 
9


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 8 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 DOCUMENTS 
This statistical analysis plan is based on the study protocol SPI‑1005‑251, version 1.00 dated 21AUG2017. 
 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the relevant sections of study protocol and includes also the 
Tables, Listings and Figures (TLF) Specifications. The purpose of the SAP is to describe in more detail how 
the analyses are to be performed and presented. It quotes the relevant statements directly from the protocol, 
but it does not give a full description of study design etc. 
The TLF Specifications specify the output to support the analysis. The TLF Specifications are considered as 
a guideline for producing the output.  
The SAP will be finalized prior to database lock or any unblinding of study team members. 
The objectives of this Phase 2b, randomized, double-blind, Placebo-controlled study are to 
demonstrate the safety and efficacy of SPI-1005 for the treatment of Meniere’s disease. 
 STUDY OBJECTIVES 
5.1 
Primary Objectives 
➢
To determine the Safety of SPI-1005 treatment in adults with Meniere’s disease.
➢
To determine the Efficacy of SPI-1005 with the following clinically validated methods and
measures (responder analysis):
▪
Primary pure-tone audiometry assessment (250, 500 or 1000 Hz): Improvements from
baseline of ≥10 dB at 1 frequency
▪
Secondary pure-tone audiometry assessments (250, 500 or 1000 Hz): Improvements
from baseline of ≥10 dB at 2 adjacent frequencies or ≥20 dB at 1 frequency
▪
Primary Words-in-Noise Test assessment (0-35): Improvements from baseline of
≥10%
▪
Secondary Words-in-Noise Test assessments (0-35): Improvements from baseline of
≥20% or ≥4 words
▪
Tinnitus Functional Index (TFI): (0-100) ≥ 10 pt. reduction from baseline
▪
Tinnitus Loudness: Q#2 of TFI: (0-10) ≥ 2 pt. reduction from baseline
▪
Vertigo Symptom Scale (0-60): ≥ 6 pt. reduction from baseline
The responder analysis from each method and measure will be compared between treatment groups 
for significance. 
• The efficacy of SPI-1005 treatment in adults with Meniere’s disease will be based on:
➢
Improvement in sensorineural hearing loss using pure-tone audiometry at 250, 500, or 1000
Hz; or
ECRON ACUNOVA 
3 
4 
5 
10


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 9 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
➢ Word recognition score using WINT at 24, 20,16, 12, 8, 4 and 0 SNR; or 
➢ Improvement in the Tinnitus Functional Index (TFI); or 
➢ Improvement in Tinnitus Loudness (TL); or 
➢ Improvement in the Vertigo Symptoms Scale (VSS) 
5.2 
Secondary Objectives 
To determine the pharmacokinetics at each dosing level of SPI-1005. 
 STUDY DESIGN 
6.1 
Overview 
This clinical trial is a phase 2b, randomized, double-blind, placebo-controlled study to evaluate the 
safety and efficacy of SPI-1005 in Meniere’s disease. The study is planned to be conducted in adult 
volunteers with Meniere’s Disease (probable or definitive diagnosis) with active symptoms in the 
months preceding study enrollment. Study participants will be randomized into three dosing arms: 
SPI-1005 200 mg/BID, SPI-1005 400 mg/BID, or placebo (1:1:1). This double-blind study will 
evaluate both safety and efficacy of the investigational treatment. 
 
Participants aged 18-75 years, with probable or definitive Meniere’s disease will undergo baseline 
testing to assess severity of sensorineural hearing loss, tinnitus and vertigo. This is a multicenter study 
that includes patients from approximately 12 US sites.  
 
During the study, and 28 days after completion of treatment, participants will be evaluated for safety 
(adverse events, physical examinations, vital signs and clinical laboratory testing (CBC, serum 
chemistry). Trough plasma levels of ebselen and its major metabolite (2-glucuronyl 
selenobenzanilide) will be evaluated using liquid chromatography-mass spectrometry (LCMS) at 
specified visits. Additionally, plasma will be analyzed for selenium at the corresponding visits. 
Female participants will receive pregnancy testing at visit 1, and those found to be pregnant will be 
excluded from the study and monitored for adverse events. 
 
The effect of SPI-1005 on hearing and balance will be evaluated. Hearing will be evaluated at     
baseline, at the end of 28 days of study treatment, and 28 days after completing study treatment.  
Tinnitus and vertigo will be evaluated with the Tinnitus Functional Index (TFI) and the Vertigo 
Symptoms Scale (VSS), respectively. These tests will be administered at baseline, on days 14 and 28 
ECRON ACUNOVA 
6 
11


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 10 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
of treatment, and 28 days after treatment. Hearing thresholds (HL) will be determined using pure-
tone audiometric (air conduction) testing at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz, 
bilaterally. In addition, bone conduction testing with masking will be conducted if the air conduction 
threshold is >15 dBHL at 250, 500, 1000, 2000, or 4000 Hz. Bone conduction testing will only be 
performed at screening and in the affected ear (>15 dBHL). A word recognition test using the Words-
in-Noise Test (WINT) at 24, 20, 16, 12, 8, 4, and 0 Signal-to-Noise ratio (SNR) will be used to 
evaluate hearing. 
Following completion of informed consent process and baseline assessments, the study participants 
will be evaluated by the investigator for enrollment eligibility. Participants that meet enrollment 
criteria will be randomized and assigned a Subject Identification Code from the list of Subject 
Identification Codes. The Subject Identification Code must be carefully matched to the study drug 
before the study drug is dispensed at Clinic Visits 1, and 2.  
A general diagram of the study design is provided in Figure 1. 
ECRON ACUNOVA 
12


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 11 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
6.2 
Parameters 
All parameters through which the study objectives will be carried out, should be listed. Exact computations 
will be declared in section 7.8 Definitions and Derived Variables. 
6.2.1 
Primary Parameter 
➢
Efficacy of SPI-1005 will be determined by the following clinically significant methods and
measures (responder analysis):
➢
Pure-tone audiometry assessment (250, 500 or 1000 Hz): Improvements from baseline of ≥10 dB
at 1 frequency
➢
Words-in-Noise Test assessment (0-35): Improvements from baseline of ≥10%
▪
Tinnitus Functional Index (TFI) (0-100) ≥ 10 pt. reduction from baseline
Screen for 
Eligibility 
Day -28 to 1 
Day 14 
Day28 
Day56 
ECRON ACUNOVA 
Screen participants (n=l 68 estimate) by inclusion and exch1Siou criteria 
including history and review of systems. 
Estimated Excluded (n=48) 
• Did noc me~t IfB crice:ria (11=25) 
• DecliDed to pamcipar~ (n=l 3) 
• 0th.er reasons (n= l 0) 
Clinic Yisif l 
Informed consent process, perform baseline assessments, confirm 
eligibility, randomize, complete enrollment by providing study drug. 
Clinic Yisit 2 
Perform protocol required assessments_ 
Clinic Yisit 3 
Petforn.1 protocol required assessments. 
Clinic Yisit 4 
FinaJ Assessments 
13


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 12 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
▪ 
Tinnitus Loudness: Q#2 of TFI (0-10) ≥ 2 pt. reduction from baseline 
▪ 
Vertigo Symptom Scale (0-60) ≥ 6 pt. reduction from baseline 
 
6.2.2 
Secondary Parameters 
Pharmacokinetics parameters will be analyzed for the following parameters: 
1. AUC0-t (mg_h/L) 
2. Cmax (mg/L)  
6.2.3 
Safety Parameters 
➢ Safety of SPI-1005 treatment in adults with Meniere’s disease will be analysed using: 
▪ 
Physical examinations 
▪ 
Vital signs 
▪ 
Adverse events 
▪ 
Hematology (CBC) 
▪ 
Serum chemistries. 
6.2.4 
Exploratory Parameters 
▪ 
Secondary pure-tone audiometry assessments (250, 500 or 1000 Hz): Improvements from 
baseline of ≥10 dB at 2 adjacent frequencies or ≥20 dB at 1 frequency 
▪ 
Secondary Words-in-Noise Test assessments (0-35): Improvements from baseline of ≥20% 
or ≥4 words 
 GENERAL STATISTICAL CONSIDERATIONS  
7.1 
Descriptive Statistics  
The following descriptive statistics will be calculated for continuously distributed data:  
• 
n                                                                                                                                                                  
• 
Mean 
• 
Standard Deviation (also denoted as SD) 
• 
Minimum (also denoted as Min) 
• 
Median 
• 
Maximum (also denoted as Max) 
• 
Inter Quartile Range (IQR) 
 
ECRON ACUNOVA 
7 
14


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 13 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
For categorical variables, counts and percentages will be calculated. 
 
For continuous variables, the decimal places for n, minimum and maximum will be provided as per 
the reported value. Decimal places for mean, Q1, Q3 and median will be reported one decimal place 
more than the reported value. The decimal place for standard deviation will be reported two decimal 
places more than the reported value. 
 
In all statistical tables, p-values will be reported as specified by the statistical program used, at least 
up to three decimal places. P-values less than 0.001 will be reported as provided by SAS®, Version 
9.2 or higher (e.g. '<0.0001'). All tests will be two-sided at the  = 0.05 level of significance, if not 
stated otherwise. 
 
In by-visit summary tables only scheduled visits will be presented. All visits (both scheduled and 
unscheduled) will be presented in listings. 
 
7.2 
Randomization and Blinding Process 
This study is a randomized, double-blind, placebo-controlled study design. Patients will be 
randomized to treatment, either placebo or two different doses of SPI-1005 (1:1:1). 
Study center and sponsor personnel involved in the conduct and interpretation of the study will not 
have access to treatment codes. Laboratory personnel, and contracted designees of SPI who 
statistically analyze the data, will be blinded to the study treatment received by each study participant. 
The bioanalytical staff analyzing PK samples will be provided a copy of the random codes but will 
not report unblinded data until after database lock. The sponsor’s medical monitor will receive each 
treatment code in individual envelopes for use in emergency unblinding. 
 
Apart from this, the data management and biostatistics team will be blinded until the database closure. 
The lead statistician will receive a copy of the unblinded treatment group after the database lock upon 
receiving a written authorization from the head of Biometrics/Statistics Lead from Sound Pharma to 
unblind the study. 
 
ECRON ACUNOVA 
15


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 14 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
7.3 
Analysis Population 
7.3.1 
Randomized Population  
The randomized population includes all patients who are randomized for treatments.  Patients who 
have a missing randomization number will be included in this population. This includes patients who 
answer the question “Is the subject to be randomized?” = ‘Yes” and with a non- missing “Subject 
Identification Code”. 
 
7.3.2 
Intent-to-Treat  (ITT) Analysis Population  
The ITT Efficacy Analysis population includes all patients from the randomized population who have 
received at least one dose of study drug and who have  an evaluated post baseline efficacy assessment. 
The efficacy assessments include the evaluation of: 
• 
Non- missing Pure-tone audiometry at Visit 3 or Visit 4  
• 
Non- missing Words-in-Noise Test at Visit 3 or Visit 4 
• 
Non- missing Tinnitus Functional Index (TFI) at Visit 2 or Visit 3 or Visit 4 
• 
Non- missing Tinnitus Loudness (TL) at Visit 2 or Visit 3 or Visit 4 
• 
Non- missing Vertigo Symptom Scale (VSS) at Visit 2 or Visit 3 or Visit 4 
 
7.3.3 
Safety Analysis Population 
             All study participants receiving at least one study treatment dose will be included in the safety          
analysis, whether or not they complete the study. The safety population is derived from the patients 
with evidence of receiving the study treatment in the “Drug Accountability” and eCRF form met with 
the following criteria: 
• 
 “Study Medication dispensed?” as ‘Yes’ and 
• 
 “Date of Dispensing” and 
• 
The value entered for “Number of Capsules Taken” is greater than or equals 1 (missing values 
are excluded) 
The safety population will be the primary population for the safety analysis. Analyses on the safety 
population will be based on actual treatment received. 
 
7.3.4 
Per-Protocol Population 
The Per-Protocol Population includes all patients who receive study treatment and have efficacy 
parameters at Visit 3 and have no major protocol deviations. 
ECRON ACUNOVA 
16


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 15 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
The major protocol deviations include: 
• 
Treatment compliance of <80% and >120%  
• 
Did not meet inclusion/exclusion criteria 
• 
Baseline overall WINT score ≥ 2x Standard Deviations above the mean (rounded down to nearest 
integer) 
• 
Major protocol deviations impacting the primary efficacy outcome measure.  
 
7.3.5 
PK Analysis Population  
The PK analysis population includes all randomized patients performing PK evaluations, with the 
study medication compliance, and have a PK profile at all visits. The patients with major protocol 
deviations impacting PK results will be excluded from the analysis. 
 
7.4 
Protocol Violation 
Protocol deviations will be summarized by deviation category and treatment group. This analysis 
will be performed for all randomized patients.  
7.5 
Data Handling  
7.5.1 
Imputation of Missing data 
Imputation for missing values are not applicable. 
7.6 
Sample Size Calculation 
120 male and female adults with probable or definitive Meniere’s disease. This Phase 2b study (SPI-
1005-251), is adequately powered to demonstrate a 50% improvement in a symptom of MD using the 
responder analysis detailed in below with 40 study participants per treatment group. 
7.7 
Interim Analysis 
        There is no interim analysis planned for this study. 
 
 
ECRON ACUNOVA 
17


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 16 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
7.8 
Definitions and Derived Variables 
For the statistical analysis, two different doses and placebo will be denoted according to the following 
table. 
Treatment 
Label 
SPI-1005 po BID  200mg 
SPI-1005 200 mg 
SPI-1005 po BID 400mg 
SPI-1005 400 mg 
Placebo po BID  
Placebo  
 
In the following table, the definitions and calculation of derived variables are summarised. 
Variable / Term 
Definition / Way of calculation 
Baseline 
The last assessment on or before to the treatment start date. The most recent 
measurement prior to treatment start regardless of whether the measurement 
is collected at a scheduled or unscheduled visit will be considered for the 
baseline. 
End of study 
The date on which the last patient completes the last visit (includes follow-
up visit). 
BMI 
Weight in kg / Height in m2 
Treatment Start 
The earliest date of ‘date of drug dispense’ (Date of dispensing) from Study 
Drug Dispensing and Drug Accountability eCRF form, where the patient 
has: 
• 
Answered ‘Yes’ to question, Study medication dispensed? And, 
• 
Recorded at least one capsule used for the question, ‘Number of 
capsules taken’ 
If the drug administration date is unavailable and only the last dose date of 
the patient is available, then the Randomization date will be considered as 
the treatment start date. 
ECRON ACUNOVA 
18


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 17 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
Variable / Term 
Definition / Way of calculation 
Treatment End 
The treatment end date is taken from the field: 
‘Date of last study medication taken’ from ‘Study Completion or Early 
Termination’ page. 
If the ‘Date of last study medication taken’ is missing and there is evidence 
that the patient has taken the study medication, the last visit date will be 
considered as ‘Treatment end date’. 
Treatment Emergent 
AE (TEAE) 
An adverse event (AE) will be considered as treatment-emergent if the time 
of onset is on or after the time of the first randomized study drug 
administration (treatment start date).  
Duration of 
exposure 
Treatment end date - treatment start date + 1, refer to section 8.2.1 in SAP 
for details 
Treatment 
compliance 
(Total number of capsules used/Total number of capsules to be taken) *100, 
refer to section 8.2.2 in SAP for details 
Geo CV% 
sqrt(exp(log SD)-1)*100 
7.9 
Statistical Software 
All statistical analyses will be performed with SAS®, Version 9.2 or higher on a MS-Windows 
platform. 
 STATISTICAL ANALYSES 
8.1.1 
Subject Disposition 
The number of patients who have completed the study or early termination from the study and reasons 
for discontinuations will be grouped by treatment. The summary of patient disposition will be 
tabulated for all randomized, safety, ITT and PK analysis populations. 
8.1.2 
Inclusion/Exclusion Criteria 
The number and percentage of patients violating each inclusion/exclusion criterion will be presented 
by criterion. Violation of inclusion/exclusion criteria will be listed. 
ECRON ACUNOVA 
8 
19


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 18 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
8.1.3 
Demographic Data and Baseline Characteristics 
Demographic characteristics include age, gender, ethnicity. Baseline characteristics include height, 
weight, BMI, TFI, VSS, PTA and WINT. 
Frequency and percentage will be presented for gender, ethnicity. Descriptive statistics will be 
presented for age (years), height (cm), weight (Kg), BMI (kg/m2). These analyses will be performed 
for the Randomized, Safety, ITT and Per-Protocol populations. 
Demographic and baseline characteristics will be presented in the by-patient listings. A data listing 
will be produced for the randomization details. 
8.1.4 
Medical History 
Medical history terms will be coded using MedDRA dictionary version 19.1. 
Medical history will be summarized by MedDRA system organ class and preferred term for safety 
population. All medical history will be listed by patient and treatment group. 
8.1.5 
Prior and Concomitant Medication 
Prior and concomitant medications will be assessed at screening and at each subsequent study visit. 
Medications will be coded using WHO Drug Dictionary version MAR2017. 
Medication will be classified as prior, if the end date is known and is before the first use of the study 
medication. Medications that are ongoing or ended after the first use of the study medication will be 
classified as concomitant. If the end date of the medication is unknown, it will also be considered 
concomitant. If the end date is partially known, the medication will be considered concomitant, unless 
the known part of the end date rules out the possibility that the medication could have ended before 
the start of the study drug. 
Prior and concomitant medications will be separately summarized by ATC class (the highest available 
level) and preferred name for the safety population. The prior and concomitant medications will be 
listed in a by-patient listing.  
ECRON ACUNOVA 
20


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 19 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
8.2 
Extent of Exposure and Compliance 
8.2.1 
Treatment Exposure 
Treatments will be dispensed at baseline to patients based on the randomized group assignments and 
the patients will receive the treatment for a duration of 28 days. 
The earliest date of ‘date of drug dispense’ (Date of dispensing) from Study Drug Dispensing and 
Drug Accountability eCRF form, where the patient has: 
       •  Answered ‘Yes’ to question, ‘Study medication dispensed?’ and, 
       •  Recorded at least one capsule used for the question, ‘Number of capsules taken’ 
If the drug administration date is unavailable and the last dose date of the patient is only available, 
then the Randomization date will be considered as treatment start date. 
 
The treatment end date is taken from the field: 
• 
‘Date of last study medication taken’ from ‘Study Completion or Early Termination’ page. If 
the date of last study drug administration is missing and there is evidence that the patient has 
taken study medication, last visit date will be considered as ‘Treatment end date’.  
 
• 
Duration of treatment exposure is derived as treatment end date - treatment start date + 1 
 
The duration of treatment exposure will be summarized descriptively by treatment group for safety 
population. Data listing will be presented for study drug administration. 
 
8.2.2 
Treatment Compliance 
Treatment compliance is defined as intake of 80% to 120% of the dispensed capsules by an individual 
patient during the treatment period. Hence the compliance is computed as: 
• 
(Total number of capsules used/Total number of capsules to be taken) *100 
Where the total number of capsules used is derived as the sum of results recorded for the question 
‘Number of capsules taken’ in the drug accountability form. 
Data listing also will be presented for treatment compliance. 
8.3 
Efficacy Analysis 
8.3.1 
Analysis of Primary Endpoint  
Primary analyses will use the Per-Protocol analysis population and Intent-To-Treat analysis 
population. 
ECRON ACUNOVA 
21


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 20 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
8.3.1.1 
Pure-Tone Audiometry 
Pure-tone audiometry (PTA) will be measured at visit 1, visit 3 and visit 4. 
Both the actual ear value and calculated change from baseline PTA data will be summarized by visits 
and treatment groups.  
PTA data will be analyzed with a mixed-effects model for repeated measures, and a post-hoc 
Bonferroni correction analysis with significance set to 0.05. The calculated change of PTA data will 
be calculated by the difference of the actual ear value at baseline and the actual ear value at each visit 
post baseline. The primary assessment of PTA data will consider a ≥10 dBHL improvement from 
baseline as a clinically relevant response (only low frequency: 250, 500, 1000 Hz). The secondary 
assessments of PTA data will consider an improvement from baseline of ≥10 dBHL at two adjacent 
frequencies or ≥20 dBHL at one frequency as clinically relevant responses (only low frequency: 250, 
500, 1000 Hz).  The final processed data will be analyzed using a chi-square test or Fisher’s Exact 
test to assess the improvement between treatment groups. 
 
8.3.1.2 
Words-in-Noise Test 
The Words-in-Noise Test (WINT) will be measured at visit 1, visit 3 and visit 4. 
Both the actual ear value and calculated change from baseline WINT data will be summarized by 
visits and treatment groups.  
WINT data will be analyzed with a mixed-effects model for repeated measures, and a post-hoc 
Bonferroni correction analysis with significance set to 0.05. The calculated change of WINT data will 
be calculated by the difference of the actual ear value at baseline and the actual ear result at each visit 
post baseline. The primary assessment of WINT data will consider a ≥10% improvement from 
baseline as a clinically relevant response. The secondary assessments of WINT data will consider an 
improvement from baseline of ≥20% or ≥4 words as clinically relevant responses. The final processed 
data will be analyzed using a chi-square test or Fisher’s Exact test to assess the improvement between 
treatment groups. 
8.3.1.3 
Tinnitus Functional Index (TFI) 
The Tinnitus Functional Index (TFI) will be measured at visit 1, visit 2, visit 3 and visit 4. 
The actual patient reported outcome (PRO) value and change from baseline TFI will be summarized 
by visits and treatment groups.  
TFI will be analyzed as a composite score and for the following individual subscales: Intrusiveness, 
Sense of control, Cognition, Sleep, Auditory, Relaxation, Quality of life, and Emotional.  
ECRON ACUNOVA 
22


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 21 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
The overall total score will be calculated by the sum of all valid answers from both TFI pages and 
will be divided by the number of questions for which that respondent provided valid answers and then 
multiplied by 10. 
 
SUBSCALE NAME 
ITEMS IN SUBSCALE 
INTRUSIVE 
#1, #2, #3 
SENSE OF CONTROL 
#4, #5, #6 
COGNITIVE 
#7, #8, #9 
SLEEP 
#10, #11, #12 
AUDITORY 
#13, #14, #15 
RELAXATION 
#16, #17, #18 
QUALITY OF LIFE (QOL) 
#19, #20, #28, #22 
EMOTIONAL 
#23, #24, #25 
Each of the 8 subscales consists of 3 items (except for the Quality of life subscale, which 
consists of 4 items). For subscale scores to be valid no more than 1 item should be omitted. 
Computation of subscale scores is calculated as: 
1) Sum all respondent's valid answers for a given subscale. 
2) Divide that number by the number of valid answers that were provided by that 
respondent for that subscale. 
3) Multiply by 10. For the respondent in question, this procedure generates a subscale 
score in the range 0-100 for each valid subscale. 
Overall TFI score is not valid if the respondent omits seven or more items. To be considered a valid 
measure of tinnitus severity, the respondent must answer at least 19 items. 
The TFI data will be analyzed with a mixed-effects model for repeated measures, and a post-hoc 
Bonferroni correction analysis with significance set to 0.05. The calculated change of TFI data will 
be calculated as the difference of the PRO value at baseline and the PRO value at each post baseline 
timepoint. The improvement will be considered only if the difference between post baseline and 
baseline value is ≥10 pts. The final processed data will be analyzed using a chi-square test or Fisher’s 
Exact test to assess the improvement between treatment groups. 
 
ECRON ACUNOVA 
23


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 22 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
8.3.1.4 
Tinnitus Loudness 
Tinnitus loudness (TL) will be measured at visit 1, visit 2, visit 3 and visit 4. TL is assessed from 
question number two of the TFI.  
The actual patient reported outcome (PRO) value and change from baseline for TL will be 
summarized by visits and treatment groups. TL data will be analyzed with a mixed-effects model for 
repeated measures, and a post-hoc Bonferroni correction analysis with significance set to 0.05. The 
calculated change of TL data will be calculated as the difference of the PRO value at baseline and the 
PRO value at each post baseline timepoint. The improvement will be considered only if the difference 
between post baseline and baseline value is ≥2 pts. The final processed data will be analyzed using a 
chi-square test or Fisher’s Exact test to assess the improvement between treatment groups. 
8.3.1.5 
Vertigo Symptom Scale 
Vertigo Symptom Scale (VSS) will be measured at visit 1, visit 2, visit 3 and visit 4. 
The actual patient reported outcome (PRO) value and change from baseline for VSS will be 
summarized by visits and treatment groups. 
VSS will be analyzed for Total Scale, Vertigo/balance sub-scale and Autonomic/anxiety sub-scale. 
The Vertigo/balance sub-scale will be calculated as the sum of questions 1, 3, 4, 6, 8, 10, 13  and 15. 
The Autonomic/anxiety sub-scale will be calculated as the sum of questions 2, 5, 7, 9, 11, 12  and 14. 
The range for the Vertigo/balance sub-scale will be 0 – 32 and the  range for Autonomic/anxiety sub-
scale will be 0 – 28. 
VSS data will be analyzed with a mixed-effects model for repeated measures, and a post-hoc 
Bonferroni correction analysis with significance set to 0.05. 
The calculated change of VSS data will be calculated as the difference of the PRO value at baseline 
and the PRO value at each post baseline timepoint. The improvement will be considered only if the 
difference between post baseline and baseline value is ≥6 pts. The final processed data will be 
analyzed using a chi-square test or Fisher’s Exact test to assess the improvement between treatment 
groups. 
ECRON ACUNOVA 
24


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 23 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
8.4 
Safety Analysis 
8.4.1 
Adverse Events 
Adverse Events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA 
version 19.1), the coded terms will be used for summarizing the AE(s). 
An AE will be considered as treatment-emergent if the time of onset is on or after the time of the first 
randomized study drug administration. AEs with unknown start dates will be counted as treatment-
emergent unless the AE resolution date is prior to the study drug start date. If the start date is partially 
missing, AE will be considered treatment-emergent unless the known part of the start date or the end 
date rules out that it occurred after the start of the study drug.  
An overall summary table which summarizes, the number and percentages of patients with adverse 
events, treatment emergent adverse events, serious adverse events, adverse events leading to death 
and adverse events related to study drug will be provided by treatment groups. 
Patients experiencing any adverse events will be summarized by Preferred Term (PT), SOC and 
treatment. Furthermore, listings of SAEs and AEs that lead to withdrawal will be provided. The 
number and percentage of patients with at least one TEAE, SAE and discontinuation of study 
treatment due to AE (DAE) will be summarized by system organ class, preferred term and treatment 
group. 
Adverse Events will be summarized by System Organ Class, Preferred Term and Treatment for Any 
Adverse Events, Serious Adverse Events, Adverse Events leading to medication discontinuation, 
Adverse leading to death, Adverse Events by severity, Adverse Events by outcome and Adverse 
Events by relationship. 
A patient experiencing the same AE multiple times will be counted only once for that preferred term. 
Similarly, if a patient experiences multiple AEs within the same system organ class that patient will 
be counted only once in that system organ class. In summaries by severity or by relationship, if a 
patient has the same AE on multiple occasions, the highest severity, and the closest relationship to 
study drug, respectively, will be used for summary.  
All information pertaining to adverse events noted during the study regardless of treatment emergent 
or not will be listed by patient, detailing verbatim, preferred term, system organ class, start date, stop 
date, TEAE status, severity, outcome, action taken and causal relationship to the study drug. 
 
ECRON ACUNOVA 
25


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 24 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
8.4.2 
Clinical Laboratory Evaluations 
Blood samples for clinical safety laboratory assessments will be collected at the following time Visit 
1, Visit 2, Visit 3 and Visit 4. The following parameters will be analyzed under these categories: 
 
 
 
Laboratory results will be summarized descriptively for actual and change from baseline values by 
visits and treatment for each category of clinical chemistry and hematology. In addition, baseline shift 
tables will be presented for the lab parameters by visits and treatmnts for laboratory categories, the 
results falling out of normal ranges will be classified as Normal, Abnormal High and Abnormal Low 
and will be used for the shift tables. The ‘Normal’, ‘Abnormal Low’ and ‘Abnormal High’ values are 
determined based on the laboratory normal ranges. The number and percentage of patients reaching 
‘Normal’, ‘Abnormal CS’ and ‘Abnormal NCS’ results for laboratory parameters will be summarized 
All laboratory results will be listed in data listings, the abnormal values will be flagged in the listings. 
 
 
 
ECRON ACUNOVA 
Hematology 
Chemistry 
RBC 
Sodium 
Albumin 
Hematocrit 
Potassium 
AST (SGOT) 
Hemoglobin 
Chloride 
ALT (SGPT) 
Platelets 
Bicarbonate 
GGT 
WBC 
Glucose 
Total bilirubin 
Neutrophils 
Blood urea nitrogen 
Alkaline phosphatase 
(BUN) or Urea 
Lymphocytes 
Creatinine 
Uric acid 
Monocytes 
Calcium 
LOH 
Basophils 
Magnesium 
Cholesterol 
Eosinophils 
Inorganic phosphorus 
Triglycerides 
Total protein 
26


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 25 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
8.4.3 
Vital Signs 
Vital signs will be measured at Visit 1, Visit 2, Visit 3 and Visit 4. 
The vital signs parameters include:  
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (Beats/min) 
• 
Oral Temperature (°C) 
 
The actual and change from baseline vital signs parameters will be summarized descriptively by visits 
and treatment groups. 
In addition, number and percentage of patients reaching ‘Normal’, ‘Abnormal CS’ and ‘Abnormal 
NCS’ results for vital signs parameters will be summarized by visits and treatment groups. Data 
listings will be presented for vital signs parameters. 
Shift tables for the overall interpretation of vital signs parameters will be summarized by visits and 
treatment groups. 
 
8.4.4 
Physical examination  
Physical examination will be performed at Visit 1, Visit 2, Visit 3 and Visit 4. Physical examination 
will 
include 
an 
examination 
of 
skin, 
HEENT 
(Otoscopic 
exam) 
Head/ 
Eyes/ 
Ears/Nose/Throat/Thyroid, Respiratory, Cardiovascular, Abdomen, Musculoskeletal, Neurological 
(and reflexes), Gastrointestinal, Endocrine, Lymph nodes and others. 
A summary of these findings , number and percentages of patients achieving ‘Normal‘, ‘Abnormal 
CS‘, ‘Abnormal NCS‘ will be presented by visit, body system and treatment group. Results will also 
be listed. 
 
 
8.5 
Pharmacokinetic Analysis 
The PK analysis will be performed based on PK analysis population. 
Three (3) mL of blood will be collected at visit 1, visit 2, visit 3 and visit 4. Study participants should 
be instructed to refrain from taking their morning dose until after their blood is drawn at Clinic Visit 
2 and Clinic Visit 3. Sample collection times (actual clock time using 24:00) are to be recorded and 
will be captured in the CRF. 
ECRON ACUNOVA 
27


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 26 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
The patient listings as well as Patient’s PK profile plots in actual and semi-logarithmic views will be 
prepared for the PK concentrations. Descriptive summary statistics table including geometric mean 
& CV% geometric mean will be presented by timepoints and treatment groups. In addition, mean ± 
SD graphs will be prepared for the concentration by timepoints and treatment groups. 
Descriptive statistics including geometric mean & CV% geometric mean will be presented for the PK 
parameters, AUC 0-t (mg. h/L) and Cmax (mg/L). 
 
8.6 
Multicentre Studies 
 Patients from thirteen sites in U.S. participated in the study and all the data across the sites will be 
presented. 
8.7 
Subgroup Analyses 
             Not Applicable 
 
 
 
ECRON ACUNOVA 
28


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 27 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
 DEVIATION FROM THE STUDY PROTOCOL 
The differences between study protocol and statistical analysis plan are summarised in the 
following table: 
Change 
Study Protocol 
Statistical Analysis Plan 
6.2 Study 
Objectives 
The primary objective of this 
Phase 2 study is to determine the: 
• Safety of SPI-1005 
treatment in adults with 
Meniere’s disease. 
• Efficacy of SPI-1005 will 
be determined by the 
following 
clinically significant methods and 
measures (responder 
analysis): 
▪ Pure tone 
audiometry (>30 
dBHL at 250, 500 
or 1000 Hz) 
>10 dB 
improvement from 
baseline 
▪ Words in Noise 
Test (0-35) 
>10 % increase 
from baseline 
▪ Tinnitus 
Functional Index 
(TFI) (0-100) 
➢ To determine the Safety of SPI-1005 
treatment in adults with Meniere’s 
disease. 
➢ To determine the Efficacy of SPI-
1005 with the following clinically 
validated methods and measures 
(responder analysis): 
▪ 
Primary pure-tone 
audiometry assessment: 
(250, 500 or 1000 Hz): 
Improvements from baseline 
of ≥10 dB Secondary pure-
tone audiometry assessments 
(250, 500 or 1000 Hz): 
Improvements from baseline 
of ≥10 dB at 2 frequencies or 
≥20 dB at 1 frequency 
▪ 
Primary Words-in-Noise 
Test assessment (0-35): 
Improvements from baseline 
of ≥10%  
▪ Secondary Words-in-Noise 
Test assessments (0-35): 
Improvements from baseline 
of ≥20% or ≥4 words 
▪ Tinnitus Functional Index 
(TFI): (0-100) ≥ 10 pt. 
reduction from baseline 
ECRON ACUNOVA 
9 
29


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 28 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
>10 pt. reduction 
from baseline 
▪ Tinnitus 
Loudness: Q#2 of 
TFI (0-10) 
>2 pt. reduction 
from baseline 
▪ Vertigo Symptom 
Scale (0-60) 
>6 pt. reduction 
from baseline 
The responder analysis from each 
method and measure will be 
compared between treatment 
groups for significance. 
o Efficacy of SPI-
1005 treatment in 
adults with 
Meniere’s disease 
based on 
▪ Improvement in 
sensorineural hearing loss 
using pure tone 
audiometry at 250, 500, or 
1000 Hz; or 
▪ Word recognition score 
using WIN testing at 24, 
20,16, 12, 8, 4 and 0 SNR; 
or 
▪ Tinnitus Loudness: Q#2 of 
TFI: (0-10) ≥ 2 pt. reduction 
from baseline 
▪ 
Vertigo Symptom Scale 
(0-60): ≥ 6 pt. reduction 
from baseline 
The responder analysis from each 
method and measure will be compared 
between treatment groups for 
significance. 
   • The efficacy of SPI-1005 treatment in 
adults with Meniere’s disease will be 
based on: 
➢ Improvement in sensorineural 
hearing loss using pure tone 
audiometry at 250, 500, or 1000 
Hz; or 
➢ Word recognition score using 
WINT at 24, 20,16, 12, 8, 4 and 0 
SNR; or 
➢ Improvement in the Tinnitus 
Functional Index (TFI); or 
➢ Improvement in Tinnitus Loudness 
(TL); or 
➢ Improvement in the Vertigo 
Symptoms Scale (VSS) 
9.1.1 Exploratory Analysis 
▪ 
Primary 
pure-tone 
audiometry 
assessment: (250, 500 or 1000 Hz): 
Improvements from baseline of ≥10 
dB 
ECRON ACUNOVA 
30


Statistical Analysis Plan  
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 29 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
 
 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
▪ Improvement in 
the Tinnitus 
Functional Index 
(TFI); or 
▪ Improvement in 
Tinnitus Loudness 
(TL); or 
▪ Improvement in 
the Vertigo 
Symptoms Scale 
(VSS). 
▪ The secondary 
objectives of this 
study are to 
determine the: 
• Pharmacokinetics of SPI-1005. 
▪ 
Secondary pure-tone audiometry 
assessments (250, 500 or 1000 
Hz): 
Improvements 
from 
baseline of ≥10 dB at 2 
frequencies or ≥20 dB at 1 
frequency 
▪ Primary 
Words-in-Noise 
Test 
assessment (0-35): Improvements 
from baseline of ≥10%  
▪ Secondary Words-in-Noise Test 
assessments (0-35): Improvements 
from baseline of ≥20% or ≥4 words 
 
 
 
 
SOPS FOR ANALYSIS AND REPORTING 
Ecron Acunova’s standard operating procedures as well as the ICH guideline E9 will be applied to 
this analysis. The structure of post-text-tables and the appendices will be in accordance with the ICH 
guideline E3. 
 
DATABASE LOCK AND UNBLINDING 
 
After the data cleaning process is finalised according to the data management manual and the 
assignment of patients to the analysis population is agreed and signed by the sponsor, the data base 
will be locked. SAS datasets will be extracted from the data.  
After the data base closure, unblinding of randomization will be initiated and the randomisation  
dataset will be prepared, and it will be validated by a second person. 
ECRON ACUNOVA 
10 
11 
31


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 30 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
REFERENCES 
Further references are given in the study protocol. 
ECRON ACUNOVA 
12 
32


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 31 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
LIST OF REPORTED TABLES 
Table No. 
Table 
14.1 
Demography Analysis 
TABLE 14.1.1 
Summary of Patient Disposition (Randomized Population) 
TABLE 14.1.1.1 
Summary of Patient Disposition (Safety Population) 
TABLE 14.1.1.2 
Summary of Patient Disposition (Intent-to-Treat Population) 
TABLE 14.1.1.3 
Summary of Patient Disposition (Per-Protocol Population) 
TABLE 14.1.2 
Summary of Eligibility Status (All Screened Subjects) 
TABLE 14.1.3 
Number of Patient Included and Excluded from Analysis Population 
TABLE 14.1.4 
Reason for Patient Excluded from Analysis Population (Randomized 
Population) 
TABLE 14.1.5 
Summary of Protocol Deviations (Randomized Population) 
TABLE 14.1.6 
Number of Patient at Each Visit (Randomized Population) 
TABLE 14.1.7 
Number of Patient Enrolled by Study Center (Randomized Population) 
TABLE 14.1.8 
Summary of Patient Demographic Characteristics at Baseline 
(Randomized Population) 
TABLE 14.1.8.1 
Summary of Patient Demographic Characteristics at Baseline (Safety 
Population) 
TABLE 14.1.8.2 
Summary of Patient Demographic Characteristics at Baseline (Intent-to-
Treat Population) 
TABLE 14.1.8.3 
Summary of Patient Demographic Characteristics at Baseline (Per-
Protocol Population) 
TABLE 14.1.9 
Summary of Medical History Classified by MedDRA Preferred Term 
(Safety Population) 
TABLE 14.1.10 
Summary of Prior Medications by ATC Class and Preferred Term (Safety 
Population) 
TABLE 14.1.11 
Summary of Concomitant Medication by ATC Class and Preferred Term 
(Safety Population) 
TABLE 14.1.12 
Summary of Study Treatment Taken by the Patient: (Safety Population) 
14.2 
Efficacy Analysis 
TABLE 14.2.1 
Summary and Analysis of Actual and Change from Baseline of Pure- Tone 
Audiometry(PTA) – Continuous variable (Intent-to-Treat Population) 
ECRON ACUNOVA 
13 
33


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 32 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
Table No. 
Table 
TABLE 14.2.1.1 
Summary and Analysis of Actual and Change from Baseline of Pure- 
Tone Audiometry(PTA)  – Continuous variable (Per-Protocol Population) 
TABLE 14.2.1.2 
Post-hoc analysis for Pure-Tone Audiometry (PTA) (Intent-to-Treat 
Population) 
TABLE 14.2.1.3 
Post-hoc analysis for Pure-Tone Audiometry (PTA) (Per-Protocol 
Population) 
TABLE 14.2.1.4 
Summary and Analysis of Pure- Tone Audiometry(PTA) >=10 DB 
improvement from Baseline (Intent-to-Treat Population) 
TABLE 14.2.1.5 
Summary and Analysis of Pure- Tone Audiometry(PTA) >=10 DB 
improvement from Baseline (Per-Protocol Population) 
TABLE 14.2.1.6 
Summary and Analysis for Pure-Tone Audiometry (PTA) ≥10 dB 
Improvement from Baseline atleast 2 Frequencies  
(Intent-to-Treat Population) 
TABLE 14.2.1.7 
Summary and Analysis for Pure-Tone Audiometry (PTA) ≥10 dB 
Improvement from Baseline atleast 2 Frequencies  
(Per-Protocol Population) 
TABLE 14.2.1.8 
Summary and Analysis for Pure-Tone Audiometry (PTA) ≥20 dB 
Improvement from Baseline atleast 1 Frequency 
 (Intent-to-Treat Population) 
TABLE 14.2.1.9 
 Summary and Analysis for Pure-Tone Audiometry (PTA) ≥20 dB 
Improvement from Baseline atleast 1 Frequency  
(Per-Protocol Population) 
TABLE 14.2.2 
Summary and Analysis of Actual and Change from Baseline of Words-in-
Noise Test(WINT)  – Continuous Variable (Intent-to-Treat Population) 
TABLE 14.2.2.1 
Summary and Analysis of Actual and Change from Baseline of Words-in-
Noise Test (WINT) – Continuous Variable (Per-Protocol Population) 
TABLE 14.2.2.2 
Post-hoc analysis for Words-in-Noise Test (WINT) (Intent-to-Treat 
Population) 
TABLE 14.2.2.3 
Post-hoc analysis for Words-in-Noise Test (WINT) (Per-Protocol 
Population) 
TABLE 14.2.2.4 
Summary and Analysis Words-in-Noise Test(WINT)  >=10% Increase 
from Baseline (Intent-to-Treat Population) 
TABLE 14.2.2.5 
Summary and Analysis of Words-in-Noise Test(WINT)  >=10% Increase 
from Baseline (Per-Protocol Population) 
TABLE 14.2.2.6 
Summary and Analysis for Words-in-Noise Test (WINT) ≥20% Increase 
from Baseline (Intent-to-Treat Population) 
TABLE 14.2.2.7 
Summary and Analysis for Words-in-Noise Test (WINT) ≥20% Increase 
from Baseline (Per-Protocol Population) 
ECRON ACUNOVA 
34


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 33 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
Table No. 
Table 
TABLE 14.2.2.8 
Summary and Analysis for Words-in-Noise Test (WINT) ≥ 4 Words 
Increase from Baseline (Intent-to-Treat Population) 
TABLE 14.2.2.9 
Summary and Analysis for Words-in-Noise Test (WINT) ≥ 4 Words 
Increase from Baseline (Per-Protocol Population) 
TABLE 14.2.3 
Summary and Analysis of Actual and Change from Baseline of Tinnitus 
Functional Index (TFI) – Continuous Variable (Intent-to-Treat Population) 
TABLE 14.2.3.1 
Summary and Analysis of Actual and Change from Baseline of Tinnitus 
Functional Index (TFI) – Continuous Variable  (Per-Protocol Population) 
TABLE 14.2.3.2 
Post-hoc analysis for Tinnitus Functional Index (TFI) (Intent-to-Treat 
Population)   
TABLE 14.2.3.3: 
Post-hoc analysis for Tinnitus Functional Index (TFI) (Per-Protocol 
Population) 
TABLE 14.2.3.4 
Summary and Analysis of Tinnitus Functional Index (TFI) ≥ 10pt. 
reduction from Baseline (Intent-to-Treat Population) 
TABLE 14.2.3.5 
Summary and Analysis of Tinnitus Functional Index (TFI) ≥ 10pt. 
reduction from Baseline (Per-Protocol Population) 
TABLE 14.2.4 
Summary and Analysis of Actual and Change from Baseline of Tinnitus 
Loudness(TL) – Continuous Variable (Intent-to-Treat Population) 
TABLE 14.2.4.1 
Summary and Analysis of Actual and Change from Baseline of Tinnitus 
Loudness (TL) – Continuous Variable (Per-Protocol Population) 
TABLE 14.2.4.2 
Post-hoc analysis for Tinnitus Loudness (TL) (Intent-to-Treat Population) 
TABLE 14.2.4.3 
Post-hoc analysis for Tinnitus Loudness (TL) (Per-Protocol Population) 
TABLE 14.2.4.4 
Summary and Analysis of Tinnitus Loudness (TL) ≥ 2pt. reduction from 
Baseline (Intent-to-Treat Population) 
TABLE 14.2.4.5 
Summary and Analysis of Tinnitus Loudness (TL) ≥ 2pt. reduction from 
Baseline (Per-Protocol Population) 
TABLE 14.2.5 
Summary and Analysis of Actual and Change from Baseline of Vertigo 
Symptom Scale (VSS) – Continuous Variable (Intent-to-Treat Population) 
TABLE 14.2.5.1 
Summary and Analysis of Actual and Change from Baseline of Vertigo 
Symptom Scale (VSS) – Continuous Variable (Per-Protocol Population) 
TABLE 14.2.5.2 
Post-hoc analysis for Vertigo Symptom Scale (VSS) (Intent-to-Treat 
Population) 
TABLE 14.2.5.3 
Post-hoc analysis for Vertigo Symptom Scale (VSS) (Per-Protocol 
Population) 
ECRON ACUNOVA 
35


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 34 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
Table No. 
Table 
TABLE 14.2.5.4 
Summary and Analysis of Vertigo Symptom Scale (VSS) ≥ 6pt. reduction 
from Baseline (Intent-to-Treat Population) 
TABLE 14.2.5.5 
Summary and Analysis of Vertigo Symptom Scale (VSS) ≥ 6pt. reduction 
from Baseline (Per-Protocol Population) 
TABLE 14.2.6 
Summary of PK Concentration values (PK Population) 
TABLE 14.2.7 
Summary of PK parameters by (PK Population) 
14.3 
Safety Analysis 
TABLE 14.3.1 
Overall Summary of Adverse Events (Safety Population) 
TABLE 14.3.2 
Number (and Percentage) of Patient with Adverse Events Classified by 
System Organ Class, Preferred Term During The Study (Safety 
Population) 
TABLE 14.3.2.1 
Number (and Percentage) of Patient with Adverse Events Classified by 
Treatment Emergent Adverse Events (Safety Population) 
TABLE 14.3.2.2 
Number (and Percentage) of Patient Discontinuation of Study Treatment 
Due to AE Classified by System Organ Class, Preferred Term During The 
Study (Safety Population) 
TABLE 14.3.2.3 
Number (and Percentage) of Patient Death Classified by System Organ 
Class, Preferred Term During The Study (Safety Population) 
TABLE 14.3.3 
Number (and Percentage) of Patient with Adverse Events Classified by 
Severity (Safety Population) 
TABLE 14.3.4 
Number (and Percentage) of Patient with Adverse Events Classified by 
System Organ Class, Preferred Term and Relation to Study Medication 
(Safety Population) 
TABLE 14.3.5 
Number (and Percentage) of Patient With Adverse Events Classified by 
Action taken with Study Drug (Safety Population) 
TABLE 14.3.6 
Number (and Percentage) of Patient with Adverse Events Classified 
Outcome (Safety Population) 
TABLE 14.3.7 
Number (and Percentage) of Patient With Serious Adverse Events System 
Organ Class and Preferred Term (Safety Population) 
TABLE 14.3.8 
Summary of Physical Examination by Visit (Safety Population) 
TABLE 14.3.9 
Summary of  Actual and Change from Baseline for Vital Signs by Visit: 
Continuous Variable (Safety Population) 
TABLE 14.3.10 
Summary of Vital Signs by Visit: Categorical Variable (Safety Population) 
ECRON ACUNOVA 
36


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 35 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
Table No. 
Table 
TABLE 14.3.11 
Summary of Shift from Baseline of Vital Signs by Visit: Categorical 
Variable (Safety Population) 
TABLE 14.3.12 
Summary and Change from Baseline of Lab parameters(Hematology) by 
Visit and Treatment (Safety Population) 
TABLE 14.3.13 
Summary and Change from Baseline Lab Parameters (Clinical Chemistry) 
by Visit and Treatment (Safety Population) 
TABLE 14.3.14 
Summary of Shift from Baseline of Lab Parameter (Hemotology)   Results 
Based on the Refernce Range by Visit and Treatment: Categorical Variable 
(Safety Population) 
TABLE 14.3.15 
Summary of Shift from Baseline of Lab Parameter (Hemotology)   Results 
Based on the Refernce Range by Visit and Treatment: Categorical Variable 
(Safety Population) 
TABLE 14.3.16 
Summary of Lab Parameters (Urine Pregnancy) (Point of care testing) by 
Treatment (Safety Population) 
ECRON ACUNOVA 
37


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 36 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
LIST OF REPORTED FIGURES 
15.1 Mean (± SD) Graph for Pure Tone Audiometry (PTA) (Intent to Treat Population)       
15.1.1 Mean (± SD) Graph  for Pure Tone Audiometry (PTA) (Per-Protocol Population)      
15.2  Mean (± SD) Graph for Words in Noise Test (WINT) (Intent-to-Treat Population) 
15.2.1 Mean (± SD) Graph for Words in Noise Test (WINT) (Per-Protocol Population)  
15.3 Mean (± SD) Graph for Tinnitus Functional Index (TFI) (Intent-to-Treat Population) 
15.3.1  Mean (± SD) Graph for Tinnitus Functional Index (TFI) (Per-Protocol Population)  
15.4 Mean (± SD) Graph for Mean (± SD) Graph for Tinnitus Loudness(Intent-to-Treat Population)  
15.4.1 Mean (± SD) Graph for Tinnitus Loudness (Per-Protocol Population) 
15.5  Mean (± SD) Graph for Vertigo Symptom Scale(Intent-to-Treat Population) 
15.5.1 Mean (± SD) Graph for Vertigo Symptom Scale (Per-Protocol Population)  
15.6 Graph for Pure-tone audiometry ≥10 dB improvement from baseline (Intent-to-Treat Population) 
15.6.1 Graph for Pure-tone audiometry ≥10 dB improvement from baseline (Per-Protocol Population) 
15.6.2 Graph for Words-in-Noise Test ≥10% increase from baseline (Intent-to-Treat Population) 
15.6.3 Graph for Words-in-Noise Test ≥10% increase from baseline (Per-Protocol Population) 
15.6.4 Graph for Tinnitus Functional Index (TFI) ≥10 pt. Reduction from baseline (Intent-to-Treat 
Population) 
15.6.5 Graph for Tinnitus Functional Index (TFI) ≥10 pt. Reduction from baseline (Per-Protocol 
Population) 
15.6.6 Graph for Tinnitus Loudness ≥2 pt Reduction from baseline (Intent-to-Treat Population) 
15.6.7 Graph for Tinnitus Loudness ≥2 pt Reduction from baseline (Per-Protocol Population) 
15.6.8 Graph for Vertigo Symptom Scale ≥6 pt. Reduction from baseline (Intent-to-Treat Population) 
15.6.9 Graph for Vertigo Symptom Scale ≥6 pt. Reduction from baseline (Per-Protocol Population) 
15.6.10 Graph for Pure-Tone Audiometry (PTA) ≥10 dB Improvement from Baseline at 2 Frequencies 
(Intent-to-Treat Population) 
15.6.11 Graph for Pure-Tone Audiometry (PTA) ≥10 dB Improvement from Baseline at 2 Frequencies 
(Per-Protocol Population) 
15.6.12 Graph for Pure-Tone Audiometry (PTA) ≥20 dB Improvement from Baseline at 1 Frequency 
(Intent-to-Treat Population) 
15.6.13 Graph for Pure-Tone Audiometry (PTA) ≥20 dB Improvement from Baseline at 1 Frequency 
(Per-Protocol Population) 
ECRON ACUNOVA 
14 
38


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 37 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
15.6.14 Graph for Words-in-Noise Test (WINT) ≥20% Increase from Baseline (Intent-to-Treat 
Population) 
15.6.15 Graph for Words-in-Noise Test (WINT) ≥20% Increase from Baseline (Per-Protocol 
Population) 
15.6.16 Graph for Words-in-Noise Test (WINT) >= 4 Words Increase from Baseline (Intent-to-Treat 
Population) 
15.6.17 Graph for Words-in-Noise Test (WINT)  >= 4 Words Increase from Baseline (Per-Protocol 
Population) 
15.7 Individual Profile Graph for PK Concentration (PK Population) 
15.8 Mean Graph for PK Concentration (PK Population) 
ECRON ACUNOVA 
39


Statistical Analysis Plan 
Sponsor Study No:  SPI‑1005‑251 
Version No.: Final 1.0 
Page 38 of 38 
Sponsor Name: Sound Pharmaceuticals, Inc. 
NLS Study Code: SPI‑1005‑251 
Short Title of Study: SPI‑1005‑251 (Sound Pharmaceuticals, Inc) 
Confidentiality Statement 
This document is confidential and proprietary to Sponsor and EA and for restricted circulation and access 
only. No part of it may be transmitted, reproduced, published or used by any person/s  
without prior written authorization. 
 
LIST OF REPORTED SUBJECT DATA LISTINGS 
16.2.1 Discontinued Patient 
16.2.1.1 Inclusion / Exclusion Criteria 
16.2.1.2 Randomization  
16.2.1.3 Protocol Violations
16.2.2 Patient excluded from the analysis 
16.2.2.1  Patient Excluded from the Analysis population 
16.2.2.2 Comments 
16.2.3 Demographic and baseline data 
16.2.3.1 Patient Demographic, Exposure  and Disposition 
16.2.3.2 Medical History  
16.2.3.3 Prior/Concomitant Medications       
16.2.4 Compliance 
       16.2.4.1  Study Drug Administration, Accounting and Compliance 
16.2.5 Individual efficacy response data 
 16.2.5.1 Tinnitus Functional Index Results 
 16.2.5.2 Vertigo Symptom Scale(VSS) Scores Results 
 16.2.5.3 Words-in-Noise Test Results (WINT) 
        16.2.5.4 Pure-tone audiometry Results-Air Conduction(dB) 
         16.2.5.5 Pure-tone audiometry Results-Bone Conduction(dB) 
 16.2.5.6 PK Sampling 
 16.2.5.7 PK Parameters 
16.2.6 Adverse event  
 16.2.6.1 Patient Adverse Event  
16.2.7 Listing of Individual Lab Measurements by Patient 
 16.2.7.1 Clinical Lab Results     
 16.2.7.2 Vital Signs  
 16.2.7.3 Physical Examination 
ECRON ACUNOVA 
15 
40