Conditions: Unilateral Severe to Profound Hearing Loss OR Bilateral Severe to Profound Hearing Loss
Keywords: gene therapy unilateral hearing loss bilateral hearing loss balance vestibular cochlear implant hearing restoration
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
The goal of the study was to evaluate the safety, tolerability, and the potential ability of CGF166 delivered through IL-infusion to improve hearing. CGF166 is a recombinant adenovirus 5 (Ad5) vector containing a cDNA encoding the human Atonal transcription factor (Hath1).

Detailed description:
This study evaluated the safety, tolerability, and potential efficacy of CGF166 and the associated delivery procedures in patients with severe-to-profound unilateral or bilateral hearing loss. Eligible patients were required to have documented, non-fluctuating hearing loss.

Arms:
arm 1: single dose volume #1 arm 2: single dose volume #2 arm 3: single dose volume #3 arm 4: single dose volume #4 arm 5: Single dose volume #5

Interventions: intervention 1: CGF166
Intervention descriptions: intervention 1: CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CGF166
Clinical Trial Protocol CCGF166X2201
A three-part, multicenter, open label, single dose study 
to assess the safety, tolerability, and efficacy of intra-
labyrinthine (IL) CGF166 in patients with severe-to-
profound hearing loss
Document type:
Amended Protocol Version
Version number:
v06 (Clean)
Study phase:
I/II
Release date:
30-Apr-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Notification of serious adverse events
A serious adverse event (SAE) is any event which is fatal or life-threatening, which requires 
or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, 
which constitutes a congenital anomaly or a birth defect, or which is medically significant, 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed above.
Any SAE occurring in a patient from consent until 30 days after stopping study 
participation (defined as time of last dose of study drug taken or last visit whichever is the 
later) must be reported either on the paper SAE report form or via the electronic SAE form 
within the clinical data capture system (where available).
For SAEs reported using the paper SAE report form, the investigator will ensure that the 
form is completed and faxed by the investigator to the local Novartis Chief Medical Office 
and Patient Safety (CMO & PS) Department within 24 hours of learning of the occurrence 
of the SAE even if the SAE does not appear to be drug-related. The original SAE form, 
together with the fax confirmation sheet, must be kept with the case report forms at the study 
site.
For SAEs recorded electronically in the Novartis clinical data capture system, information 
should be entered, saved and e-signed within 24 hours of awareness of the SAE. 
These data will automatically be submitted to CMO & PS Department.
More details in Section 7 of this protocol.
Fax numbers of local Novartis Chief Medical Office and Patient Safety (CMO & 
PS) Departments
North America
Fax (+ 1) 877 778 9739
(+ 1) 888 299 4565 (toll free number)
Any update to the Novartis CMO & PS or personnel information required during the course of 
the study will be communicated directly to the relevant Investigator site(s); a specific protocol 
amendment should not be required.


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Table of contents
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol synopsis...............................................................................................................22
Assessment schedule .........................................................................................................27
1
Introduction .......................................................................................................................29
1.1
Background............................................................................................................29
1.1.1
Relevant data summary.........................................................................29
1.2
Study purpose ........................................................................................................37
2
Study objectives.................................................................................................................38
2.1
Primary objective(s)...............................................................................................38
2.2
Secondary objective(s)...........................................................................................38
2.3
Exploratory objective(s) ........................................................................................38
3
Investigational plan ...........................................................................................................39
3.1
Study design...........................................................................................................39
3.2
Rationale of study design.......................................................................................44
3.3
Rationale of dose/regimen, duration of treatment .................................................44
3.4
Rationale for choice of comparator .......................................................................45
3.5
Purpose and timing of interim analyses / design adaptations................................45
3.6
Risks and benefits..................................................................................................46
3.6.1
Risks of clinical assessments ................................................................46
3.6.2
Risks of general anesthesia and stapedotomy surgery..........................46
3.6.3
Risks of administering volume and CGF166 into the inner ear............46
3.6.4
Potential benefits of CGF166 administration........................................47
4
Population..........................................................................................................................47
4.1
Inclusion criteria ....................................................................................................48
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4.2
Exclusion criteria...................................................................................................48
5
Treatment...........................................................................................................................50
5.1
Protocol requested treatment .................................................................................50
5.1.1
Investigational treatment.......................................................................50
5.1.2
Additional study treatment....................................................................50
5.2
Treatment arms......................................................................................................50
5.3
Treatment assignment............................................................................................51
5.4
Treatment blinding.................................................................................................51
5.5
Treating the patient................................................................................................51
5.5.1
Treatment / Patient numbering..............................................................51
5.5.2
Dispensing the study treatment.............................................................52
5.5.3
Handling of study treatment..................................................................52
5.5.4
Instructions for prescribing and taking study treatment........................53
5.5.5
Permitted dose adjustments and interruptions of study treatment ........53
5.5.6
Recommended treatment of adverse events..........................................53
5.5.7
Rescue medication ................................................................................53
5.5.8
Concomitant treatment..........................................................................54
5.5.9
Prohibited treatment..............................................................................54
5.5.10
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................54
5.5.11
Withdrawal of informed consent...........................................................55
5.5.12
Study completion and post-study treatment..........................................56
5.5.13
Early study termination.........................................................................56
6
Visit assessments...............................................................................................................56
6.1
Dietary, fluid and other restrictions.......................................................................57
6.2
Patient demographics / other baseline characteristics ...........................................57
6.3
Treatment exposure and compliance .....................................................................57
6.4
Efficacy assessments .............................................................................................57
6.4.1
Auditory assessments............................................................................58
6.4.2
Vestibular assessments..........................................................................59
6.5
Safety.....................................................................................................................61
6.5.1
Physical examination ............................................................................61
6.5.2
Vital signs..............................................................................................61
6.5.3
Height and weight .................................................................................61
6.5.4
Laboratory evaluations..........................................................................61
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6.5.5
Electrocardiogram (ECG) .....................................................................63
6.5.6
Hearing and balance assessments..........................................................63
6.5.7
Magnetic resonance Imaging (MRI) .....................................................63
6.6
Pharmacokinetic assessments................................................................................63
6.7
Other assessments..................................................................................................63
7
Safety monitoring..............................................................................................................65
7.1
Adverse events.......................................................................................................65
7.2
Serious adverse event reporting.............................................................................67
7.3
Liver safety monitoring .........................................................................................68
7.4
Pregnancy reporting...............................................................................................69
7.5
Prospective suicidality assessment ........................................................................69
7.6
Early phase safety monitoring ...............................................................................69
8
Data review and database management.............................................................................70
8.1
Site monitoring ......................................................................................................70
8.2
Data collection.......................................................................................................70
8.3
Database management and quality control............................................................71
8.4
Data Safety Monitoring Board...............................................................................71
8.5
Adjudication Committee........................................................................................71
9
Data analysis......................................................................................................................72
9.1
Analysis sets ..........................................................................................................72
9.2
Patient demographics and other baseline characteristics.......................................72
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................72
9.4
Analysis of the primary variable(s) .......................................................................72
9.4.1
Variable(s).............................................................................................72
9.4.2
Statistical model, hypothesis, and method of analysis..........................72
9.4.3
Handling of missing values/censoring/discontinuations.......................73
9.4.4
Supportive analyses...............................................................................73
9.5
Analysis of secondary 
 variables ..................................................73
9.5.1
Efficacy .................................................................................................73
9.5.2
Safety.....................................................................................................73
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9.6
Sample size calculation..........................................................................................74
9.7
Power for analysis of key secondary variables......................................................75
9.8
Interim analyses.....................................................................................................75
10 Ethical consideration .........................................................................................................75
10.1
Regulatory and ethical compliance........................................................................75
10.2
Informed consent procedures.................................................................................75
10.3
Responsibilities of the investigator and IRB/IEC..................................................76
10.4
Publication of study protocol and results...............................................................76
11 Protocol adherence ............................................................................................................77
11.1
Protocol amendments.............................................................................................77
12 References .........................................................................................................................78
13 Appendix 1: Sample Log table – all matrices ...................................................................80
15 Appendix 3: Liver event definitions and follow-up requirements ....................................83
List of tables
Table 15-1
Liver Event Definitions.........................................................................83
Table 15-2
Liver Event Follow Up Requirements ..................................................84
List of figures
Figure 3-1
Study design..........................................................................................40
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List of abbreviations
ABR
Auditory brainstem evoked response
Ad5
Adenovirus serotype 5
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANA
anti-nuclear antibody
ANCA
anti-neutrophil cytoplasmic antibody
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATOH1
Atonal
Atoh1
Atonal gene
BAER
Brainstem auditory evoked response evaluations
BEAP
Brainstem Auditory Evoked Potentials
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CO2
carbon dioxide
COWS
Cool – Opposite, Warm – Same
CRO
Contract Research Organization
CT
Computerized tomography
CV
coefficient of variation
dB
decibels
DP
Directional preponderance
DPT
Distortion product
DPOAE
Distortion product otoacoustic emissions
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DSMB
Data Safety Monitoring Board  
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFAP
Glial fibrillary acidic protein
GFP
Green fluorescent protein
GV11
Adenovector backbone used for CGF166
Hath1
Human atonal Protein
h
hour
HINT
Hearing-in-noise test
HIV
human immunodeficiency virus
HL
Hearing Loss
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDPN
3’, 3’-iminodipropionitrile
IEC
Independent Ethics Committee
IL
Intra-labyrinthine
i.v.
intravenous
IRB
Institutional Review Board
kHz
Kilohertz
LDH
lactate dehydrogenase
LLQ
lower limit of quantification
LLN
lower limit of normal
LO
Labyrinthitis Ossificans
mg
milligram(s)
mL
milliliter(s)
MRI
Magnetic resonance imaging
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PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PTA
Pure tone average
RBC
red blood cell(s)
REB
Research Ethics Board
SAE
serious adverse event
SCM
sternocleidomastoid muscle
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SPV
slow phase velocity
TBL
total bilirubin
TRQ
Tinnitus reaction questionnaire
ULN
upper limit of normal
ULQ
upper limit of quantification
VCR
vestibulocollic reflex
vHIT
video Head Impulse Test
VOR
Vestibulo-ocular reflex
vp
Viral particles
WBC
white blood cell(s)
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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Enrollment
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e., prior to starting any 
of the procedures described in the protocol).
Investigational drug
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 
and is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational treatment
All investigational drug(s) whose properties are being tested 
in the study as well as their associated treatment controls.
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination.
Investigational treatment generally does not include other 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used within 
approved indication/dosage.
Part
A major subdivision of the study timeline; begins and ends 
with 
major 
study 
milestones 
such 
as 
enrollment, 
randomization, completion of treatment, etc.
Patient
An individual who has consented to participate in this study. 
The term Patient may be used to describe either a healthy 
volunteer or a patient.
Patient number
A number assigned to each patient who enrolls in the study. 
When combined with the center number, a unique identifier is 
created for each patient in the study.
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, 
titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is 
transferred to Novartis for the purpose of the clinical trial. 
This data includes subject identifier information, study 
information and biological samples.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.


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Study completion
Point/time at which the patient came in for a final evaluation 
visit or when study drug was discontinued whichever is later.
Study drug discontinuation
Point/time when patient permanently stops taking study drug 
for any reason; may or may not also be the point/time of 
premature patient withdrawal.
Study drug/treatment
Any drug (or combination of drugs) administered to the 
patient as part of the required study procedures; includes 
investigational drug, active drug run-ins or background 
therapy.
Treatment number
A unique identifier assigned to each treated patient, 
corresponding to a specific treatment arm assignment.
Variable
Information used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified timepoints.
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs only when a 
subject does not want to participate in the study any longer, 
and does not allow any further collection of personal data


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Protocol synopsis
Protocol number
CCGF166X2201
Title
A three-part, multicenter, open label, single dose study to assess the safety, 
tolerability, and efficacy of intra-labyrinthine (IL) CGF166 in patients with 
severe-to-profound hearing loss
Brief title
A study of the gene therapy CGF166 in patients with severe-to-profound
hearing loss
Sponsor and 
Clinical Phase
Novartis
Phase 1/2
Investigation type
Gene therapy
Study type
Interventional
Purpose and 
rationale
The current study is to evaluate the safety, tolerability, and the potential 
ability of CGF166 delivered through IL-infusion to improve hearing and 
vestibular function. CGF166 is recombinant adenovirus 5 (Ad5) vector 
containing the human Atonal transcription factor (Hath1) cDNA
Primary 
Objective(s) and 
Key Secondary 
Objective

To assess the safety and tolerability of  IL CGF166

To assess the efficacy of IL CGF166 as determined by the change in
pure tone audiometry compared to pretreatment values
Secondary 
Objectives

To assess the efficacy of CGF166 as determined by the change in
brainstem auditory evoked responses (BAER) compared to
pretreatment values

To evaluate the effects of CGF166 on various assessments of
vestibular function compared to pretreatment values

To compare the changes in auditory functions (speech recognition)
and vestibular functions before and after IL infusion of CGF166 into
the study ear


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Study design
The current three part study utilizes an open label, single dose design for the 
investigation of CGF166 and will be conducted in multiple centers. Part A, B,
and C will be conducted in a sequential manner.
The current study will evaluate the safety, tolerability, and potential efficacy of 
CGF166 and the associated delivery procedures in patients with severe-to-
profound bilateral or unilateral hearing loss with intact vestibular function in 
the non-operative ear. Patients are required to have documented non-
fluctuating hearing loss.
Part A
Part A will include a safety and tolerability cohort (N=3). Patient dosing will be 
staggered; dosing the next patient in a cohort will be based on a safety data 
review including all data available through 4 weeks post-dose of the 
previously dosed patient(s).
Part B
Part B will include a volumetric escalation design to evaluate infusion 
volumes of the same CGF166 concentration 
 in 3 cohorts of 
patients (n=3/cohort; total of 9 patients).
Each subsequent cohort will be dosed only after the volume delivered in the 
prior cohort is deemed to be safe and tolerable as determined by the dose 
safety review meeting based on safety data review of the complete previous 
cohort including all data through 4 weeks post-dose.
Safety review meetings will be organized to evaluate available safety data 
and to determine if it is appropriate to escalate to the next infusion volume.
Part C
Based on the DSMB review of data from Part A and Part B of the study, Part 
C of the study will administer a dose volume of 30 µL at the rate of 10 µL/min.
A total of 10 patients will be enrolled in Part C of the study.
Population

Patients with severe-to-profound bilateral or unilateral hearing loss
with intact vestibular function in the non-operative ear

Adult patients who are candidates for a cochlear implant
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Inclusion criteria

For all Parts A, B and C of the study, male or female patients, 18 to
75 years old, inclusive, with severe-to-profound bilateral hearing loss
or unilateral hearing loss with intact vestibular function in the non-
operative ear. Non-fluctuating severe-to-profound hearing loss is
required for the study ear and is defined as:

Pure-tone average (PTA) within 10 dB of the PTA obtained at
least 11 months previously

Word recognition within 20% of previous test at least 11 months
previously

Candidate ear (“study ear”): Minimal residual hearing based on the
pure tone average of 0.5, 1, 2, and 4 kHz thresholds of ≤110 dB HL.

Candidate ear (“study ear”): pure tone audiometric thresholds of
≥50 dB HL for each testable octave frequency of 0.125 and 0.250
kHz, ≥70 dB for each testable octave frequency from 0.5 through
8 kHz, and sentence recognition ≤50% at screening.

Patients with intact vestibular function in at least one ear (non-study
ear) as measured by  vestibular evoked myogenic potential (VEMP)

MRI scan within 6 months or at screening to confirm suitability for
inner ear surgery

Ability to understand the study and provide informed consent;
willingness to comply with the protocol
Exclusion criteria

Patients with hearing loss caused by genetic/developmental
disorders, e.g., cochlea aplasia or autoimmune ear disease

Patients with existing conductive hearing loss or mixed hearing loss
as judged by the Principal Investigator following a thorough review of
all of the trial hearing assessments and MRI scan

Patients with cochlear implants or past cochlear implant in the
candidate study ear

Hearing loss due to any other cause that would not be expected to
respond to hair cell regeneration, for example trauma or central
auditory lesions or lack of an auditory nerve

Patients who will require ototoxic drugs as routine therapy over the
course of the study, such as cystic fibrosis patients

Any contraindication to the planned surgery or anesthesia as
determined by the surgeon, anesthesiologist, or designee

Previous surgery in the study ear

Any otological history, such as chronic otitis, cholesteatoma,
tympanic membrane perforation, that suggests poor candidacy for
cochlear implant or inner ear surgery or suggests potential
interference with study auditory or vestibular function tests

Pregnant women

Abnormal vital signs and/or ECG that suggest potential
contraindication for planned study anesthesia

Past serious adverse reaction to anesthesia

Meniere’s Disease

History of radiation therapy to the head and neck

Participation in a clinical trial within the last 30 days


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Investigational and 
reference therapy

CGF166 is recombinant adenovirus 5 (Ad5) vector containing the
human Atonal transcription factor (Hath1) cDNA. CGF166 will be
provided in a septum vial, containing 0.5 mL 
 of
opalescent liquid viral vector.

In Part A and Part B all investigational infusion volume was infused
at a rate of 10 µL/min except 1 patient where in fusion volume was
infused at a rate of 20 µL/min. In Part C all following protocol
amendment 5 all investigational infusion volumes will be infused at a
rate of up to 10 µL/min in to the perilymphatic space
Efficacy 
assessments
Auditory assessments

Pure tone audiometry, including immittance testing

Speech audiometry

Brainstem auditory evoked response evaluations (BAER)
Vestibular assessments

Head Impulse test
Safety 
assessments

Physical examination

Otoscopy

Neurological exam

FSH verification and Pregnancy test (serum at screening and urine
at subsequent visits)

Vitals and body measurements (height, weight, temperature, blood
pressure, and pulse rate)

ECG

Clinical laboratory tests (hematology, chemistry, and urinalysis)

MRI with gadolinium (within 3 months or performed at screening)

Adverse events
Other assessments
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Data analysis

Tone thresholds will be analyzed for each frequency tested
separately.

Pure tone audiometry air conduction threshold data will be listed and
graphically displayed by patient, infusion volume, frequency, and
visit/time.

Summary statistics will be provided by infusion volume, frequency,
ear and visit/time.

Change from baseline of the thresholds (mean of screening and
baseline visit) will also be summarized by infusion volume,
frequency, ear and visit/time
Key words
Hearing loss, cochlear implant, gene therapy


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Assessment schedule
Stu d y Ph as e
Scr e e n in g  
vis it
Bas e lin e
T r e atm e n t d ay
En d  o f Stu d y 5
Day -63 to  -4
Day -3 to -1
Day 2
Day 4
Day 6
Day 15
Day 29
Day 57
Day 113
Day 169
V is it Nu m b e r s
1
2
4
5
6
7
8
9
11
13 / 777
777
T im e  (h )
p r e -in fu s io n
Po s t-in fu s tio n
4 h r
In clu s io n /Exclu s io n
x
x
Re le van t m e d ical 
h is to r y/C u r r e n t m e d ical 
co n d itio n s
x
x
De m o g r ap h y
x
A u d ito r y an d  ve s tib u lar  
functio n  as s e s s m e n ts
x
x
x
x
x
x
x
His tor y o f alco h o l an d  
d r u g  d e p e n d e n ce
x
x
Ge n e r al Ph ys ical e xam
x
x
Otos co p y
x
x
x
x
x
x
x
x
Ne u r o lo g ical e valu atio n
x
x
x
x
x
x
x
x
x
x
x
Pr e g n an cy te s t
x  (s erum)
x
x 6
x
HIV  an d  He p atitis
x
V itals  Sig n s  an d  b o d y 
m e as u r e m e n ts
Bo d y He ig h t
x
Bo d y W e ig h t
x
x
x
x
x
x
Bo d y T e m p e r atu r e
x
x
x
x
x
x
x
x
x
x
x
Blo o d  p r e s s u r e  / Pu ls e  
r ate
x
x
x
x
x
x
x
x
x
x
x
EC G
x
x
x
x
x
x
x
He m ato lo g y, Blo o d  
ch e m is tr y, Ur in alys is
x
x
x
x
x
x
x
x
x
Po s t- o p  Ob s e r vatio n  p e r io d
Fo llo w -u p  Pe r io d
as  needed
1
Day 1
3
5 - Pts . W h o  h ave  co m p le te d  Day 169 in  th e  s tu d y w ill r e tu r n  to s ite  as  s o o n  as  p o s s b ile  an d  co m p le te  e n d  of s tu d y vis it 777; Patie n ts  w h o  h ave  n o t co m p le te d  Day 169 
in  th e  s tu d y w ill co m p le te  e n d  o f s tu d y (vis it 777) as s e s s m e n t o n  Day 169
6  - as s e s s m e n t d o n e  if it is  e n d  o f s tu d y as s e s s m e n t.
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Study Phase
Screening 
visit
Baseline
Treatment day
End of Study5
Day -63 to -4
Day -3 to -1
Day 2 Day 4 Day 6
Day 15
Day 29
Day 57
Day 113
Day 169
Visit Numbers
1
2
4
5
6
7
8
9
11
13 / 777
777
MRI with gadolinium
x
x3
x3
x3
x
C-SSRS
x
x
x
x
x
x
Comments
Adverse events
Concomitant 
meds/Therapies
Study Surgery
Dose administration
Study Completion
x6
x
6 - assessment done if it is end of study assessment.
Post-op Observation period
Follow-up Period
5 - Pts. Who have completed Day 169 in the study will return to site as soon as possbile and complete end of study visit 777; Patients who have not completed Day 169 
in the study will complete end of study (visit 777) assessment on Day 169
Day 1
3
as needed
as needed
as needed
x
x
C-SSRS- Columbia Suicide Severity Rating Scale;
3 MRI may be performed if the audiometery meets one of the stopping criteria
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1
Introduction
1.1
Background
Sensorineural hearing loss and vestibular dysfunction may result from destruction of inner ear 
sensory hair cells and/or auditory nerves. Humans are born with ~30,000 sensory hair cells. 
Sensory hair cells in the organ of Corti, located within the mammalian cochlea, are critical for 
auditory function while vestibular sensory hair cells located in the vestibular canals and the 
utricle and saccule provide the basis for vestibular function. Sensory cells can be damaged or 
destroyed by pharmacological agents (chemotherapy and aminoglycosides), loud noises, 
infections or simply aging and loss of these cells is permanent as they do no regenerate. 
Hearing loss is currently treated with a hearing aid or a cochlear implant in patients with 
severe impairment; patients are eligible for a cochlear implant when they have severe to 
profound hearing loss with the inability to discriminate 40% of speech. No pharmacologic 
agents exist to restore hearing function. More than 300,000 people worldwide have received 
cochlear implants. Cochlear implants improve auditory function but require invasive surgery, 
require ongoing maintenance and patient training; they also are expensive. Severe vestibular 
dysfunction patients may experience debilitating vertigo and nausea. There is no therapy other 
than rehabilitation to acquire environmental signals to compensate for vestibular dysfunction. 
There are no therapeutic options available to regenerate sensory hair cells to restore auditory 
or balance function and as such this represents a significant medical need.
The atonal gene, Atoh1, is a basic helix-loop-helix (bHLH) transcription factor that is required 
for initiation of the required gene regulatory pathway for differentiation of hair cells from 
progenitors during prenatal development. The ATOH1 protein is called Hath1 in humans 
 
 Moreover, ATOH1 expression can force the supporting cells, which 
normally surround the sensory hair cells and lack sensory function, to transdifferentiate into 
new sensory hair cells.
1.1.1
Relevant data summary
CGF166 is a replication-incompetent Adenovirus 5 (Ad5) vector engineered to deliver Hath1 
expressed under the control of the GFAP (glial fibrillary acidic protein) promoter. CGF166 is 
provided as a solution in single-use septum vials that are stored frozen at -20°C and thawed 
prior to use.
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Pharmacology
The GFAP promoter will provide for low level expression restricted to supporting and 
neuronal cells.
CGF166 contains the GFAP promoter, which will limit the Hath1 transgene expression to 
cells that have endogenous GFAP protein expression. Studies by (Rio et al 2002) and 
(Schlecker et al 2011) show endogenous GFAP protein expression by immunohistochemistry 
in the normal inner ear: cochlear supporting cells, organ of corti, vestibular supporting cells, 
and glial cells in the spiral ganglion. Sensory hair cells did not show positive GFAP staining. 
FAP protein positive cells 
included the supporting cells in the organ of Corti and in the macular organ ampulla as well as 
in the glial cells of the spiral ganglion. Additionally, (Staecker et al 2011) report a similar 
distribution pattern obtained using an adenoviral vector expressing GFP under the control of 
the GFAP promoter. These studies taken together support that the GFAP promoter contained 
in CGF166 will limit expression of Hath1 to the supporting cells in the normal and injured ear.
The GFAP promoter was chosen for its selectivity to limit transgene expression to supporting 
cells and also for its ability to promote the generation of sensory hair cells. 
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CGF166 regenerates sensory hair cells in human vestibular explants ex vivo
Human vestibular explants, harvested from mature human vestibular end organs at the time of 
labyrinthectomy, provide a unique opportunity to study gene transfer agents designed to treat 
inner ear disorders. CGF166-mediated Hath1 expression has been shown to regenerate 
sensory hair cells was evaluated in human macular organ cultures. These studies demonstrated 
that CGF166 mediated Hath1 expression effectively regenerated sensory hair cells in human 
explants cultures compared with the neomycin-treated control sample.
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Development of IL delivery for inner ear exposure
IL delivery is the intended clinical route of administration for inner ear gene delivery of 
CGF166. This route of delivery is expected to distribute the vector throughout the cochlea and 
vestibular fluid space to allow access to the target supporting cells in the organ of Corti and 
vestibular organs. While IL delivery was successfully developed for clinical and non-clinical 
use, the point of access varied between species due to anatomical variations of the external 
auditory canal (EAC), middle ear, and skull. The clinical access point is via the stapes 
footplate/oval window and will deliver CGF166 into the scala vestibuli perilymph. 
Also, human temporal bone studies were conducted to optimize the IL delivery method via 
the stapes footplate for clinical studies (Investigator’s Brochure).
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1.1.1.5
Human pharmacokinetic data
Not applicable.
1.1.1.6
Human pharmacodynamic data
Not applicable.
1.2
Study purpose
The current study is to evaluate the safety, tolerability, and the potential ability of CGF166 
delivered through IL-infusion to improve hearing and vestibular function. CGF166 is 
recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor 
(Hath1) cDNA.
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2
Study objectives
2.1
Primary objective(s)

To assess the safety and tolerability of IL CGF166

To assess the efficacy of IL CGF166 as determined by the change in pure tone audiometry
compared to pretreatment values
2.2
Secondary objective(s)

To assess the efficacy of CGF166 as determined by the change in brainstem auditory
evoked responses (BAER) compared to pretreatment values

To assess the efficacy of CGF166 in regenerating vestibular function as determined by the
change in phase compared to pretreatment values

To compare the changes in auditory functions (speech recognition) and vestibular
functions before and after IL infusion of CGF166 between the study ear
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This non-confirmatory three part study utilizes an open label, single dose, sequential cohort
design for the investigation of CGF166 and will be conducted in multiple centers.
The current study will evaluate the safety, tolerability, and potential efficacy of CGF166 and 
the associated delivery procedures in patients with severe-to-profound bilateral or unilateral 
hearing loss with intact vestibular function in the non-operative ear. Patients are required to 
have documented non-fluctuating severe-to-profound bilateral or unilateral hearing loss prior 
to enrollment. A maximum of 22 patients will be enrolled in this 3 Part, 5 cohort trial (Figure 
3-1).


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Part A
Part A will assess the safety and tolerability as well as potential efficacy following a single IL 
dose of 20 uL of CGF166 concentration 
. Patient enrollment will be 
staggered so that a safety data review can be done after each
treated
patient
(~4 weeks after treatment) prior to dosing each subsequent patient.
Part B
Part B will include a volumetric escalation design to evaluate up to 3 infusion volumes 
(between 20 and 60 µL) of the same CGF166 concentration
 in 3 cohorts of 
patients (n=3/cohort; total of 9 patients). All dose volumes are subject to change based on trial 
safety data.
Each subsequent cohort will be dosed only after the volume delivered in the prior cohort is 
deemed to be safe and tolerable as determined by the Drug Safety Monitoring board (DSMB). 
The DSMB will consist of internal Novartis personnel as well as at least one external subject 
matter expert who is not serving as an investigator or otherwise privy to trial data. 
The membership and workings of the DSMB will be detailed in the DSMB Charter. 
In addition, the scheduling and dosing of the first patient in each cohort will be staggered to 
allow at least a four week interval in between treating the remaining 2 patients in each cohort.
Part C
Considering the preliminary overall review of the data including changes observed in 
audiometry for patients from Cohort 1 through Cohort 4, the DSMB endorsed the team’s 
proposal that 30 µL is the maximum tolerated dose (volume) observed in the study.
The highest safe and tolerable volume determined in Part B will be used for IL-infusion in 
Part C patients. A total of 10 patients will be required for Part C of the current study. A safety 
review analogous to that described for parts A and B will take place whenever a block of five
patients completes the first 4 weeks of study assessments.
Part A-C
Patients will undergo the same protocol-required assessments and visit schedule in all Parts of 
the trial (A-C). Part C of the study will only commence once preliminary safety and 
tolerability has been established for CGF166 and the associated delivery methods in patients 
in Part A and B.
The trial duration will consist of 63 day screening period followed by a 1-3 day baseline
assessment period and in house surgical dose/post operation assessment period (~6-14 days)
followed by a 6 month post-dose assessment period. In addition, all dosed patients in all 
Parts A-C will be advised of the opportunity to enroll in a separate protocol 
During the screening period, eligibility of potential patients will be verified at the study centers.
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Potential patients will be evaluated for fitness to undergoing protocol-required surgery and for 
the planned therapy based on physical exam, MRI, past/current medical history, and 
laboratory testing. During the screening period, potential patients will also undergo 
pre-treatment 
, auditory and vestibular function tests.
At least two outpatient visits during the screening period are anticipated in order to complete 
the required verification and assessments. If all screening assessments can be completed in 
one visit, that is allowed. Additional outpatient screening visits (i.e., more than 2 visits) are 
permitted pending patients’ and clinic schedule and the need for re-verifications and potential 
re-testing.
Based on the screening assessments, one ear will be selected as the study ear and will undergo 
the study required surgery; criteria for the selection of the study ear are described as follow:

The ear with more severe hearing loss as determined by pure tone audiometry and speech
recognition score

If both ears have equal severity in hearing loss, then the study ear will be selected by the
investigator’s preference
Upon completing the screening visits, eligible patients will be scheduled for a baseline visit 
and surgery.
Baseline (Day -3 to -1)
Eligible patients will return to the study center at baseline (Day –3 to -1) and undergo 
pre-operative preparation as well as pre-treatment functional assessments.
Day 1 visit
On Day 1, study patients will undergo the required protocol assessments and the stapedotomy 
for delivery of the study drug to the scala vestibuli perilymphatic space of the inner ear. At the 
completion of the surgery and study drug infusion, study patients will recover in the surgical 
center’s post-op facility and undergo post-surgery evaluations and assessments. Study patients 
may be transitioned to either the inpatient unit of the surgical center or pre-arranged 
temporary housing close to the surgical center.
Day 2 to Day 6 visits
Study patients will be followed up for the next 5 post surgery days (Day 2 to Day 6) and will 
undergo the protocol-required safety follow up evaluations. Study patients will be discharged 
home if there are no significant adverse events requiring prolonged monitoring. Patients will 
have the option to remain in the provided housing until the completion of the Day 14 visit.
Subsequent visits will be scheduled with the study patients prior to being discharged.
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Day 15 visit
Study patients will return to the study center to have surgical packing removed from their ear 
and will also undergo study required assessments. Patients will be discharged home or to their 
local housing at the end of all study required evaluations. Patients will be reminded of their 
next scheduled visit.
Follow up and end of study visits
Total follow-up period in the trial will be 6 months after administration of CGF166. The 
follow-up visits will be at 2, 4, and 6 months/EOS. 
Patient who have already completed Day 169 assessment (~ 6 month) will return to site to 
complete end of study visit (visit 777) as soon as practically possible. Patients who have not 
completed Day 169 will complete end of study visit (visit 777) on Day 169.   
During each visit to the study center, post-operative recovery of the study ear will be 
monitored and evaluated. Study patients will also undergo the study-required safety, 
auditory, and vestibular function tests during each visit. Bio-distribution blood samples 
will also be collected during each visit. Samples for immunogenicity testing will be collected 
as per the blood log. At completion of the 6 month post-surgery visit (end of study visit), if 
there are no significant adverse events requiring prolonged monitoring, study patients will be 
considered to have completed the study and will be discharged from the study.
Detail on the pre-surgery preparation, the surgical procedure, and the preparation of study 
drug as well as infusion procedure can be found in the study surgical and pharmacy and drug 
delivery manual.
Detail on performing the study auditory and vestibular assessments can be found in the study 
auditory and vestibular evaluation manual.
Safety Data Reviews:
Prior to dosing each patient in Part A (cohort 1) and prior to dosing the 2 remaining patients in 
Part B (cohorts 2-4), a review of all safety and tolerability data as well as a review of selected 
auditory and vestibular function data will be conducted. Data considered for review will be 
those available up to 4 weeks post-dose, as outlined in the DSMB Charter. Safety and 
tolerability must be assessed as satisfactory in order to proceed with the remaining patients in 
the cohort. For cohorts 2-4, the decision to dose the remaining 2 patients will be made by the 
DSMB. If notable adverse events or safety concerns are found at one of the planned dose 
levels, the next planned dose level may be changed, as summarized in Section 5.5.5.
After completion of one cohort and prior to proceeding to the next cohort, a review of all 
safety and tolerability data, as well as limited auditory and vestibular data will be performed 
for all patients who received a dose of CGF166 and have completed at least 4 weeks of study 
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assessments. Safety and tolerability must be assessed as satisfactory in order to proceed to the 
next cohort. This decision will be made by the DSMB. Should notable adverse events or 
safety concerns be found at one of the planned dose levels, the next planned dose level may be 
changed, as summarized in Section 5.5.5.
For Part C, the safety review described above will be performed as each 5 patients complete 
their first 4 weeks of study assessments.
3.2
Rationale of study design
The open label, adaptive gene therapy trial design is intended to assess the safety, tolerability 
and efficacy of a single dose of CGF166. The trial design uses a staggered patient enrollment 
with continuous data reviews to limit as much unforeseen risk as possible prior to enrolling 
each patient in Part A or initiating another cohort in Part B, while also allowing for a potential 
clinical benefit. In addition, the trial design uses a sequential three Part design (Part A - Safety; 
Part B - Volume escalation; Part C - Efficacy) with cohort safety data reviews as described
above. Based on the preliminary review of the data including changes observed in audiometry 
for patients from Cohort 1 through Cohort 4, the DSMB endorsed the team’s proposal that 30 
µL is the maximum tolerated dose (volume) and start the Part C of the study.
3.3
Rationale of dose/regimen, duration of treatment
As a gene therapy that requires surgical administration, this will be a single dose study to 
assess the safety and tolerability as well as efficacy of CGF166.
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3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses / design adaptations
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3.6
Risks and benefits
3.6.1
Risks of clinical assessments
Magnetic resonance imaging with contrast will be performed during the course of this study.
Common risks associated with MRI include interference with implanted metallic objects and 
there is a risk nephrogenic systemic fibrosis in patients with severe renal impairment who 
receive gadolinium. Accordingly, these patients must be excluded from this study. Some of 
the vestibular assessments may provoke nausea, vomiting and disequilibrium; these symptoms 
should be anticipated and managed expectantly.
3.6.2
Risks of general anesthesia and stapedotomy surgery
Foreseeable risks for the administration of CGF166 are largely those known for general 
anesthesia, which are uncommon, and those associated with modern stapedotomy.
In published series that describe stapedotomy outcomes, many patients experience transient 
vestibular symptoms that are procedure-related including dizziness and nausea.
Post-operatively, it is possible that symptoms and signs of vestibular dysfunction may be 
more frequent or more severe than are usually observed after stapedotomy, or may persist for 
a longer period of time.  Strategies to avoid patient Valsalva maneuvers and possible effects 
on the stapedotomy plug or the re-positioned tympanic membrane
are important. 
Such preemptive approaches might include treatment with dexamethasone and anti-histamines, 
for example.
Known surgical risks of mild to moderate severity include persistent alteration of taste due to 
injury of the chorda tympani, infectious otitis media, perilymph fistula, reparative granuloma 
and perforation of the tympanic membrane, and worsened hearing. Each of the foregoing 
items carries a risk of 5% or less. Rare, but more serious adverse effects include facial nerve 
palsy, infective labyrinthitis or meningitis.
3.6.3
Risks of administering volume and CGF166 into the inner ear
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3.6.4
Potential benefits of CGF166 administration
Potential clinical benefits envisioned include improved hearing that may manifest as 
improved speech recognition and the ability to benefit from a hearing aid and avoid the need 
for a cochlear implant. Hearing correction achieved by the stapedotomy procedure often 
improves tinnitus in otosclerosis patients who have a post-operative improvement in their 
air-bone gap, so for those patients with tinnitus, it’s possible that CGF166 therapy could 
improve the severity of their tinnitus too.
For more details please refer to the Investigator Brochure.
4
Population
The study population will be comprise of patients who have severe-to-profound bilateral 
hearing loss or unilateral hearing loss with intact vestibular function in the non-operative ear. 
Patients are required to have documented non-fluctuating severe-to-profound hearing loss 
prior to enrollment. Up to 22 patients will be enrolled in the trial.
The investigator must ensure that all patients being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all inclusion/exclusion criteria at 
screening and baseline. A relevant record (e.g., checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
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4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. For all Parts (A, B and C) of the study, male or female patients, 18 to 75 years old,
inclusive, with severe-to-profound bilateral or unilateral hearing loss with intact vestibular
function. Non-fluctuating severe-to-profound hearing loss is required for the study ear and
is defined as:

PTA within 10 dB of the PTA obtained at least 11 months previously.

Word recognition within 20% of previous test at least 11 months previously
[AAO-HNS Hearing Classification System]
3. Candidate ear (“study ear”): Minimal residual hearing based on the pure tone average of
0.5, 1, 2, and 4 kHz thresholds of ≤110 dB HL
4. Candidate ear (“study ear”): Pure tone audiometric thresholds of ≥50 dB HL for each
testable octave frequency of 0.125 and 0.250 kHz, ≥ 70 dB HL for each testable octave
frequency from 0.5 through 8 kHz and sentence recognition scores ≤50% at screening.
Subject responses will be monitored for vibrotactile sensation, particularly for the low-
frequency stimuli (e.g., 125 and 250 Hz). A frequency that elicits vibrotactile responses at
levels below 70 dB HL will be considered “not testable” for hearing threshold and only
those frequencies that are testable for hearing threshold will be considered for patient
inclusion/exclusion in the study.
5. Patients with intact vestibular function in at least one ear (non-study ear) as measured by
vestibular evoked myogenic potential (VEMP)
6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study
7. Meet surgical requirements/eligibility (including MRI scan within 3 months or at
screening to confirm suitability for inner ear surgery)
8. Patients must weigh at least 40 kg to participate in the study, and must have a body mass
index (BMI) <45 kg/m2. BMI = Body weight (kg) / [Height (m)]2
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer;
or longer if required by local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.
3. Patients with hearing loss caused by genetic/developmental disorders, e.g., cochlea aplasia.
4. Patients with existing conductive hearing loss or mixed hearing loss as judged by the
Principal Investigator following a thorough review of all of the trial hearing assessments,
air-bone gap assessment based on air and bone pure tone audiometry and MRI scan.
5. Patients with a history of cochlear implant in the study ear.


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6. Hearing loss due to any other cause that would not be expected to respond to hair cell
regeneration, for example trauma or central auditory lesions or lack of an auditory nerve
7. Patients who will require ototoxic drugs as routine therapy over the course of the study,
for example cystic fibrosis patients.
8. Any contraindication to the planned surgery or anesthesia as determined by the surgeon,
anesthesiologist, or designee.
9. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 6 months following treatment period of the investigational
medication. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a.
Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate <1%),
for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c.
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception women should have been stabile on the same pill 
for a minimum of 3 months before taking study treatment.
10. Sexually active males must use a condom during intercourse after investigational drug
treatment and for 6 months after stopping investigational medication and should not father
a child in this period. A condom is required to be used also by vasectomized men in order
to prevent delivery of the drug via seminal fluid.
11. Bilateral cochlear implants or a past attempt for cochlear implant in the study ear or any
other inner ear surgery that could interfere with drug efficacy.
12. Any other otologic history, including but not limited to chronic otitis, cholesteatoma,
tympanic membrane perforation, head and neck radiation or Meniere’s disease, that
suggests poor candidacy for cochlear implant or inner ear surgery or suggests potential
interference with study auditory or vestibular function tests.
13. Abnormal vital signs and/or ECG that suggest potential contraindication for planned study
anesthesia or past serious adverse reaction to anesthesia.
14. Patients with estimated glomerular filtration rate (GFR) < 30 ml/min (MDRD formula) at
screening.
15. Patients with heart failure NYHA class III or IV.


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16. Patients with Child-Pugh class C cirrhosis.
17. History of myocardial infarction, coronary bypass surgery, or any percutaneous coronary
intervention (PCI) within 6 months prior to screening.
18. Patients who require chronic anticoagulation, except daily aspirin.
19. A psychiatric disease or substance abuse history likely to interfere with protocol
compliance.
20. Any medical condition, judged by the investigator, that is likely to interfere with the
patient’s participation in the study, or likely to cause serious adverse events during the study.
21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
22. Immunocompromised patients, as judged by the investigators based on patient history,
physical exam and CBC
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal 
transcription factor (Hath1) cDNA. 
CGF166 will be delivered using an infusion pump system with a blunt needle cannula 
(as per the Surgical and Pharmacy/Drug Delivery Manuals details provided separately).
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
Patients will be assigned to one of the 5 cohorts. Part A and Part B of the study have been 
completed; dose volumes administered reflect the study treatment for each cohort including 
planned dose volume for Part C of the study (see Table 5-1 for estimated viral particle 
delivery quantity and normalized doses estimates).
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Study treatments are defined as:

Part A:

Cohort 1: single dose of 20 µL CGF166

Part B:

Cohort 2: single dose of 40 or 30 µL CGF166

Cohort 3: single dose of 40 µL CGF166

Cohort 4: single dose of 60 µL CGF166

Part C:

Cohort 5: single dose of 30 µL @ 10 µL/minCGF166
5.3
Treatment assignment
Treatment numbers will be assigned in ascending, sequential order to eligible patients 
(see Section 5.5.1 for details). The investigator will enter the Treatment number on the CRF.
5.4
Treatment blinding
This is an open label trial.
5.5
Treating the patient
5.5.1
Treatment / Patient numbering
Screening number
Each patient screened is assigned a unique screening number. The screening number is a 
combination of the center number, that is provided by Novartis, and a three digit number 
starting with 001 for each patient which is assigned by the Investigator. Therefore, if the 
center number is 1 (any leading 0’s in the center number are dropped) the screening numbers 
will be assigned such as 1001001, 1001002, 1001003 in ascending order. If the center number 
is 2 (or 0002), the screening numbers will be 1002001, 1002002, 1002003 in an ascending 
order.
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Treatment number
If the patient is deemed eligible for the study and will commence dosing, a treatment number 
will be assigned. Once assigned to a patient, a treatment number will not be reused.
The treatment number becomes the definitive patient number as soon as a patient receives the 
first dose of the respective study treatment.
There should be a source document maintained at the site which links the screening number to the 
treatment assignment number (once assigned). This source document should be provided to all 
appropriate parties (i.e., Central Laboratory, ECG Laboratory) as soon as this is available.
5.5.2
Dispensing the study treatment
The investigational drug, CGF166 will be prepared by Novartis and supplied to the 
Investigator site as open labeled bulk medication in single dose septum vials.
For preparation of the study medication, please refer to the separate Pharmacy/Drug Delivery
manual.
Appropriate documentation of the patient specific dispensing process must be maintained.
The medication labels will be in the local language, will comply with the legal requirements of each 
country, and will include storage conditions for the drug but no information about the patient.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received at the study site by a designated person, handled 
and stored safely and properly, and kept in a secured location to which only the Investigator 
and designated staff have access. Upon receipt, the study drugs should be stored according to 
the instructions specified on the labels and in the Pharmacy/Drug Delivery Manual provided 
separately.
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Storage conditions must be adequately monitored and appropriate temperature/humidity logs 
maintained as Source data.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the Monitor during 
site visits and/or at the completion of the trial.
All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any partly used or unused drug supply.
At the conclusion of the study, and, if allowed during the course of the study (e.g., an open 
label study), the Investigator will provide a copy of the drug accountability ledger to the Monitor.
Only after receiving a written authorization by Novartis, the Investigator/designee will send 
all the unused and partly used drug supplies as well as the empty containers to the address 
provided at the time of authorization for destruction or have the unused and partly used drug
supplies as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate.
5.5.3.2
Handling of other study treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
The dose prescribed and dispensed to the patient must be recorded on the Dosage 
Administration Record CRF including any observed leaking from the ear canal during dosing.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted, unless during surgical 
procedure the surgeon deems the patient ineligible or is unable to dose the patient.
In case of notable adverse events and safety concerns during dose escalation of the study, the 
following changes to the next planned dose level may be considered:

Administration of a dose below the starting dose

Administration of an intermediate dose between the current and preceding dose

Administration of an intermediate dose between the current and next planned dose

Repeated administration of the current dose

Termination of any further dose escalation
These changes must be recorded on the Dosage Administration Record CRF.
5.5.6
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
5.5.7
Rescue medication
Not applicable.


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5.5.8
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
5.5.9
Prohibited treatment
Use of known ototoxins, for example systemic aminoglycoside antibiotics, should be avoided 
if possible following dose administration through study completions. If a known, potent 
ototoxin should be required, for example cisplatin, then the patient may remain in the study 
but should be excluded from the efficacy analysis.
5.5.10
Discontinuation of study treatment and premature patient withdrawal
Study and cohort “Stopping rules”
The study will be put on hold and no new patients dosed pending a full safety review if any of 
the following criteria should be met:

3 or more patients with study drug-related or surgical procedure-related SAEs are reported

At least 2 patients in the same cohort experience a similar AE which is assessed as severe
in intensity, and is related to the study drug or surgical procedure

Clinical evidence of post-operative vestibular dysfunction of moderate severity (impairs
instrumental activities of daily living, such as preparing meals or housework) that persists
longer than 4 weeks in 2 patients.


1 patient develops a severe systemic immune response attributed to study drug

1 patient develops a severe infection consistent with those caused by adenovirus
(if confirmed to be related to study drug).
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Individual patient withdrawal
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
If a patient withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s withdrawal from the study and record this 
information on the CRF.
The investigator should withdraw the patient from study if, on balance, he/she believes that 
continuation would be detrimental to the patient’s well-being. A patient may withdraw
consent from the study at any time.
A decision to not administer the single dose study treatment and patient withdrawal will be at 
the discretion of the Investigator, under the following circumstances:

Complication during surgery or patient ear anatomy does not allow the surgeon to 
properly administer the dose infusion

Use of prohibited treatment

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should NOT automatically be considered withdrawn 
from the study. As single dose gene therapy, every effort will be to follow up with all treated 
patients whom have discontinued for whatever reason. See Section 6 for the required 
assessments of these patients after discontinuation of study treatment.
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show “due diligence” by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc.
Patients who are withdrawn from the study for reasons other than safety or lack of efficacy 
will not be replaced by an equal number of newly enrolled patients.
5.5.11
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require
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All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
5.5.12
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. The study will complete when the last patient 
completes their Study Completion visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator. After completion of 
the trial, each patient will be offered the opportunity to participate in a separate follow-up trial.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
All patients will be expected to participate in a separate long term follow-up observational study.
5.5.13
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
6
Visit assessments
The full Assessment schedule is presented at the end of the synoptic section, above.
Patients should be seen for all visits on the designated day or as close to it as possible.
Patients who discontinue study before completing the study, and those who prematurely 
withdraw from the study for any reason, should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed.
Acceptable deviations ranges from assessment times based on logistical and operational 
considerations are detailed in separate data management module documents.


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6.1
Dietary, fluid and other restrictions
During recruitment, screening/informed consent review, and baseline visit, the patients will be 
informed and reminded of the following restrictions:

Avoid strenuous physical exercise (e.g., weight training, aerobics, football) before each
visit and until after Study Completion evaluation.

Avoid alcohol for 48 hours before each visit until after Study Completion evaluation.

Patients should avoid getting water into their external auditory canal for 2 weeks after
surgery.

Patients may not swim for 4 weeks after surgery.

Patients may not be passengers in airplanes for 2 weeks after surgery.
All patients will fast prior to surgery as instructed in the surgical procedure manual and 
continue to fast for at least 4 hours thereafter.
6.2
Patient demographics / other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, predominant ethnicity.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
6.3
Treatment exposure and compliance
Not required.
6.4
Efficacy assessments
Efficacy/Pharmacodynamics will be measured in this clinical study by the following 
assessments:
Auditory assessments

Pure tone audiometry

Speech audiometry

Brainstem auditory evoked response evaluations (BAER)
Vestibular assessments

Head Impulse Test
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6.4.1
Auditory assessments
6.4.1.1
Pure tone audiometry
Hearing sensitivity to frequency-specific pure tone stimuli will be determined by measuring 
audiometric thresholds through earphones (air conduction) and bone-conduction vibrator 
(bone conduction) using a standard loudness bracketing procedure. The patient will be asked 
to respond when s/he hears the tone, and the softest sound detected will be defined as 
threshold for that tone. Immittance testing is completed as part of standard audiometric 
assessment.

Air conduction thresholds will be measured for standard-frequency and extended-
frequency ranges: 0.125, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12.5, 14, 16 kHz.

Bone conduction will be measured for frequencies 0.25 -4 kHz. Masking to determine
ear-specific bone conduction thresholds will be performed when necessary.
6.4.1.2
Speech audiometry
For all speech perception tests, the patient repeats the words and/or sentences after they are 
presented. Speech perception is scored in percent of words correctly repeated.

Ear-specific speech recognition threshold (SRT) will be measured using two-syllable
spondee words via monitored live voice through headphones. SRT is defined as the lowest
stimulation level at which speech perception is 50% correct.

Ear-specific word recognition at 40 dB sensation level (SL), or maximum comfortable
level if 40 dB SL not possible, will be tested using NU-6 words via monitored live voice
through headphones.

Aided word recognition testing for individual ears using consonant-nucleus-consonant
(CNC) words (Peterson and Lehiste 1962) will be presented at 60 dB SPL-A in the sound
field. The CNC is a test of 50 monosyllable words, and the stimuli are a pre-recorded test
of 50 monosyllabic words.
6.4.1.3
AzBio Sentence test
The Minimum Speech Test Battery (MSTB) for cochlear implant evaluation was updated in 
2011 to include more challenging sentence test materials, such as the AzBio Sentences Test 
(Spahr and Dorman 2004), due to ceiling effects in performance observed with the Hearing in 
Noise Test (Gifford et al 2008). The AzBio Sentences Test consists of 15 sentence lists, with 
the MSTB including 8 additional lists, and is scored in percent of words correctly repeated.
The AzBio sentence test presented at 60 dB SPL-A, both in quiet and with background 
10-talker speech babble noise presented at +5 dB signal-to-noise-ratio (SNR). Presentation is
in the soundfield in an individual-ear aided condition.
6.4.1.4
Hearing-in-Noise-Test (HINT)
The Hearing in Noise Test (HINT) (Nilsson et al 1994) consists of 25 lists of recorded 
sentences presented at 60 dB SPL-A in quiet and in speech-weighted noise at +8 SNR. 
The HINT sentences are relatively easy to understand and often show ceiling effects of 
performance with cochlear implant testing. For this reason, the cochlear implant test battery 


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has recently been updated to replace the HINT with the AzBio Sentences Test. However, the 
HINT can also be administered adaptively, with the sentences remaining at a fixed stimulation 
level and the noise level adapted until the patient scores 50% correct understanding. 
Performance is quantified as signal-to-noise ratio (SNR) in dB. This adaptive testing method 
avoids ceiling effects observed when using fixed stimulation levels; however, this method is 
not routinely used clinically in the US. One potential future benefit is it resembles adaptive 
sentence in noise testing in other languages, such as the German Oldenburger 
Satztest/Oldenburg Sentence Test (OLSA). Presentation is in the sound field in an individual-
ear aided condition.
6.4.1.5
Brainstem auditory evoked response evaluations (BAER)
The BAER provides electrophysiologic information on the status of the auditory pathway 
from the periphery up through the brainstem. The BAER waveform reflects responses from 
different neural generators, with the most robust neural response arising from the inferior 
colliculus, observed as wave V. The BAER can be elicited by click or tone-burst stimuli, the 
latter providing more frequency-specific information.
Surface electrodes are placed as non-inverting on the vertex, inverting on lobe or mastoid of 
the test ear, and ground on the forehead. The patient is at rest, and the click or toneburst 
stimuli are presented through insert earphones at a high level (starting level depends on degree 
of hearing loss), and the stimulation level is decreased until BAER threshold is obtained, 
defined as the lowest stimulation level at which a repeatable wave V is observed.
6.4.2
Vestibular assessments
6.4.2.1
Head Impulse Testing
The head impulse test (HIT) is a clinical maneuver used to assess the vestibulo-ocular reflex 
(VOR) during quick head rotations. The examiner delivers small-amplitude (<20 degree) head 
rotations with high peak velocities in the planes corresponding to each of the six semicircular 
canals. (Halmagyi and Curthoys 1988, Cremer 1998). A normal VOR results in a smooth eye 
movement equal and opposite direction to the head movement, thus achieving gaze 
stabilization without the need of a compensatory eye saccade. A patient with a deficient VOR 
fails to keep his/her eyes on target and subsequently makes a corrective, quick eye movement 
(a corrective/catch-up saccade) to refixate the target. When this refixation saccade occurs after 
the head has come to rest at the end of the head movement, it is visible to an examiner and 
serves as an indicator of hypofunctional sensation in the semicircular canal predominantly 
excited by the head motion. Head impulses can be directed in each of 6 directions, thereby 
selectively testing the function of each of the 3 semicircular canals in each of the two 
labyrinths. 
Over time, a patient with a hypofunctional semicircular canal may develop an ability to make 
corrective saccades that begin and end during the head rotation. While this improves the 
patient’s ability to maintain visual fixation of a target during head movements, it also 
degrades the examiner’s ability to detect hypofunction of the semicircular canal. In such cases, 
a video Head Impulse Test (vHIT) is useful to identify VOR abnormalities that are not 
obvious to the examiner. A vHIT system comprises an eye-tracking camera and motion sensor 


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mounted on light, securely fit, head-worn goggles. Because the vHIT system’s camera travels 
with the head, it is less susceptible to missing corrective saccades that occur during the head 
movement. Because the vHIT quantitatively measures head and eye angular velocities 
throughout a head movement, it provides a numerical estimation of VOR gain, which is 
calculated as the ratio of slow phase (VOR-driven) eye velocity divided by head velocity.  
The vHIT has been well validated against the magnetic field scleral search coil technique, 
which 
is 
the 
gold 
standard 
for 
HIT 
measurements 
(MacDougall et al 2013, 
Agrawal et al 2013). 
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6.5
Safety
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded the CRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History CRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event CRF.
6.5.2
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. After the patient has been 
sitting for 3 minutes, with back supported and both feet placed on the floor, systolic and 
diastolic BP will be measured using an automated validated device, with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the patient’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
If vital signs are out-of-range at screening and baseline, the Investigator may obtain two 
additional readings, so that a total of up to three consecutive assessments are made, with the 
patient seated quietly for approximately five minutes preceding each repeat assessment.
6.5.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
6.5.4
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening and/or at the initial baseline, the 
assessment may be repeated once prior to randomization. If the repeat value remains outside 
of protocol-specified ranges, the patient is excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator and shall 
be based, in part, upon the nature and degree of the observed abnormality. The assessment 
may be repeated once prior to randomization.
Further retests at screening or baseline could be permitted if deemed necessary by the 
investigator; however, each case must be discussed and agreed with the Sponsor on a case-by-
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In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the patient to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured.
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, CK, -GT, glucose, LDH, inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, BUN, and uric acid (for all 
laboratory assessments). 
Anti-Nuclear Antibody (ANA), anti-neutrophil cytoplasmic 
antibody (ANCA), rheumatoid factor, and anti-cyclic citrullinated peptides will be measured 
at screening only.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
6.5.4.3
Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative “dipstick” evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
6.5.4.4
Special clinical laboratory evaluations
Not applicable.


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6.5.5
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed seated. Interpretation of the tracing must be made 
by a qualified physician and documented on the ECG / in the ECG section of the CRF. 
Each ECG tracing should be labeled with the

study number

patient / patient initials

patient / patient number

date
and kept in the source documents at the study site. Clinically significant abnormalities should 
be recorded on the relevant medical history/Current medical conditions CRF page prior to 
informed consent signature and on the Adverse Events page thereafter. Clinically significant 
findings must be discussed with the sponsor.
The CRF will contain:

date and time of ECG

heart rate

PR interval

QT interval 

QTcF

QRS duration
Original ECG tracings, appropriately signed, will be archived at study site.
6.5.6
Hearing and balance assessments
The assessments for efficacy outlined in Section 6.4 will also serve as safety assessments.
6.5.7
Magnetic resonance Imaging (MRI)
Magnetic resonance imaging with gadolinium (MRI) will be used to assess the structural 
integrity of the inner to determine if the patients study ear is suitable for enrolling the trial as 
well as following treatment to assess the inner ear structural integrity and evaluate for other 
potential complications of treatment, including labyrinthitis ossificans. The imaging 
acquisition will follow the local facility procedures indicating the specific hardware and 
software settings for acquisition of all inner ear structural parameters.
6.6
Pharmacokinetic assessments
Not applicable.
6.7
Other assessments
Not applicable.


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7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. Pre-existing medical conditions/diseases (i.e., Medical 
History(ies)) are considered AEs if they worsen after providing written informed consent. 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, or are considered clinically significant, or they require therapy.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.
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Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate:
sufficiently discomforting to interfere with normal activities

severe:
prevents normal activities
2. its relationship to study treatment
3. its duration (e.g., start and end date)
4. whether it constitutes a serious adverse event (SAE)
5. action taken regarding study treatment
6. whether other medication or therapies have been taken (concomitant medication /
non-drug therapy)
7. its outcome
An SAE is defined as any AE which meets any one of the following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent form

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e.,
further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given. The action taken to treat the 
adverse event should be recorded on the Adverse Event CRF.


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Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the informed consent 
and should be discussed with the patient during the study as needed.
7.2
Serious adverse event reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis. 
Treated subjects
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the patient has stopped study participation 
(defined as time of last dose of study drug taken or last visit whichever is the later) must be 
reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit if there are post-treatment 
follow-up visits with no required procedures must be reported to Novartis within 24 hours of 
learning of its occurrence. Any SAEs experienced after the 30 day period should only be 
reported to Novartis if the investigator suspects a causal relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow-up information) is collected and recorded 
on the Serious Adverse Event Report Form. The investigator must assess the relationship of 
any SAE to each specific component of the study treatment (if the study treatment consists of 
several components), complete the SAE Report Form in English, and send the completed, 
signed form by fax within 24 hours of the awareness of the SAE to the local CMO & PS
Department and also a copy to the Novartis Medical Expert and/or Clinical Trial Leader 
(according to page 2). The telephone and fax numbers of the contact persons in the local Drug 
Safety and Epidemiology department, specific to the site, are listed on page 2 of this protocol 
and/or in the investigator folder provided to each site. The original copy of the SAE Report 


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Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site. Follow-up information should be provided using a new paper SAE Report 
Form stating that this is a follow-up to a previously reported SAE.
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities,
relevant ethics committees and additional regulatory bodies as required for Gene Therapy 
studies (e.g the NIH in the United States) in accordance with Directive 2001/20/EC or as per 
national regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Liver events are divided into two categories:

Liver events of special interest (AESI) which consist of LFTs elevations

Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events.
Please refer to Table 15-1-Appendix 3 for complete definitions of liver events.
Any liver event which meets the criteria for a “medically significant” event should follow the 
standard procedures for SAE reporting as described in Section 7.2.
Every liver event as defined in Table 15-1-Appendix 3 should be followed up by the 
investigator or designated personal at the trial site, as summarized below and detailed in 
Table 15-2-Appendix 3.

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes 
(e.g., disease, co-medications)

An investigation of the liver event which needs to be followed until resolution


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These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF.
7.4
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local CMO & PS Department. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the 
investigational/study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
7.5
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior using a semi-structured interview to probe 
patient responses, has to be administered.
If at any assessment after screening and/or baseline the score is 4 or above on the Suicidal 
Ideation item or any “yes” on the Suicidal Behavior item, the patient must be referred to a 
health care professional for further assessment and/or treatment. The decision on whether the 
study treatment should be discontinued is to be taken by the health care professional to whom 
the patient is referred.
7.6
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required s will be made jointly between medically 
qualified personnel representing the Sponsor and Investigator. Such evaluations may occur 
verbally, but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.


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8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis or the CRO working on behalf of Novartis. The Investigator 
must certify that the data entered into the Electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive a CD-ROM or paper copies of the 
patient data for archiving at the investigational site.
All data captured for this study will have an external originating source (either written or 
electronic). The CRF is not considered as source.


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8.3
Database management and quality control
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Novartis staff or CRO working on Novartis’s behalf will review the data entered into the 
eCRFs by investigational staff for completeness and accuracy and instruct the site personnel 
to make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be sent (e.g., fax, e-mail) to the site. Site personnel will complete and sign the copy, 
then send it (with original signature) back to Novartis staff who will make the correction to 
the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
8.4
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) has been assembled for this compound to monitor
safety data for the combined First In Man and Proof of Concept study. This committee is 
autonomous and comprises one external expert as well as selected Novartis associates who 
have subject matter expertise in auditory and vestibular clinical diagnosis, as well as general
expertise in safety monitoring, monitoring of clinical trials, and statistical analysis and data
visualization.
The DSMB will convene as outlined in the DSMB Charter to review adverse events, 
including clinical laboratory data, pure tone audiometry assessment and vestibular safety 
assessment will be continuously reviewed.
8.5
Adjudication Committee
Not required.
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9
Data analysis
9.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
9.2
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
patient. Summary statistics will be provided.by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and patient.
9.4
Analysis of the primary variable(s)
The primary aim of this study is to determine the effect of a single injection of CGF166 on 
pure tone audiometry measured at 4 week intervals from month 1 to month 6 after surgery. 
The second primary objective is to assess the safety and tolerability of IL CGF166.
9.4.1
Variable(s)
The primary analysis variable is the audiometric threshold measured on a dB HL (hearing loss) 
scale at these frequencies: 0.125, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12.5, 14, 16 kHz.
9.4.2
Statistical model, hypothesis, and method of analysis
Tone thresholds will be analyzed for each frequency tested separately. 
For pure tone audiometry, a measure that depends on a patient being able to hear a tone, the 
following imputation will be done: If a patient is unable to hear the tone at a specific 
frequency it can be inferred that the threshold value exceeds the upper limit of the machine. In 
this case the value will be imputed to 5dB above the upper limit of the machine.
All pure tone audiometry air conduction threshold data will be listed and graphically 
displayed by patient, infusion volume, frequency, and visit/time. Summary statistics will be 
provided by infusion volume, frequency, ear and visit/time. Change from baseline of the 
thresholds (mean of screening and baseline visit) will also be summarized by infusion volume, 
frequency, ear and visit/time. 


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In addition, safety and tolerability is a co-primary endpoint, and will be analyzed as in 
Section 9.5.2 (Safety).
9.4.3
Handling of missing values/censoring/discontinuations
All missing data, which are missing due to an assessment not having been made, will be 
treated as “missing at random”. Patients with partial data will be included in the primary 
analysis. Where a missing data value occurs, this will be set to missing in the analysis. For the 
combined baseline of screening and baseline data, where only screening or baseline data is 
available, this value will be taken as the baseline. If no pre-treatment data is available, the 
subject will be excluded from the analysis when comparing the change to pre-treatment values. 
Pure tone audiometry values which are missing because the hearing threshold exceeded the 
upper limit of the machine will be imputed with the value of 5dB above the upper limit of the 
machine.
9.4.4
Supportive analyses
Not applicable.
9.5
Analysis of secondary 
 variables
Secondary variables will be analyzed descriptively.
9.5.1
Efficacy
Secondary efficacy variables will be reported descriptively.
9.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and patient.
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The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Exact 95% binomial confidence intervals may be provided for AE rates. If a dose-related 
safety signal is suspected, this may be confirmed by a permutation contrast test t using the 
nominal dose level as contrast.
Other safety evaluations
Not applicable.
9.6
Sample size calculation
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9.7
Power for analysis of key secondary variables
Not applicable.
9.8
Interim analyses
No interim analyses are planned in the study.
10
Ethical consideration
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
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so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e., all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study.
The study includes an optional pharmacogenetic component which requires a separate 
signature if the patient agrees to participate. It is required as part of this protocol that the 
Investigator presents this option to the patient. The process for obtaining consent should be 
exactly the same as described above for the main informed consent.
Declining to participate in these pharmacogenetic assessments will in no way affect the 
patient’s ability to participate in the main research study.
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be obtained.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee / Research Ethics 
Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC/REB must be given to Novartis before 
study initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs/REBs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 


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finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are permitted. 
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the Health Authorities 
(where required) and the IRB/IEC/REB at the study site should be informed within 
10 working days or less, if required by local regulation.


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References
Available upon request.
Agrawal Y, Platz EA, Niparko JK (2008) Prevalence of hearing loss and differences by 
demographic characteristics among US adults: data from the National Health and Nutrition 
Examination Survey, 1999-2004. Arch Intern Med. 16:1522-1530.
Agrawal Y, Schubert MC, Migliaccio AA, et al (2013) Evaluation of Quantitative Head 
Impulse Testing Using Search Coils vs. Video-oculography in Older Individuals. Otol 
Neurotol. 
Balkany TJ, Connell SS, Hodges AV, et al (2006) Conservation of residual acoustic hearing 
after cochlear implantation. Otol Neurotol. 2006 Dec;27(8):1083-8.
Carlson ML, Driscoll CL, Gifford RH, et al (2011). Implications of minimizing trauma during 
conventional cochlear implantation. Otol.Neurotol., 32, (6) 962-968.
Clark JG (1981) Uses and abuses of hearing loss classification. American Speech-Language-
Hearing Association 2475(81-230):493-500.
Cremer PD, Halmagyi GM, Aw ST, et al (1998). Semicircular canal plane head impulses 
detect absent function of individual semicircular canals. Brain;121 (Pt 4):699-716.
Gifford RH, Shallop JK, Peterson AM, et al (2008) Speech recognition materials and ceiling 
effects: considerations for cochlear implant programs. Audiology & Neurotology 13:193-205.
Halmagyi GM and Curthoys IS (1988) A clinical sign of canal paresis. Arch Neurol. 1988 
Jul;45(7):737-9.
MacDougall HG, McGarvie LA, Halmagyi GM, et al (2013) The video Head Impulse Test 
(vHIT) detects vertical semicircular canal dysfunction. PLOS One. 2013 Apr 22;8(4):e61488. 
doi: 10.1371/journal.pone.0061488.
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Nilsson M, Soli SD, Sullivan JA, et al (1994) “Development of the Hearing in Noise Test for 
the measurement of speech reception thresholds in quiet and in noise.” J Acoust Soc Am 
95(2): 1085-1099.
Peterson GE and Lehiste I (1962) “Revised CNC lists for auditory tests.” J Speech Hear 
Disord 27: 62-70.
Rio C, Dikkes P, Liberman MC, et al (2002) Glial fibrillary acidic protein expression and 
promoter activity in the inner ear of developing and adult mice. J.Comp Neurol., 442, (2) 
156-162.
Schlecker C, Praetorius M, Brough DE, et al (2011) Selective atonal gene delivery improves 
balance function in a mouse model of vestibular disease. Gene Ther. 18, 884-890.
Skarzynski H, Furmanek MI, Piotrowska A, et al (2007) [Value of multidetector computed 
tomography in detection of congenital inner ear malformations and its usefulness in 
qualification for cochlear implantation]. Otolaryngologia Polska 61(4):585-90.
Spahr AJ and Dorman MF (2004) “Performance of subjects fit with the Advanced Bionics CII 
and Nucleus 3G cochlear implant devices.” Arch Otolaryngol Head Neck Surg 130(5): 
624-628.
Staecker H, Brantley J, Hsu C, et al (2011) RD-2011-50368: CGF166 In Vivo Dose Response 
to the Inner Ear in a Mouse Model of Vestibular Hypofunction.
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Appendix 1: Sample Log table – all matrices
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15
Appendix 3: Liver event definitions and follow-up 
requirements
Table 15-1
Liver Event Definitions
Definition / threshold
Adverse event of special 
interest
Laboratory values
ALT or AST > 3 x ULN
ALP > 2 x ULN
TBL > 1.5 x ULN
Medically significant event 
(SAE)
Laboratory values
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction])
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction])
TBL > 3 x ULN
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and 
TBL > 2 x ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 x ULN)
Adverse events
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms


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Table 15-2
Liver Event Follow Up Requirements
Criteria
Event type
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea
Medically 
significant
Hospitalize, if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists for more 
than 2 weeks, discontinue the 
study drug
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 x ULN
accompanied by 
symptomsb
Medically 
significant
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 3 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
ALP (isolated)
> 5 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, report to 
Novartis as an SAE
Establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
> 2 to ≤5 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 2 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit


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Amended Protocol Version v06 (Clean)
Protocol No. CCGF166X2201
Criteria
Event type
Actions required
Follow-up monitoring
TBL (isolated)
> 3 x ULN
Medically 
significant
Repeat LFT within 48 hours
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 3 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 1.5 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
Preferred terms
Jaundice
Medically 
significant
Hospitalize the patient
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
“Drug-related 
hepatic 
disorders - severe 
events only” SMQ 
AE
Medically 
significant
hospitalization if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
Investigator discretion
a
Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN
b
General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia
c
Resolution is defined as an outcome of one of the following: return to baseline values, stable values at three 
subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a maximum of 6 months, liver 
transplantation, and death.

SAP_001.pdf: 
Clinical Development
CGF166
CCGF166X2201
A three-part, multicenter, open label, single dose study to 
assess the safety, tolerability, and efficacy of intra-
labyrinthine (IL) CGF166 in patients with severe-to-
profound hearing loss
TSc RAP Module 3: Detailed Statistical Methodology
Author(s):
Document type:
Amendment 2 TSc RAP Module 3: Detailed Statistical 
Methodology
Document status:
Final
Release date:
17-Aug-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Amendment 2 TSc RAP Module 3
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................2
1
Introduction to RAP documentation....................................................................................4
1.1
Scope........................................................................................................................4
1.2
Changes to RAP documentation (M3).....................................................................4
2
Study objectives and design ................................................................................................5
2.1
Study objectives.......................................................................................................5
2.1.1
Primary objectives...................................................................................5
2.1.2
Secondary objectives...............................................................................5
2.1.3
Exploratory objectives ............................................................................5
2.2
Study design and treatment......................................................................................5
3
First interpretable results (FIR) ...........................................................................................7
4
Interim analyses...................................................................................................................7
5
Statistical methods: Analysis sets........................................................................................7
6
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
7
Statistical methods for Pharmacodynamic (PD) parameters...............................................8
7.1
Analysis of the primary variable..............................................................................8
7.1.1
Variable...................................................................................................8
7.1.2
Statistical model, hypothesis, and method of analysis............................8
7.1.3
Handling of missing values/censoring/discontinuations.........................8
7.2
Analysis of secondary and exploratory variables ....................................................9
7.2.1
Auditory assessments..............................................................................9
7.2.2
Vestibular assessments............................................................................9
8
Statistical methods for safety and tolerability data............................................................10
8.1
Safety.....................................................................................................................10
List of tables
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Amendment 2 TSc RAP Module 3
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Amendment 2 TSc RAP Module 3
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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCGF166X2201”. 
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, Module 7 (M7) details the presentation of the data, including shells of summary tables, 
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived 
variables and derived datasets, to support the creation of CSR outputs.
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidances and Translational Sciences (TSc) RAP Addendum template 
for detailed information on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes occurring before database lock to 
the statistical methodology should be reflected in the RAP M3 documentation via version 
control (new document version to be approved by the trial team as the original module.
Major changes include, but are not limited to, changes in protocol that affect study design and 
statistical methodology. 
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / 
note in RAP Addendum or within the CSR itself. Minor changes include, but are not limited 
to, change in statistical model. Corrections of typographical errors or modification of spelling 
(from English to American, for example) do not need to be incorporated into the RAP M3 
documentation.


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Amendment 2 TSc RAP Module 3
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2
Study objectives and design 
2.1
Study objectives
2.1.1
Primary objectives

To assess the safety and tolerability of Intra-labyrinthine (IL) CGF166

To assess the efficacy of IL CGF166 as determined by the change in pure tone audiometry
compared to pretreatment values
2.1.2
Secondary objectives

To assess the efficacy of CGF166 as determined by the change in otoacoustic emission
testing compared to pretreatment values

To assess the efficacy of CGF166 as determined by the change in brainstem auditory
evoked responses (BAER) compared to pretreatment values

To assess the efficacy of CGF166 in regenerating vestibular function as determined by the
change in caloric nystagmography and vestibulo-ocular reflex (VOR) phase compared to
pretreatment values

To compare the changes in auditory functions (speech recognition) and vestibular
functions before and after IL infusion of CGF166 between the study ear and the
contralateral ear
2.1.3
Exploratory objectives
2.2
Study design and treatment
The current three part study utilizes an open label, single dose design for the investigation of 
CGF166 and will be conducted in multiple centers. Part A, B and C will be conducted in a 
sequential manner.
The current study will evaluate the safety, tolerability, and potential efficacy of CGF166 and 
the associated delivery procedures in patients with severe-to-profound bilateral hearing loss 
with intact vestibular function in the non-operative ear. Patients are required to have 
documented non-fluctuating hearing loss.
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Amendment 2 TSc RAP Module 3
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Part A
Part A will include a safety and tolerability cohort (N=3). Patient dosing will be staggered; 
dosing the next patient in a cohort will be based on a safety data review including all data 
available through 4 weeks post-dose of the previously dosed patient(s).
Part B
Part B will include a volumetric escalation design to evaluate infusion volumes of the same 
CGF166 concentration
in 4 cohorts of patients 
(N=3/cohort; total of 12 patients).
Each subsequent cohort will be dosed only after the volume delivered in the prior cohort is 
deemed to be safe and tolerable as determined by the dose safety review meeting based on 
safety data review of the complete previous cohort including all data through 4 weeks post-
dose.
Safety review meetings will be organized to evaluate available safety data and to determine if 
it is appropriate to escalate to the next infusion volume.
Part C
Once the highest safe and tolerable volume is determined in previous cohorts, it will be used 
for IL-infusion in Part C patients. A total of 20 patients, possibly increasing to 30 based on a 
sample size re-estimation after a data review of the Part A and B (cohorts 1-5), will be 
required for Part C of the current study.
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Amendment 2 TSc RAP Module 3
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3
First interpretable results (FIR)
4
Interim analyses 
5
Statistical methods: Analysis sets
All patients that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
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Amendment 2 TSc RAP Module 3
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6
Statistical methods for Pharmacokinetic (PK) parameters
Not applicable.
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Analysis of the primary variable
The primary aim of this study is to determine the effect of a single injection of CGF166 on 
pure tone audiometry measured at 4 week intervals from month 1 to month 6 after surgery.
7.1.1
Variable
The primary variable is the audiometric threshold (air conduction) measured on a dB HL 
(hearing loss) scale at these frequencies: 0.125, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12.5, 14, 16 kHz.
7.1.2
Statistical model, hypothesis, and method of analysis
For pure tone audiometry, a measure that depends on a patient being able to hear a tone, the 
following imputation will be done: If a patient is unable to hear the tone at a specific 
frequency it can be inferred that the threshold value exceeds the upper limit of the machine. In 
this case the value will be imputed to 5dB above the upper limit of the machine.
All pure tone audiometry air conduction threshold data will be listed and graphically 
displayed by patient, infusion volume, frequency, and visit/time. 
7.1.3
Handling of missing values/censoring/discontinuations
All missing data, which are missing due to an assessment not having been made, will be 
treated as “missing at random”. Patients with partial data will be included in the primary 
analysis. Where a missing data value occurs, this will be set to missing in the analysis. For the 
combined baseline of screening and baseline data, where only screening or baseline data is 
available, this value will be taken as the baseline. If no pre-treatment data is available, the 
subject will be excluded from the analysis when comparing the change to pre-treatment values. 
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Amendment 2 TSc RAP Module 3
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Pure tone audiometry values which are missing because the hearing threshold exceeded the 
upper limit of the machine will be imputed with the value of 5dB above the upper limit of the 
machine.
7.2
Analysis of secondary 
 variables
Unless stated specifically, the baseline result will be the result measured at Baseline (Visit 2). 
Where a patient has missing data at Visit 2, Screening (Visit 1) data may be used as their 
baseline.
7.2.1
Auditory assessments
7.2.1.1
Pure tone audiometry
Hearing sensitivity to frequency-specific pure tone stimuli will be determined by measuring 
audiometric thresholds through earphones (air conduction) and bone-conduction vibrator 
(bone conduction). Air conduction thresholds will be reported as described in Section 7.1. 
Bone conduction will be measured for frequencies 0.25 – 4 kHz. All bone conduction 
threshold data will be listed by infusion volume, patient, frequency, and visit/time. 
7.2.1.2
Speech audiometry
For all speech recognition tests (ear-specific speech recognition threshold [SRT], ear-specific 
word recognition at 40 dB sensation level [SL], aided word recognition) the data will be listed 
by infusion volume, patient and visit/time. 
7.2.1.3
AzBio Sentence test
The Minimum Speech Test Battery (MSTB) and AzBio Sentences Test data will be listed by 
infusion volume, patient and visit/time. 
7.2.1.4
Hearing-in-Noise-Test (HINT)
The data from the HINT will be listed by infusion volume, patient and visit/time. 
7.2.1.5
Brainstem auditory evoked response evaluations (BAER)
The BAER data will be listed by infusion volume, patient and visit/time. 
7.2.1.6
Distortion Product Otoacoustic emission testing (DPOAE)
The DPOAE data will be listed by infusion volume, patient and visit/time. 
7.2.2
Vestibular assessments
7.2.2.1
Rotary Chair
Rotational chair tests assess the component of the vestibule-ocular reflex (VOR) mediated by 
the horizontal semicircular canals. The VOR responses are quantified and analyzed as gain, 
phase, and asymmetry. The rotary chair response data will be listed by infusion volume,
frequency, patient and visit/time. 
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7.2.2.2
Head Impulse Testing
The head impulse testing data will be listed by infusion volume, patient and visit/time. 
8
Statistical methods for safety and tolerability data
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by infusion volume and 
patient. Summary statistics will be provided by infusion volume.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by infusion volume and patient.
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by infusion volume and patient.
8.1
Safety
The second primary objective is to assess the safety and tolerability of IL CGF166.
Vital signs
All vital signs data will be listed by infusion volume, patient and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by infusion volume and visit/time.
ECG evaluations
All ECG data will be listed by infusion volume, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by infusion volume and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by infusion volume, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
infusion volume and visit/time.
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Adverse events
All information obtained on adverse events will be displayed by infusion volume and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by infusion volume where applicable. A patient with 
multiple adverse events within a body system is only counted towards the total of this body 
system. 
Magnetic Resonance Imaging (MRI)
An MRI will be used to assess the structural integrity of the inner ear at screening and 
following treatment. The MRI data will be listed by infusion volume, patient and visit.
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Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS data will be listed by infusion volume, patient and visit/time.