Clinical trial NCT02706730
Conditions: Meniere's Disease
Sponsor: Otonomy, Inc.
Start date: 2016-02-01; Completion date: 2017-09-01
Enrollment: 189 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label extension study of a single intratympanic injection of OTO-104 given every 3 months for a total of 2 injections. Subjects must have completed either Otonomy study 104-201102 (Phase 2b study of OTO-104) or 104-201506 (Phase 3 study of OTO-104) in order to be eligible for this open-label extension study.

Detailed description:

Arms: arm 1: 12 mg dexamethasone
Interventions: intervention 1: OTO-104
Intervention descriptions: intervention 1: Single intratympanic injection of 12 mg OTO-104

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
  
 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A 6 -M O N T H , M U L TI C E N T E R, P H A S E 3 , O P E N -L A B E L  E X T E N SI O N S A F E T Y 
S T U D Y O F O T O -1 0 4  GI V E N A T 3 -M O N T H I N T E R V A L S B Y I N T R A T Y M P A NI C 
I N J E C TI O N I N S U B J E C T S 
WI T H U NI L A T E R A L 
M E NI E R E’ S DI S E A S E  
 
Prot oc ol N u m be r:  1 0 4 -2 0 1 5 0 9  
 
 
 
S p o ns or C o ntact:  
 
 
 
 
 
 
 
 
 
Me dical M o nit or:  
 
 
 
 
 
  
 
  
  
  
 
 
 
 
Versio n:  
2 . 0 
Date of Pr ot oc ol:  
2 2 Fe br uar y 2 0 1 6  
Pr o prietar y N otice  
T he c o nce pts a nd infor mati o n c o ntaine d in t his d oc u me nt or ge nerate d 
d uring t he st ud y are c o nsidere d pr o prietar y a nd ma y not be disclose d in 
w hole or in part wit ho ut t he e xpresse d, writte n c o nse nt of Ot o no my, 
I nc. 
 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T h e i nf or mati o n i n t his d o c u me nt c o nt ai ns tra d e s e crets a n d c o m mercial i nf or mati o n t h at are pri vile g e d or c o nfi d e ntial 
a n d ma y n ot b e dis cl os e d u nles s s u c h dis cl os ure is re q uire d b y a p plic a ble la ws a n d re g ulati o ns. I n a n y e v e nt, p ers o ns 
t o w h o m t h e i nf or mati o n is dis cl os e d must b e i nf or me d t h at t h e i nf or mati o n is pri vile g e d or c o nfi d e ntial a n d ma y n ot 
b e f urt h er dis cl os e d b y t h e m. T h es e restricti o ns o n dis cl os ure will a p pl y e q u all y t o all f ut ure i nf or mati o n s u p plie d t o 
y o u w hic h is i n dic at e d as pri vile g e d or c o nfi d e ntial.  




 
 
 
                                                              3   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
P R O T O C O L A M E N D M E N T, V E R SI O N 2. 0  ................................................................................7  
S P O N S O R C O N T A C T I N F O R M A TI O N .......................................................................................8  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................9  
A B B R E V I A TI O N S .......................................................................................................................1 0  
S Y N O P SI S  ....................................................................................................................................1 1  
1.  
B A C K G R O U N D  ........................................................................................................1 5  
1. 1.  
Rati o nale f or Safet y St ud y  ..........................................................................................1 6  
2.  
O BJ E C TI V E S  .............................................................................................................1 6  
3.  
O V E R VI E W O F S T U D Y D E SI G N  ...........................................................................1 6  
4.  
S T U D Y P O P U L A TI O N  .............................................................................................1 7  
4. 1.  
Ge neral C o nsider atio ns ...............................................................................................1 7  
4. 2.  
I ncl usi o n Crit eria ........................................................................................................1 7  
4. 3.  
E xcl usio n Criteria  .......................................................................................................1 7  
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G ....................................................................1 8  
5. 1.  
E nr oll me nt Pr oce d ures ................................................................................................1 8  
5. 1. 1.  
Assi g n me nt of S ubject I de ntificatio n N u mbers ..........................................................1 8  
6.  
D O S A G E A N D A D MI NI S T R A TI O N  .......................................................................1 8  
6. 1.  
St ud y Dr u g A d mi nistratio n .........................................................................................1 8  
6. 2.  
C o mplia nce  .................................................................................................................1 9  
7.  
P RI O R, C O N C O MI T A N T, A N D S U B S E Q U E N T T H E R A P Y  ................................1 9  
7. 1.  
Pr oscribe d T hera p y or Pr oc e d ures D uri n g t he St ud y Perio d  ......................................1 9  
7. 2.  
S y mpt o matic Relief Me dicatio ns  ...............................................................................2 0  
8.  
S T U D Y E V A L U A TI O N S  ..........................................................................................2 0  
8. 1.  
St ud y Pr oce d ures b y Visit  ..........................................................................................2 0  
8. 1. 1.  
Visit 1: Da y 1 ( Scree ni n g/ Baseli ne/ D os e N o. 1)  ........................................................2 0  
8. 1. 2.  
Visit 2: M o nt h 3 ( ± 2 wee ks) ( F oll o w U p a nd D ose N o. 2)  .......................................2 0  
8. 1. 3.  
Visit 3: M o nt h 6 ( ± 2 wee ks) ( E nd of St ud y/ Earl y T er mi nati o n) ...............................2 1  
8. 1. 4.  
U nsc he d ule d Visit .......................................................................................................2 1  
8. 2.  
Safet y E val uatio ns  ......................................................................................................2 2  
8. 2. 1.  
Vit al Si g n, Hei g ht a nd Wei g ht M eas ure me nts  ...........................................................2 2  


 
 
 
                                                              4   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
8. 2. 2.  
Uri ne Pre g na nc y Test  .................................................................................................2 2  
8. 2. 3.  
T y mpa no metr y ............................................................................................................2 2  
8. 2. 4.  
A udio gra ms .................................................................................................................2 2  
8. 2. 5.  
Ot osc o p y  .....................................................................................................................2 3  
8. 2. 6.  
C -S S R S Assess me nt  ...................................................................................................2 3  
8. 3.  
A d diti o nal E val uati o ns  ...............................................................................................2 3  
8. 3. 1.  
Me niere’s S y mpt o m Q uestio n naire  ............................................................................2 3  
9.  
A D V E R S E E V E N T ( A E) R E P O R TI N G  ...................................................................2 4  
9. 1.  
A d verse E ve nt Classificati o n Defi niti o ns ...................................................................2 4  
9. 1. 1.  
Assess me nt of Se verit y  ...............................................................................................2 5  
9. 1. 2.  
Assess me nt of C a usalit y  .............................................................................................2 5  
9. 1. 3.  
F oll o w up of A d verse E ve nts  .....................................................................................2 6  
9. 2.  
M o nit ori n g of A d vers e E ve nts ....................................................................................2 6  
9. 2. 1.  
All A d verse E ve nts  .....................................................................................................2 6  
9. 2. 2.  
Serio us A d verse E ve nts  ..............................................................................................2 7  
9. 2. 3.  
Pre g na ncies  .................................................................................................................2 7  
9. 3.  
C o ntacti n g S p o ns or R e gar di n g Safet y  ........................................................................2 7  
1 0.  
S U BJ E C T C O M P L E TI O N .........................................................................................2 8  
1 0. 1.  
C o mpleti o n  .................................................................................................................2 8  
1 0. 2.  
Wit hdra wal  .................................................................................................................2 8  
1 0. 2. 1.  
Ha ndli n g of Wit hdra wals ............................................................................................2 8  
1 0. 2. 2.  
Re plac e me nts  ..............................................................................................................2 9  
1 1.  
S T A TI S TI C A L M E T H O D S .......................................................................................2 9  
1 1. 1 . 
Sa mple Size  ................................................................................................................2 9  
1 1. 2.  
A nal ysis Sets ...............................................................................................................2 9  
1 1. 3.  
Descri pti o n of S ub gr o up s t o be A nal yze d  ..................................................................2 9  
1 1. 4.  
S ubje ct De mo gr a p hics, Baseli ne Disease Stat us, a nd Dis p ositio n  .............................2 9  
1 1. 5.  
Efficac y E val uati o ns  ...................................................................................................2 9  
1 1. 6.  
Ge neral A nal ytic Met ho ds  ..........................................................................................3 0  
1 1. 7.  
Safet y E val uatio ns  ......................................................................................................3 0  
1 1. 7 . 1. 
A d verse E ve nts  ...........................................................................................................3 0  
1 1. 7. 2.  
Vit al Si g ns  ..................................................................................................................3 0  
1 1. 7. 3.  
Ot osc o pic E xa mi nati o ns  .............................................................................................3 0  


 
 
 
                                                              5   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
1 1. 7. 4.  
A udio metr y Assess me nts ............................................................................................3 1  
1 1. 7. 5.  
T y mpa no metr y ............................................................................................................3 1  
1 1. 7. 6.  
C o nc o mita nt Me dicati o ns  ...........................................................................................3 1  
1 1. 7. 7.  
C -S S R S  .......................................................................................................................3 1  
1 1. 7. 7. 1.  
C -S S R S: Baseli ne Versi o n  .........................................................................................3 1  
1 1. 7. 7. 2.  
C -S S R S: Si nce Last Visit Versi o n ..............................................................................3 1  
1 1. 8.  
Ot her E val uati o ns  .......................................................................................................3 2  
1 1. 8 . 1. 
Me niere’s S y mpt o m Q uestio n naire  ............................................................................3 2  
1 1. 9.  
Ha ndli n g of Missi n g Data, S ubject Wit hdra wals, a nd Treat me nt Fail ur es  ................3 2  
1 1. 1 0.  
I nteri m A nal ys es .........................................................................................................3 2  
1 2.  
S T U D Y D R U G I N F O R M A TI O N ..............................................................................3 2  
1 2. 1.  
P h ysical Descripti o n of St ud y Dr u g(s)  .......................................................................3 2  
1 2. 2.  
Dire ctio ns for Use  .......................................................................................................3 3  
1 2. 3.  
Pac ka gi n g a nd La beli n g ..............................................................................................3 3  
1 2. 3. 1.  
Pac ka gi n g ....................................................................................................................3 3  
1 2. 3. 2.  
La bels a nd La beli n g I nstr uctio ns  ................................................................................3 3  
1 2. 4.  
Ma na ge me nt of Cli nical S up plies ...............................................................................3 3  
1 2. 4. 1.  
St ora ge of Kits  ............................................................................................................3 3  
1 2. 5.  
Dr u g A cc o u nta bilit y  ...................................................................................................3 3  
1 3.  
E T HI C A L A S P E C T S  .................................................................................................3 4  
1 3. 1.  
I n vesti gat or Res p o nsibilities.......................................................................................3 4  
1 3. 2.  
I nstit uti o nal Re vie w B oar d (I R B)...............................................................................3 4  
1 3. 3.  
I nf or me d C o ns e nt .......................................................................................................3 4  
1 4.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ..................................................................3 5  
1 4. 1.  
Pr ot oc ol M o dificati o ns  ...............................................................................................3 5  
1 4. 2.  
Re g ulat or y D oc u me ntati o n  .........................................................................................3 5  
1 4. 3.  
S ubje ct I de ntificatio n Re gister  ...................................................................................3 6  
1 4. 4.  
Rec or d Ret e ntio n  ........................................................................................................3 6  
1 4. 5.  
Electr o nic C ase Re p ort F or m ......................................................................................3 6  
1 4. 6.  
Ter mi natio n .................................................................................................................3 7  
1 4. 7.  
Data a nd Safet y M o nit ori n g Pla n  ...............................................................................3 7  
1 4. 8.  
M o nit ori n g  ..................................................................................................................3 7  
1 4. 9.  
Data Q ualit y Ass ura nce  ..............................................................................................3 8  


 
 
 
                                                              6   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
1 4. 1 0.  
O n -Site A udits  ............................................................................................................3 8  
1 4. 1 1.  
Use of I nfor mati o n a nd P ublicati o n ............................................................................3 8  
1 5.  
LI S T O F R E F E R E N C E S ............................................................................................4 0  
 


 
 
 
                                                              7  
 
  
 
Ot o n o m y 1 0 4- 2 0 1 5 0 9 Pr ot oc ol  V 2. 0: 2 2 Fe br uar y 2 0 1 6
P R O T O C O L A M E N D M E N T, V E R SI O N 2. 0 
T his pr ot oc ol a me n d me nt ser ves t o ma ke t he f oll o wi n g c ha n ges. 
Ite m 
N o. 
C h a n ge 
Secti o n a n d P a ge N u m ber 
1  
U p date d date a n d versi o n of pr ot oc ol.  
Title pa ge, p g. 1  
F o oter, e ver y pa ge 
2  
Safet y re p orti n g c ha n ge d t o 
 
 
S p o ns or C o ntact I nf or mati o n, p g. 8  
Secti o n 9. 3 C o ntacti n g S p o ns or Re gar di n g 
Safet y, p g. 2 7  
3  
A d de d a d diti o nal e xcl usi o n criteria t o 
h y perse nsiti vit y t o de xa met has o ne or a n y of 
t he O T O- 1 0 4 e xci pie nts. 
S y n o psis, p g. 1 2  
Secti o n 4. 3 E xcl usi o n Criteria, p g. 1 8  
 
4  
A d de d 3- di git i de ntificati o n n u m ber t o t he 
s u bject n u m b er t o i n dicate w hic h st u d y t he 
s u bject was pre vi o usl y e nr olle d i n. 
Secti o n 5. 1. 1 Assi g n me nt of S u bject 
I de ntificati o n N u m b ers, p g. 1 8  
5  
C orrecte d visit n u m bers. 
Secti o n 6. 2 C o m plia nce, p g. 1 9  


 
 
 
                                                              8   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
S P O N S O R C O N T A C T I N F O R M A TI O N  
M e dic al M o nit or:  
 
N a me  
 
Title  
 
Office P ho ne N u mber  
   
M o bile P ho ne N u mber  
    
E -Mail  
 
 
 
Ot he r A p pro pri ate Tri al C o nt act Pe rs o n nel:  
N a me  
 
Title  
 
Office P ho ne N u mber  
 
M o bile P ho ne N u mber  
 
E -Mail  
 
 
 
S afet y E mail : 
 
 
If a ny s p o ns or c o ntact infor matio n nee ds t o be c ha nge d d uring t he c o urse of t he st ud y, t his will 
be d o ne b y t he s p o ns or, wit h writte n notificatio n t o t he investi gat or, a nd will not re q uire a 
pr ot oc ol a me nd me nt.  


 
 
 
                                                              9   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
I N V E S TI G A T O R A G R E E M EN T  
I ha ve rea d t his pr ot oc ol a nd a gree t hat it c o ntains all necessar y details for carr yin g o ut t his 
st ud y. I will c o nd uct t he st ud y as o utli ne d herein a nd will c o mplete t he st ud y wit hi n t he ti me 
designate d a nd will a bide b y all o bligatio ns state d o n t he F or m F D A 1 5 7 2 a nd ot her local 
re gulat or y a ut horit y re q uire d d oc u me nt(s). 
I will pr o vide c o pies of t he pr ot oc ol a nd all pertine nt infor mati o n t o all indivi d uals res p o nsible t o 
me w ho assist in t he c o nd uct of t his st ud y. I will disc uss t his material wit h t he m t o e ns ure t he y 
are full y infor me d re gar din g t he dr ug a nd t he c o nd uct of t he st ud y.  
I will use o nly t he infor me d c o nse nt for m a p pr o ve d b y t he s p o ns or or its re prese ntative a nd 
a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d (I R B) res p o nsible for t his st ud y a nd will fulfill all 
res p o nsibilities for s ub mitti n g pertine nt infor mati o n t o t he I R B res p o nsible for t his st ud y.  I will 
ass ure that eac h s ubject e nr olle d int o t he trial, or le gall y a ut horize d re prese ntative, rea ds, 
understa nds, a nd signs t he a p pr o priate versio n of t he infor me d c o nse nt. I a gree t hat t he s p o ns or 
or its re prese ntati ves s hall ha ve access t o a ny origi nal s o urce d oc u me nt s t o verify data ca pt ure d 
for t his clinical trial. 
I furt her a gree not t o origi nate or use t he na me of t he Ot o no my, I nc. a nd/ or O T O -1 0 4, or a ny of 
its e mplo yees, in a ny p ublicit y, ne ws release or ot her p ublic a nno unce me nt, writte n or oral, 
w het her t o t he p ublic, press or ot her wise, relatin g t o t his pr ot oc ol, t o a ny a me nd me nt heret o, or 
t o t he perfor ma nce here under, wit ho ut t he prior writte n c o nse nt of Ot o no my, I nc. 
 
 
 
 
 
 
I n v esti g at or's Si g n at ure 
 
Dat e  
Na me of I n v esti g at or (t y p e d or pri nt e d) 
I nstit uti o n Na me  
 
 
 


 
 
 
                                                              1 0   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
A B B R E VI A TI O N S  
A b bre vi ati o n  
E x pl a n ati o n  
A A O -H N S  
A meric a n A c a de m y of Ot olar y n g olo g y - H e a d a n d N e c k S ur ger y  
A E  
A d vers e E ve nt  
B C A  
B o ne C o n d uctio n A vera ge  
C  
Celsius  
C R F/e C R F  
Cas e Re p ort F or m/ele ctr o nic Cas e Re p ort F or m  
C R O  
C o ntra ct Res e arc h Or ga nizatio n  
C -S S R S  
C olu m bia -S uicide Se verit y Ratin g Sc ale  
d B  
D e cibel  
E D C  
Ele ctr o nic D ata Ca pt ure S yste m  
F  
Fa hre n heit  
F A X  
Fa csi mile  
F D A  
F o o d a n d Dr u g A d ministratio n  
G C P  
Go o d Clinic al Pra ctic e  
HI P A A  
H e alt h I ns ura nc e P orta bilit y a n d  A c c o u nta bilit y A ct  
H z  
H ertz  
I C H 
I nter natio nal C o nfere nc e o n H ar m o nizatio n 
I R B 
I nstit utio nal Re vie w B oar d 
I T 
I ntrat y m pa nic 
Me d D R A  
Me dic al Dictio nar y f or Re g ulat or y A ctivities  
m L  
Milliliter  
m g  
Milligra m  
m m  
Milli meter  
O T O -1 0 4  
I n vestigatio nal Pr o d uct 
P T A  
P ure T o ne A vera ge  
S A E  
Serio us A d vers e E ve nt  
S A P  
Statistic al A nalysis Pla n  
S O C  
S yste m Or ga n Class  
T E A E  
Tre at me nt E mer ge nt A d vers e E ve nt  
 


 
 
 
                                                              1 1   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
S Y N O P SI S  
N A M E O F S P O N S O R/ C O M P A N Y:  
 
Ot o n o m y, I nc.  
N A M E O F I N V E S TI G A TI O N A L P R O D U C T:  
 
O T O -1 0 4  
N A M E O F A C TI V E I N G R E DI E N T: 
 
D e xa met has o ne  
Title of St u d y: A 6 -m o nt h , m ultic e nter, P has e 3,  o pe n -la bel e xte nsio n s afet y st u d y of O T O-1 0 4 give n 
at 3-m o nt h inter vals b y intrat y m pa nic inje ctio n in s u bje cts wit h u nilateral Me niere’s dis e as e.  
St u d y C e nte r(s ): T his st u d y will  be c o n d ucte d at a p pr o xi mately 6 0 -7 0 sites in t he U nite d States.  
St u die d Pe ri o d : 1 8  m o nt hs  
P h as e of D e vel o p me nt: P has e 3  
St u d y D e si g n:  
T his is a 6 -m o nt h, m ultic e nter, P has e 3 , o pe n-la bel e xte nsio n s afet y st u d y in s u bje cts wit h u nilateral 
Me niere’s dis e as e.  S u bje cts will re c eive 1 intrat y m pa nic (I T) inje ctio n of 1 2 m g O T O -1 0 4 at 3 -
m o nt h inter vals f or a t otal of 2 inje ctio ns.  Safet y data t o be c olle cte d inclu de a d vers e e ve nts, 
c o nc o mita nt me dic atio ns, ot os c o p y, vital sig ns, a u diolo g y, t y m pa n o metr y, C olu m bia -S uicide Se verit y 
Ratin g Sc ale ( C -S S R S) q uestio n naire a n d a Me niere’s dis e as e s y m pt o m q uestio n naire.  
O bje cti v e:  
T he o bje ctive is t o ass ess t he s afet y of re pe at I T inje ctio ns of 1 2 m g O T O -1 0 4 at 3 -m o nt h inter vals in 
a n o pe n -la bel st u d y. 
M et h o d ol o g y:  
T he d uratio n of t he st u d y f or e a c h s u bje ct will be 6 m o nt hs.   
O nc e s u bje cts me et all eligibilit y criteria, t he y will be e nr olle d a n d ma y re c eive u p t o 2 I T inje ctio ns 
of O T O -1 0 4 at  3 -m o nt h inter vals.  All s u bje cts will re main o n sta n dar d of c are tre a t me nt f or u nilateral 
Me niere’s dis e as e.  S u bje cts will ret ur n t o t he st u d y sites at M o nt h 3 f or s afet y ass ess me nts a n d 
a n ot her I T inje ctio n of O T O -1 0 4.   Safet y ass ess me nts will be c o m plete d at t he e n d of t he st u d y 
( M o nt h 6) or u p o n e arly wit h dra w al fr o m t he st u d y. 
N u m be r of S u bje cts :  
U p t o 3 0 0 s u bje cts will  be e nr olle d . 
Di a g n osis a n d M ai n C rite ri a fo r I ncl usi o n:  
S u bje cts e nr olle d in t he st u d y will ha ve u nilateral Me niere’s dis e as e  as o utline d b y t he A meric a n 
A c a de m y of Ot olar y n g olo g y - H e a d a n d N e c k S ur ger y ( A A O -H N S) C o m mitte e o n H e arin g a n d 
E q uilibri u m in 1 9 9 5 ( C o m mitte e o n H e arin g a n d E q uilibriu m, 1 9 9 5 ). 
T o be eligible f or t his st u d y, e a c h of t he f ollo win g criteria m ust be s atisfie d wit h a “ Y E S” a ns w er 
( u nless n ot a p plic a ble): 
1.  S ubject is a male or fe male a ge d 1 8 years or older.  
2.  S ubject has c o mplete d t he P hase 2 b ( 1 0 4 -2 0 1 1 0 2) or P hase 3 ( 1 0 4 -2 0 1 5 0 6) clinical 
st ud y. 
3.  Fe male s u bje cts of c hild be arin g p ote ntial [i. e., n ot s ur gic ally sterile a n d/ or n ot p ost -
me n o pa us al ( ≥1 2  m o nt hs sinc e last me nstr ual perio d a n d 4 5 ye ars of a ge or older)] m ust ha ve 


 
 
 
                                                              1 2   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
a ne gative urine pre g na nc y test bef ore e nr oll me nt. W o me n of c hild be arin g p ote ntial w h o are 
n ot a bstine nt fr o m s e x wit h male part ners ma y be e ntere d int o t he st u d y i f t he y are usin g a n d 
willin g t o c o ntin ue t o us e hig hly effe ctive or “ d o u ble barrier” c o ntra c e ptive pre c a utio ns f or 
t he d uratio n of t he st u d y (e. g., oral c o ntra c e ptives, c o ntra c e ptive i m pla nt or inje ctio n, 
intra uterine de vic e, or “ d o u ble barrier” met h o ds inclu din g c o n d o m wit h dia p hra g m, male 
c o n d o m wit h c er vic al c a p, male c o n d o m wit h s per micide, or dia p hra g m a n d s per micide).   
4.  S ubject is willi n g t o c o mply wit h t he pr ot oc ol a nd atte nd all st ud y visits.  
5.  S ubject is a ble t o pr o vide writte n infor me d c o nse nt, incl udi n g a gree me nt t o privac y 
la ngua ge eit her wit hi n t he infor me d c o nse nt or in a ncillar y d oc u me nts c o mplia nt wit h 
Healt h I ns ura nce P orta bilit y a nd Acc o unta bilit y Act ( HI P A A), before t he initiati o n of 
a ny st ud y-relate d pr oce d ures. 
 
Di a g n osis a n d M ai n C rite ri a  fo r E x cl usi o n: 
T o be eligible f or t his st u d y, e a c h of t he f ollo win g criteria m ust be s atisfie d wit h a “ N O ” a ns w er:                    
( u nless n ot a p plic a ble): 
1.  S ubject has a n infectio n in t he ear, sinuses, or up per res pirat or y s yste m.  
2.  S ubject is pre gna nt o r lactatin g. 
3.  S ubject has a hist or y of i m m u no deficie nc y disease.  
4.  S ubject has active or rece nt ( < 1 mo nt h prior t o scree ning) mid dle ear disease, 
includi n g b ut not li mite d t o:  c hr o nic otitis me dia, ac ute otitis me dia, mid dle ear 
effusio ns, mid dle ear atelect asis, or c holesteat o ma.  
5.  S ubject has a n a b nor malit y of t he t y mpa nic me mbra ne in t he affecte d ear t hat w o uld 
increase t he ris k ass ociate d wit h intrat y mp a nic injectio n includi n g b ut not li mite d t o a 
mo no meric, atelectatic or atr o p hic t y mpa nic me mbra ne.  
6.  S ubjec t has a hist or y of t y mpa nost o m y t ubes t hat includes e vide nce of perforatio n or 
lac k of clos ure. 
7.  S ubject has a hist or y of pre vio us e nd oly mp hatic sac s ur ger y.  
8.  S ubject has a hist or y of pre vio us use of intrat y mpa nic ge nta mici n in t he affecte d ear.  
9.  S ubject has hist or y of dr o p attac ks.  
1 0.  S ubject has use d s yste mic ster oids wit hin 1 mo nt h prior t o Visit 1.  
1 1.  S ubject has ha d intrat y m pa nic ster oids wit hi n 1 mo nt h prior t o Visit 1.  
1 2.  S ubject has e xperie nce d a n a d verse reactio n t o intrat y mpa nic injectio n of ster oids.  
1 3.  S ubject  has a hyperse nsiti vit y t o de xa met has o ne or a ny of t he e xcipie nts in O T O -1 0 4.  
1 4.  S ubject has a ny ot her clinicall y significa nt illness or me dical c o nditio n t hat, in t he 
investi gat or’s a nd t he me dical mo nit or’s o pinio n, w o uld pr o hibit t he s ubject fr o m 
participa ti n g in t he st ud y. 
1 5.  S ubject has participate d in a clinical trial wit hi n 3 0 da ys of Visit 1, not includi n g t he 
O T O -1 0 4 P hase 3 st ud y ( 1 0 4 -2 0 1 5 0 6).  


 
 
 
                                                              1 3   
 
  
 
Ot o no my 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6  
C rite ri a fo r E v al u ati o n:  
 
Safet y E valuatio ns :  
K e y s afet y ass ess me nts  inclu de: 
 
A d vers e e ve nts  
 
A u dio metr y ass ess me nts  
 
T y m pa n o metr y  
 
L oc al t olera bilit y ( ot os c o pic e xa minatio ns)  
 
Vital sig n me as ure me nts  
 
C olu m bia -S uicide Se verit y Ratin g Sc ale ( C -S S R S): Bas eline a n d Sinc e Last Visit 
versio ns   
 
Ot her E valuatio n s: 
 Me niere’s s y mpt o m q uestio n naire  
St atistic al M et h o ds:  
T his is a n o pe n la bel s afet y st u d y wit h o ne tre at me nt gr o u p.  All statistic al a nalys es will be des criptive 
in nat ure. 
I n v e sti g ati o n al Pr o d uct, D os a ge a n d M o de of A d mi nistr ati o n:  
O T O -1 0 4 1 2 m g, sin gle, intrat y m pa nic inje ctio n, 0. 2 m L  
D ur ati o n of T re at me nt:  
Sin gle I T  inje ctio n give n  at D a y 1  a n d M o nt h 3  
R efe re nce T he r a p y, D os a ge a n d M o de of A d mi nistr ati o n:  
N o ne  
Ti me a n d E v e nts Sc he d ule: Se e  Ta ble  1 . 
 


 
 
 
 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 4   
 
T a ble  1 : 
Ti me a n d E ve nts T a ble  
Pr oc e d ur e  
S c r e e ni n g/ 
B as eli ne/ D os e   
N o. 1  
Foll o w -u p/ D os e 
N o. 2  
En d -of -St u d y/  
Earl y Te r m.  
Uns c he d ul e d 
Visit  
Visit 1
1  
Visit 2  
Visit 3
2  
Uns c he d ul e d  
D a y 1  
Mo nt h 3              
( ± 2 we e ks) 
Mo nt h 
6               
( ± 2 we e ks) 
N/ A  
I nf or me d c o ns e nt (i n cl u di ng 
pri v a c y d o c u me nts)  
X  
 
 
 
Eli gi bilit y crit eria  
X  
 
 
 
M e dic al hist or y
3  
X  
 
 
 
Co n c o mit a nt me dic ati o ns  
X  
X  
X  
X  
Vit al si g n me as ure me nts
4  
X  
X  
X  
X  
Hei g ht a n d wei g ht 
me as ure me nts  
X  
 
X
5  
 
Uri n e Pre g n a n c y t est
6  
X  
X  
X  
 
T y mp a n o metr y  
X  
X  
X  
X as i n dic at e d  
A u di o metr y  
X  
X  
X  
X as i n dic at e d  
Ot os c o p y  
X  
X  
X  
X  
C -S S R S as s es s me nt
7  
X  
X  
X  
X  
M e niere’s s y mpt o m 
q u esti o n n aire  
X  
X  
X  
 
A d mi nist er st u d y dr u g  
X  
X  
 
 
A d v ers e e v e nt mo nit ori n g  
X  
X  
X  
X  
1  Visit 1 ma y als o b e t h e last st u d y visit f or 1 0 4 -2 0 1 5 0 6.  
2  Pr o c e d ures  s c h e d ule d f or Visit 3 will b e p erf or me d at t h e e n d of t h e f oll o w -u p p eri o d ( ± 2 we e ks) or u p o n e arl y 
dis c o nti n u ati o n fr o m t h e st u d y.  
3  M e dic al hist or y t o i n cl u d e i nf or mati o n o n d e mo gra p hics.  
4  Vit al si g n me as ure me nts i n cl u d e bl o o d pres s ure a n d p uls e rat e.  
5  O nl y wei g ht will b e t a ke n at St u d y Visit 3.  
6  Fe male s u bje cts of c hil d b e ari n g p ot e ntial will h a v e a uri n e pre g n a n c y t est via di pstic k at e v er y s c h e d ule d visit.  O n 
Visit 1 a n d 2, t h e pre g n a n c y t est must b e c o mplet e d a n d c o nfir me d n e g ati v e pri or t o d osi n g.  If a s u bje ct is f o u n d 
t o b e pre g n a nt aft er d osi n g wit h O T O-1 0 4, t h e y will c o mplet e t h e f oll o w -u p p eri o d b ut will n ot b e d os e d f urt h er 
wit h O T O -1 0 4.  
7  At Visit 1, t h e Si n c e Last Visit v ersi o n of t h e C-S S R S will b e us e d f or s u bje cts e nr olli n g fr o m St u d y 1 0 4 -2 0 1 5 0 6 
w hile t h e Bas eli n e v ersi o n will b e us e d f or all s u bje cts e nr olli n g fr o m St u d y 1 0 4 -2 0 1 1 0 2.  T h e Si n c e Last Visit 
v ersi o n of t h e C -S S R S will b e us e d at all s u bs e q u e nt visits.


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 5   
 
1.  
B A C K G R O U N D  
Me niere’s disease is a n idio pat hic s yndr o me of e nd oly mp hatic 
hydr o ps ( C o m mitte e o n Hearing 
a nd E q uilibri u m, 1 9 9 5 ).  It is ass ociate d wit h a distinct patter n of clinical s y mpt o ms c o mprise d 
of vertigo, hearing loss, tinnit us a nd  a ural full ness. It is more fre q ue ntl y unilateral t ha n bilateral.  
E pis o dic vertigo is c o nsidere d t he most pr o mine nt s y mpt o m, wit h e pis o des t ypicall y lastin g at 
least 2 0 minutes a nd res ulti n g in significa nt patie nt mor bidit y.  The dia gnosis is pri maril y a 
clinical o ne, since t here are no s pecific dia gnostic tests for Me niere’s disease.  The disease is 
k no w n t o wa x a nd wa ne, b ut e ve nt uall y res ults in irre versible se ns orine ural hearing loss at all 
fre q ue ncies in t he affecte d ear.  W hile t he pat ho ge nesis of Meniere’s disease has not bee n 
elucidate d, o ne well-acce pte d mec ha nis m invol ves t he d ysre gulati o n of la b yrint h fluid 
volu me/i o n bala nce res ulti n g in e nd oly mp hatic hydr o ps ( S hea, 1 9 9 3 ).  The increase in fluid 
volu me a nd c o nse q ue n t increase d la b yrint h press ure ma y t he n be e xpresse d as t he Me niere’s 
s pectr u m of s y mpt o ms. 
T here is no c ure for Me niere’s disease.  Treat me nt te nds t o foc us o n relie vi n g t he vertigo 
s y mpt o ms, w here it is hyp ot hesize d t hat re d ucing inner ear fluid volu me w ill relie ve t he hydr o ps 
a nd ass ociate d clinic al pict ure.  It is for t his reas o n t hat ma ny s ubjects are initiall y starte d o n lo w 
salt diets a nd diuretics (Barritt, 2 0 0 8 ).  A nu mber of me dical s yste mic treat me nts are als o use d to 
relie ve 
Me niere’s disease s y mpt o ms, incl udi n g b ut not li mite d t o a ntihista mi nes, 
a ntic holi ner gics, p he not hia zi nes, be nzo diaze pi nes, a nd c ortic oster oids; ho we ver, t hese 
inter ve ntio ns are ofte n ina de q uate in relie vi n g t he s y mpt o ms of Me niere’s disease.  A de vice t hat 
ge nerates lo w -press ure p ulses, t he Me niett ®  de vice, is indicate d for t he s y mpt o matic treat me nt of 
Me niere’s disease.  H o we ver, t he de vice is not widely use d a nd is not c urre ntl y c o nsidere d 
sta ndar d of care (Ki m et al, 2 0 0 5 ).  S ur gical dec o mpressio n ma y be atte mpte d in se vere cases 
unres p o nsi ve t o me dical inter ve nti o n, b ut s ur gical o utc o mes are fre q ue ntl y unsatisfact or y.  
Finall y, patie nts wit h unres p o nsi ve disease ma y under go c he mical or s ur gical ne ur oa blatio n, 
res ulti n g in s y mpt o m relief at t he c ost of destr uctio n of t he 8t h cra nial ner ve. Thus, t here 
c o ntinues t o be a n un met me dical nee d for t hera pies t o a d dress t his de bilitati n g disease.  
O T O -1 0 4 is a s us pe nsio n of de xa met has o ne in a b uffere d s olutio n 
 
  S o me p olo xa mers, includi n g p olo xa mer 4 0 7, ha ve t her more versi ble pr o perties 
a nd functio n as liq uid p har mace utical ve hicles t hat gel at b o d y te mperat ure.  Ot o no my ha s 
for mulate d de xa met has o ne, a s ynt hetic me mber of t he gluc oc ortic oi d class of ster oid hor mo nes, 
in 
 for t he p ur p ose of st ud yin g t he p ote ntial be nefits of intrat y mpa nic (I T) 
injectio ns of O T O-1 0 4 in s ubjects wit h Me niere’s disease. S ingle a nd re peat-d ose no ncli nical 
safet y st udies in guinea pigs, rats a nd cats ha ve  bee n c o nd ucte d t o s up p ort clinical de velo p me nt.  
S pecial e mp hasis in t he t o xic olo g y st udies has bee n place d o n t he effects of O T O -1 0 4 a nd 
 c o ntr ol o n mid dle a nd inner ear c o mpart me nts, w here b ot h functio nal a nd 
hist olo gical  assess me nts ha ve bee n c o nd ucte d.  A d ditio nall y, p har mac o ki netic assess me nts ha ve 
bee n c o nd ucte d in guinea pigs, rats , cats, a nd s hee p t hat pr o vide a c o mplete pr ofile of e xp os ure 
of O T O -1 0 4 t o t he inner ear c o mpart me nt, as well as s yste mic e xp os ure.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 6   
 
1. 1.  
R ati o n ale f o r S afet y  St u d y  
T w o clinical st udies ha ve bee n c o nd ucte d in t he U nite d States: a P hase 1 b st ud y a nd a P hase 2 b 
st ud y.  T he ra nd o mize d, place b o-c o ntr olle d, d o uble -bli nd, multi-ce nter P hase 2 b  st ud y in 1 5 4 
unilat eral 
Me niere’s disease patie nts de mo nstra te d t hat a single I T a dministrati o n of O T O -1 0 4 
res ulte d in i mpr o ve me nts in vertigo c o ntr ol.  The c o mplete d a nd o ngoing clinical st udies ha ve 
bee n eit her single-d ose wit h a 3 -mo nt h or 4 -mo nt h follo w-up perio d  or a re peat -d ose wit h 4 
d oses a d ministere d o ver o ne year .  Beca use Me niere’s disease is c hr o nic a nd inter mitte nt, t he 
safet y of re peat a d ministratio n nee ds t o be e valuate d.  This st ud y was designe d wit h a t w o 
injectio n design t o lo o k at re peat d oses o ver t he c o urse of six mo nt hs.  Three  mo nt hs was c hose n 
as t he d ose inter val d ue t o  infor matio n gaine d d uring t he follo w-up perio d in re gar d t o effect a nd 
safet y in t he c o mpleted  P hase 1 b  a nd P hase 2 b st udies .  
2.  
O B J E C TI V E S  
T he o bjective is t o assess t he safet y of re peat I T injectio ns of 1 2 mg O T O-1 0 4 at 3 -mo nt h 
inter vals in a n o pe n-la bel st ud y in s ubjects wit h unilateral 
Me niere’s disease. 
3.  
O V E R VI E W O F S T U D Y D E SI G N  
T his is a 6 -mo nt h, multic e nter, P hase 3 , o pe n-la bel e xte nsio n safet y st ud y in s ubjects wit h 
unilat er al 
Me niere’s disease.  S ubjects will receive 1 I T injectio n of 1 2 mg O T O -1 0 4 at 3 -mo nt h 
inter vals for a t otal of 2 injectio ns.  Safet y data t o be c ollecte d include a d verse e ve nts, 
c o nc o mita nt me dicatio ns, ot osc o p y, vital signs, a udiolo g y, t y mpa no metr y, C ol u mbia -S uicid e 
Se verit y Rating Scale ( C -S S R S) q uestio nnaire a nd a Me niere’s disease s y mpt o m q uestio nnaire.  
O nce s ubjects meet all eligibilit y criteria, t he y will be e nr olle d a nd ma y receive up t o 2 I T 
injectio ns of O T O-1 0 4 at 3 -mo nt h inter vals.  All s ubjects will re main o n sta ndar d of care 
treat me nt for unilateral 
Me niere’s disease.  S ubjects will ret ur n t o t he st ud y sites at M o nt h 3 for 
safet y assess me nts a nd a not her I T injectio n of O T O -1 0 4.  Safet y assess me nts will be c o mplete d 
at t he e nd of t he st ud y ( M o nt h 6) or up o n early wit hdra wal fr o m t he st ud y.


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 7   
 
4.  
S T U D Y P O P U L A TI O N  
4. 1.  
G e ne r al C o nsi de r ati o ns  
U p t o 3 0 0  s ubjects will be e nr olle d  at a p pr o xi matel y 6 0 -7 0 sites in t he U nite d States .  S ubjects 
will be e nr olle d o nly if t he y meet all of t he inclusio n criteria a nd no ne of t he e xclusio n criteria  
4. 2.  
I ncl usi o n C rite ri a 
S ubjects e nr olle d in t he st ud y will ha ve unilater al 
Me niere’s disease as o utli ne d b y t he A merica n 
Aca de my of Ot olar yngolo g y - Hea d a nd N ec k S ur ger y ( A A O -H N S) C o m mitte e o n Hearing a nd 
E q uilibri u m in 1 9 9 5  (C o m mittee o n Hearing a nd Eq uilibri u m, 1 9 9 5 ). 
T o be eligible for  t his st ud y, eac h of t he follo wi n g criteria must be satisfie d wit h a " Y E S" a ns wer 
( unless not a p plica ble): 
1.  S ubject is a male or fe male a ge d 1 8 years or older.  
2.  S ubject has c o mplete d t he P hase 2 b ( 1 0 4 -2 0 1 1 0 2) or P hase 3 ( 1 0 4 -2 0 1 5 0 6) clinical 
st ud y. 
3.  Fe male s u bjects of c hild beari n g p ote ntial [i.e., not s ur gicall y sterile a nd/ or not p ost -
me no pa usal ( 1 2 mo nt hs since last me nstr ual perio d a nd 4 5 years of a ge or older)] must 
ha ve a ne gative urine pre gna nc y test before e nr oll me nt. 
W o me n of c hild beari n g p ote ntial 
w ho  are not a bstine nt fr o m se x wit h male part ners ma y be e ntere d int o t he st ud y if t he y 
are using a nd willi n g t o c o ntinue t o use highl y effecti ve or "d o uble barrier" c o ntrace ptive 
preca utio ns for t he d uratio n of t he st ud y (e. g., oral c o ntrace ptives, c o ntrace p tive i mpla nt 
or injectio n, intra uteri ne de vice, or "d o uble barrier" met ho ds includi n g c o nd o m wit h 
dia p hra g m, male c o nd o m wit h cer vical ca p, male c o nd o m wit h s per micide, or dia p hra g m 
a nd s per micide).   
4.  S ubject is willi n g t o c o mply wit h t he pr ot oc ol a nd atte nd all st ud y visits.  
5.  S ubject is a ble t o pr o vide writte n infor me d c o nse nt, includi n g a gree me nt t o privac y 
la ngua ge eit her wit hi n t he infor me d c o nse nt or in a ncillar y d oc u me nts c o mplia nt wit h 
Healt h I ns ura nce P orta bilit y a nd Acc o unta bilit y Act ( HI P A A), b efore t he initiati o n of a ny 
st ud y-relate d pr oce d ures. 
4. 3.  
E xcl usi o n C rite ri a  
T o be eligible for t his st ud y, eac h of t he follo wi n g criteria must be satisfie d wit h a “ N O ” a ns wer:                     
( unless not a p plica ble): 
1.  S ubject has a n infectio n in t he ear, si nuses, or up per res pirat or y s yste m.  
2.  S ubject is pre gna nt or lactatin g.  
3.  S ubject has a hist or y of i m m u no deficie nc y disease.  
4.  S ubject has active or rece nt ( < 1 mo nt h prior t o scree ning) mid dle ear disease, includi n g 
b ut not li mite d t o:  c hr o nic otitis me dia, ac u te otitis me dia, mid dle ear effusio ns, mid dle 
ear atelectasis, or c holesteat o ma.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 8   
 
5.  S ubject has a n a b nor malit y of t he t y mpa nic me mbra ne in t he affecte d ear t hat w o uld 
increase t he ris k ass ociate d wit h intrat y mp a nic injectio n includi n g b ut not li mite d t o a 
mo n o meric, atelectatic or atr o p hic t y mpa nic me mbra ne.  
6.  S ubject has a hist or y of t y mpa nost o m y t ubes t hat includes e vide nce of perforatio n or lac k 
of clos ure.  
7.  S ubject has a hist or y of pre vio us e nd oly mp hatic sac s ur ger y.  
8.  S ubject has a hist or y of pre vio us use of i ntrat y mpa nic ge nta mici n in t he affecte d ear.  
9.  S ubject has hist or y of dr o p attac ks.  
1 0.  S ubject has use d s yste mic ster oids wit hin 1 mo nt h prior t o Visit 1.  
1 1.  S ubject has ha d intrat y m pa nic ster oids wit hi n 1 mo nt h prior t o Visit 1.  
1 2.  S ubject has e xperie nce d a n a d verse  reactio n t o intrat y mpa nic injectio n of ster oids. 
1 3.  S ubject has a hyperse nsiti vit y t o de xa met has o ne or a ny of t he e xcipie nts in O T O -1 0 4.  
1 4.  S ubject has a ny ot her clinicall y significa nt illness or me dical c o nditio n t hat, in t he 
investi gat or's a nd t he me dical mo nit or's o pinio n, w o uld pr o hibit t he s ubject fr o m 
participati n g in t he st ud y.  
1 5.  S ubject has participate d in a clinical trial wit hi n 3 0 da ys of Visit 1, not includi n g t he 
O T O -1 0 4 P hase 3 st ud y ( 1 0 4 -2 0 1 5 0 6).  
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G 
T his st ud y is a n o pe n-la bel st ud y wit h all s ubjects receivi n g O T O -1 0 4; t herefore, no 
ra nd o mizatio n or blindi n g is re q uire d. 
5. 1.  
E nr oll me nt P r o c e d ures  
5. 1. 1.  
Assi g n me nt of S u bje ct I de ntific ati o n N u m be rs  
All s ubjects will retain t he sa me uniq ue s ubject ide ntificatio n nu mber as t he o ne assigne d 
in 
clinical st ud y 1 0 4 -2 0 1 1 0 2  or 1 0 4 -2 0 1 5 0 6  plus a 3 -digit nu mber t o indicate w hic h st ud y t he 
s ubject participate d in pre vio usl y.  T he s ubject ide ntificati o n nu mber will be use d t o ide ntif y t he 
s ubject t hr o ugho ut t he st ud y a nd will re main wit h t he s ubject t hr o ugho ut t he d uratio n of t he 
st ud y.  All s ubjects wit h a signe d infor me d c o nse nt for t he st ud y, w het her e nr olle d or not (scree n 
failures, s ubject refusal, etc.), will be d oc u me nte d. 
6.  
D O S A G E A N D A D MI NI S T R A TI O N  
6. 1.  
St u d y D r u g A d mi nistr ati o n  
O T O -1 0 4 1 2 mg will be a d ministere d as a single, 0. 2 m L intrat y m pa nic injectio n of 6 0 mg/ m L 
O T O -1 0 4. T he rec o m me nde d injectio n pr oce d ure for intrat y m pa nic a d ministrati o n of O T O -1 0 4 
in Me niere's disease s ubjects is as follo ws:   


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              1 9   
 
1.  Place t he s ubject in a rec u mb e nt p ositio n wit h t he treate d ear up war ds.  A nest hetize t he 
t y mpa nic me mbra ne b y c o vering t he e xter nal s urface of t he p osterior inferior q ua dra nt 
wit h t o pical lid ocai ne/ priloc ai ne crea m (i.e.,
 until t he t y mpa nic 
me mbra ne is nu mb.  If a p plica bl e, s uctio n a wa y t he t o pical lid ocai ne/ pril ocai ne crea m.  
2.  Using t he 1 m L s yringe pre -loa de d wit h O T O-1 0 4 a nd e q uip pe d wit h a 2 5 or 2 6 ga uge 
nee dle, insert t he nee dle t hr o ugh t he t y mpa nic me mbra ne wit h t he be vel facing in a n 
infer o p osteri or directio n t o a dept h of a p pr o xi matel y 2 -3 m m j ust inferior t o t he r o und 
wind o w nic he, a nd wit h fir m b ut ge ntle press ure, inject 0. 2 m L ta king care not t o insert 
t he nee dle furt her t ha n necessar y.  Use of t his tec hniq ue will mini mize t he p ossibilit y of 
O T O -1 0 4 a d hering t o t he underside of t he t y mpa nic me mbra ne.  D o not incise t he 
t y mpa nic me mbra ne t o for m a ve ntilatio n hole as t his is not nee de d d ue t o t he s mall 
injectio n volu me. 
6. 2.  
C o m pli a nc e  
O T O -1 0 4 will be a d minist ere d b y site pers o nnel as a single, intrat y mpa nic injectio n  at Visit 1 
a nd 2 e xce pt w he n wit hheld d ue t o p ote ntial safet y c o ncer ns .  A ny de viatio ns in a d ministrati o n 
will be d oc u me nte d in t he s o urce d oc u me nts a nd t he e C R F.  
T he site will maintai n a lo g of all st ud y dr ug dis pe nse d a nd ret ur ne d. Dr ug s up plies for eac h 
s ubject will be inve nt orie d a nd acc o unte d for t hr o ugho ut t he trial.  
7.  
P RI O R, C O N C O MI T A N T, A N D S U B S E Q U E N T T H E R A P Y  
Use of all c o nc o mita nt me dicatio ns will be rec or de d in t he s ubject’s e C R F.  This will include all 
s y mpt o matic relief me dicatio ns for Me niere’s d isease s y mpt o ms, prescriptio n dr ugs, her bal 
pr o d ucts, vita mi ns, minerals, a nd o ver -t he-c o unter me dicatio ns ta ke n wit hi n 3 0 da ys before 
e nr oll me nt, w hic h will be c o nsidere d prior t hera p y.  A ny c o nc o mita nt me dicatio n dee me d 
necessar y for t he welfare of t he s ubject d uring t he st ud y ma y be give n at t he discretio n of t he 
I nvesti gat or e xce pt for t hose liste d in Sectio n 7. 1.  A ny c ha nges in c o nc o mita nt me dicatio ns will 
be rec or de d in t he s ubject’s e C R F.  
7. 1.  
P r os c ri be d T he r a p y o r P r o c e d ures D uri n g t he St u d y P e ri o d  
T he follo wi n g t hera pies are pr o hibite d d uring t he st ud y: 
 S yste mic c ortic oster oids  
 I m munos up pressi ve me dicatio ns 
 P he nol for use in a nest h etizi n g t he t y mpa nic me mbra ne  
 I ntrat y mpa nic injectio n ot her t ha n t hat o utli ne d in t he c urre nt st ud y 
 S ur ger y for treat me nt of  Me niere’s disease  
 Ot her investi gatio nal dr ug(s) or de vice(s)  
Use of a ny of t hese pr oscribe d t hera pies will be c o nsidere d a pr ot oc ol de viatio n. 


 
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7. 2.  
S y m pt o m atic R elief Me dic ati o ns  
It is rec o gnize d t hat s ubjects ma y at ti mes use certain me dicatio ns for relief of s y mpt o ms relate d 
t o Me niere’s disease d uring t he c o urse of t he st ud y.  I nter mitte nt use of vestib ular s up pressa nts 
a nd a nti-e metics is allo we d as s y mpt o matic relief me dicatio ns.  The use of ge nta mici n , 
c ortic oster oids  or s ur ger y at a ny ti me d uring t he st ud y will be c o nsidere d a pr ot oc ol de viatio n.  
A ny c ha nges re p orte d b y t he s ubjects in c o nc o mita nt me dicatio ns s ho uld be rec or de d in t he 
s ubject’s e C R F. 
8.  
S T U D Y E V A L U A TI O N S  
8. 1.  
St u d y P r o c e d ures b y Visit  
8. 1. 1.  
Visit 1: D a y 1 ( Scre e ni ng/ B as eli ne/ D os e N o. 1)  
T he follo wi n g  assess me nts will be perfor me d at Visit 1.  F or s ubjects e nr olli n g directly ( wit hi n 1 
mo nt h) fr o m St ud y 1 0 4 -2 0 1 5 0 6, t he t y mpa no metr y, a udio metr y, ot osc o p y a nd C -S S R S 
assess me nt data c ollecte d at t he final visit of St ud y 1 0 4 -2 0 1 5 0 6 will ser ve as t he Baselin e data 
for Visit 1. 
T he follo wi n g assess me nts will be perfor me d at Visit 1.  
 I nfor me d c o nse nt 
 C o nfir m eligibilit y  criteria 
 Me dical hist or y  
 C o nc o mita nt me dicatio ns  
 Vital signs  
 Height a nd weight meas ure me nts  
 Urine pre gna nc y test (for fe male s ubjects of c hild b eari n g p ote ntial o nly)  
 T y mpa no metr y  
 A udio metr y   
 Ot osc o p y 
 C -S S R S assess me nt : Baseline versio n or Since Last Visit versio n  
 Me niere’s s y mpt o m q uestio n naire  
 A d minister O T O -1 0 4 (all assess me nts in t he a b o ve list must be c o nd ucte d prior t o 
O T O -1 0 4 a d ministrati o n) 
 A d verse e ve nts (t o be c ollecte d d uring or after O T O -1 0 4 a d ministratio n)  
8. 1. 2.  
Visit 2: M o nt h 3  ( ± 2 we e ks) ( Foll o w U p a n d D os e N o. 2) 
T he follo wi n g assess me nts will be perfor me d at Visit 2 . 


 
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 C o nc o mita nt me dicatio ns  
 Vital signs  
 Urine pre gna nc y test  (for fe male s ubjects of c hild beari n g p ote ntial o nly) 
 A udio metr y  
 T y mpa no metr y  
 Ot osc o p y 
 C -S S R S assess me nt, Since Last Visit versio n  
 Me niere’s s y mpt o m q uestio n naire 
 
 A d minister O T O -1 0 4 (all assess me nts in t he a b o ve list must be c o nd ucte d prior t o 
O T O -1 0 4 a d ministrati o n) 
 A d verse e ve nts (t o be c ollecte d d uring or  after O T O -1 0 4 a d ministratio n)  
8. 1. 3.  
Visit 3 : M o nt h 6  ( ± 2 we e ks) ( E n d of St u dy/ E arl y Te r mi nati o n) 
T he follo wi n g assess me nts will be perfor me d at Visit 3 . 
 C o nc o mita nt me dicatio ns  
 Vital signs  
 Weight  meas ure me nt  
 Urine pre gna nc y test (for fe male s ubjects  of c hild beari n g p ote ntial o nly)  
 T y mpa no metr y  
 A udio metr y   
 Ot osc o p y 
 C -S S R S assess me nt, Since Last Visit versio n  
 Me niere’s s y mpt o m  q uestio n naire  
 A d verse e ve nts  
8. 1. 4.  
U ns c he d ule d Visit  
T he follo wi n g assess me nts will be perfor me d at a n unsc he d ule d visit . 
 C o nc o mita nt me dicatio ns  
 Vital signs  
 T y mpa no metr y , as indicate d 
 A udio metr y , as indicate d 
 Ot osc o p y 
 C -S S R S assess me nt, Since Last Visit versio n  


 
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 A d verse e ve nts  
8. 2.  
S afet y E v al u ati o ns  
Safet y assess me nts include:  
 Vital Signs, Height a nd Weight 
Meas ure me nts  
 T y mpa no metr y  
 A udio metr y  
 Ot osc o p y  
 C -S S R S Assess me nt  
 C o nc o mita nt 
Me dicatio ns  
 A d verse e ve nts (see  Sectio n  9 ) 
8. 2. 1.  
Vit al Si g n , Hei g ht a n d 
Wei g ht M e as ure me nts  
Vital sign meas ure me nts (incl udi n g s yst olic a nd diast olic blo o d press ure a nd p ulse rate) will be 
c ollecte d at all st ud y visits.  Blo o d press ure a nd p ulse rate will be meas ure d after s ubjects ha ve 
bee n seate d for 5 minutes a nd w hile s ubjects are in a sittin g p ositio n.  Height a nd weight will be 
meas ure d at  Visit 1  a nd weight will be meas ure d a gain at Visit  3 . 
8. 2. 2.  
Uri ne Pre g na nc y Test  
A urine pre gna nc y test via dipstic k will be c o nd ucte d  o nly o n w o me n of c hild beari n g p ote ntial at 
all st ud y visits.  T he urine pre gna nc y test must be c o nd ucte d a nd c o nfir me d ne gative prior t o 
a d ministr atio n of O T O -1 0 4  at St ud y Visits 1 a nd 2 . 
8. 2. 3.  
T y m pa no met ry  
T y mpa no metr y assess me nts will be use d t o assess t he mo bilit y a nd c o mplia nce of t he t y mpa nic 
me mbra ne, press ure a nd volu me in t he mid dle ear, a nd functio n of t he t y mpa nic me mbra ne, 
ossicles a nd e ustac hia n t ube.  T y mpa no gra ms will be c o mplete d in b ot h ears a t all st ud y visits.  
S ubjects wearing hearing aids s ho uld be instr uct e d not t o wear t heir hearing aids d uring t he 
t y mpa no metr y assess me nt. 
8. 2. 4.  
A u di o gra ms  
A udio metric assess me nts will be use d t o assess hearing functio n in b ot h ears.  A udio gra ms 
s ho uld be c o nd ucte d at 5 0 0, 1 0 0 0, 2 0 0 0, 4 0 0 0 a nd 8 0 0 0 Hz for b ot h air a nd b o ne c o nd uctio n at 
all st ud y visits.  B ot h air a nd b o ne c o nd uctio n t hres holds will be assesse d.  P ure t o ne a vera gin g 
b o ne a nd air c o nd uctio n testing will be d o ne at 5 0 0, 1 0 0 0, a nd 2 0 0 0 Hz fre q ue ncie s.  S ubjects 
wearing hearing aids s ho uld be instr ucte d not t o wear t heir hearing aids d uring t he a udio gra m.  
A udio metric assess me nts must be c o nd ucte d in acc or da nce wit h  A merica n -S peec h -La n g ua ge -
Hearing Ass ociatio n G uideli nes  (A S H A, 2 0 0 5 ).  Eq uip me nt calibratio n must be c urre nt a nd 
d oc u me nte d.  T he a udio metric assess me nts must be c o nd ucte d b y a lice nse d a udiolo gist or a 


 
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q ualifie d assista nt wit h a p pr o priate traini n g under t he direct s uper visio n of a lice nse d 
a udiolo gist.  
8. 2. 5.  
Ot os c o py  
Ot osc o pic e xa ms will be use d t o assess t he a udit or y ca nal, t he a p peara nce of t he t y mpa nic 
me mbra ne, a nd t he healin g of t he intrat y mp a nic injectio n site.  Ot osc o pic e xa minatio ns will be 
perfor me d in b ot h ears at all st ud y visits d uring t he st ud y b y t he p hy sicia n.  Prese nce a nd size of 
t y mpa nic me mbra ne perforatio ns will be rec or de d.  Perforatio ns of t he t y mpa nic me mbra ne will 
be ca pt ure d as a d verse e ve nts (A Es ) o nly if t he perforatio n increases in size a nd d oes not res olve 
b y t he e nd of t he st ud y.  S ubjects  wearing hearing aids s ho uld be instr ucte d not t o wear t heir 
hearing aids d uring t he ot osc o pic e xa m.  
8. 2. 6.  
C -S S R S Ass ess me nt  
T he C -S S R S assess me nt will be a d ministere d at all st ud y visits.  The Since Last Visit versio n of 
t he C-S S R S will be use d for s ubjects e nr olli n g fr o m St ud y 1 0 4 -2 0 1 5 0 6 w hile t he Baseline 
versio n will be use d for all s ubjects  e nr olli n g fr o m St ud y 1 0 4 -2 0 1 1 0 2 .  The Since Last Visit 
versio n of t he C -S S R S will be use d at all s ubse q ue nt visits.  A ny s ubject wit h a p ositive sc ore o n 
t he Baseline versio n or a n a p peara nce of a ny ne w s uicidal ideatio n or s uicide be ha vior since t he 
Baseline versio n ( w het her a d ministere d in t his st ud y or St ud y 1 0 4-2 0 1 5 0 6) s ho uld be referre d t o 
t heir pri mar y care pr o vider for follo w-up.  
If a s ubject has a ny p ost-Baseline  C -S S R S sc ore of 1 -3 for I deatio n (i.e., a “yes” a ns wer t o 
Q uestio ns 1, 2, or 3) or a “yes” res p o nse t o t he N o n -S uicidal Self -I nj uri o us Be ha vior q uestio n) 
a nd t he sc ore is higher t ha n t he Baseline  C -S S R S sc ore, t he n t his assess me nt s ho uld be rec or de d 
as a n a d verse e ve nt ( A E).  T his infor matio n is re p orte d as indicate d in Sectio n  9. 1 . ( P ossible A E 
ter ms: S uicidal pla ns, S uicidal ideatio n, S uicidal te nde nc y, S uicidal be ha vior, S uicidal inte ntio n, 
S uicidal de pressio n, Active s uicidal ideatio n, Passive s uicidal ideatio n, Self -inj urio us be ha vior 
wit ho ut s uicidal inte nt).  
If a s ubject has a ny p ost-Baseline  C -S S R S sc ore of 4 or 5 for I deatio n (i.e., a “yes” a ns wer t o 
q uestio n 4 or 5) a nd/ or a ny q uestio ns a ns were d yes for S uicidal Be ha vior ( wit h t he e xce ptio n of 
a “yes” res p o nse t o t he N o n-S uicidal Self -I nj uri o us Be ha vior q uestio n), a nd t his was not 
o bser ve d at Baseline , t he n t his assess me nt s ho uld be rec or de d as a serio us ad verse eve nt ( S A E).  
T his infor matio n is re p orte d as indicate d in Sectio n  9. 2. 2 . 
8. 3.  
A d diti o n al E v al u ati o ns  
8. 3. 1.  
M e nie re’s S y m pt o m  Q uesti o n naire  
T he Me niere’s s y mpt o m q uestio n naire is a set of  q uest io ns t hat will be a d ministere d at St ud y 
Visits 1, 2,  a nd 3 .  Eac h q uestio n has 5 p ossible res p o nses:  1) N o Vertigo/ N o Tinnit us/ N o Ear 
F ullness/ N o H earing Diffic ult y ( de pe nding o n t he q uestio n a d minister e d ), 2) Mild , 3) M o derate , 
4) Se vere , a nd 5) E xtre mel y Se vere.   T his assess me nt is c o nsidere d a n a d ditio nal e nd p oint.  


 
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9.  
A D V E R S E E V E N T ( A E) R E P O R TI N G  
Ti mel y, acc urate, a nd c o mplete re p orting a nd a nalysis of safet y infor mati o n fr o m clinical trials 
will be c o nd ucte d in acc or da nce wit h G o o d Clinical Practice.  
All A Es, includi n g S A Es re p orte d or o bser ve d d uring or after d osing wit h t he st ud y dr ug will be 
rec or de d o n t he A E pa ge of t he e C R F for all e nr olle d s ubjects.  I nfor mati o n t o be c ollecte d 
includes descriptio n of e ve nt, date of o nset, investi gat or-s pecifie d assess me nt of t he se verit y a nd 
relatio ns hi p t o st ud y dr ug, date of res olutio n of t he e ve nt, serio us ness, a ny re q uire d treat me nt or 
e valuatio ns, a nd o utc o me.  A d verse e ve nts res ulti n g fr o m c o nc urre nt illnesses, reactio ns t o 
c o nc urre nt ill nesses, reactio ns t o c o nc urre nt me dicatio ns, or pr o gressio n of disease states must 
als o be re p orte d.  Perforatio ns of t he t y mpa nic me mbra ne will be ca pt ure d as A Es o nly i f t he 
perforatio n increases in size a nd d oes not res olve b y t he e nd of t he st ud y.  
If t he e xisti n g me dical c o nditio n w orse ns at a ny ti me after a p plicatio n of st ud y dr ug, it s ho uld be 
rec or de d as a n A E. 
9. 1.  
A d ve rs e E ve nt Cl assific ati o n D efi niti o ns  
A dve rs e E ve nt:  
A n  A E is a ny unfa vora ble a nd uninte nde d dia gnosis , s y mpt o m, sign, s yndr o me or disease w hic h 
occ urs d uring t he st ud y, ha ving bee n a bse nt at baseline, or, if prese nt at baseline, a p pears t o 
w orse n.  
T his includ es a ny occ urre nce t hat is ne w in o nset or a ggra v ate d in se verit y or fre q ue nc y fr o m t he 
baseline c o nditio n, includi n g a b nor mal res ults of dia gnostic pr oce d ures a nd/ or la b orat or y test 
a b nor malities, w hic h are c o nsidere d A Es if t he y: 
 res ult in disc o nti n uati o n fr o m t he st ud y 
 re q uire treat me nt or a ny ot her thera pe utic inter ve nti o n  
 re q uire furt her dia gnostic e valuatio n (e xcludi n g a re petitio n of t he sa me pr oce d ure t o 
c o nfir m t he a b nor malit y)  
 are ass ociate d wit h clinical signs or s y mpt o ms j ud ge d b y t he investi gat or t o ha ve a 
significa nt clinical i mpact 
Se ri o us A dve rs e E ve nt ( S A E):  
A n S A E is define d as a ny unt o war d me dical occ urre nce t hat: 
 res ults in deat h, 
 is life-t hreate ni n g (N ote: t he ter m “life -t hreate ni n g” refers t o a n e ve nt in w hic h t he 
s ubject was at ris k of deat h at t he ti me of t he e ve nt rat her t ha n t o a n e ve nt w hic h 
hyp ot heticall y might ha ve ca use d deat h if it were more se vere. ), 
 re q uires in-patie nt hos pitalizatio n or pr olo ngat io n of e xistin g hos pitalizati o n, 
 res ults in persiste nt or significa nt disa bilit y/i nca pacit y, or 
 is a c o nge nital a no mal y/ birt h defe ct. 


 
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Me dical a nd scie ntific j ud g me nt s ho uld be e xercise d in decidin g w het her e xpe dite d re p orting is 
a p pr o priate in ot her sit uatio ns, s uc h as i mp orta nt me dical e ve nts t hat ma y not be i m me diatel y 
life-t hr eate ni n g or res ult in deat h or hos pitalizatio n b ut ma y je o par dize t he s ubject or ma y re q uire 
inter ve ntio n t o pre ve nt o ne of t he ot her o utc o mes liste d in t he a b o ve definitio n.  These e ve nts 
s ho uld be c o nsidere d serio us. 
9. 1. 1.  
Ass ess me nt of Se ve rit y  
T he investi gat or will assess t he inte nsit y of t he A E a nd rate t he A E as mild, mo derate, or se vere 
using t he follo wi n g criteria:  
Gra de 1 –  Mil d:  T hese e ve nts are easily t olerate d, re q uire mini mal or no treat me nt, a nd d o 
not interfere wit h t he s ubject’s daily activities.  
Gra de 2 –  M o de rate:  T hese e ve nts ca use s ufficie nt disc o mfort t o interfere wit h daily 
activit y a nd/ or re q uire a si mple d ose of me dicatio n, e. g., a nalgesics or a nti -e metics.  
Gra de 3 –  Se ve re:  T hese e ve nts inca pacitate a nd pre ve nt us ual activit y or re q uire c o mple x 
me dicatio n/tre at me nt or hos pitalizati o n.  
Gra de 4 –  Life T hre ate ni ng : T hese  e ve nts are t hose for w hic h t he s ubject was at ris k of 
deat h at t he ti me of t he e ve nt rat her t ha n a n e ve nt w hic h hyp ot heticall y might ha ve ca use d 
deat h if it were more se vere . 
Gra de 5 –  D e at h:  T he e ve nt res ulte d in t he deat h of t he  s ubject. 
C ha nges in t he se verit y of a n A E s ho uld be d oc u me nte d t o allo w for a n assess me nt of t he 
d uratio n of t he e ve nt at eac h le vel of inte nsit y t o be perfor me d.  
9. 1. 2.  
Ass ess me nt of C a us alit y  
T he investi gat or’s assess me nt of a n A E’s relatio ns hip t o st ud y dr ug  will be part of t he 
d oc u me ntatio n pr ocess, b ut will not be a fact or in deter mini n g w hat is or is not re p orte d in t he 
st ud y. 
T he investi gat or will assess t he relatio ns hi p or ass ociatio n of t he st ud y dr ug in ca using or 
c o ntrib uti n g t o t he A E, w hic h will be c haracterize d using t he follo wi n g classificatio n a nd 
criteria: 
D efi nite : A d verse e ve nts t hat, after careful me dical e valuatio n, are c o nsidere d definitel y 
relate d t o t he st ud y dr ug; ot her c o nditio ns (c o nc urre nt ill ness, pr o gressio n/ e xpressi o n of 
disease sta te, or c o nc urre nt me dicatio n reactio n) d o not a p pear t o e xplain t he e ve nt. 
Pro ba ble : A d verse e ve nts t hat, after careful me dical e valuatio n, are c o nsidere d wit h a high 
de gree of certaint y t o be relate d t o t he st ud y dr ug.  The follo wi n g c haracteristics will a p ply: 
 a reas o na ble te mp oral relatio ns hip e xists bet wee n t he e ve nt a nd e xp os ure t o t he st ud y 
dr ug, a nd  
 the e ve nt is a k no w n reactio n t o t he st ud y dr ug t hat ca nnot be e xplaine d b y a n 
alter nati ve ca use c o m mo nl y occ urring in t he p o p ulatio n/i ndi vid ual, or  
 the e ve nt is not a k no w n reactio n t o t he st ud y dr ug b ut ca nnot be reas o na bly 
e xplaine d b y a n alter nati ve ca use.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              2 6   
 
P ossi ble : A d verse e ve nts t hat, after careful me dical e valuatio n, d o not meet t he criteria for a 
definite or pr o ba ble relatio ns hi p t o t he st ud y dr ug,  b ut for w hic h a c o nnectio n ca nnot be r ule d 
o ut wit h certaint y.  T he follo wi n g c haracteristics will a p ply:  
 the e ve nt occ urs after e xp os ure t o t he st ud y dr ug, a nd  
 there is a reas o na ble te mp oral relatio ns hi p t o t he a p plicatio n, b ut t he e ve nt is not a 
k no w n r eactio n t o t he st ud y dr ug a nd c o uld be e xplaine d b y a c o m mo nl y occ urring 
alter nati ve ca use, or  
 in t he a bse nce of a reas o na ble te mp oral relatio ns hip, t he e ve nt ca nnot be e xplaine d b y 
a n alter nati ve ca use.  
N ot rel ate d : A d verse e ve nts in t his cate gor y will have eit her of t he follo wi n g c haracteristics:  
 the e ve nt d oes not ha ve a reas o na ble te mp oral relatio ns hip t o st ud y dr ug 
a d ministr atio n a nd / or ca n be e xplaine d b y a c o m mo nl y occ urring alter nati ve ca use.  
9. 1. 3.  
F oll o w u p of A dve rs e E ve nts  
T he investi gat or will follo w a no n-serio us A E until res olutio n, sta bilizati o n, or t he End of St ud y 
Visit.  T he investi gat or will follo w a n S A E (re gar dless of relatio ns hi p t o st ud y dr ug) until t he 
e ve nt res olves, sta bilizes, or bec o mes no n-serio us.  All A Es ide ntifie d o n t he last sc he d ule d 
c o ntact must be rec or de d o n t he A E pa ge of t he e C R F a nd t he c urre nt stat us ( o ngoin g or 
res olve d) will be note d.  I n a d ditio n, S A Es will be re p orte d t o Pr o d uct Safet y  acc or ding t o t he 
re p orting guideli nes ide ntifie d in Sectio n 9. 2. 2 . 
9. 2.  
M o nit o ri n g of A d ve rs e E ve nts  
9. 2. 1.  
All A dve rs e E ve nts  
All A Es will be a nalyze d for safet y.  T hose meetin g t he definitio n of S A E must be re p orte d using 
t he S A E F or m.  S ubjects s ho uld voluntaril y re p ort a ny A Es or re p ort A Es in res p o nse t o ge neral, 
no n-directe d q uestio ni n g (e. g., " H o w has yo ur healt h bee n since t he last visit? ").  F or ea c h A E 
volunteer e d b y t he s ubject , t he investi gat or s ho uld o btain all t he infor matio n re q uire d t o 
c o mplete t he A E pa ge of t he eC R F, in acc or da nce wit h t he guideli nes t hat acc o mpa ny it.  
All A Es, re gar dless of serio us ness, se verit y, or pres u me d relatio ns hip t o st ud y t hera p y, must be 
rec or de d using me dical ter minol o g y in t he s o urce d oc u me nt a nd o n t he eC R F.  W he ne ver 
p ossible, dia gnoses s ho uld be give n w he n signs a nd s y mpt o ms are d ue t o a c o m mo n etiolo gy 
(e. g., c o ugh, r unny nose, s neezin g, s ore t hr oat, a nd hea d c o ngestio n s ho uld be re p orte d as "up per 
res pirat or y infectio n").  I nvesti gat ors must rec or d o n t he eC R F t heir o pinio n c o ncer nin g t he 
relatio ns hi p of t he A E t o st ud y t hera p y.  All meas ures re q uire d for A E ma na ge me nt must be 
rec or de d in t he s o urce d oc u me nt a nd re p orte d acc or ding t o s p o ns or instr uctio ns.  
A ny no n -serio us A E t hat occ urs after t he d ose of st ud y dr ug must be re p orte d in detail o n t he 
a p pr o priate e C R F pa ge a nd follo we d until res olutio n, sta bilizatio n, or t he End  of St ud y V isit.  
T he descriptio n of t he A E will include descriptio n of e ve nt, date of o nset, date of res olutio n, 
investi gat or assess me nt of se verit y a nd relatio ns hip t o st ud y dr ug, serio us ness, a ny re q uire d 
treat me nt or e valuatio ns, a nd o utc o me.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              2 7   
 
T he s p o ns or ass u mes res p o nsibilit y for a p pr o priate re p orting of A Es t o t he re gulat or y a ut horities.  
T he s p o ns or will als o re p ort t o t he investi gat ors all serio us A Es t hat are unlist e d a nd ass ociate d 
wit h t he use of t he dr ug.  T he investi gat ors must re p ort t hese e ve nts t o t he a p pr o priate 
I nstit uti o nal Re vie w B oar d (I R B) in acc or da nce wit h local re gulatio ns.  
9. 2. 2.  
Se ri o us A dve rs e E ve nts  
All S A Es occ urring d uring clinical trials must be re p orte d wit hi n 2 4 ho urs t o Pr o d uct Safet y.  
T he ca use of deat h of a s ubject in a clinical trial, w het her t he e ve nt is e xpecte d or ass ociate d wit h 
t he investi gatio nal a ge nt, is a n S A E. 
T he initial re p ort  of a n S A E ma y be ma de b y tele p ho ne , e-mail  or facsi mile (fa x).  The 
investi gat or must pr o vide t he mini mal infor matio n: i.e., pr ot oc ol nu mber, s ubject's initials a nd 
date of birt h, s ubject nu mber or me dicatio n c o de nu mber, nat ure of t he A E a nd investi gat or 's 
attrib utio n.  
All oral re p orts of a n S A E must be c o nfir me d wit hin 2 4 ho urs b y a writte n, more detaile d re p ort 
a nd signe d b y t he investi gat or.  F or t his p ur p ose, t he s p o ns or will pr o vide t he investi gat or wit h 
t he Serio us A d verse E ve nt F or m for Clinical Trials. 
All S A Es t hat ha ve not res olve d b y t he e nd of t he st ud y, or t hat ha ve not res olve d up o n 
disc o nti n uati o n of t he s ubject's participatio n in t he st ud y, must be follo we d until eit her:  
 t he e ve nt res olves, 
 t he e ve nt sta bilizes, or 
 t he e ve nt bec o mes no n-serio us 
T he investi gat or s ho uld re p ort a ny follo w -up infor matio n as it bec o mes a vaila ble.  
9. 2. 3.  
Pre g na ncies  
Pre gna ncies occ urrin g after t he first d ose of investi gati o nal pr o d uct  a nd d uring participatio n of 
t he st ud y are c o nsidere d i m me diatel y re p orta ble e ve nts.  W h ile not c o nsidere d a S A E unless a 
serio us criterio n is met, pre gna ncies occ urring in s ubjects e nr olle d o n t he st ud y must be re p orte d 
a nd follo we d t o o utc o me.  T he investi gat or s ho uld c o mplete t he pre gna nc y re p ort e C R F wit hi n 
o ne w or king da y of k no wle d ge of  t he pre gna nc y.  F ollo wi n g deliver y or ter minatio n of 
pre gna nc y, t he follo w -up pre gna nc y re p ort for m s ho uld be c o mplete d o n t he pre gna nc y C R F.  
S p o nta ne o us a b ortio ns s ho uld al wa ys be re p orte d as S A Es.  F ollo w -up infor matio n re gar ding t he 
o utc o me of t he pre gna nc y a nd a ny p ost natal se q uelae in t he infa nt will be re q uire d.  
9. 3.  
C o nt a cti n g S p o ns o r R e g a r di n g S afet y  
A ny A E c o nsidere d serio us b y t he investi gat or, or t hat meets t he S A E criteria state d in t his 
pr ot oc ol, must be re p orte d t o Pr o d uct Safet y wit hi n 2 4 ho urs  fr o m t he ti me t hat st ud y site 
pers o nnel first lear ns of t he e ve nt.  T he st ud y site must e nter t he S A E int o t he E D C s yste m.  
  
 
 


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              2 8   
 
S o urce d oc u me nts will be re q ueste d fr o m t he st ud y sites for S A Es a nd s ho uld be pr o vide d t o 
Pr o d uct Safet y.  If t he s ubject is hos pitalize d d uring t he st ud y, a c o p y of t he hos pital disc har ge 
s u m mar y s ho uld be pr o vide d t o t he Pr o d uct Safet y as s o o n as it bec o mes a vaila ble.  
1 0.  
S U B J E C T C O M P L E TI O N  
1 0. 1.  
C o m pleti o n  
S ubjects w ho wit hdra w  fr o m furt her a d ministr atio n of st ud y dr ug or w ho wit hdra w t heir c o nse nt 
t o be follo we d or are lost-t o-follo w-up before c o mpletio n of Visit 3  ( M o nt h 6 ) will not be 
c o nsidere d t o ha ve c o mplete d  t he st ud y. 
1 0. 2.  
Wit h dr a w al  
All s ubjects ha ve t h e right t o wit hdra w fr o m st ud y dr ug a d ministrati o n a nd/ or st ud y e valuatio ns  
at a ny ti me, for a ny reas o n, wit ho ut prej udice; no net heless, investi gat ors s ho uld atte mpt t o 
e nc o ura ge s ubjects t o c o mplete t he pr ot oc ol e ve n if t he s ubject has wit hdra w n fr o m st ud y dr ug 
s o t hat c o ntinue d o bser vatio n a nd follo w-up meas ure me nts ma y be o btaine d.  The investi gat or 
ma y disc o ntin ue a s ubject’s participatio n in t he st ud y at his/ her discretio n for reas o ns includi n g, 
b ut not li mite d t o, t he follo wi n g:  
1.  S ubject e xperie nces a serio us or int olera ble A E t hat, in t he o pinio n of t he investi gat or, 
re q uires wit hdra wal fr o m t he st ud y. 
2.  S ubject is in violatio n of t he pr ot oc ol.  
3.  S ubject de velo ps a c o nditio n d uring t he c o urse of t he st ud y t hat ma kes it un wise t o 
c o ntinue wit h t he trial.  
4.  S u bject re q uires a me dicatio n t hat is pr o hibite d b y t he pr ot oc ol.  
5.  S ubject re q uests a n early disc o ntin uatio n for a ny reas o n.  
At a ny p oint, t he investi gat or ma y disc o ntin ue t he s ubject’s st ud y participatio n at his/ her 
discretio n a nd e ns ure t he s ubject receives  a p pr o priate me dical care; t he investi gat or ma y als o 
c o ns ult t he me dical mo nit or t o disc uss o ut -of-ra nge test res ults. 
1 0. 2. 1.  
H a n dli ng of Wit h dra w als  
S ubjects will be free t o wit hdra w fr o m furt her st ud y dr ug a d ministratio n a nd furt her follo w-up 
t he st ud y at a ny ti me.  S ubject participatio n in t he st ud y ma y be st o p pe d at a ny ti me at t he 
discretio n of t he investi gat or or at t he re q uest of t he s p o ns or.  
W he ne ver p ossible, all s ubjects w ho wit hdra w fr o m furt her st ud y dr ug a d ministratio n s ho uld be 
e nc o ura ge d t o re main o n-st ud y for furt her follo w-up t hr o ugh t he s ubject last sc he d ule d visit.  
H o we ver, s ho uld a re q uest for early wit hdra wal fr o m t he st ud y wit h no furt her follo w -up be 
ma de, t he s ubject s ho uld be e nc o ura ge d t o ret ur n t o t he st ud y site for a last follo w up visit a nd  
under go all e nd of st ud y/earl y ter minati o n assess me nts.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              2 9   
 
W he n a s ubject wi t hdra ws fr o m furt her a d ministrati o n of st ud y dr ug or t he st ud y prior t o 
c o mpleti n g Visit 3  ( M o nt h 6 ), t he reas o n for wit hdra wal is t o be d oc u me nte d o n t he eC R Fs a nd 
in t he s o urce d oc u me nt.   
1 0. 2. 2.  
R e pl ace me nts  
S ubjects w ho disc o nti n ue participatio n in t he st ud y for a ny reas o n after d osing will not be 
re place d. 
1 1.  
S T A TI S TI C A L M E T H O D S  
T he e mp hasis of t he a nalysis will be wit h res pect t o descriptio n a nd esti matio n rat her t ha n  
hyp ot hesis testing .  T he follo wi n g statistical sectio ns describe t he ge neral a nalytic met ho ds t o be 
i mple me nt e d t o assess t he o verall st ud y o bjectives.  M ore detaile d descriptio ns of t he 
met ho d olo g y will be pr o vide d in t he Statistical A nalysis Pla n ( S A P).    
1 1. 1.  
S a m ple Siz e  
It is e xpecte d t hat up t o 3 0 0 s ubject s fr o m P hase 2 b (1 0 4 -2 0 1 1 0 2 ) or P hase 3 ( 1 0 4 -2 0 1 5 0 6)  
clinical trials will be e nr olle d int o t his st ud y.  The sa mple size was not base d o n a ny p o wer 
calc ulatio n.   
1 1. 2.  
A n al ysis S ets  
T he follo wi n g definitio ns wi ll be use d t o derive t he a nalysis sets for t his st ud y.    
S afet y A nal ysis Set :  T he safet y a nalysis set will include all s ubjects w ho receive at least o ne 
d ose of st ud y dr ug.   
1 1. 3.  
D es c ri pti o n of S u b g r o u ps t o be A n al yze d  
K e y safet y data will be describe d  for t he follo wi n g s ub gr o ups using t he safet y a nalysis set: 
 S ubject De mo gra p hics  
 Ge nder  
A d ditio nal de mo gra p hic a nd baseline c haracteristic s ub gr o ups will be c o nsidere d a nd ide ntifie d 
in detail in t he S A P. 
1 1. 4.  
S u bje ct D e m o g r a p hics, B aseli ne Dis e ase St at us, a n d Dis p ositi o n  
Descripti ve statistics for s ubject de mo gra p hics, baseline disease stat us, a nd s ubject dis p ositio n 
will be pr o vide d.  If feasible, a K a pla n -Meier plot of ti me -t o-st ud y wit hdra wal will als o be 
esti mate d.  Pr ot oc ol de viatio ns will be a nalyze d b y aggre gate s u m mar y a nd/ or line listi n gs if t he 
nu mber of de viatio ns is s mall. 
1 1. 5.  
Effic a c y E v al u ati o ns  
N ot a p plica ble  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              3 0   
 
1 1. 6.  
G e ne r al A n al ytic Met h o ds  
T he pri mar y a nalytic a p pr oac h for t his trial will be descripti ve.  S u m mar y statistics will be 
calc ulate d a nd w here rele va nt, 9 5 % c o nfide nce inter vals prese nte d.  Details of t he a nalysis will 
be describe d in t he S A P.  
1 1. 7.  
S afet y E v al u ati o ns  
Safet y e valuatio ns include : 
 Vital Signs, Height a nd Weight 
Meas ure me nts  
 T y mpa no metr y  
 A udio metr y  
 Ot osc o p y  
 C -S S R S Assess me nt  
 C o nc o mita nt 
Me d icatio ns 
 A d verse e ve nts  
1 1. 7. 1.  
A dve rs e E ve nts  
V ersio n 1 8. 1  of Me dical Dictio nar y for Re gulat or y Activities  ( Me d D R A) will be use d t o c o de all 
A Es.  
T he pri mar y a nalysis of A Es will c o nsider o nly treat me nt e mer ge nt A Es (T E A Es ), e ve nts 
occ urring for t he first ti me, or w orse nin g d uring or after t he first d ose of st ud y dr ug.  S ubject 
incide nce of T E A Es a nd S A Es will be ta b ulate d b y preferre d ter ms a nd s yste m or ga n class.  
T hese a nalyses ma y als o be ta b ulate d b y visit , ti me of o nset a nd/ or c u mulati ve e xp os ure.  I n 
a d ditio n, se verit y a nd relatio ns hi p t o st ud y dr ug will als o be prese nte d.   A d verse e ve nts  will be 
prese nte d b y desce nding or der of fre q ue nc y in Me d D R A s yste m or ga n class a nd preferre d ter m.  
S ub gr o up a nalyses of A Es b y  ge nder will be e xa mine d.   Listi n gs of all S A Es, A Es lea ding t o 
st ud y wit hdra wal, a nd deat hs o n-st ud y will als o be include d.  D uratio n a nd o utc o me of eac h A E 
will be re p orte d in s ubject listi n gs.   
1 1. 7. 2.  
Vit al Si g ns  
T he a nalysis of vital signs will include descriptive statistics for t he c ha nge fr o m basel ine t o eac h 
p ost -baseline visit  w here vital signs are c ollecte d.  The  c ha nge fr o m baseline t o t he w orst p ost -
baseline value (increase/ decrease) ma y als o be e xa mine d.   W eight meas ure me nts for baseline 
a nd p ost-baseline visits will be ta b ulate d  as will height meas ure me nts for baseline . 
1 1. 7. 3.  
Ot os c o pic E x a mi nati o ns  
O bser vatio ns rec or de d d uring t he c o nd uct of ot osc o pic e xa ms will be descriptive.  The nu mber 
a nd perce nt of s ubjects prese ntin g wit h eac h ot osc o pic classificatio n will be pr o vide d b y st ud y 
visit using s hift ta bles w here a p pr o priate .  Data will be ta b ulate d se parately for t he treate d a nd 
untreate d ear.  


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              3 1   
 
1 1. 7. 4.  
A u di o metry Ass ess me nts  
Descripti ve s u m mar y statistics a nd/ or s hift ta bles for a udio metric assess me nts of air a nd b o ne 
c o nd uctio n t hres holds at eac h fre q ue nc y will be pr o vide d b y st ud y visit.  I n a d ditio n, t he p ure 
t o ne a vera ge (P T A ) a nd b o ne c o nd uctio n a vera ge ( B C A) will be calc ulate d as t he a vera ge air  or 
b o ne  c o nd uctio n t hres hold for fre q ue ncies of 5 0 0, 1 0 0 0, a nd 2 0 0 0 .  
Air -B o ne Ga p assess me nts  at eac h fre q ue nc y a nd st ud y visit will be ta b ulate d as t he pr o p ortio n 
of s ubjects wit h air minus b o ne c o nd uctio n t hres holds of:   
 ≤ 1 0 d B or  
 > 1 0 d B.  
All a udio metr y assess me nts will be ta b ulate d se parately for t he treate d a nd untreate d ear. 
1 1. 7. 5.  
T y m pa no met ry  
S hift ta bles re prese nti n g t he pr o p ortio n of s ubjects wit h c ha nges in t heir t y mpa no gra m fr o m 
baseline t o eac h p ost -baseline st ud y visit will be calc ulate d .  Ty mpa no gra m c ha nges will include 
b ot h t he t ype of t y mpa no gra m ( A, B -s mall volu me a nd/ or nor mal, B-lar ge volu me, or C).   
1 1. 7. 6.  
C o nc o mit a nt 
M e dic ati o ns  
C o nc o mita nt me dicatio ns will be c o de d b y W H O Dr ug a nd will be ta b ulate d b y dr ug class a nd 
preferre d dr ug na me.  
1 1. 7. 7.  
C -S S R S  
T he C -S S R S will be a d minist ere d at eac h visit using t he a p pr o priate versio n i.e. Baseline or 
Since Last Visit. A nalysis of t his scale will be perfor me d o n t he Safet y A nalysis Set.  
1 1. 7. 7. 1.  C -S S R S: B as eli ne Ve rsi o n  
T he C -S S R S assess me nt will be a d ministere d at all st ud y visits.  The Since Last Visit versio n of 
t he C-S S R S will be use d for s ubjects e nr olli n g directly ( wit hi n 1 mo nt h) fr o m St ud y 1 0 4 -2 0 1 5 0 6 
w hile t he Baseline versio n will be use d for all ot her s ubjects.  The Since Last Visit versio n of t he 
C -S S R S will be use d at all s ubse q ue nt visits.  The Baseline versio n of t he scale ca pt ures b ot h 
s uicide ideatio n a nd s uicide be ha vior (lifeti me).  There are 5 s uicidal ideatio n q uestio ns, eac h 
ca pt ure d as yes/ no for t he s ubject’s lifeti me.  A d ditio nall y a sixt h s uicidal ideatio n varia ble will 
be create d t o indicate if t here was a ny ideatio n, re gar dless of t ype.  There are 4 s uicidal be ha vior 
q uestio ns, eac h ca pt ure d as yes/ no for t he s ubject’s lifeti me.  A fift h s uicidal be ha vior varia ble 
will be create d t o ca pt ure if t here was a ny s uicidal be ha vior re gar dless of t ype.  A n a d ditio nal 
q uestio n as ks if s uicidal be h a vior is prese nt d uring t he visit.  All s uicidal ideatio n a nd be ha vioral 
varia bles as o utline d here will be ta b ulate d o verall a nd b y treat me nt gr o up.  All C -S S R S data 
will be include d in data listi n gs.   T here is no inclusio n or e xclusio n criterio n ass ociate d wit h t he 
Baseline C -S S R S sc ore.  
1 1. 7. 7. 2.  C -S S R S: Si nce L ast Visit V e rsi o n 
T he Since Last Visit versio n of t he C -S S R S will be a d ministere d at eac h st ud y visit includi n g 
Visit 1 or after Visit 1  de pe nding o n w het her t he s ubject was a participa nt fr o m St ud y 1 0 4 -


 
Ot o no m y 1 0 4 -2 0 1 5 0 9 Pr ot oc ol V 2. 0: 2 2 Fe br uar y 2 0 1 6                                                              3 2   
 
2 0 1 1 0 2 or 1 0 4 -2 0 1 5 0 6 .  T he sa me o verall individ ual varia bles for s uicidal ideatio n a nd be ha vior 
will be assesse d as in t he Baseline versio n.  I n a d ditio n, o verall s uicidalit y ( yes/ no) will be 
define d as a ny s ubject ha ving a ny s uicidal ideatio n or be ha vior since t he last visit.  All s uicidal 
ideatio n a nd be ha vior varia bles will be ta b ulate d o verall a nd b y treat me nt gr o up for eac h st ud y 
visit.  All C -S S R S data will be include d in data listi n gs.  
1 1. 8.  
Ot he r E v al u at i o ns 
A d ditio nal e nd p oints include:  
 Me niere’s s y mpt o m q uestio n naire  
1 1. 8. 1.  
M e nie re’s S y m pt o m Q uesti o n naire  
Descripti ve s u m mar y statistics de noting t he c ha nge fr o m baseline a nd/ or s hift ta bles for t he 
vertigo, tinnit us, a ural full ness a nd s ubjective hearing will be  pr o vide d.  F or t he Glo bal 
Me niere’s Disease q uestio n, not meas ure d at baseline, s u m mar y statistics for eac h visit will be 
pr o vide d.  
1 1. 9.  
H a n dli n g of Missi n g D at a, S u bje ct Wit h dr a w als, a n d T re at me nt 
F ail ures  
E ver y effort will be ma de t o follo w s ubjects for st ud y o bser vatio n a nd e nc o ura ge c o mplia nce 
wit h st ud y meas ure me nts t o mini mize t he a mo unt of missin g data.  
E xce pt for partial dates, safet y data will not be i mp ute d.  The i mp utatio n algorit h m for partial 
dates will be define d in t he S A P.  
1 1. 1 0.  
I nte ri m A n al ys es 
T here  are no for mal interi m a nalyses pla nne d .  Re vie w of safet y data will be c o nd ucte d as 
describe d in  Sectio n  1 4. 7 ; ho we ver, t he re vie w of s uc h data is not inte nde d t o i mpact t he st ud y 
c o nd uct unless t here are safet y c o ncer ns.  As s uc h, it is e xpecte d t hat t he trial will c o ntinue t o its 
sc he d ule d c o mpletio n barring a ny une xpecte d safet y iss ues.  
1 2.  
S T U D Y D R U G I N F O R M A TI O N  
1 2. 1.  
P h ysic al D es c ri pti o n of St u d y D r u g(s)  
T he investi gati o nal dr ug pr o d uct a d ministere d t o s ubjects in t his st ud y will be O T O -1 0 4.  The 
O T O -1 0 4 final pr o d uct s us pe nsio n for d osing will be pre pare d fr o m t w o se parate c o mp o ne nts, 
O T O -1 0 4 Dilue nt ( o ne vial nee de d) a nd O T O -1 0 4 Active ( o ne vial nee de d).  A n a p pr o priate 
volu me of O T O -1 0 4 Dilue nt will be wit hdra w n a nd delivere d int o t he O T O -1 0 4 Active vial t o 
ac hie ve a vis uall y ho mo ge ne o us s us pe nsio n of a tar get dr ug c o nce ntratio n of 6 0 mg/ m L.  
T he pr o d uct will be s up plies as a kit c o ntaini n g o ne vial of O T O -1 0 4 Active a nd o ne vial of 
O T O -1 0 4 Dilue nt.  


 
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1 2. 2.  
Dire cti o ns f o r Us e  
O T O -1 0 4 is t o be pre pare d in a clea n locatio n wit h a r o o m te mperat ure prefera bly at or belo w 
2 3° C ( 7 3° F).  Please refer t o t he P har mac y 
Ma nual for detaile d st ud y dr ug pre paratio n 
instr uctio ns.  
1 2. 3.  
P a c k a gi n g a n d L a beli n g  
1 2. 3. 1.  
P ac k a gi ng  
All st ud y dr ug kits will be la bele d wit h infor mati o n t hat will meet t he a p plica ble re gulat or y 
re q uire me nts.  
1 2. 3. 2.  
L a bels a n d L a beli ng I nstr ucti o ns  
A la bel will be affixe d t o eac h kit b o x , O T O-1 0 4 Active a nd O T O -1 0 4 Dilue nt vials  indicati n g 
c o nte nts a nd st ora ge instr uctio ns.  
1 2. 4.  
M a n a g e me nt of Cli nic al S u p plies  
T he clinic al s up plies will be ma na ge d b y t he C R O .  The S p o ns or  will create s hip me nt re q uests 
t hat will be generate d o n inve nt or y t hres holds t hat are set for eac h site.  A s hip me nt re q uest will 
be ge nerate d a nd se nt t o t he clinical s up plies ve nd or.  U p o n s hip me nt a nd receipt of t he clinical 
trial material, t he site pers o nnel will ac k no wle d ge t he s hip me nt a nd ide ntif y a ny da ma ge d, 
missi n g, or unusa ble kits s o t he y will not be dis pe nse d.   
1 2. 4. 1.  
St ora ge of Kits  
All kits will be st ore d at -2 0° C ( ± 5 C), wit h allo wa ble te mperat ure e xc ursio ns as high as 2 5° C 
for up t o 7 2 ho urs.  All te mperat ure e xc ursio ns of t he st ud y dr ug must be d oc u me nte d in t he 
st ud y dr ug acc o unta bilit y lo g.  A ny e xc ursio ns wit hi n t he allo wa ble te mperat ure ra nge a nd 
c o nditio ns s ho uld be d oc u me nte d, b ut t he st ud y dr ug is still acce pta ble for use a nd dis pe nsi n g t o 
s ubjects.  If a ny e xc ursio ns are o utside of t hese c o nditio ns, t he st ud y dr ug s ho uld not be use d t o 
treat s ubjects.  If t his occ urs, t he st ud y dr ug s ho uld i m me diatel y be q uara ntine d  a nd re mo ved  
fr o m inve nt or y. 
1 2. 5.  
D r u g Ac c o u nt a bilit y  
It is t he res p o nsibilit y of t he clinical investi gat or t o e ns ure t hat all st ud y dr ug receive d at t he site 
will be inve nt orie d a nd acc o unte d for t hr o ugho ut t he st ud y a nd t he res ult rec or de d o n t he dr ug 
acc o unta bilit y for m maintai ne d in t he P har mac y 
Ma nual.  The must  ret ur n all original c o ntainers, 
w het her e mpt y or c o ntaini n g st ud y dr ug, w he n instr ucte d b y t he st ud y mo nit or t o ret ur n.  St ud y 
dr ug ret ur ne d b y t he clinical site staff will be st ore d a nd dis p o se d of acc or ding t o t he s p o ns or's 
instr uctio ns.  Dr ug acc o unta bilit y will be verifie d b y t he s p o ns or's st ud y mo nit or d uring o n-site 
mo nit ori n g visits.  St ud y dr ug will be st ore d in a li mite d access area or in a loc ke d ca binet under 
a p pr o priate e nvir o n me nta l c o nditio ns.  
T he investi gat or a grees not t o s up ply t he st ud y dr ug t o a ny pers o n ot her t ha n s ub -investi gat ors, 
designate d staff a nd t he s ubjects participati n g in t he st ud y.  St ud y dr ug ma y not be rela bele d or 
reassigne d for use b y ot her s ubjects e xce pt under s pecial circ u msta nces a p pr o ve d b y Ot o no my.  


 
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T he investi gat or will retain a nd st ore all original c o ntainers ret ur ne d b y t he clinical site staff until 
t hese c o ntainers are inve nt orie d b y t he st ud y mo nit or.  U nless ot her wise instr ucte d b y t he 
s p o ns or, t he investi gat or a grees at t he e nd of t he st ud y t o ret ur n all origi nal c o ntainers, w het her 
e mpt y or c o ntaini n g st ud y dr ug, t o t he s p o ns or as instr ucte d b y t he st ud y ma na ger.  The 
investi gat or a grees t o neit her dis pe nse t he st ud y dr ug fr o m, nor st ore it at, a ny site ot her t ha n t he 
st ud y sites a gree d up o n wit h t he s p o ns or. 
T he s p o ns or will e ns ure pr o per dis p ositio n of original c o ntainers e mpt y or full wit h ret ur ne d or 
unuse d st ud y dr ug.  A p pr o priate d oc u me ntatio n will be maintai ne d.  Per missio n ma y be gra nte d 
for local dis p ositio n, wit h s up p orting d oc u me ntatio n. 
1 3.  
E T HI C A L A S P E C T S  
1 3. 1.  
I n vesti g at o r R es p o nsi bilities  
T he investi gat or is res p o nsible for e ns urin g t hat t he clinical st ud y is perfor me d in acc or da nce 
wit h t he pr ot oc ol, t he Declaratio n of Helsinki, as well as wit h  t he N ote for G uida nce o n G o o d 
Clinical Practice (I C H/ 1 3 5/ 9 5), a nd a p plica ble re gulat or y re q uire me nts.  These d oc u me nts set 
fort h t hat t he infor me d c o nse nt of t he s ubjects is a n esse ntial prec o nditio n for participatio n in t he 
clinical st ud y.  
1 3. 2.  
I nstit uti o n al R e vie w B o a r d (I R B)  
T his trial will be underta ke n o nly after full a p pr o val of t he pr ot oc ol a nd a d de nda has bee n 
o btaine d fr o m a designate d I R B a nd t he s p o ns or has receive d a c o p y of t his a p pr o val.  
T he I R B must be infor me d of all s ubse q ue nt pr ot oc ol a me nd me n ts iss ue d b y t he s p o ns or. 
Re p orts o n, a nd re vie ws of, t he trial a nd its pr o gress will be s ub mitte d t o t he I R B b y t he 
investi gat or at inter vals stip ulate d in t heir guideli nes. 
1 3. 3.  
I nf o r me d C o ns e nt 
Eac h s ubject must give writte n c o nse nt (a nd sign ot her locall y r e q uire d d oc u me nts) acc or ding t o 
local re q uire me nts after t he nat ure of t he st ud y has bee n full y e xplaine d.  The c o nse nt for m must 
be signe d prior t o perfor ma nce of a ny st ud y -relate d activit y.  The c o nse nt for m t hat is use d must 
be a p pr o ve d b ot h b y t he s p o n s or a nd b y t he re vie wi n g I R B.  The infor me d c o nse nt s ho uld be in 
acc or da nce wit h t he c urre nt re visio n of t he Declaratio n of Helsinki, c urre nt I nter natio nal 
C o nfere nce o n Har mo nizati o n (I C H) G o o d Clinical Practice ( G C P) guideli nes, a nd Ot o no my 
p olic y.  
T he i nvesti gat or must e xplain t o p ote ntial s ubjects t he ai ms, met ho ds, reas o na bly a nticipate d 
be nefits a nd p ote ntial hazar ds of t he trial a nd a ny disc o mfort it ma y e ntail.  S ubjects will be 
infor me d t hat t he y are free not t o participate in t he trial a nd t hat t he y ma y wit hdra w c o nse nt t o 
participate at a ny ti me.  T he y will be t old w hic h alter nati ve treat me nts are a vaila ble if t he y refuse 
t o ta ke part, a nd t hat s uc h refusal will not prej udice fut ure treat me nt.  Finall y, t he y will be t old 
t hat t heir rec or ds ma y be e xa mine d b y c o mpete nt a ut horities a nd a ut horize d pers o ns, b ut t hat 
pers o nal infor mati o n will be treate d as strictly c o nfide ntial a nd will not be p ublicl y a vaila ble.  
S ubjects must be give n t he o p p ort unit y t o as k q uestio ns.  After t his e xpla natio n a nd befor e e ntr y 


 
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int o t he trial, c o nse nt s ho uld be a p pr o priately rec or de d b y mea ns of t he s ubject's date d signat ure.  
If a s ubject is una ble t o rea d, a n i mpartial wit ness must be prese nt d uring t he e ntire infor me d 
c o nse nt disc ussio n.  T he signat ure of t he i mpartial  wit ness will certify t he s ubject's c o nse nt.  The 
s ubject s ho uld receive a signe d a nd date d c o p y of t he infor me d c o nse nt for m.  
1 4.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  
1 4. 1.  
P r ot o c ol M o dific ati o ns  
All pr ot oc ol a me nd me nts must be iss ue d b y t he s p o ns or, signe d a nd date d b y t he  investi gat or, 
a nd s ho uld not be i mple me nte d wit ho ut prior I R B ap pr o val, e xce pt w here necessar y t o eli mi nate 
i m me diat e hazar ds t o t he s ubjects or w he n t he c ha nge(s) invol ves o nly lo gistical or 
a d ministr ati ve as pects of t he trial (e. g., c ha nge in mo nit or, c ha nge of tele p ho ne nu mber).  
Res p o nsibilities for re p orting pr ot oc ol a me nd me nts t o a ny Re gulat or y A ut horit y (if a p plica ble) 
a nd/ or I R B are furt her describe d in t he Et hical As pects sectio n of t he pr ot oc ol.  
I n sit uatio ns re q uirin g a de part ure fr o m t he pr ot ocol, t he investi gat or or ot her p hysicia n in 
atte nda nce will c o ntact t he site ma na ger , Me dical 
M o nit or or ot her a p pr o priate s p o ns or 
re prese ntati ve b y fa x, e mail or tele p ho ne (see S p o ns or C o ntact I nfor mati o n  pa ge).  If p ossible, 
t his c o ntact will be ma de before i mple me nti n g a ny de part ure fr o m pr ot oc ol.  I n all cases, c o ntact 
wit h t he s p o ns or must be ma de as s o o n as p ossible in or der t o disc uss t he sit uatio n a nd a gree o n 
a n a p pr o priate c o urse of actio n.  T he eC R F a nd s o urce d oc u me nt will describe a ny de part ure 
fr o m t he pr ot oc ol a nd t he circ u msta nces re q uiri n g it. 
1 4. 2.  
R e g ul at o r y D o c u me nt ati o n  
D oc u me nts t hat must be pr o vide d t o t he s p o ns or prior t o st ud y dr ug s hip me nt are as follo ws:  
 U p -t o-date c urric ul u m vitae for eac h investi gat or a nd s ub -investi gat or. 
 Signe d a nd date d I nvesti gat or A gree me nt.  
 A p plica ble local re gulat or y d oc u me ntatio n  
 A c o p y of t he for mal writte n notificatio n t o t he investi gat or re gar ding a p pr o val of t he 
pr ot oc ol b y a n I R B t hat is in c o mplia nce wit h re gulat or y guideli nes.  The writte n 
notificati o n is t o be signe d b y t he c hair ma n or a ut horize d designee a nd must ide ntif y 
t he s pecific pr ot oc ol.  I n cases w here a n I R B me mber has a k no w n c o nflict of 
interest, a bste ntio n of t hat indivi d ual fr o m voting s ho uld be d oc u me nte d; a n 
investi gat or ( or s ub-investi gat or) ma y be a me mber of t he I R B, b ut ma y not vote o n 
a ny researc h in w hic h he or s he is invol ve d.  
 Fina ncial disclos ure d oc u me ntati o n for eac h investi gat or a nd s ub -investi gat or. 
 N a me a nd a d dress of t he I R B wit h a state me nt t hat it is or ga nize d a nd o perates 
acc or ding t o G C P a nd t he a p plica ble la ws a nd re gulatio ns, a nd a c urre nt list of t he 
I R B me mbers .  T he I R B Attestatio n for m ca n be  use d t o ca pt ure t his infor matio n.  


 
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 A c o p y of t he I R B a p pr o ve d infor me d c o nse nt for m a nd ot her a dj unct ive materials 
(e. g., a d vertisi n g) t o be use d in t he st ud y, includi n g writte n d oc u me ntatio n of I R B 
a p pr o val of t hese ite ms . 
 Re q uire d fina ncial a gree me nt.  
I n a d ditio n t o t he d oc u me nts re q uire d prior t o t he st ud y, ot her d oc u me ntatio n ma y be re q uire d 
d uring t he c o urse of t he st ud y.  
1 4. 3.  
S u bje ct I de ntific ati o n R e giste r  
T he investi gat or a grees t o c o mplete a s ubject ide ntificatio n re gister, w hic h will be use d for t he 
p ur p ose of lo ng -ter m follo w-up, if nee de d.  This for m will be treate d as c o nfide ntial, a nd will be 
filed b y t he investi gat or in t he Trial Site File.  Ot her wise, all re p orts a nd c o m municatio ns 
relatin g t o t he st ud y will ide ntif y s ubjects b y initials a nd assigne d nu mber o nly.  
1 4. 4.  
R e c o r d R ete nti o n  
I n c o mplia nce wit h t he I C H/ G C P guideli nes t he investi gat or/i nstit ut i o n will maintai n all e C R Fs 
a nd all s o urce d oc u me nts t hat s up p ort t he data c ollecte d fr o m eac h s ubject, a nd all trial 
d oc u me nts as s pecifie d in Esse ntial D oc u me nts for t he C o nd uct of a Clinical Trial a nd as 
s pecifie d b y t he a p plica ble re gulat or y re q uire me nt(s).  The investi gat or/i nstit utio n will ta ke 
meas ures t o pre ve nt accide ntal or pre mat ure destr uctio n of t hese d oc u me nts.  Esse ntial 
d oc u me nts must be retaine d until at least t w o years after t he last a p pr o val of a mar ketin g 
a p plicatio n in a n I C H re gio n or at least t w o years ha ve ela pse d since t he for mal disc o ntin uatio n 
of clinical de velo p me nt of t he investi gati o nal pr o d uct.  These d oc u me nts will be retaine d for a 
lo nger perio d if re q uire d b y t he a p plica ble re gulat or y re q uire me nts or b y a n a gree me nt wit h t he 
s p o ns or.  It is t he res p o nsibilit y of t he s p o ns or t o infor m t he investi gat or/i nstit utio n as t o w he n 
t hese d oc u me nts no lo nger nee d t o be retaine d.  If t he res p o nsible investi gat or retires, relocates, 
or for ot her reas o ns wit hdra ws fr o m t he res p o nsibilit y of kee ping t he st ud y rec or ds, c ust o d y must 
be tra nsferre d t o a pers o n w ho will acce pt t he res p o nsibilit y.  The s p o ns or must be notifie d in 
writin g of t he na me a nd a d dress of t he ne w c ust o dia n.  
1 4. 5.  
Ele ctr o nic C as e R e p o rt F o r m  
Electr o nic C ase Re p ort F or ms (e C R F s) will be c o mplete d for eac h s ubject.  Access for data e ntr y 
will be pr o vide d t o a p pr o priate site staff me mbers.  All data must be e ntere d int o t he e C R Fs in 
E nglis h a nd signe d a nd date d  electr o nicall y b y t he investi gat or.   
T he e C R Fs s ho uld be c o mplete d b y investi gat or site staff at t he ti me of t he s ubject's visit, wit h 
t he e xce ptio n of res ults of tests perfor me d o utside t he investi gat or's office, s o t hat t he y al wa ys 
reflect t he latest o bser vatio ns o n t he s ubjects participati n g in t he trial.  
As t he site staff e nters data, discre pa ncies will be a ut o maticall y ge nerate d wit hi n t he Electr o nic 
Data C a pt ure ( E D C) s yste m for t he site staff t o res olve i m me diatel y.  I n a d ditio n, as a res ult of 
data re vie w b y t he S p o ns or or designee, ma nual q ueries will be raise d el ectr o nicall y in t he E D C 
s yste m.  Q ueries ma y als o be raise d as a res ult of s o urce data verificati o n b y t he clinical mo nit or.  
All c orrectio ns will be ma de wit hi n t he E D C s yste m b y t he investi gat or or ot her a ut horize d st ud y 
site pers o nnel.  T he clinical mo nit or a nd data ma na ge me nt tea ms will e ns ure a p pr o priate 


 
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res olutio n of q ueries.  T he investi gat or must a ut horize c ha nges t o t he rec or de d safet y a nd 
efficac y data.   
1 4. 6.  
T e r mi n ati o n  
A n initiati ve for ce nter clos ure or trial ter minatio n ca n be ta ke n at a ny ti me eit her b y t he s p o ns or 
or b y t he investi gat or, pr o vide d t here is reas o na ble ca use a nd s ufficie nt notice is give n in 
a d va nce of t he inte nde d ter minatio n.  Reas o ns for s uc h actio n ta ke n b y t he s p o ns or include, b ut 
are not li mite d t o: 
 S uccessful c o mpletio n of t he  trial at t he ce nter 
 T he ma xi m u m 
nu mber of eligible s ubjects for t he trial has bee n e nr olle d  
 Failure of t he investi gat or t o c o mply wit h t he pr ot oc ol, t he s p o ns or's pr oce d ures, or 
G C P guideli nes  
 Safet y c o ncer ns  
 I na de q uate recr uit me nt of s ubjects b y t he investi gat or 
 B usiness reas o ns  
1 4. 7.  
D at a a n d S afet y M o nit o ri n g Pl a n  
T he s p o ns or s hall pr o mptly re vie w all infor mati o n rele va nt t o t he safet y of t he dr ug o btaine d or 
ot her wise receive d fr o m foreign or d o mestic s o urces, includi n g infor matio n derive d fr o m t his 
clinical st ud y a nd a ny ot her clinic al st ud y c o nd ucte d wit h O T O -1 0 4.  I n or der t o c o mply wit h 
t his, t he s p o ns or a nd C R O me dical pers o nnel will ha ve t he a bilit y t o re vie w safet y infor mati o n as 
it is e ntere d a nd verifie d in t he electr o nic data ca pt ure s yste m (Sectio n  1 4. 5 ).  De pe nding o n t he 
e nr oll me nt rate, all A Es in t he ear a nd la b yrint h dis or ders S O C will be re vie we d at least e ver y 
ot her mo nt h.  I n a d ditio n, reas o ns for st ud y disc o nti n uati o n will be re vie we d t o see if a ny tre nds 
in st ud y disc o nti n uati o n are ide ntifie d. 
I nvesti gat ors are instr ucte d t o c o ntact t he Pr o d uct Safet y wit hi n 2 4 ho urs follo wi n g t he 
ide ntificatio n of a S A E (Sectio n  9. 2. 2 ).  All S A Es will be re vie we d b y t he s p o ns or a nd C R O 
me dical pers o nnel wit hi n 1 -2 da ys after receipt w het her or not t he e ve nt was c o nsidere d 
associate d wit h st ud y dr ug. T he s p o ns or ass u mes res p o nsibilit y for a p pr o priate re p orting t o t he 
re gulat or y a ut horities. T he investi gat or ass u mes res p o nsibilit y for re p orting e ve nts t o t he I R B in 
acc or da nce wit h t he I R B re q uire me nts.  All S A E’s will be part of  t he C R O me dical 
pers o nnel/s p o ns or safet y re vie w.  
If, t hr o ugh t his o ngoing re vie w, t he s p o ns or deter mines t hat O T O -1 0 4 prese nts a n unreas o na ble 
a nd significa nt ris k t o s ubjects, t he s p o ns or s hall ta ke a p pr o priate ste ps t o s us pe nd or disc o nti n ue 
t he st ud y and notif y re gulat or y a ut horities, investi gat ors a nd I R Bs as a p pr o priate.  
1 4. 8.  
M o nit o ri n g  
T he s p o ns or or its re prese ntati ves will perfor m o n -site mo nit ori n g visits as fre q ue ntl y as 
necessar y  base d o n site activit y t o re vie w pr ot oc ol c o mplia nce, c o mpare e C R Fs wit h indivi d ual 
s ubject’s me dical rec or ds a nd clinic c harts, a nd e ns ure t hat t he st ud y is being c o nd ucte d 
acc or ding t o pertine nt re gulat or y re q uire me nts .  The dates of t he visits will be rec or de d b y t he 


 
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mo nit or in a trial ce nter visit lo g t o be ke pt at t he si te.  The first p ost-initiatio n visit will us uall y 
be ma de as s o o n as p ossible after e nr oll me nt has be gun.  At t hese visits, t he mo nit or will 
c o mpare t he data e ntere d o nt o t he eC R Fs wit h t he hos pital or clinic rec or ds (s o urce d oc u me nts).  
T he re vie w of me di cal rec or ds will be perfor me d in a ma nner t hat e ns ures s ubject c o nfide ntialit y 
is maintai ne d.  At a mini m u m, s o urce d oc u me ntatio n must be a vaila ble t o s ubsta ntiate pr o per 
infor me d c o nse nt pr oce d ures, a d here nce t o pr ot oc ol pr oce d ures, a de q uate re p orting a nd follo w-
up of A E s, a d ministratio n of c o nc o mita nt me dicatio n, dr ug receipt/ dis pe nsi n g/ret ur n rec or ds, a nd 
st ud y dr ug a d ministrati o n infor matio n.  S pecific ite ms re q uire d as s o urce d oc u me nts will be 
re vie we d wit h t he investi gat or prior t o t he st ud y.  Findin gs fr o m t his re vie w of eC R Fs a nd s o urce 
d oc u me nts will be disc usse d wit h t he investi gat or.  The s p o ns or e xpects t hat, d uring mo nit ori n g 
visits, t he investi gat or (a nd as a p pr o priate, t he st ud y c o or dinat or) will be a vaila ble, t he s o urce 
d oc u me ntatio n will be a vaila ble, a nd a s uita ble e nvir o n me nt will be pr o vide d for re vie w of 
st ud y-relate d d oc u me nts. 
1 4. 9.  
D at a Q u alit y Ass ur a nc e  
Ste ps t o be ta ke n t o ass ure t he acc urac y a nd relia bilit y of data include t he selectio n of q ualifie d 
investi gat ors a nd a p pr o priate st ud y ce nters, re vie w of pr ot oc ol pr oce d ures wit h t he investi gat or 
a nd ass ociate d pers o nnel prior t o st ud y initiatio n, a nd perio dic mo nit ori n g visits b y t he s p o ns or  
or its re prese ntati ves .  C ase re p ort for m s will be re vie we d for acc urac y a nd c o mplete ness in t he 
E D C  s yste m data base b y t he s p o ns or or its re prese ntati ves d uring a nd after o n-site mo nit ori n g 
visits, a nd a ny discre pa ncies will be res olve d wit h t he investi gat or or designees, as a p pr o priate , 
a nd d oc u me nte d in t he E D C s yste m. 
1 4. 1 0.  
O n -Site A u dits  
Re prese ntati ves o f t he s p o ns or's Q ualit y Ass ura nce de part me nt ma y visit t he site t o carr y o ut a n 
a udit of t he st ud y in c o mplia nce wit h re gulat or y guideli nes a nd c o mpa ny p olic y.  S uc h a udits 
will re q uire access t o all st ud y rec or ds, includi n g s o urce d oc u me nts, for ins pectio n a nd 
c o mparis o n wit h t he eC R Fs. S ubject privac y must, ho we ver, be res pecte d.  S ufficie nt prior 
notice will be pr o vide d t o allo w t he investi gat or t o pre pare pr o perly for t he a udit.  
Si milar a uditi n g pr oce d ures ma y als o be c o nd ucte d b y a ge nts of a ny re gulat o r y b o d y re vie wi n g 
t he res ults of t his st ud y in s up p ort of a Lice nsi n g A p plicatio n.  The investi gat or s ho uld 
i m me diat el y notify t he s p o ns or if t he y ha ve bee n c o ntacte d b y a re gulat or y a ge nc y c o ncer nin g a n 
upc o min g ins pectio n.  
1 4. 1 1.  
Us e of I nf o r m ati o n a n d P u blic at i o n 
All infor matio n c o ncer nin g O T O -1 0 4, Ot o no my o peratio ns, pate nt a p plicatio n, for mulas, 
ma nufact uri n g pr ocesses, basic scie ntific data, a nd for mulati o n infor matio n, s up plie d b y t he 
s p o ns or t o t he investi gat or a nd not pre vio usl y p ublis he d, is c o nsidere d c o nfide ntial a nd re mains 
t he s ole pr o pert y of Ot o no my.  T he investi gat or a grees t o use t his infor matio n o nly t o 
acc o mplis h t his st ud y a nd will not use it for ot her p ur p oses wit ho ut t he s p o ns or's writte n c o nse nt.  
T he investi gat or understa nds t hat t he infor ma tio n de velo pe d in t he clinic al st ud y will be use d b y 
Ot o no my in c o nnectio n wit h t he c o ntinue d de velo p me nt of O T O -1 0 4, a nd t hus ma y be disclose d 
as re q uire d t o ot her clinical investi gat ors or go ver n me nt re gulat or y a ge ncies.  To per mit t he 


 
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infor mati o n derived fr o m t he clinical st udies t o be use d, t he investi gat or is o bligate d t o pr o vide 
t he s p o ns or wit h all data o btaine d in t he st ud y. 
A ny p ublicatio n or ot her p ublic prese ntatio n of res ults fr o m t his st ud y re q uires prior re vie w a nd 
writte n a p pr o val of Ot o no my.   Draft a bstracts, ma nuscripts, a nd materials for prese ntatio n at 
scie ntific meetings s ho uld be pr o vide d t o t he s p o ns or at least 3 0 w or king da ys prior t o a bstract or 
ot her rele va nt s ub missio n dea dlines.  A ut hors hip of p ublicatio ns res ulti n g fr o m t his st ud y  will be 
base d o n ge nerall y acce pte d criteria for maj or me dical j o ur nals.  
 
 


 
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1 5.  
LI S T O F R E F E R E N C E S  
A merica n S peec h -La ngua ge -Heari n g Ass ociatio n. ( 2 0 0 5). G uideli nes for ma nual p ure -t o ne 
t hres hold a udio metr y [ G uideli nes]. A vaila ble fr o m w w w.as ha. or g/ p olic y. - Se e more at: 
htt p:// w w w.as ha. or g/ p olic y/ G L 2 0 0 5 -0 0 0 1 4. ht m#st has h. 0 X g5 w h C S. d p uf  
Barritt L. Me niere’s Disease . X P h ar m 2 0 0 8 ( 1 -6).  
C o m mittee o n Hearing a nd E q uilibri u m. C o m mittee o n Hearing a nd Eq uilibri u m guideli nes for 
t he dia gnosis a nd e valuatio n of t hera p y in Me niere’s disease.  Ot o -l ary n g ol He a d N eck S ur g.  
1 9 9 5;  1 1 3( 3):1 8 1 -1 8 5.  
Ki m H H, Wiet RJ, Batista R A. Tre nds in t he dia gnosi s a nd ma na ge me nt of Me niere’s disease: 
res ults of a s ur ve y. Ot ol ary n g ol He a d N eck S ur g.  2 0 0 5; 1 3 2:7 2 2 -6.  
S hea JJ: Classificatio n of Me niere’s Disease. A m J Ot ol  1 9 9 3: 1 4:2 2 4 -2 2 9.