Conditions: Meniere's Disease
Keywords: Meniere's Disease Vertigo
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 176
Healthy volunteers: no

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

Detailed description:

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

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

Protocol document:
Prot_SAP_000.pdf: 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1   
  
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E B LI N D, P L A C E B O -C O N T R O L L E D, 
M U L TI C E N T E R, P H A S E 3  E F FI C A C Y  A N D S A F E T Y S T U D Y O F O T O -1 0 4  GI V E N A S 
A SI N G L E  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  
 
Pr ot oc ol N u m ber:  1 0 4 -2 0 1 5 0 8  
E u dr a C T N u m ber: 2 0 1 5 -0 0 4 4 9 6 -7 1  
 
 
 
S p o ns or C o ntact:  
 
 
 
 
 
 
 
 
 
 
Me dical M o nit or:  
 
 
 
 
 
 
  
   
 
 
 
 
 
Versi o n:  
3 . 0 
Date of Pr ot oc ol:   
1 3  J a n uar y 2 0 1 6 
Pr o prietar y N otice   
T he c o nce pts a n d i nf or m ati o n c o ntai ne d i n t his d oc u me nt or ge nerate d 
d uri n g t he st u d y are c o nsi dere d pr o prietar y a n d ma y n ot b e discl ose d i n 
w h ole or i n part wit h o ut t he e x presse d, writte n c o nse nt of Ot o n o m y, 
I n c. 
 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T he i nf or mati o n i n t his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat are pri vile ge d or 
c o nfi de ntial a n d ma y n ot be discl ose d u nless s uc h discl os ure is re q uire d b y a p plica ble la ws a n d re g ulati o ns. I n a n y 
e ve nt, pers o ns t o w h o m t he i nf or mati o n  is discl ose d m ust be i nf or me d t hat t he i nf or mati o n is pri vile ge d or 
c o nfi de ntial a n d ma y n ot be f urt her discl ose d b y t he m. T hese restricti o ns o n discl os ure will a p pl y e q uall 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 dicate d as pri vile ge d or c onfi de ntial.  




 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
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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 3. 0  ................................................................................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  .......................................................................................7  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................8  
A B B R E V I A TI O N S .........................................................................................................................9  
S Y N O P SI S  ....................................................................................................................................1 0  
1.  
B A C K G R O U N D  ........................................................................................................1 7  
1. 1.  
Rati o nale f or St u d y a n d D ose Selecti o n  .....................................................................1 8  
2.  
O BJ E C TI V E S  .............................................................................................................1 8  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................1 8  
2. 2.  
Sec o n dar y O bj ecti ve  ...................................................................................................1 8  
3.  
O V E R VI E W O F S T U D Y D E SI G N  ...........................................................................1 8  
4.  
S T U D Y P O P U L A TI O N  .............................................................................................1 9  
4. 1.  
Ge neral C o nsi derati o ns  ...............................................................................................1 9  
4. 2.  
I n cl usi o n Criteria ........................................................................................................1 9  
4. 3.  
E x cl usi o n Criteria  .......................................................................................................2 0  
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G ....................................................................2 1  
5. 1.  
O ver vie w  .....................................................................................................................2 1  
5. 2.  
E nr oll me n t Pr oce d ures ................................................................................................2 1  
5. 3.  
Bli n di n g  ......................................................................................................................2 2  
6.  
D O S A G E A N D A D MI NI S T R A TI O N  .......................................................................2 3  
6. 1.  
St u d y Dr u g A d mi nistrati o n .........................................................................................2 3  
6. 2.  
C o m plia nce  .................................................................................................................2 3  
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  .................................2 3  
7. 1.  
Pr oscri be d T hera p y D uri n g t he St u d y Peri o d  .............................................................2 3  
7. 2.  
S y m pt o matic Relief Me dicati o ns  ...............................................................................2 4  
8.  
S T U D Y E V A L U A TI O N S  ..........................................................................................2 4  
8. 1.  
St u d y Pr oce d ures b y Visit  ..........................................................................................2 4  
8. 2.  
Efficac y E val uati o ns  ...................................................................................................2 6  
8. 3.  
Safet y E val uati o ns  ......................................................................................................2 7  
9.  
A D V E R S E E V E N T R E P O R T I N G ............................................................................3 0  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
4   
9. 1.  
A d verse E v e nt Classificati o n Defi niti o ns  ...................................................................3 0  
9. 2.  
M o nit ori n g of A d v erse E ve nts  ....................................................................................3 2  
9. 3.  
C o ntacti n g S p o ns or Re gar di n g Safet y  ........................................................................3 3  
1 0.  
S U BJ E C T C O M P L E TI O N  .........................................................................................3 4  
1 0. 1.  
C o m pleti o n  .................................................................................................................3 4  
1 0. 2.  
Wit h dra wal  .................................................................................................................3 4  
1 1.  
S T A TI S TI C A L M E T H O D S  .......................................................................................3 5  
1 1. 1.  
Sa m ple Size  ................................................................................................................3 5  
1 1. 2.  
A nal ysis Sets  ...............................................................................................................3 6  
1 1. 3.  
Descri pti o n of S u b gr o u ps t o be A nal yze d  ..................................................................3 6  
1 1. 4.  
S u bject De m o gra p hics, Baseli ne Disease Stat us, a n d Dis p ositi o n  .............................3 7  
1 1. 5.  
Efficac y E val uati o ns  ...................................................................................................3 7  
1 1. 6.  
Safet y E val uati o ns  ......................................................................................................3 9  
1 1. 7.  
Ha n dli n g of Missi n g Dat a, S u bject Wit h dra wals, a n d Treat me nt Fail ures  ................4 2  
1 1. 8.  
I nteri m A nal yses .........................................................................................................4 2  
1 2.  
S T U D Y D R U G I N F O R M A TI O N  ..............................................................................4 2  
1 2. 1.  
P h ysical D escri pti o n of St u d y Dr u g(s)  .......................................................................4 2  
1 2. 2.  
Directi o ns f or Us e  .......................................................................................................4 3  
1 2. 3.  
Pac ka gi n g a n d La b eli n g  ..............................................................................................4 3  
1 2. 4.  
Ma na ge me nt of Cli nical S u p plies  ...............................................................................4 3  
1 2. 5.  
Dr u g Acc o u nta bilit y  ...................................................................................................4 4  
1 3.  
E T HI C A L A S P E C T S  .................................................................................................4 4  
1 3. 1.  
I n v esti gat or Res p o nsi bilities .......................................................................................4 4  
1 3. 2.  
Researc h Et hics C o m mittee ( R E C)  ............................................................................4 4  
1 3. 3.  
I nf or me d C o nse nt .......................................................................................................4 5  
1 4.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ..................................................................4 5  
1 4. 1.  
Pr ot oc ol M o dificati o ns  ...............................................................................................4 5  
1 4. 2.  
Re g ulat or y D oc u me ntati o n  .........................................................................................4 5  
1 4. 3.  
S u bject I d e ntificati o n Re gister  ...................................................................................4 6  
1 4. 4.  
Rec or d Rete nti o n  ........................................................................................................4 6  
1 4. 5.  
Electr o nic Case Re p ort F or m  ......................................................................................4 7  
1 4. 6.  
Ter mi nati o n  .................................................................................................................4 7  
1 4. 7.  
Data a n d Safet y M o nit ori n g Pla n  ...............................................................................4 7  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
5   
1 4. 8.  
M o nit ori n g  ..................................................................................................................4 8  
1 4. 9.  
Data Q ualit y Ass ura nce  ..............................................................................................4 8  
1 4. 1 0.  
O n -Site A u dits  ............................................................................................................4 8  
1 4. 1 1.  
Use of I nf or mati o n a n d P u blicati o n  ............................................................................4 9  
1 5.  
R E F E R E N C E S  ...........................................................................................................5 0  
 
 


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
6   
P R O T O C O L A M E N D M E N T, V E R SI O N 3 . 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 h a 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   
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. 2 0  
 
3   
M o difie d Secti o n 1. 1, St u d y Rati o nale t o 
i ncl u de rati o nale f or d ose selecti o n. 
Secti o n 1. 1 Rati o nale f or St u d y a n d D ose 
Selecti o n , p g. 1 8  
4   
M o difie d state me nt re gar di n g c o ntacti n g t he 
me dical m o nit or if a n u n bli n di n g has occ urre d.  
Secti o n 5. 3 Bli n di n g, p g. 2 2  
5   
Safet y re p orti n g c ha n ge d t o Pr o P har ma fr o m 
I N C. 
S p o ns or C o ntact I nf or mati o n , p g. 7  
Secti o n  9. 3 C o ntacti n g S p o ns or Re gar di n g 
Safet y, p g. 3 4  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
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  
Me dic al M o nit or:  
 
Na me  
 
Title  
 
Office P h o ne N u m ber  
 
M o bile P h o ne N u m ber  
  
E -Mail  
 
 
 
Ot her A p pr o pri ate Tri al C o nt act Pers o n nel:  
Na me  
 
Title  
 
Office P h o ne N u m ber  
 
M o bile P h o ne N u m ber  
 
E -Mail  
 
 
 
S afet y E m ail : 
 
 
If a n y s p o ns or c o ntact i nf or mati o n nee ds t o be c h a n ge d d uri n g t he c o urse of t he st u d y, t his will 
be d o ne b y t he s p o ns or, wit h writte n n otificati o n t o t he i n vesti gat or, a n d will n ot re q uire a 
pr ot oc ol a me n d me nt.  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
8   
I N V E S TI G A T O R A G R E E M EN T  
I h a ve rea d t his pr ot oc ol a n d a gree t hat it c o ntai ns all necessar y details f or carr yi n g o ut t his 
st u d y. I will c o n d uct t he st u d y as o utli ne d herei n a n d will c o m plete t he st u d y wit hi n t he ti me 
desi g nat e d a n d will a bi de b y all a p plica ble l ocal a n d nati o nal re g ulat or y o bli gati o ns.  
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y. I will disc uss t his material wit h t he m t o e ns ure t he y 
are f ull y i nf or m e d re gar di n g t he dr u g a n d t he c o n d uct of t he st u d y.  
I will use o nl y t he i nf or me d c o nse nt f or m a p pr o ve d b y t he s p o ns or or its re prese ntati ve a n d 
a p pr o ve d b y t he Res earc h Et hics C o m mittee  (R E C ) res p o nsi ble f or t his st u d y an d will f ulfill all 
res p o nsi bilities f or s u b mitti n g perti ne nt i nf or mati o n t o t he R E C  res p o nsi ble f or t his st u d y.  I will 
ass ure t hat eac h s u bject e nr olle d i nt o t he trial, or le gall y a ut h orize d re prese ntati ve, rea ds, 
u n dersta n ds, a n d si g ns t h e a p pr o pri ate v ersi o n of t he i nf or me d c o ns e nt. I a gree t hat t he s p o ns or 
or its re prese nt ati ves s hall ha ve access t o a n y ori gi nal s o urce d o c u me nts t o verif y data ca pt ure d 
f or t his cli nical trial. 
I f urt her a gree n ot t o ori gi nate or use t he na me of t he Ot o n o m y, I nc. a n d/ or O T O -1 0 4 , or a n y of 
its e m pl o yees, i n a n y p u blicit y, ne ws releas e or ot her p u blic a n n o u nce me nt, writte n or oral, 
w het her t o t he p u blic, press or ot her wise, relati n g t o t his pr ot oc ol, t o a n y a me n d me nt heret o, or 
t o t he perf or ma n ce h ere u n der, wit h o ut t he prior writte n c o nse nt of Ot o n o m y, I n c.  
 
 
 
 
 
I n vesti gat or's Si g nat ure 
  
Date  
Na me of I n vesti gat or (ty pe d or pri nte d) 


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
9   
A B B R E VI A TI O N S  
A E   
A d verse E v e nt  
A N C O V A   
A nal ysis of C o varia nce  
A A O -H N S    
A merica n Aca d e m y of Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y   
C  
Celsi us  
C R O   
C o ntract Researc h Or ga nizati o n  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
D V D   
Defi niti ve Verti g o Da y  
e C R F  
Electr o nic Case Re p ort F or m  
E D C   
Electr o nic Data Ca pt ure  
F A S   
F ull A nal ysis Set  
F A X   
Facsi mile  
G C P   
G o o d Cli nical Practice  
Hz  
Hertz  
I C H  
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I T 
I ntr at y m p a nic 
I T T  
I nte nt t o Treat 
IV R S/I W R S   
I nteracti ve V oice/ We b R a n d o mizati o n S yste m  
Me d D R A   
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m g  
Milli gra m  
m L   
Milliliter  
O T O -1 0 4   
I n v esti gati o nal Pr o d uct ( St u d y Dr u g)  
P T A   
P ure T o ne A vera ge  
Q M P   
Q ualifie d Me dical Pr ofessi o nal  
R E C  
Researc h Et hics C o m mittee  
S A E   
Seri o us A d verse E v e nt  
S A P   
Statistical A nal ysis Pla n  
S F  
S h ort F or m  
S O C   
S yste m Or ga n Class   
T FI   
Ti n nit us F u ncti o nal I n d e x  
V F  
Verti g o Fre q ue n c y  
W H O Dr u g   
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 0   
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 FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O -1 0 4  
 
De xa met has o ne  
 
Pr ot oc ol N o.:  1 0 4 -2 0 1 5 0 8  
Title of St u d y:  A pr os pecti ve, ra n d o mize d, d o u ble bli n d, place b o -c o ntr olle d, m ultice nter, P hase 3  efficac y 
a n d safet y st u d y of O T O-1 0 4 gi ve n as a si n gle i ntrat y m pa ni c i nj ecti o n i n s u bj ects wit h u nilateral Me niere’s 
disease.  
St u d y Ce nter(s):   T his st u d y wi ll be c o n d ucte d at a p pr o xi matel y 5 0 -7 0  sites i n u p t o fi ve c o u ntries i n t he 
E ur o pea n U ni o n, i ncl u di n g U nite d Ki n g d o m, Ger ma n y a n d P ola n d.  
St u d y Peri o d:  1 -1. 5 years  
P h ase of De vel o p me nt:  3  
St u d y Desi g n:  
T his is a ra n d o mize d, d o u ble bli n d, place b o -c o ntr olle d, m ultice nter 1 6 -wee k P hase 3  st u d y.  F oll o wi n g a n 
i nitial 4-wee k lea d -i n peri o d, eli gi ble s u bj ects will be ra n d o ml y assi g ne d t o eit her 1 2 m g O T O-1 0 4 or place b o 
usi n g a 1: 1 all ocati o n  rati o stratifie d b y ge n der.  S u bj ects will be o bser ve d f or 1 2  wee ks f oll o wi n g a si n gle  
i ntrat y m pa nic i nj ecti o n of eit her 1 2 m g O T O-1 0 4 or place b o.  
St u d y O bjecti ve s: 
Pri mar y : T o c o nfir m t he effica c y of O T O-1 0 4 i n s u bj ects wit h Me niere’s disease, as meas ure d b y t he n u m ber 
of defi niti ve verti g o da ys ( D V D) at Wee k 1 2 (t he 4 -wee k i nt er val fr o m Wee k 9 t hr o u g h W ee k 1 2).  
  
Sec o n dar y :  T o descri be t he safet y pr ofile of O T O-1 0 4 i n s u bj ects wit h M e niere’s disease.  
M et h o d s: 
T he d urati o n of t he st u d y f or eac h s u bj ect will be a ma xi m u m of a p pr o xi matel y 1 6  wee ks, i ncl u di n g a 4 -wee k 
lea d-i n peri o d bef ore d osi n g (a si n gle i nj ecti o n), f oll o we d b y a 12 -wee k f oll o w -u p peri o d.  
After scree ni n g ( Visit 1), all eli gi ble s u bj ects will e nter i nt o a 4-wee k lea d -i n peri o d.  D uri n g t he lea d -i n 
peri o d, s u bjects will rec or d t heir dail y verti g o e x perie nce t o all o w f or a baseli ne assess me nt of t hese e ve nts.  
A n y da y wit h a rec or de d defi niti v e verti g o e pis o de, a n e pis o de lasti n g at least 2 0 mi n utes ( c orres p o n di n g t o a 
Verti g o Se verit y Sc ore of 2 or m ore), will be defi ne d as a defi niti ve verti g o da y ( D V D).  F oll o wi n g t he lea d -i n 
peri o d, eli gi ble s u bj ects will b e ra n d o mize d t o 1 2 m g O T O -1 0 4 or p lace b o usi n g a 1: 1 all ocati o n rati o.   T he 
ra n d o mizati o n is stratifie d b y ge n der. 
After a si n gle i ntrat y m pa nic i nj ecti o n wit h O T O -1 0 4  or place b o o n Da y 1, s u bj ects will c o nti n ue t o rec or d 
t heir dail y verti g o e x perie nce d uri n g t he 1 2 -wee k f oll o w -u p peri o d . S u bj ects will visit t he st u d y site at Wee ks 
4 a n d 8 f or a d diti o nal efficac y a n d safet y assess me nts. Effic ac y a n d safet y assess me nts will als o be c o m plete d 
at t he e n d of st u d y ( Wee k 1 2 ) or u p o n earl y disc o nti n uati o n  fr o m t he st u d y. 
N u m ber of S u bjects:  
T he pla n ne d sa m ple size f or t his st u d y is 1 6 0  s u bj ects (8 0  assi g ne d t o 1 2 m g O T O -1 0 4 a n d 8 0  t o place b o). 
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
S u bj ects e nr olle d i n t he st u d y will ha ve u nilateral Me niere’s disease as o utli ne d b y t he A merica n Aca de m y of 
Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y ( A A O -H N S) C o m mittee o n Heari n g a n d E q uili bri u m i n 1 9 9 5  
(C o m mittee o n Heari n g a n d E q uili bri u m, 1 9 9 5 ). 
T o be eli gi ble f or t his st u d y, e ac h of t he f oll o wi n g criteria m ust be satisfie d wit h a  “ Y E S” a ns wer ( u nless n ot 
a p plica ble): 
1.  S u bj ect is a male or fe male a ge d 1 8 t o 8 5  years, i ncl usi ve.  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 1   
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 FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O -1 0 4  
 
De xa met has o ne  
 
2.  S u bj ect has a dia g n osis of defi nite u nilateral Me niere’s disease b y 1 9 9 5 A A O -H N S criteria.  
3.  S u bj ect self -re p orts acti ve, defi niti ve verti g o  e pis o des f or t he 2 m o nt hs pri or t o t he st u d y le a d -i n 
peri o d.  
4.  S u bj ect has d oc u me nte d as y m metric se ns ori ne ural heari n g l oss at scree ni n g or wit hi n t he past 1 2 
m o nt hs acc or di n g t o A A O -H N S 1 9 9 5 criteria defi ne d as o ne of t he f oll o wi n g:   
a. 
T he arit h metic mea n of heari n g t hres h ol ds  ( p ure t o ne a vera ge, P T A) at 2 5 0, 5 0 0 a n d 
1 0 0 0  Hz of 1 5 d B or m ore hi g her t ha n t he P T A of 1 0 0 0, 2 0 0 0, a n d 3 0 0 0 Hz , 
b.  T he arit h metic mea n of  P T A at 5 0 0, 1 0 0 0, 2 0 0 0 a n d 3 0 0 0 Hz is 2 0 d B or m ore p o orer i n t he 
ear i n q uesti o n t ha n o n t he o p p osite si de, 
c. 
It is t he j u d g me nt of t he i n vesti gat or t hat t he s u bj ect’s heari n g l oss meets reas o na ble 
a u di o metric criteria f or heari n g l oss c haracteristic of Me nier e’s disease, a n d if s o, it s h o ul d 
be j ustifie d a n d d oc u me nte d.  
5.  S u bj ect a grees t o mai ntai n t heir c urre nt tr eat me nts f or Me ni ere’s disease w hile o n -st u d y. 
6.  Fe male s u bj ects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-me n o pa usal 
( ≥1 2 m o nt hs si nce last me nstr ual peri o d a n d 4 5 years of a ge or ol der) ] m ust ha ve a ne gati ve uri ne 
pre g na nc y te st bef ore e nr oll me nt. W o me n of c hil d beari n g p ote ntial w h o are n ot a bsti ne nt fr o m se x 
wit h male part ners ma y be e nt ere d i nt o t he st u d y if t he y are usi n g a n d willi n g t o c o nti n ue t o use 
hi g hl y effecti ve or “ d o u ble barrier” c o ntrace pti ve preca uti o ns f or t he d u rati o n of t he st u d y (e. g., oral 
c o ntrace pti ves, c o ntrace pti ve i m pla nt or i nj ecti o n, i ntra uteri ne de vice, or “ d o u ble barrier” met h o ds 
i ncl u di n g c o n d o m wit h dia p hr a g m, male c o n d o m wit h cer vi cal ca p, male c o n d o m wit h s p er mici de, or 
dia p hra g m a n d s per mici de).   
7.  S u bj ect is willi n g t o c o m pl y wit h t he pr ot oc ol a n d atte n d all st u d y visits.  
8.  S u bj ect is a ble t o use t he tele p h o ne t o c o m plete t he ir dail y di ar y . 
9.  S u bj ect is a ble t o pr o vi de writte n i nf or me d c o nse nt, i ncl u di n g a gree me nt t o l ocal pri vac y l a n g ua ge 
re q uire me nts eit her wit hi n t he i nf or me d c o nse nt or i n a ncillar y d oc u me nts c o m plia nt wit h l ocal 
pri vac y la ws  bef ore t he i nitiati o n of a n y st u d y -relate d pr oce d ures. 
At t he c o m pleti o n of t he first 2 8 da ys of t he lea d -i n peri o d: 
1 0.  S u bj ect has e x perie nce d a n d rec or de d at lea st 4 a n d a ma xi m u m of 2 2 defi niti ve verti g o  da y s d uri n g 
t he 4-wee k lea d -i n peri o d. 
1 1.  S u bj ect c o m plete d at least 2 2 of 2 8 diar y e ntries d uri n g t he 4-wee k lea d -i n peri o d. 
 
Di a g n osis a n d M ai n Criteri a f or E x cl usi o n:  
T o be eli gi ble f or t his st u d y, e ac h of t he f oll o wi n g criteria m ust be satisfie d wit h a “ N O” a ns wer: ( u nless n ot 
a p plica ble): 
1.  S u bj ect has a n i nfecti o n i n t he ear, si n uses, or u p per res pirat or y s yste m  at t he ti me of ra n d o mizati o n . 
2.  S u bj ect is pre g na nt or lactati n g.  
3.  S u bj ect has a hist or y of i m m u n o defic ie nc y disease. 
4.  S u bj ect has acti ve or rece nt ( < 1 m o nt h pri or t o scree ni n g) mi d dle ear disease, i ncl u di n g b ut n ot 
li mite d t o:  c hr o nic otitis me di a, ac ute otitis me dia, mi d dle ear eff usi o ns, mi d dle ear atelectasis, or 
c h olesteat o ma.  
5.  S u bj ect has a n a b n or malit y of t he t y m pa nic me m bra ne i n t he affecte d ear t hat w o ul d i ncrease t he ris k 
ass ociate d wit h i ntrat y m pa nic i nj ecti o n i ncl u di n g b ut n ot li mite d t o m o n o meric t y m pa nic me m bra ne.  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 2   
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 FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O -1 0 4  
 
De xa met has o ne  
 
6.  S u bj ect has a hist or y of pre vi o us e n d ol y m p hatic sac s ur ger y.  
7.  S u bj ect has a hist or y  of pre vi o us use of i ntrat y m pa nic ge nta mici n i n t he affecte d ear.  
8.  S u bj ect has a hist or y of t y m pa n ost o m y t u bes wit h e vi de nce of perf orati o n or lac k of cl os ure.  
9.  S u bj ect has use d s yste mic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea d -i n peri o d. 
1 0.  S u bj ect h as ha d i ntrat y m pa nic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea n -i n peri o d. 
1 1.  S u bj ect has e x perie nce d a n a d verse reacti o n t o i ntrat y m pa ni c i nj ecti o n of ster oi ds.  
1 2.  S u bj ect has a h y perse nsiti vit y t o de xa met has o ne or a n y of t he e xci pie nts i n O T O -1 0 4.  
1 3.  S u bj ect has hist or y of mi grai n o us verti g o.  
1 4.  S u bj ect has hist or y of dr o p attac ks.  
1 5.  S u bj ect is n ot a ble t o acc uratel y i de ntif y a n d re p ort e pis o des of verti g o.  
1 6.  S u bj ect has a n y ot her cli nicall y si g nifica nt ill ness , m e dical c o n diti o n or me dical hist or y t hat, i n t he 
in vesti gat or’s or t he me dical m o nit or’s o pi ni o n, w o ul d pr o hi bit t he s u bj ect fr o m partici pati n g i n t he 
st u d y at scree ni n g or at t he ti me of ra n d o mizati o n . 
1 7.  S u bj ect has use d a n i n vesti gati o nal dr u g or de vice i n t he 3 m o nt hs pri or t o scree ni n g.  
1 8.  S u bj ect has a h ist or y of s u bsta nce a b use wit hi n t he prece di n g 6 m o nt hs pri or t o scree ni n g. 
1 9.  S u bj ect has pre vi o usl y bee n ra n d o mize d t o a trial of O T O -1 0 4.  
Test Pr o d uct, D ose a n d M o de of A d mi nistr ati o n:  
1 2  m g O T O -1 0 4 , si n gle 0. 2 m L i ntrat y m pa nic i nj ecti o n t o t he affecte d ear  
D ur ati o n of Tre at me nt:    
Si n gle 0. 2 m L i ntrat y m pa nic i nj ecti o n t o t he affecte d ear  
Refere nce T her a p y, D ose a n d M o de of A d mi nistr ati o n:  
O T O -1 0 4 Dil ue nt  ( place b o), si n gle 0. 2 m L i ntrat y m pa nic i nj ecti o n t o t he affecte d ear 
O utc o me M e as ures f or E v al u ati o n: 
Pri mar y Efficac y E n d p oi nt:  
T he pri mar y efficac y e n d p oi nt is t he n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 1 2 [t he 4-wee k  
( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2].  A D V D is defi ne d as a da y w here t he s u bj ect rec or de d at 
least o ne verti g o e pis o de lasti n g at least 2 0 mi n utes a n d c orres p o n ds t o a Verti g o Se verit y Sc ore of 2 or m ore.  
If m ulti ple e pis o des occ ur o n a gi ve n da y, s u bj ects will be i nstr ucte d t o rec or d t he Verti g o Se verit y Sc ore  f or 
t he w orst e pis o de e x perie nce d d uri n g t he da y.  
Sec o n dar y Efficac y E n d p oi nt s: 
  T he n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 8 [t he 4 -wee k  ( 2 8-da y) i nter val fr o m Wee k 5  
t hr o u g h Wee k 8]  
  T he n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 4 [t he 4-wee k  ( 2 8-da y) i nter val fr o m Wee k 1  
t hr o u g h Wee k 4]  
  T he c ha n ge fr o m  baseli ne i n verti g o fre q ue nc y ( V F) d uri n g t he 4 -wee k st u d y i nter val  (W ee k 9 
t hr o u g h W ee k 1 2) , w here verti g o fre q ue nc y is defi ne d as t he pr o p orti o n of da ys d uri n g t he 4 -wee k 
i nter val w here a defi niti ve verti g o e pis o de was rec or de d  di vi de d b y t he n u m ber of n o n -missi n g diar y 
e ntries f or t he rele va nt i nter val 


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 3   
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 FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O -1 0 4  
 
De xa met has o ne  
 
  T he c ha n ge  fr o m baseli ne wit h res pect t o se verit y of verti g o e pis o des as meas ure d b y t he mea n 
Verti g o Sc ore d uri n g t he 4 -we e k st u d y i nter val ( Wee k 9 t hr o u g h Wee k 1 2)  
  T he c ha n ge fr o m baseli ne i n a vera ge  d ail y c o u nt of verti g o e pis o des,  d uri n g  t he 4 -wee k st u d y i nter val 
(W ee k 9 t hr o u g h W ee k 1 2)  
  Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d Be d ri d de n 
e ve nts as a c o nse q ue nce of verti g o  at W ee k 1 2   
  S F -3 6 at Wee k 1 2  
o  
P h ysical Healt h S u m mar y Me as ure  
o  
Me ntal Healt h S u m mar y Meas ure  
o  
8 Scales  
E x pl orat or y Efficac y E n d p oi nts:  
  T he c ha n ge  fr o m baseli ne i n verti g o fre q ue nc y ( V F) d uri n g t he 4 -wee k st u d y i nter val ( W ee k 1 
t hr o u g h W ee k 4) a n d (W ee k 5 t hr o u g h W ee k 8), w here verti g o fre q ue nc y is defi ne d as t he pr o p orti o n 
of da ys d uri n g t he 4 -wee k i nter val w here a defi niti ve verti g o e pis o de was rec or de d di vi de d b y t he 
n u m ber of n o n -missi n g diar y e ntries f or t he rele va nt i nter val  
  T he c ha n ge fr o m baseli ne wit h res pect t o se verit y of verti g o e pis o des as meas ure d b y t he  mea n 
Verti g o Sc ore d uri n g  eac h 4 -wee k st u d y i nter val ( Wee k 1  t hr o u g h Wee k 4 ) a n d ( W ee k 5 t hr o u g h 8).  
  T he c ha n ge fr o m baseli ne i n  a vera ge dail y c o u nt of verti g o e pis o des,  d uri n g eac h 4 -wee k st u d y 
i nter val (W ee k 1 t hr o u g h W ee k 4) a n d (W ee k 5 t hr o u g h W ee k 8 ) 
  Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d Be d ri d de n 
e ve nts as a c o nse q ue nce of v erti g o  at W ee k 4 a n d 8  
  S F -3 6 at Wee ks 4 a n d 8  
o  
P h ysical Healt h S u m mar y Me as ure  
o  
Me ntal Healt h S u m mar y Meas ure  
o  
8 Scales  
  Ti n nit us F u ncti o nal I n de x ( T FI) at Wee k s 4, 8, a n d 1 2  
 
Safet y Assess me nts : 
S afet y assess me nts  i ncl u de: 
  A d verse e ve nts  
  A u di o metr y assess me nts  
  T y m pa n o metr y  
  L ocal t olera bilit y ( ot osc o pic e xa mi nati o ns)  
  Cli nical la b orat or y meas ure me nts  
  Vital si g n meas ure me nts  
  C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S): Baseli ne a n d Si nce Last Visit versi o ns  


 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 4   
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 FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O -1 0 4  
 
De xa met has o ne  
 
 St atistic al M et h o ds:  
T he pri mar y efficac y e n d p oi nt is t he n u m ber of D V D at Wee k 1 2 [t he 4-wee k ( 2 8-da y) i nter val fr o m Wee k 9 
t hr o u g h Wee k 1 2].  T he tar get t otal sa m ple size f or t he st u d y is 1 6 0 ra n d o mize d wit h 1: 1 all ocati o n, 8 0 i n eac h 
treat me nt gr o u p, stratifie d b y ge n der.  The sa m ple size esti mate was c h ose n t o ac hie ve m ore t ha n 9 0 % p o wer 
wit h si g nifica nce le vel of 0. 0 5 t w o -si de d t o rej ect t he n ull h y p ot hesis of n o treat me nt differ e nce f or t he 
pri mar y e n d p oi nt of D V D.  
T he p o wer esti mate was base d o n t he esti mate d treat me nt gro u p mea n s f or D V D at W ee k 1 2 [t he 4-wee k  
( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] fr o m t he rece ntl y c o m plete d P hase 2 b trial i n t his i n dicati o n.  
T he O T O -1 0 4 a n d place b o treat me nt gr o u ps i n t hat st u d y re cei ve d a si n gle d ose of t he st u d y dr u g at D a y 1.  
T he O T O -1 0 4 treat me nt gr o u p recei ve d t he sa me d ose as will be e val uate d i n t his P hase 3 st u d y.   A P oiss o n 
ge neralize d li near re gressi o n m o del was use d t o esti mate t he mea n n u m ber of D V Ds f or t he O T O -1 0 4 a n d 
place b o gr o u ps d uri n g t he pri mar y e n d p oi n t 4-wee k st u d y i nter val.  T he m o del i ncl u de d treat me nt gr o u p as a 
fact or (cate g orical), a n d t he le a d-i n peri o d as a c o variate.  A n offset f or t he n u m ber of diar y e ntries rec or de d 
f or t hat 4-wee k i nter val (i nter val fr o m Wee k 9 t hr o u g h 1 2) was i ncl u de d f or e ac h s u bj ect  t o acc o u nt f or 
missi n g diar y e ntries .  T he n u m ber of lea d-i n peri o d D V D was a dj uste d t o 2 8 da ys.  T he m o del was als o 
a dj uste d f or o ver -dis persi o n usi n g P ears o n resi d ual s as t he scale fact or.  T he esti mate d me a n n u m ber of D V D 
f or t he O T O-1 0 4 a n d  place b o gr o u ps were 4. 5 a n d 2. 1, res pecti vel y wit h a n esti mate d mea n differe nce of 
(acti ve –  place b o) -2. 4 da ys, a dj uste d f or lea d -i n peri o d n u m ber of D V D.  T he m o del resi d ual varia nce was 
4. 7 9.    F or t he p ur p ose of t he sa m ple size calc ulati o n t he resi d ua l varia nce a n d tr ue mea n differe nce was 
c o nsi dere d as 5. 0 a n d 2. 2, res pecti vel y.  
T he P oiss o n re gressi o n m o del  will be use d t o a nal yze t he pri mar y e n d p oi nt i n t his st u d y.   T he pri mar y 
a nal ysis p o p ulati o n f or t his st u d y is f ull a nal ysis set ( F A S). T he f ull a nal ysis set will i ncl u d e all s u bj ects w h o 
are ra n d o mize d, recei ve st u d y dr u g, ha ve a baseli ne D V D meas ure me nt f or t he 4 -wee k lea d -i n peri o d, a n d 
ha ve at least o ne 4 -wee k D V D meas ure me nt p ost -baseli ne.    
I n t he pri mar y efficac y a nal ysis if a s u bj ect misses all diar y d ata f or t he pri mar y e n d p oi nt t he n a n i m p utati o n 
met h o d w hic h will be s pecifie d i n t he Statistical A nal ysis Pla n ( S A P) will use d.  . 
S u bj ects will be i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d re gar dless of t he act ual st u d y 
d r u g recei ve d.  
If t he pri mar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is statisticall y si g nifi ca nt i n fa v or of 
O T O -1 0 4 t he n a cl ose d testi n g, gate -kee pi n g pr oce d ure, will be use d t o c o m pare t he f oll o wi n g sec o n dar y 
efficac y e n d p oi nts se q ue ntial l y:  
1.  T he n u m ber of D V D at Wee k 8  [t he 4-wee k ( 2 8-da y) i nter val fr o m Wee k 5 t hr o u g h Wee k 8] 
2.  T he n u m ber of D V D at Wee k 4  [t he 4-wee k ( 2 8-da y) i nter val fr o m Wee k 1 t hr o u g h Wee k 4]  
I n t his pr oce d ure if t he first se c o n dar y e n dp oi nt  c o m paris o n bet wee n t he t w o treat me nt gr o u ps is statisticall y 
si g nifica nt i n fa v or of O T O-1 0 4 t he n t he sec o n d sec o n dar y  e n d p oi nt  will be c o m pare d a n d teste d .  If t he 
c o m paris o n of t he first sec o n d ar y e n d p oi nt  is n ot statisticall y si g nifica nt i n fa v or of O TO -1 0 4 t he n t he re p orte d 
p -val ue f or t he sec o n d sec o n d ar y e n d p oi nt will be c o nsi dere d as a n o mi nal p -val ue.  
T he re mai ni n g sec o n dar y e n d p oi nts c o m paris o n will n ot g o  t hr o u g h t he gate kee pi n g pr oce d ure a n d t heref ore 
t he re p orte d p -val ues will be re p orte d  as no mi nal p -val ues .  T his pr oce d ure c o ntr ols t he st u d y -wise T y pe I 
err or.  Si nce t he st u d y -wise err or is mai ntai ne d wit h t he a b o ve pr oce d ure, t here is n o α pe nalt y ass ociate d wit h 
it.  All efficac y h y p ot hesis tests will be 2-si de d a n d perf or me d at α = 0. 0 5 sig nifica nce le vel . 
Ti me a n d E ve nts Sc he d ule:  See  Ta ble  1 . 


 
 
 
 
 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 5   
T a ble  1 :  
Ti me a n d E ve nts Sc he d ule  
Pr oce d ure  
Scree ni n g   
Le a d -I n 
B aseli ne
1/ 
Tre at me nt 
Visit  
F oll o w -u p 
Visit  
F oll o w -u p 
Visit  
E n d -of -St u d y/  
E arl y 
Ter mi n ati o n  
U nsc he d ule d 
Visit  
Visit 1  
–  
Visit 2   
Visit 3   
Visit 4  
Visit 5
2 
U nsc he d ule d  
–  
–  
–  
Wee k 4   
Wee k 8   
Wee k 1 2   
N/ A  
U p t o 1 4 d a ys 
pri or t o st art 
of le a d -i n 
D a y -2 8 t o -1 
( + 3 d a ys) 
D a y 1  
D a y 2 8  
( ± 2 d a ys)  
D a y 5 6  
( ± 2 d a ys)  
D a y 8 4  
(+ 4  d a ys)  
N/ A  
I nf or me d c o nse nt (i ncl u di n g 
pri vac y la n g ua ge/ d oc u me nts)  
X  
 
 
 
 
 
 
Eli gi bilit y criteria  
X  
X
3 
X  
 
 
 
 
Me dical hist or y
4 
X  
 
X  
 
 
 
 
C o nc o mita nt me dicati o ns  
X  
 
X  
X  
X  
X  
X  
Vital si g n meas ure me nts
5 
X  
 
X  
X  
X  
X  
X  
Hei g ht a n d wei g ht meas ure me nts  
X  
 
 
 
 
X
6 
 
Pre g na nc y test
7 
X  
 
X  
 
 
X  
 
Cli nical la b orat or y test
8 
X  
 
X  
 
 
X  
X as i n dicate d  
T y m pa n o metr y  
X  
 
X  
X  
X  
X   
X as i n dicate d  
A u di o metr y  
X  
 
X  
X  
X  
X   
X as i n dicate d  
Ot osc o p y  
X  
 
X  
X  
X  
X  
X  
T FI -2 5  
 
 
X  
X  
X  
X  
 
S F -3 6 assess me nt  
 
 
X  
X  
X  
X  
 
C -S S R S assess me nt
9 
X  
 
X  
X  
X  
X  
X  
Re vie w s u bj ect I V R S diar y 
c o m plia nce a n d i nstr uct s u bj ect 
o n I V R S d iar y use
1 0 
X  
 
X  
X  
X  
 
 
Ra n d o mizati o n
1 1 ,1 2 
 
 
X  
 
 
 
 


 
 
 
 
 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3. 0: 1 3  J a n uar y 2 0 1 6 
1 6   
Pr oce d ure  
Scree ni n g   
Le a d -I n 
B aseli ne
1/ 
Tre at me nt 
Visit  
F oll o w -u p 
Visit  
F oll o w -u p 
Visit  
E n d -of -St u d y/  
E arl y 
Ter mi n ati o n  
U nsc he d ule d 
Visit  
Visit 1  
–  
Visit 2   
Visit 3   
Visit 4  
Visit 5
2 
U nsc he d ule d  
–  
–  
–  
Wee k 4   
Wee k 8   
Wee k 1 2   
N/ A  
U p t o 1 4 d a ys 
pri or t o st art 
of le a d -i n 
D a y -2 8 t o -1 
( + 3 d a ys) 
D a y 1  
D a y 2 8  
( ± 2 d a ys)  
D a y 5 6  
( ± 2 d a ys)  
D a y 8 4  
(+ 4  d a ys)  
N/ A  
A d mi nister st u d y dr u g 
 
 
X  
 
 
 
 
A d verse e ve nt m o nit ori n g  
 
 
X  
X  
X  
X  
X  
1 Baseli ne  assess me nts o n Da y 1 are t o be perf or me d bef ore a d mi nistrati o n of st u d y dr u g s h o w n. Re vie w eli gi bilit y criteria at t he baseli ne visit t o e ns ure s u bj ects 
re mai n eli gi ble f oll o wi n g t he l ea d-i n peri o d. 
2 Pr oce d ures sc he d ule d f or Visit 5 will be perf or me d at t he e n d of t he f oll o w -u p peri o d ( + 4 da ys) or u p o n earl y disc o nti n uati o n fr o m t he st u d y.  
3 O nce t he s u bj ect has met t he i ncl usi o n/e xcl u si o n criteria as a p pr o priate at scree ni n g, t he s u bj ect will e nter a 4 -wee k lea d -i n peri o d.  D uri n g t he lea d-i n, t he 
s u bj ect will rec or d t heir dail y verti g o e x perie nce.  A deter mi nati o n of w het her t he s u bj ect meets I ncl usi o n Criteria N o. 1 0 a n d 1 1 will be d eter mi ne d 2 8 da ys 
after s u bj ects e nter t he lea d -i n peri o d. 
4 Me dical hist or y t o i ncl u de i nf or mati o n o n de m o gra p hics.  
5 Vital si g n meas ure me nts i ncl u de bl o o d press ure a n d p ulse rate.  
6 O nl y wei g ht is t o be meas ure d at Visit 5.  
7 Fe male s u bj ects of c hil d beari n g p ote nti al will ha ve a ser u m pre g na nc y test at scree ni n g a n d a uri ne pre g na nc y test at bas eli ne, pri or t o ra n d o mizati o n. If t he 
scree ni n g or baseli ne pre g na nc y test res ult is p ositi ve, t he s u bj ect is n ot eli gi ble f or e nr oll me nt i nt o t he st u d y. If a s u bj ect is f o u nd t o be pre g na nt after d osi n g 
wit h st u d y dr u g, t he y will c o m plete t he f oll o w -u p peri o d. All ser u m pre g na nc y tests will be a nal yze d b y a ce ntral la b orat or y. Ser u m pre g na nc y test res ults fr o m 
Visit 1 as well as t he uri ne pre g na nc y test at baseli ne pri or t o r a n d o mizati o n m ust be i ncl u d e d i n eli gi bilit y assess me nt at Visit 2.  
8 Cli nical la b orat or y tests i ncl u de he mat ol o g y, cli nical c he mistr y, a n d uri nal ysis a n d will be a nal yze d b y a ce ntral la b orat or y . 
9 C ol u m bia -S uici de Se verit y Rati n g Scale: T he Baseli ne versi o n will be use d at t he Scree ni n g visit a n d t he Si nce Last Visit versi o n will  be use d at all s u bse q ue nt 
visits.  
1 0 S u bj ects will be i nstr ucte d a n d trai ne d h o w t o rec or d dail y verti g o e x perie nce usi n g t he I V R S diar y.  
1 1 A s u bj ect is c o nsi dere d ra n d o mize d w he n a ra n d o mi zati o n n u m ber has bee n assi g ne d b y I W R S.  Ra n d o mizati o n m ust occ ur pri or t o a d mi nistrati o n of st u d y 
dr u g. St u d y sites l o g i n t o t he I W R S t o e xec ute eac h ra n d o mizati o n after a s u bj ect has met all prere q uisites f or ra n d o mizati o n a n d has c o m plete d all sc he d ul e d 
pr oce d ures f or Da y 1.  
,1 2 S u bj ects will be ra n d o mize d usi n g la b orat or y res ults fr o m Visit 1; la b orat or y res ults fr o m Visit 2 are n ot re q uire d f or ra n d o mizati o n.  


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
1 7   
 
1.   
B A C K G R O U N D  
Me niere’s dis ease is a n i di o pat hic s y n dr o me of e n d ol y m p hatic h y dr o ps (C o m mittee o n Heari n g 
a n d E q uili bri u m, 1 9 9 5 ).  It is ass oci ate d wit h a disti nct patter n of cli nical s y m pt o ms c o m prise d 
of verti g o, heari n g l oss, ti n nit us a n d a ural f ull ness. It is m ore fre q u e ntl y u nilateral t ha n bilateral.  
E pis o dic verti g o is c o nsi dere d t he m ost pr o mi ne nt s y m pt o m, wit h e pis o des t y picall y la sti n g at 
least 2 0 mi n utes a n d res ulti n g i n si g nifica nt patie nt m or bi dit y.  T he dia g n osis is pri maril y a 
cli nical o ne, si nce t here are n o s pecifi c dia g n ostic tests f or Me niere’s diseas e.  T he diseas e is 
k n o w n t o wa x a n d wa ne, b ut e ve nt uall y res ults i n irre v ersi ble se ns ori ne ural heari n g l oss at all 
fre q ue n cies i n t he affecte d ear.  W hile t he pat h o ge nesis of Me niere’s diseas e has n ot bee n 
el uci date d, o ne well -acce pte d mec ha nis m i n v ol ves t he d ysre g ulati o n of la b yri nt h fl ui d 
v ol u me/i o n bala nce res ulti n g i n e n d ol y m p h atic h y dr o ps ( S hea, 1 9 9 3 ).  T h e i ncreas e i n fl ui d 
v ol u me a n d c o nse q ue nt i ncreas e d la b yri nt h press ure ma y t he n be e x presse d as t he Me niere’s 
s pectr u m of s y m pt o ms. 
T here is n o c ure f or Me niere’s disease.  Treat me nt te n ds t o f oc us o n relie vi n g t he verti g o 
s y m pt o ms, w here it is h y p ot hesize d t hat re d uci n g i n ner ear fl ui d v ol u me will relie ve t he h y dr o ps 
a n d ass ociate d cli nical pict ure.  It is f or t his reas o n t hat ma n y s u bjects are i nitiall y starte d o n l o w 
salt diets a n d di uretics (Barritt, 2 0 0 8 ).  A n u m ber of me dical s yste mic treat me nts are als o use d t o 
relie ve Me ni ere’s disease s y m pt o ms, i ncl u di n g b ut n ot li mite d t o a nti hista mi nes, 
a ntic h oli ner gics, p he n ot hiazi nes, be nz o diaze pi nes, a n d c ortic oster oi d s; h o w e ver, t hes e 
i nter ve nti o ns are ofte n i n a de q uate i n relie vi n g t he s y m pt o ms of Me niere’s disease.  A de vi ce t hat 
ge n erat es l o w -press ure p ulses, t he Me niett ® de vice, is i n dicate d f or t he s y m pt o matic treat me nt 
of Me niere’s diseas e.  H o we ver, t he d e vice is  n ot wi del y us e d a n d is n ot c urre ntl y c o nsi dere d 
sta n dar d of care (Ki m et al, 2 0 0 5 ).  S ur gi cal dec o m pressi o n ma y b e atte m pte d i n se vere cases 
u nres p o nsi ve t o me dical i nter ve nti o n, b ut s ur gical o utc o mes  are fre q u e ntl y u nsatisfa ct or y.  
Fi nall y, p atie nts wit h u nr es p o nsi ve disease ma y u n der g o c he mical or s ur gi cal ne ur o a blati o n, 
res ulti n g i n s y m pt o m r elief at t he c ost of d estr ucti o n of t he 8t h cra ni al ner v e. T h us, t here 
c o nti n ues t o be a n u n met me dical nee d f or t hera pi es t o a d dress t his de bilitati n g disease. 
O T O -1 0 4 is a s us pe nsi o n of de x a met has o ne i n a b uffere d s ol uti o n 
 
 
  Ot o n o m y has 
f or m ulate d de x a met has o ne, a
 
 f or t he p ur p ose of st u d yi n g t h e p ote ntial be nefits of i ntrat y m pa nic (I T) 
i njecti o ns of O T O-1 0 4 i n s u bjects wit h Me niere’s disease. Si n gle a n d re p eat -d ose n o ncli nical 
safet y st u dies i n g ui n ea pi gs, rats a n d cats ha ve bee n c o n d ucte d t o s u p p ort cli nical de vel o p me nt.  
S pecial e m p hasis i n t he t o xic ol o g y st u dies has bee n place d o n t h e effects of O T O -1 0 4 a n d 
 ve hicle c o ntr ol o n mi d dle a n d i n ner ear c o m part me nts, w h ere b ot h f u ncti o nal a n d 
hist ol o gical assess me nts ha ve bee n c o n d uct e d.  A d diti o nall y, p h ar mac o ki netic assess me nts ha ve 
bee n c o n d u cte d i n g ui nea pi gs, rats, cats, a n d s hee p t hat pr o vi de a c o m plete pr ofile of e x p os ure 
of O T O -1 0 4 t o t he i n ner ear c o m p art me nt, as well as s yste mic e x p os ure.  


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
1 8   
 
1. 1.   
R ati o n ale f or St u d y  a n d D ose Selecti o n  
Ot o n o m y has c o m plete d 2  place b o -c o ntr olle d, d o u ble -bli n d, m ulti -ce nter cli nical st u dies wit h 
O T O -1 0 4 i n Me niere’s disea se: a P hase 1 b st u d y, 1 0 4-2 0 0 9 0 1, a n d a P hase 2 b st u d y, 1 0 4 -
2 0 1 1 0 2 .  T he P hase 1 b st u d y de m o nstr ate d t hat a  si n gle i ntrat y m pa nic i njecti o n of O T O-1 0 4 at 
d oses of 3 m g or 1 2 m g was  safe a n d well t olerat e d i n s u bjects wit h Me niere’s disease.  I n t h e 
e x pl orat or y P hase 1 b st u d y, t he tr e n ds i n t he data s u g gest treat me nt wit h 1 2 m g O T O -1 0 4 is 
ass ociate d wit h a cli nicall y mea ni n gf ul re d ucti o n i n verti g o fre q u e nc y at 3 m o nt hs after 
treat me nt c o m pare d t o 3 m g O T O -1 0 4 or place b o .  T he P hase 2 b st u d y t heref ore ra n d o mize d 1 5 4 
s u bjects wit h u nilateral Me niere’ s dis ease t o treat me nt wit h 1 2 m g O T O-1 0 4 or place b o .  T his 
st u d y de m o nstrate d i m pr o ve me nt i n n u m ber of defi niti ve verti g o d a ys  c o m pare d t o t he lea d -i n 
peri o d wit h a si n gl e I T i njecti o n of O T O -1 0 4 c o m pare d t o place b o  d uri n g t he W ee k 1 2 i nter val  
wit h a s maller i m pr o ve m e nt o bser ve d at Wee k 1 6 .  T heref ore, t he fi nal d os e selecte d a n d 
pri mar y o bser vati o n p oi nt f or t his st u d y is 1 2 m g O T O -1 0 4 a n d t he Wee k 1 2 i nter val, 
res pecti vel y.   
2.   
O B J E C TI V E S  
2. 1.   
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o  c o nfir m t he efficac y of O T O -1 0 4 i n s u bjects wit h Me niere’s dis ease, 
as meas ure d b y t h e n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 1 2 (t h e 4 -wee k  i nter val 
fr o m Wee k 9 t hr o u g h Wee k 1 2). 
2. 2.   
Sec o n d ar y O bjecti ve  
T he sec o n d ar y o bjecti ve is t o  descri be t he safet y pr ofile of O T O -1 0 4 i n s u bjects wit h 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 ra n d o mize d, d o u ble bli n d, place b o -c o ntr olle d, m ultice nter 1 6 -wee k P hase 3 st u d y.  
F oll o wi n g a n i nitial 4 -wee k lea d -i n peri o d, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o eit her 
1 2 m g O T O -1 0 4 or place b o usi n g a 1: 1 all ocati o n rati o  stratifie d b y ge n d er.  S u bjects will be 
o bser ve d f or 1 2  wee ks f oll o w i n g a si n gle i ntrat y m pa nic i njecti o n of eit her 1 2 m g O T O-1 0 4 or 
place b o.  
T he d urati o n of t he st u d y f or eac h s u bject will be a ma xi m u m of a p pr o xi matel y 1 6 wee ks, 
i ncl u di n g a 4-wee k l ea d -i n peri o d bef ore d osi n g (a si n gle i njecti o n), f oll o we d b y a 1 2-wee k 
f oll o w-u p peri o d.  
After scree ni n g ( Visit 1), all eli gi ble s u bjects will e nter i nt o a 4 -wee k lea d -i n peri o d.  D uri n g t he 
lea d-i n peri o d, s u bjects will rec or d t heir dail y v erti g o e x perie nce t o all o w f or a baseli ne 
assess me nt of t hese e ve nts.  A n y da y wit h a rec or de d defi niti ve verti g o e pis o de, a n e pis o de 
lasti n g at least 2 0 mi n utes (c orres p o n di n g t o a Verti g o Se verit y S c ore of 2 or m ore ), will be 
defi ne d as a defi niti ve verti g o da y ( D V D).  F oll o wi n g t he lea d -i n peri o d, eli gi ble s u bjects will be 
ra n d o mize d t o 1 2 m g O T O -1 0 4 or place b o usi n g a 1: 1 all ocati o n rati o.    


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
1 9   
 
After a si n gle i ntr at y m p a nic i njecti o n wit h O T O -1 0 4 or place b o o n Da y 1, s u bjects will c o nti n ue 
t o rec or d t heir d ail y v erti g o e x perie n ce d uri n g t he 1 2 -wee k f oll o w -u p peri o d . S u bjects will visit 
t he st u d y site at Wee ks 4 a n d 8 f or a d diti o nal efficac y a n d safet y ass ess me nts. Efficac y a n d 
safet y assess me nts will als o be c o m plete d at t he e n d of st u d y ( Wee k 1 2) or u p o n earl y 
disc o nti n uati o n fr o m t he st u d y. 
4.   
S T U D Y P O P U L A TI O N  
4. 1.   
Ge ner a l C o nsi der ati o ns 
A p pr o xi matel y 1 6 0  s u bj ects will be e nr olle d at 5 0 -7 0 sites i n u p t o fi ve c o u ntries i n t he E ur o pea n 
U ni o n, i ncl u di n g U nite d Ki n g d o m, Ger ma n y a n d P ola n d.   S u bjects will be ra n d o mize d o nl y if 
t he y meet all of t he i ncl usi o n criteria a n d n o n e of t he e x cl usi o n criteria. 
4. 2.   
I ncl usi o n Criteri a 
S u bjects e nr olle d i n t he st u d y will ha ve u nilateral Me niere’s dis ease as o utli ne d b y t he A merica n 
Aca de m y of Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y ( A A O -H N S) C o m mittee o n Heari n g a n d 
E q uili bri u m i n 1 9 9 5 ( C o m mittee o n Heari n g a n d E q uili bri u m, 1 9 9 5 ). 
T o be eli gi ble f or t his st u d y, eac h of t h e f oll o wi n g criteria m ust be satisfie d wit h a “ Y E S” a ns wer 
( u nless n ot a p plica ble): 
1.  S u bject is a male or fe m ale a ge d 1 8 t o 8 5 years, i n cl usi ve.  
2.  S u b ject has a dia g n osis of defi nite u nilateral Me niere's disease b y 1 9 9 5 A A O-H N S 
criteria.  
3.  S u bject self -re p orts acti v e, defi niti ve verti g o e pis o des f or t he 2 m o nt hs pri or t o t he st u d y 
lea d-i n peri o d. 
4.  S u bject has d oc u me nte d as y m metri c se ns ori ne ural heari n g l os s at scree ni n g or wit hi n t he 
past 1 2 m o nt hs acc or di n g t o A A O -H N S 1 9 9 5 criteria defi ne d as o ne of t he f oll o wi n g:  
a. T he arit h metic mea n of heari n g t hres h ol ds ( p ure t o ne a vera ge, P T A) at 2 5 0, 5 0 0 a n d 
1 0 0 0 Hz of 1 5 d B or m ore hi g h er t ha n t he P T A of 1 0 0 0, 2 0 0 0, a n d 3 0 0 0 Hz,  
b.  T he arit h metic mea n of  P T A at 5 0 0, 1 0 0 0, 2 0 0 0 a n d 3 0 0 0 Hz is 2 0 d B or m ore 
p o orer i n t he ear i n q uesti o n t ha n o n t he o p p osite si de,  
c. It is t he j u d g me nt of the i n vesti gat or t h at t he s u bject 's h eari n g l oss meets r eas o na ble 
a u di o metric criteria f or heari n g l oss c haract eristic of Me niere's dis ease, a n d if s o, it 
s h o ul d be j ustifie d a n d d oc u me nte d. 
5.  S u bject a grees t o mai ntai n t heir c urre nt treat me nts f or Me niere's diseas e w hile o n -st u d y. 
6.  Fe male s u bjects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-
me n o pa usal ( ≥1 2  m o nt hs si nce last me nstr ual peri o d  a n d 4 5 years of a ge or ol der )] m ust 
ha ve a n e gati ve uri ne pre g na n c y test bef ore ra n d o mizati o n. W o me n of c hil d beari n g 
p ote ntial w h o are n ot a bsti ne nt fr o m se x wit h male part ners ma y  be e nt ere d i nt o t he st u d y 
if t he y are usi n g a n d willi n g t o c o nti n ue t o use hi g hl y effecti ve or “ d o u ble barrier”  
c o ntrace pti ve preca uti o ns f or t he d urati o n of t he st u d y (e. g., oral c o ntrace pti ves, 


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
2 0   
 
c o ntrace pti ve i m pla nt or i njecti o n, i ntra uteri ne de vice, “ do u ble barrier” met h o ds 
i ncl u di n g male c o n d o m wit h dia p hra g m, male c o n d o m wit h cer vical ca p, male c o n d o m 
wit h  s per mici de, or dia p hra g m a n d s per mici d e).  
7.  S u bject is willi n g t o c o m pl y wit h t he pr ot oc ol a n d atte n d all st u d y visits.  
8.  S u bject is a ble t o use t he t ele p h o ne t o c o m plete t h eir dail y di ar y . 
9.  S u bject is a ble t o pr o vi de writte n i nf or me d c o ns e nt, i ncl u di n g a gree me nt t o l ocal pri vac y 
la n g u a ge re q uire me nts eit her wit hi n t he i nf or me d c o nse nt or i n a ncillar y d o c u me nts 
c o m plia nt wit h l ocal pri vac y la ws bef ore t h e i nitiati o n of a n y st u d y-relate d pr oce d ures. 
At t he c o m pleti o n of t he first 2 8 da ys of t he lea d-i n peri o d: 
1 0.  S u bject has e x perie nce d a n d rec or de d at least 4 a n d a ma xi m u m of 2 2 defi niti ve verti g o 
da ys d uri n g t h e 4 -wee k l ea d -i n peri o d. 
1 1.  S u bject c o m plete d at least 2 2 of 2 8 diar y e ntries d uri n g t he 4-wee k lea d -i n peri o d. 
4. 3.   
E xcl usi o n Criteri a  
T o be eli gi ble f or t his st u d y, eac h of t h e f oll o wi n g criteria m ust be satisfie d wit h a “ N O” a ns wer: 
( u nless n ot a p plica ble): 
1.  S u bject has a n i nfecti o n i n t he ear, si n uses, or u p p er res pir at or y s yste m  at t he ti me of 
ra n d o mizati o n. 
2.  S u bject is pre g n a nt or lactati n g.  
3.  S u bject has a hist or y of i m m u n o deficie nc y disease.  
4.  S u bject has acti ve or rece nt ( < 1 m o nt h pri or t o scree ni n g) mi d dle ear diseas e, i ncl u di n g 
b ut n ot li mite d t o:  c hr o ni c otitis me dia, ac ute otitis me dia, mi d dle ear eff usi o ns, mi d dle 
ear at electasis, or c h olest eat o ma.  
5.  S u bject has a n a b n or m alit y of t he t y m pa nic m e m bra ne i n t he affecte d ear t hat w o ul d 
i ncreas e t he ris k ass oci ate d wit h i ntrat y m pa ni c i njecti o n i ncl u di n g b ut not li mite d t o 
m o n o meric t y m pa ni c me m bra ne.  
6.  S u bject has a hist or y of pre vi o us e n d ol y m p h atic sac s ur ger y.  
7.  S u bject has a hist or y of pre vi o us use of i ntrat y m pa nic ge nta mici n i n t he affecte d ear.  
8.  S u bject has a hist or y of t y m pa n ost o m y t u bes wit h e vi de nce of perf orati o n or lac k of 
cl os ure.  
9.  S u bject has use d s yst e mic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea d -i n peri o d. 
1 0.  S u bject has ha d i ntrat y m pa nic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea d -i n 
peri o d . 
1 1.  S u bject has e x perie nce d a n a d verse reacti o n t o i ntrat y m p a nic i njecti o n of ster oi ds.  
1 2.  S u bject has a h y perse nsiti vit y t o d e x a met has o ne or a n y of t he e x ci pie nts i n O T O -1 0 4.  
1 3.  S u bject has hist or y of mi grai n o us verti g o.  


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
2 1   
 
1 4.  S u bject has hist or y of dr o p attac ks.  
1 5.  S u bject is n ot a ble t o acc uratel y i de ntif y a n d re p ort e pis o des of verti g o.  
1 6.  S u bject has a n y ot her cli nicall y si g nifica nt ill ness , me dical c o n diti o n , or me dical hist or y 
t hat, i n t he i n vesti gat or’s or t he me dical m o nit or’s o pi ni o n, w o ul d pr o hi bit t he s u bject 
fr o m partici pati n g i n t he st u d y at scree ni n g or at t he ti me of ra n d o mizati o n. 
1 7.  S u bject has use d a n i n vesti gati o nal dr u g or de vice i n t he 3 m o nt hs pri or t o scree ni n g.  
1 8.  S u bject has a hist or y of s u bsta nce a b us e wit hi n t he prece di n g 6 m o nt hs pri or t o 
scree ni n g. 
1 9.  S u bject has pre vi o usl y b ee n ra n d o mize d t o a trial of O T O -1 0 4.  
5.   
R A N D O MI Z A TI O N A N D B L I N DI N G 
5. 1.   
O ver vie w  
At t he c o ncl usi o n of t he scree ni n g/lea d -i n peri o d, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o 
eit her O T O-1 0 4 or place b o i n a 1: 1 all ocati o n rati o , stratifie d b y ge n der,  base d o n a c o m p uter -
ge n erat e d ra n d o mizati o n sc he d ule.   
 1 2 m g O T O -1 0 4; si n gle, i ntrat y m pa nic i njecti o n  
 Place b o; si n gle, i ntr at y m pa nic i njecti o n  
5. 2.   
E nr oll me nt Pr oce d ures  
5. 2. 1.   
Assi g n me nt of S u bject I de ntific ati o n N u m bers  
At t he scree ni n g visit, Visit 1, s u bjects s i g ni n g t he i nf or me d c o nse nt will be assi g ne d a u ni q ue 
s u bject i de ntificati o n n u m ber via t he Electr o nic Data Ca pt ure s yste m ( E D C).  O nce assi g n e d, t he 
s u bject i de ntificati o n n u m ber will n ot be re-assi g ne d a n d s h o ul d n ot be c h a n ge d.  T his n u m ber 
will be use d  t o i de ntif y t he s u bject t hr o u g h o ut t he st u d y, i ncl u di n g t h e scree ni n g a n d lea d-i n 
peri o ds.  
5. 2. 2.   
Tre at me nt Assi g n me nt  
St u d y sites will l o g i n t o t he I W R S t o e xec ute eac h ra n d o mizati o n after a s u bject has met all 
prere q uisites f or ra n d o mi zati o n a n d has c o m plete d  all sc he d ule d pr o ce d ures f or Da y 1 ( Visit 2).   
St u d y site p ers o n nel, w h o are bli n de d t o treat me nt assi g n me nt, will recei ve a ra n d o mizati o n 
n otificati o n i n dicati n g t h e kit n u m ber  ( pac ka ge d st u d y dr u g), a n d t he dat e a n d ti me of 
ra n d o mizati o n f or eac h s u bject.  O nce assi g n e d, kit n u m bers ca n n ot be re -assi g ne d.  S u bjects 
will be c o nsi dere d e nr olle d i nt o t he st u d y o nce t he y are ra n d o mize d a n d assi g ne d a u ni q ue 
ra n d o mizati o n n u m ber. 
St u d y sites will pr o vi de t he i nf or mati o n c o ntai ne d i n t he I W R S ra n d o mizati o n n o tificati o n t o t he 
u n bli n de d q ualifie d me dical pr ofessi o nal ( Q M P) res p o nsi ble f or pre parati o n of t he s yri n ge 
c o ntai ni n g st u d y dr u g.  T he u ni q ue kit n u m ber pr o vi de d b y t he I W R S will c orres p o n d t o a kit of 
pac ka ge d st u d y dr u g la bele d wit h t he i de ntical kit n u m ber.  T he Q M P  will pre pare t he s yri n ge 


 
 
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fr o m t he c o nte nts of t he st u d y dr u g p ac ka ge c orres p o n di n g t o t he I W R S kit n u m ber acc or di n g t o 
t he i nstr ucti o ns i n t he st u d y P har m ac y Bi n der.  T he s u bject i de ntificati o n n u m ber a n d kit n u m ber 
m ust b ot h be rec or de d i n t he s u bject’s rec or d. 
5. 2. 3.   
R a n d o miz ati o n Al g orit h m  
S u bjects will ra n d o mize d i n a 1: 1 rati o treat me nt gr o u ps stratif yi n g b y ge n d er usi n g a  per m ute d 
bl oc k ra n d o mizati o n al g orit h m .  T he ra n d o mizati o n pr ocess will be de pl o ye d via a n i nter net -
base d I W R S w hic h is  accessi ble 2 4 h o urs a da y t o a ut h orize d users.  T he s u bject’s ra n d o mizati o n 
n u m ber will deter mi ne t h e ra n d o mize d treat me nt assi g n me nt.  N u m bere d kits will be dis pe nse d 
b y t he q ualifie d me dical pr ofessi o nal base d o n t he treat me nt assi g n me nt.  St u d y dr u g ki ts will be 
la bele d wit h a u ni q ue kit n u m ber usi n g a se parate a n d i n de pe n de nt ra n d o mizati o n al g orit h m. 
5. 3.   
Bli n di n g  
T he st u d y will be d o u ble -bli n de d.  T o mai ntai n t he bli n d f or site pers o n nel i n v ol ve d i n st u d y 
assess me nts, t he f oll o wi n g pr oce d ures will be f oll o we d:  
Treat me nt s yri n ges will be pre -l o a de d b y a n u n bli n de d Q M P .  Eac h s yri n ge will be pre pare d 
acc or di n g t o t he d etaile d i nstr ucti o ns i n t he P har mac y Bi n d er i n a ma n ner t hat pre ve nts 
vis ualizati o n of s yri n ge c o nte nts b y all ot her st u d y staff t hr o u g h t he us e of a s yri n ge o v erla b el.  
I n a d diti o n, a n y i nteracti o n wit h s u bjects wit h re gar d t o t he c ollecti o n, re vie w or disc ussi o n of 
st u d y assess me nts, wit h t he e x ce pti o n of ot osc o pic e x a ms, will be d o ne b y t he st u d y c o or di nat or, 
a u di ol o gist or s o me o ne ot her t ha n t he Q M P  w h o pre pare d t he s yri n ge a n d t he p h ysici a n w h o 
a d mi nistere d t he i ntrat y m pa nic i njecti o n of st u d y dr u g.  E ver y eff ort s h o ul d be ma de t o e ns ure 
t hat ot osc o pic e x a ms are c o n d ucte d b y t he p h ysici a n w h o a d mi nistere d t he st u d y dr u g or a n ot her 
p h ysicia n i n v ol ve d i n t he st u d y, b ut n ot res p o nsi ble f or ot her assess me nts f or t he s pecific s u bj ect .  
P h ysicia ns a d mi nisteri n g st u d y dr u g a n d c o n d ucti n g t he ot osc o pic e x a ms will be i nstr ucte d n ot 
t o disc uss a n y p ote ntial vis ual differe n ces o bser ve d i n st u d y material wit h s u bjects or st u d y staff.  
T he bli n d s h o ul d be br o ke n o nl y if k n o wi n g t he s u bject’s treat me nt all ocati o n w o ul d facilitate 
s pecific e m er ge n c y treat me nt.  T he p h ysi cia n w h o a d mi nistere d t he st u d y dr u g is u n bli n de d at 
t he ti me of i njecti o n.  If t he p h ysicia n w h o a d mi nistere d t he st u d y dr u g is n ot a vaila ble or d oes 
n ot rec ollect t he tr eat me nt a d mi nistere d, t he i n vesti gat or ca n access t he u n bli n de d dr u g 
acc o u nta bilit y rec or ds c o m plete d a n d retai n e d b y t he Q M P w he n pre p ari n g O T O -1 0 4 or place b o .  
I n all cases, t he i n v esti gat or m ust c o ntact t he me dical m o nit or as s o o n as is practical after 
u n bli n di n g has occ urre d a n d treat me nt i nitiate d . 
If t he bli n d is br o ke n, t he s u bject will c o nti n ue t o be f oll o we d a n d e val uate d per-pr ot oc ol.  T h e 
date, ti me, a n d reas o n f or t h e u n bli n di n g m ust be d oc u me nte d o n t he a p pr o priate pa ge of t he 
e C R F.  
T he ra n d o mizati o n sc he d ule or bl oc ki n g fact or(s) will n ot be re veale d t o st u d y s u bjects, 
i n vesti gat ors, cli nical staff, site ma na gers or S p o ns or re prese ntati ves u ntil all s u bjects ha ve 
co m plete d t he trial a n d t h e data bas e has bee n fi nali ze d b y Ot o n o m y.  


 
 
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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 Dr u g A d mi nistr ati o n  
O T O -1 0 4 1 2 m g will be a d mi nistere d as a si n gle, 0. 2 m L i ntrat y m pa nic i nj ecti o n of 6 0 m g/ m L 
O T O -1 0 4. T he rec o m me n de d i njecti o n pr oce d ure f or i ntrat y m p a nic a d mi nistrati o n of O T O -1 0 4 
i n Me niere’s disease s u bj ects is as f oll o ws:   
1.  Place t he s u bject i n a rec u m be nt p ositi o n wit h t he treate d ear u p war ds.  A n est hetize t he 
t y m pa nic me m bra ne b y c o veri n g t h e e xter nal s urface of t he p osteri or i nferi or q ua dra nt 
wit h t o pical li d ocai ne/ pril ocai ne crea m 
  
 u ntil t he t y m p a nic 
me m bra ne is n u m b.  If a p plica ble, s ucti o n a wa y t he t o pical li d ocai ne/ pril o cai ne crea m.  
2.  Usi n g t he 1 m L s yri n ge pre -l oa de d wit h O T O-1 0 4 a n d e q ui p pe d wit h a 2 5 or 2 6 ga u ge 
nee dle, i nsert t he n ee dle t hr o u g h t h e t y m pa ni c me m bra ne wit h t he be v el faci n g i n a n 
i nfer o p osteri or dir ecti o n t o a de pt h of a p pr o xi matel y 2-3 m m j ust i nferi or t o t he r o u n d 
wi n d o w nic he, a n d wit h fir m b ut ge ntle press ure, i nject 0. 2 m L ta ki n g care n ot  t o i nsert 
t he nee dle f urt her t ha n n ecessar y.  Use of t his tec h ni q ue will mi ni mize t he p ossi bilit y of 
O T O -1 0 4 a d h eri n g t o t he u n dersi de of t he t y m pa ni c me m bra ne.  D o n ot i ncise t he 
t y m pa nic me m bra ne t o f or m a ve ntilati o n h ole as t his is n ot nee de d d ue t o the s mall 
i njecti o n v ol u me. 
6. 2.   
C o m pli a nce  
O T O -1 0 4 will be a d mi nistere d b y site me dical pr ofessi o nals  as a si n gle, i ntrat y m pa ni c i njecti o n 
at Visit 2.  A n y de viati o ns i n a d mi nistrati o n will be d oc u me nte d i n t he s o urce d oc u me nts a n d t h e 
e C R F. 
T he site will mai nt ai n a l o g of all st u d y dr u g dis pe nse d a n d ret ur ne d. Dr u g s u p plies f or eac h 
s u bject will be i n ve nt orie d a n d acc o u nte d f or t hr o u g h o 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 n c o mita nt me dicati o ns will be rec or de d i n t he s u bject’s e C R F.  T his will i ncl u de all 
s y m pt o matic relief me dicati o ns f or Me niere’s disease s y m pt o ms, prescri pti o n dr u gs, h er bal 
pr o d ucts, vita mi ns, mi nerals, a n d o ver -t h e-c o u nt er me dicati o ns ta ke n wit hi n 3 0 da ys b ef ore 
ra n d o mizati o n, w hic h will be c o nsi dere d pri or t hera p y.  A n y c o n c o mita nt me dicati o n dee me d 
necessar y f or t he welf are of t he s u bject d uri n g t he st u d y ma y be gi ve n at t he discreti o n of t he 
I n v esti gat or e x ce pt f or t h ose liste d i n Secti o n  7. 1 .  A n y c ha n ges i n c o nc o mita nt me dicati o ns will 
be rec or de d i n t he s u bject’s e C R F.  
7. 1.   
Pr oscri be d T her a p y D uri n g t he St u d y Peri o d  
T he f oll o wi n g t h era pies are pr o hi bite d d uri n g t he st u d y:  
 S yste mic c ortic oster oi ds  
 I m m u n os u ppressi ve me dicati o ns  
 I ntr at y m p a nic i njecti o n ot her t ha n t hat o utli ne d i n t he c urre nt st u d y 


 
 
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 S ur ger y f or tr eat me nt of Me niere’s dis ease  
 Ot her i n vesti gati o nal dr u g(s) or de vice(s)  
Use of a n y of t hese pr oscri be d t hera pi es will be c o nsi dere d a pr ot oc ol de viati o n.  
7. 2.   
S y m pt o m atic Relief Me dic ati o ns  
It is rec o g nize d t hat s u bjects ma y at ti mes use certai n me dicati o ns f or relief of s y m pt o ms r elate d 
t o Me niere’s disease d uri n g t he c o urse of t he st u d y.  U s e of vesti b ular s u p pressa nts, a nti-e metics 
a n d beta histi ne  is all o we d as s y m pt o matic relief me dicati o ns.  T he use of ge nt a mici n or ear 
s ur ger y at a n y ti me d uri n g t he st u d y will be c o nsi dere d a pr ot oc ol de viati o n.  A n y c ha n ges 
re p orte d b y t he s u bjects i n c o nc o mita nt me dicati o ns s h o ul d be rec or de d i n t he s u bject’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 Pr oce d ures b y Visit  
8. 1. 1.   
Visit 1: U p t o 1 4 d a ys pri or t o i niti ati o n of le a d -i n peri o d ( Scree ni n g) 
Beca use a u di ol o g y, t y m p a n o metr y a n d ot osc o pic e x a ms are c o nsi dere d r o uti ne f or t his patie nt 
p o p ulati o n, data o btai ne d fr o m assess me nt s perf or me d pri or t o d oc u me ntati o n of i nf or me d 
c o nse nt ca n b e use d as s cree ni n g data.  I n t hese cases, t he data s h o ul d ha ve bee n c ollecte d wit hi n 
1 4 d a ys of i nitiati o n of t he lea d -i n peri o d. 
T he f oll o wi n g assess me nts will be perf or me d at Visit 1.  
 I nf or me d c o ns e nt  
 C o nfir m eli gi bilit y criteri a  
 Me dical hist or y  
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 Hei g ht a n d wei g ht meas ure me nts  
 Ser u m  pre g na n c y test (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y)  
 Cli nical la b orat or y test  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 C -S S R S assess me nt: Baseli ne versi o n  
 Re vie w I V R S diar y i nstr ucti o ns  wit h s u bject  


 
 
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8. 1. 2.   
Le a d -I n Peri o d ( D a y -2 8 t hr o u g h -1 ( + 3 d a ys))  
T he s u bject will rec or d t heir dail y v erti g o e x perie nce d uri n g t he e ntire lea d-i n peri o d u ntil 
ra n d o mizati o n, i neli gi bilit y or wit h dra wal of c o nse nt .  T he deter mi nati o n of w het her s u bjects 
meet I ncl usi o n Criteria N o. 1 0 a n d 1 1 will be c o n d ucte d 2 8 da ys after i nitiati o n of t he lea d -i n 
peri o d.  
8. 1. 3.   
Visit 2: D a y 1 ( B aseli ne/ D ose A d mi nistr ati o n)  
T he f oll o wi n g assess me nts will be perf or me d at Visit 2.  
 C o nfir m eli gi bilit y criteri a  
 Me dical hist or y  
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 Uri ne pre g n a nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y)  
 Cli nical la b orat or y test  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 T FI -2 5  
 S F -3 6 Healt h S ur ve y  
 C -S S R S assess me nt, Si nce Last Visit versi o n  
 Ra n d o mize a n d a d mi nister O T O -1 0 4 or place b o (all assess me nts i n t he a b o ve list 
m ust be c o n d ucte d pri or t o O T O -1 0 4 or place b o a d mi nistrati o n)  
 Re vie w s u bject I V R S diar y i nstr ucti o ns  
 A d verse e ve nts (t o be c ollecte d d uri n g or after O T O -1 0 4 a d mi nistrati o n)  
8. 1. 4.   
Visit 3, 4: Wee k 4 a n d 8 ( ± 2 d a ys) ( F oll o w U p)  
T he f oll o wi n g assess me nts will be perf or me d at Visit 3 a n d 4.  
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 T FI -2 5  
 S F -3 6 Healt h S ur ve y  


 
 
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 C -S S R S assess me n t, Si nce Last Visit versi o n 
 Re vie w s u bject I V R S diar y i nstr ucti o ns  
 A d verse e ve nts  
8. 1. 5.   
Visit 5 : Wee k 1 2  ( ± 4 d a ys ) ( E n d of St u d y/ E arl y Ter mi n ati o n) 
T he f oll o wi n g assess me nts will be perf or me d at Visit 5 . 
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 Uri ne pre g n a nc y test  (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y) 
 Cli nical la b orat or y test  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 T FI -2 5  
 S F -3 6 Healt h S ur ve y  
 C -S S R S assess me nt, Si nce Last Visit versi o n  
 A d verse e ve nts  
8. 2.   
Effic ac y E v al u ati o ns  
Efficac y assess me nts i ncl u de:  
 C haracterizati o n of Dail y Verti g o E x perie nce   
 T FI -2 5 (e x pl orat or y e n d p oi nt)  
 S h ort F or m 3 6 Healt h S ur ve y ( S F -3 6) (e x pl orat or y e n d p oi nt)  
T o mai ntai n t he d o u ble -bli n d of t he st u d y, it is re q uire d t hat a n y i nteracti o n wit h s u bjects i n t he 
c ollecti o n, re vie w, o r disc ussi o n of t hese assess m e nts be d o ne b y t he st u d y c o or di nat or or 
s o me o ne ot her t ha n t he in vesti gat or w h o a d mi nistere d t he i ntrat y m p a nic i njecti o n of st u d y dr u g.  
A n e x ce pti o n ma y b e ma de o nl y if it i n v ol ves t he safet y of t he s u bject.  
8. 2. 1.   
D ail y Di ar y  –  Ver ti g o E x perie nce 
S u bjects will rec or d t heir dail y verti g o e x perie nce via a n I V R S dail y di ar y b y rec or di n g  t he 
se verit y of t he w orst verti g o e pis o de e x perie nce d  d uri n g t he da y , t he effect of verti g o o n t heir 
dail y acti vities, a n d t he n u m ber of verti g o e pis o d es e x perie nce d d uri n g t he da y .  S u bjects eli gi ble 
at scree ni n g will be gi n usi n g t he I V R S dail y diar y at t he start of t he lea d-i n peri o d, a n d if 
ra n d o mize d, will c o nti n ue t o rec or d t heir dail y verti g o e x perie nce t hr o u g h o ut t he re mai n der of 
t he st u d y.  S u bjects will be a ble t o rec or d misse d diar y e ntries f or 1 da y after a misse d e ntr y.  
C o m plia nce wit h t he I V R S verti g o diar y will be m o nit ore d.   


 
 
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Usi n g t he dail y verti g o s cales  de v el o pe d b y Gat es ( Gates, 2 0 0 0 ; Gat es, 2 0 0 4 ; Gates 2 0 0 5 ; Gates, 
2 0 0 6 ) a n d a da pte d t o a n I V R S, s u bjects are i nstr ucte d t o rec or d t he sc ore t hat best c orres p o n ds t o 
t he w orst verti g o e pis o de e x perie nce d eac h d a y a n d t he effect o n t heir dail y acti vities of t heir 
t otal verti g o e x perie n ce t hat da y u si n g a 5-p oi nt sc ori n g s yst e m: 
Verti g o Se verit y Sc ore  
0 = Verti g o -free da y 
1 = Mil d - a n attac k l asti n g less t ha n 2 0 mi n utes   
2 = M o derat e - a n attac k lasti n g m ore t ha n 2 0 mi n utes  
3 = Se vere - a n attac k lasti n g m ore t ha n 2 0 mi n utes a n d acc o m p a nie d b y na usea a n d/ or 
v o miti n g  
4 = T he w orst attac k e x perie nce d t o date  
Effect of Verti g o  o n Acti vit y Le vel  
0 = N or mal Acti vit y  
1 = Sli g ht li mitati o n  
2 = M o derat e li mitati o n  
3 = Sic k at h o me  
4 = Be d ri d de n  
T he occ urre n ce of a defi niti ve verti g o e pis o d e f or a gi v e n da y is defi n e d as a rec or de d Verti g o 
Se verit y Sc ore of 2 or m ore f or t hat d a y.  If m ulti ple attac ks occ ur o n t he sa me da y, o nl y t he 
w orst attac k s h o ul d be sc ore d.  
8. 2. 2.   
Ti n nit us F u ncti o n al I n de x ( T FI -2 5)  
T he T FI -2 5 is a vali date d , 2 5-ite m q uesti o n naire t hat ca n be us e d t o q ua ntif y treat me nt -relate d 
c ha n ge i n ti n nit us (Mei kle et al., 2 0 1 3 ; He nr y et al., 2 0 1 5 ).  T he total T F I sc ore is a s u m of t he 
2 5 ite ms wit h a ma xi m u m  sc ore of 2 5 0, wit h hi g her sc ores re prese nti n g greater percei ve d 
ha n dica p.  T he 2 5 ite ms ca n als o be gr o u pe d i nt o 8 s u bscales: 1) I ntr usi ve, 2) Se nse of C o n tr ol, 
3) C o g niti ve, 4)  Slee p, 5) A u dit or y, 6) R ela x ati o n, 7) Q ualit y of Life, a n d 8) E m oti o nal.   
T he T F I-2 5 will be a d mi nistere d t o s u bjects at Visits 2, 3, 4, a n d 5 . 
8. 2. 3.   
S h ort F or m 3 6 ( S F -3 6) He alt h S ur ve y  
S F -3 6 is a vali date d, 3 6 -ite m, m ulti-p ur p ose, s h ort-f or m healt h s ur ve y (W are et al., 1 9 9 3 ; Ware 
et al., 1 9 9 4).  It c o nsists of 8 s u bscales: 1) P h ysical F u ncti o ni n g, 2) R ole -P h ysical, 3) B o dil y 
Pai n, 4) Ge neral Healt h, 5) Vitalit y, 6) S ocial F u n cti o ni n g, 7) R ole -E m oti o nal, a n d 8) Me ntal 
Healt h.  
T he S F -3 6 healt h s ur ve y  will be a d mi nistere d t o s u bjects at Visits 2, 3, 4, a n d 5.  
8. 3.   
S afet y E v al u ati o ns  
Safet y assess me nts i ncl u de : 


 
 
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 Vital S i g ns, H ei g ht a n d W ei g ht M eas ure me nts  
 Cli nical La b orat or y Test  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 C -S S R S Assess me nt  
 C o nc o mita nt Me dicati o ns  
 A d verse e ve nts (see Secti o n  9 ) 
8. 3. 1.   
Vit al Si g n, Hei g ht a n d Wei g ht Me as ure me nts  
Vital si g n meas ure me nts (i ncl u di n g s yst olic a n d di a st olic bl o o d press ure a n d p ulse rate) will be 
c ollecte d at all st u d y visits.  Vital si g ns  will be meas ure d after s u bjects ha ve bee n seate d f or 5 
mi n utes a n d w hile s u bjects are i n a sitti n g p ositi o n.  Hei g ht a n d wei g ht will be meas ure d at Visit 
1 a n d wei g ht  will be meas ure d a gai n at Visit 5 . 
8. 3. 2.   
Cli nic al L a b or at or y Test  
All cli nical la b orat or y tests will be pr ocesse d b y a Ce ntral La b orat or y.  
Bl o o d a n d uri ne s a m ples f or he mat ol o g y, ser u m c he mistr y, uri nal ysis, a n d pre g na nc y t ests will 
be pre pare d usi n g sta n dar d p r oce d ures.  Cli nical la b orat or y testi n g will be c o m plete d at Visits 1, 
2 a n d 5.  I n a d diti o n, fe m ale s u bjects of c hil d beari n g p ote ntial will ha ve s er u m pre g n a nc y test at 
Visit 1 a n d a uri ne pre g n a nc y test at Visits 2 a n d 5.  
T he bl o o d a n d uri ne sa m ples will  be use d f or t he f oll o wi n g tests:  
He mat ol o g y:  w hite bl o o d cell c o u nt wit h differe ntial, he m o gl o bi n, he m at ocrit, platelet c o u nt, 
re d bl o o d cell c o u nt, mea n c or p usc ular v ol u me, mea n c or p usc ular h e m o gl o bi n, a n d mea n 
c or p usc ular h e m o gl o bi n c o nce ntr ati o n.  
Ser u m  C he mistr y:  al b u mi n, al kali ne p h os p hatase, ala ni ne a mi n otra nsferas e ( A L T), as p artate 
a mi n otra nsferase ( A S T), bl o o d urea nitr o ge n, car b o n di o xi de, calci u m, c hl ori de, creati ni ne, 
gl uc ose, l actate d e h y dr o ge nase, p h os p h or us, p otassi u m, s o di u m, t otal bilir u bi n,  t otal pr otei n. 
Uri nal ysis:  a p p eara nce, c ol or, gl uc ose, ket o nes, nitrite, p H, pr otei n, s pecifi c gra vit y, occ ult 
bl o o d, le u k oc yt e esterase, a n d ur o bili n o ge n.  
8. 3. 3.   
T y m p a n o metr y  
T y m pa n o metr y assess me nts will be use d t o assess t he m o bilit y a n d c o m plia nce of t he t y m pa nic 
me m bra ne, press ure a n d v ol u me i n t he mi d dle ear, a n d f u ncti o n of t he t y m pa nic me m bra n e, 
ossicles a n d e ustac hi a n t u be.  T y m p a n o gra ms will be c o m plete d i n b ot h ears at all st u d y visits .  
S u bjects weari n g heari n g ai ds s h o ul d be i nstr ucte d n ot t o wear t h eir heari n g ai ds d uri n g t he 
t y m pa n o metr y assess me nt. 


 
 
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8. 3. 4.   
A u di o metr y  
A u di o metric assess me nts will be use d t o assess heari n g f u ncti o n i n b ot h ears.  A u di o gra ms 
s h o ul d be c o n d ucte d at 5 0 0, 1 0 0 0, 2 0 0 0, 4 0 0 0 a n d 8 0 0 0 Hz f or b ot h air a n d b o ne c o n d ucti o n at 
all st u d y visits .  B ot h air a n d b o ne c o n d u cti o n t hres h ol ds will be assesse d.  P ure t o ne a vera gi n g 
b o ne a n d air c o n d ucti o n testi n g will be d o ne at 5 0 0, 1 0 0 0, a n d 2 0 0 0 Hz fre q ue ncies.  S u bjects 
weari n g heari n g ai ds s h o ul d be i nstr ucte d n ot t o wear t heir heari n g ai ds d uri n g t he a u di o gra m.  
A u di o metric assess me nts m ust be c o n d ucte d i n acc or da nce wit h A meri ca n -S peec h -La n g ua ge -
Heari n g Ass o ciati o n G ui deli nes ( A S H A, 2 0 0 5 ).  E q ui p me nt cali brati o n m ust be c urre nt a n d 
d oc u me nte d.  T he a u di o metric assess me nts m ust be c o n d ucte d b y a lice ns e d a u di ol o gist or a 
q ualifie d assista nt wit h a p pr o priate trai ni n g u n der t he direct s u per visi o n of a lice nse d 
a u di ol o gist.  
8. 3. 5.   
Ot osc o p y  
Ot osc o pic e x a ms will b e use d t o assess t he a u dit or y ca nal, t he a p peara nce of t he t y m pa ni c 
me m bra ne, a n d t h e heali n g of t he i ntrat y m p a nic i njecti o n site.  Ot osc o pic e x a mi nati o ns will be 
perf or me d i n b ot h ears at all st u d y visits d uri n g t h e st u d y b y t he p h ysici a n.  Prese nce a n d s ize of 
t y m pa nic me m bra ne p erf orati o ns will be rec or de d.  Perf orati o ns of t he t y m pa nic me m bra n e will 
be ca pt ur e d as A Es o nl y if t he perf orati o n i ncreas es i n size a n d d o es n ot res ol ve b y t he e n d of t he 
st u d y.  S u bjects weari n g heari n g ai ds s h o ul d be i nstr uct e d n ot t o wear t heir heari n g ai ds d uri n g 
t he ot osc o pic e x a m. 
8. 3. 6.   
C -S S R S Assess me nt  
T he C -S S R S assess me nt will be a d mi nistere d at all st u d y visits.  T he Bas eli ne versi o n will be 
use d at Visit 1 f or all s u bjects.  F or Visits 2 t hr o u g h 5 , t he Si nce Last Visit versi o n will be use d.  
A n y s u bject wit h a p ositi ve sc ore at o n t he Baseli ne versi o n or a n a p peara nce of a n y n e w s uici dal 
i deati o n or s uici de be h a vi or si nce t he Baseli ne v ersi o n s h o ul d be referre d t o t heir pri mar y care 
pr o vi der f or f oll o w -u p.  
If a s u bject h as a n y p ost -Scree ni n g C -S S R S sc ore of 1 -3 f or I deati o n (i.e., a “ yes” a ns wer t o 
Q uesti o ns 1, 2, or 3) or a “ yes” res p o nse t o t he N o n -S uici dal Self -I nj uri o us Be ha vi or q uesti o n) 
a n d t he sc ore is hi g her t h a n t he Scree ni n g C -S S R S sc ore, t he n t his assess me nt s h o ul d be 
rec or de d as a n A E.  T his i nf or mati o n is re p orte d as i n dicate d i n Secti o n  9 . ( P ossi ble A E ter ms: 
S uici dal pla ns, S uici dal i deati o n, S uici dal te n d e nc y, S uici dal be ha vi or, S uici dal i nte nti o n, 
S uici dal de pressi o n, Acti ve s uici dal i deati o n, Passi ve s uici dal i deati o n, Self -i nj uri o us be ha vi or 
wit h o ut s uici dal i nte nt).  
If a s u bject h as a n y p ost-Scree ni n g C -S S R S sc ore of 4 or 5 f or I deati o n (i.e., a “ yes” a ns wer t o 
q uesti o n 4 or 5) a n d/ or a n y q uesti o ns a ns were d yes f or S uici dal Be ha vi or ( wit h t he e x ce pti o n of 
a “ yes” res p o nse t o t he N o n -S uici dal Self -I nj uri o us Be ha vi or q uesti o n), a n d t his was n ot 
o bser ve d at Scree ni n g, t h e n t his assess me nt s h o ul d be rec or de d as a Seri o us A d verse E ve nt 
( S A E).  T his i nf or mati o n is re p orte d as i n dicate d i n Secti o n  9. 2. 2 . 


 
 
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9.   
A D V E R S E E V E N T R E P O R T I N G 
Ti mel y, acc urate, a n d c o m ple te re p orti n g a n d a nal ysis of safet y i nf or mati o n fr o m cli nical trials 
will be c o n d ucte d i n acc or da nce wit h G o o d Cli nical Practice.  
All A Es , i ncl u di n g seri o us a d verse e ve nts ( S A Es) re p orte d or o bs er ve d d uri n g or after d osi n g 
wit h t he st u d y dr u g will be rec or de d o n t he A E pa ge of t he e C R F f or all e nr olle d s u bjects.  
I nf or mati o n t o be c ollecte d i ncl u des descri pti o n  of e ve nt, date of o nset, i n v esti gat or-s pecifi e d 
assess me nt of t he se v erit y a n d relati o ns hi p t o st u d y dr u g, d ate of res ol uti o n of t he e ve nt, 
seri o us ness, a n y re q uire d treat me nt or e v al uati o ns, a n d o utc o me.  A d verse e ve nts res ulti n g fr o m 
c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt me dicati o ns, or 
pr o gressi o n of diseas e states m ust als o be re p orte d.  Perf orati o ns  of t he t y m pa nic me m bra ne will 
be ca pt ur e d as A Es o nl y if t he perf orati o n i ncreas es i n size a n d d oes n ot res ol ve b y t he e n d of t he 
st u d y. 
If t he e xisti n g me dical c o n diti o n w orse ns at a n y ti me after a p plicati o n of st u d y dr u g, it s h o ul d be 
rec or de d as a n A E. 
9. 1.   
A d verse E ve nt Cl assific ati o n Defi niti o ns  
A d verse E ve nt:  
A n A E is a n y u nfa v ora bl e a n d u ni nte n de d dia g n osis, s y m pt o m, si g n, s y n dr o me or disease w hic h 
occ urs d uri n g t he st u d y, ha vi n g b ee n a bs e nt at bas eli ne, or, if pres e nt at bas eli ne, a p pears t o 
w orse n.  
T hi s i ncl u des a n y o cc urre nce t hat is ne w i n o ns et or a g gra v ate d i n se verit y or fre q u e nc y fr o m t he 
baseli ne c o n diti o n, i ncl u di n g a b n or mal res ults of dia g n ostic pr o ce d ures a n d/ or la b orat or y test 
a b n or malities, w hic h are c o nsi dere d A Es if t he y:  
 res ult i n disc o nti n uati o n fr o m t he st u d y 
 re q uire tr eat me nt or a n y ot her t hera p e utic i nter ve nti o n 
 re q uire f urt her dia g n ostic e val uati o n (e x cl u di n g a re petiti o n of t he sa me pr o ce d ure t o 
c o nfir m t he a b n or m alit y)  
 are ass o ciate d wit h cli nical si g ns or s y m pt o ms j u d ge d b y t h e i n vesti gat or t o ha ve a 
si g nifica nt cli nical i m pact 
Seri o us A d verse E ve nt ( S A E):  
A n S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat:  
 res ults i n 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 i n w hic h t he 
s u bject was at ris k of d eat 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 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere.),  
 re q uires i n-p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
 res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y, or 


 
 
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 is a c o n ge nital a n o mal y/ birt h defect. 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d i n t he a b o ve defi niti o n.  T hese e ve nts 
s h o ul d be c o nsi dere d s eri o us. 
9. 1. 1.   
Assess me nt of Se verit y  
T he i n vest i gat or will assess t he i nte nsit y of t he A E a n d rate t h e A E as mil d, m o derate, or s e vere 
usi n g t he f oll o wi n g criteria:  
Gr a de 1 –  Mil d:  T hese e ve nts are easil y t olerate d, re q uire mi ni mal or n o treat me nt, a n d d o 
n ot i nterfere wit h t he s u bject’s dail y acti viti es.  
Gr a de 2 –  M o der ate:  T hese e ve nts ca use s uffici e nt disc o mf ort t o i nterfere wit h dail y 
acti vit y a n d/ or re q uir e a si m ple d ose of me dicati o n, e. g., a nal gesics or a nti -e metics. 
Gr a de 3 –  Se v ere:  T hes e e ve nts i nca p acitate a n d pre ve nt us ual acti vit y or re q uir e c o m ple x 
me dicati o n/treat me nt or h os pitalizati o n.  
Gr a de 4 –  Lif e T hre ate ni n g:  T hese e ve nts are t h ose f or w hic h t h e s u bject was at ris k of 
deat h at t he ti me of t he e ve nt rat her t h a n a n e v e nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d 
deat h if it were m ore se v e re. 
Gr a de 5 –  De at h:  T h e e ve nt res ulte d i n t he deat h of t he s u bject.  
C ha n ges i n t he s e verit y of a n A E s h o ul d be d o c u me nte d t o all o w f or a n assess me nt of t he 
d urati o n of t he e v e nt at eac h le vel of i nte nsit y t o b e perf or me d.  
9. 1. 2.   
Assess me nt of C a us alit y  
T he i n ve sti gat or’s assess me nt of a n A E’s relati o ns hi p t o st u d y dr u g will be part of t he 
d oc u me ntati o n pr ocess, b ut will n ot be a fact or i n deter mi ni n g w hat is or is n ot re p orte d i n t he 
st u d y.   
T he i n vesti gat or will assess t he relati o ns hi p or ass ociati o n of t he st u d y dr u g i n ca usi n g or 
c o ntri b uti n g t o t he A E, w hic h will be c haracterize d usi n g t he f oll o wi n g classificati o n a n d 
criteria:  
Defi nite:  A d verse e ve nts t hat, after caref ul me dical e val uati o n, are c o nsi dere d defi nitel y 
relate d t o t he st u d y dr u g; ot her c o n diti ons (c o nc urre nt ill ness, pr o gressi o n/e x pressi o n of 
disease state, or c o nc urre nt me dicati o n reacti o n) d o n ot a p pear t o e x plai n t he e ve nt.  
Pr o b a ble:  A d verse e ve nts t hat, after caref ul me dical e val uati o n, are c o nsi dere d wit h a hi g h 
de gree of certai nt y t o be re late d t o t he st u d y dr u g.  T he f oll o wi n g c haracteristics will a p pl y: 
 a reas o n a ble te m p or al rel ati o ns hi p e xists bet wee n t he e ve nt a n d e x p os ure t o t he st u d y 
dr u g, a n d  
 t he e ve nt is a k n o w n reacti o n t o t he st u d y dr u g t hat ca n n ot be e x plai ne d b y a n 
alter nati ve c a use c o m m o nl y occ urri n g i n t he p o p ulati o n/i n di vi d ual, or  


 
 
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 t he e ve nt is n ot a k n o w n reacti o n t o t he st u d y dr u g b ut ca n n ot be reas o na bl y 
e x plai ne d b y a n alter nati ve ca use.  
P ossi ble:  A d verse e v e nts t hat, after caref ul me dical e val uati o n, d o n ot meet t he criter ia f or a 
defi nite or pr o ba bl e rel ati o ns hi p t o t he st u d y dr u g, b ut f or w hic h a c o n necti o n ca n n ot be r ule d 
o ut wit h certai nt y.  T he f oll o wi n g c haract eristics will a p pl y:  
 t he e ve nt occ urs aft er e x p os ure t o t he st u d y dr u g, a n d 
 t here is a reas o na bl e te m p oral relati o ns hi p t o t he a p plicati o n, b ut t he e ve nt is n ot a 
k n o w n reacti o n t o t he st u d y dr u g a n d c o ul d be e x plai ne d b y a c o m m o nl y occ urri n g 
alter nati ve ca use, or  
 i n t he a bse nce of a reas o na ble te m p oral relati o ns hi p, t he e ve nt ca n n ot b e e x plai ne d b y 
a n alter nat i ve ca use. 
N ot rel at e d:  A d verse e v e nts i n t his cate g or y will ha ve eit her of t he f oll o wi n g c h aracteristics:  
 t he e ve nt d oes n ot ha ve a reas o na bl e te m p oral relati o ns hi p t o st u d y dr u g 
a d mi nistrati o n a n d/ or ca n be e x plai ne d b y a c o m m o nl y occ urri n g alter nati v e c a use.  
9. 1. 3.   
F oll o w u p of A d verse E ve nts  
T he i n vesti gat or will f oll o w a n o n -seri o us A E u ntil res ol uti o n, sta bilizati o n, or t he E n d of St u d y 
Visit.  T he i n vesti gat or will f oll o w a n S A E (re gar dless of relati o ns hi p t o st u d y dr u g) u ntil t he 
e ve nt res ol ves, sta bilizes , or bec o mes n o n-seri o us.  All A Es i de ntifie d o n t he last sc he d ule d 
c o ntact m ust be rec or de d o n t he A E pa ge of t he e C R F a n d t he c urre nt stat us ( o n g oi n g or 
res ol ve d) will be n ote d.  I n a d diti o n, S A Es will be re p orte d t o Pr o d uct Safet y acc or di n g t o t he 
re p orti n g g ui deli nes i de ntifie d i n Secti o n  9. 2. 2 . 
9. 2.   
M o nit ori n g of A d verse E ve nts  
9. 2. 1.   
All A d verse E ve nts  
All A Es will be a nal yze d f or safet y.  T h ose meeti n g t he d efi niti o n of S A E m ust be re p orte d usi n g 
t he S A E F or m.  S u bjects s h o ul d v ol u ntaril y re p ort a n y A Es or re p ort A Es i n res p o nse t o ge n eral, 
n o n -directe d q uesti o ni n g (e. g., " H o w has y o ur healt h bee n si nce t he last visit?").  F or eac h A E 
v ol u nteere d b y t he s u bj ect, t he i n vesti gat or s h o ul d o btai n all t he i nf or mati o n re q uire d t o 
c o m plete t he A E pa ge of t he e C R F, i n acc or da n ce wit h t he g ui deli nes t hat acc o m pa n y it.  
All A Es, re gar dl ess of seri o us ness, se verit y, or pres u me d relati o ns hi p t o st u d y t hera p y, m ust be 
rec or de d usi n g me dical t er mi n ol o g y i n t he s o urce d oc u me nt a n d o n t he e C R F.  W he ne ver 
p ossi ble, dia g n oses s h o ul d be gi v e n w he n si g ns a n d s y m pt o ms are d u e t o a c o m m o n eti ol o g y 
(e. g., c o u g h, r u n n y n os e, s neezi n g, s ore t hr oat, a n d hea d c o n gesti o n s h o ul d be re p orted as " u p per 
res pirat or y i nf ecti o n").  I n vesti gat ors m ust rec or d o n t he e C R F t heir o pi ni o n c o ncer ni n g t he 
relati o ns hi p of t he A E t o st u d y t hera p y.  All meas ures re q uire d f or A E ma na ge me nt m ust be 
rec or de d i n t he s o urce d o c u me nt a n d re p orte d acc or di n g t o s p ons or i nstr ucti o ns.  
A n y n o n -seri o us A E t hat occ urs after t he d os e of st u d y dr u g m ust be re p orte d i n detail o n t he 
a p pr o priate e C R F pa ge a n d f oll o we d u ntil res ol uti o n, sta bilizati o n, or t he E n d of St u d y Visit.  
T he descri pti o n of t he A E will i ncl u de descri pt i o n of e ve nt, date of o nset, date of res ol uti o n, 


 
 
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i n vesti gat or assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g, seri o us n ess, a n y re q uire d 
treat me nt or e v al uati o ns, a n d o utc o me.  
T he s p o ns or ass u mes res p o nsi bilit y f or a p pr o priate re p orti n g of A Es t o t h e re g ulat or y a ut h orities.  
T he s p o ns or will als o re p ort t o t he i n vesti gat ors all seri o us A Es t hat are u nliste d a n d ass ociate d 
wit h t he use of t he dr u g.  T he i n vesti gat ors m ust re p ort t hese e ve nts t o t he a p pr o priate Researc h 
Et hics C o m mittee  (R E C ) i n acc or da nce wit h l ocal re g ulati o ns.  
9. 2. 2.   
Seri o us A d verse E ve nts  
All S A Es occ urri n g d uri n g cli nical trials m ust be re p orte d wit hi n 2 4 h o urs t o Pr o d uct Safet y.  
T he ca us e of deat h of a s u bject i n a cli nical trial, w het her t he e ve nt is e x pecte d or ass oci ate d wit h 
t he i n vesti gati o nal a ge nt, is a n S A E. 
T he i nitial re p ort of a n S A E ma y be ma de b y t ele p h o ne, e -mail or facsi mile (fa x).  T he 
i n vesti gat or m ust pr o vi de t he mi ni mal i nf or mati o n: i.e., pr ot oc ol n u m ber, s u bject's i nitials a n d 
date of birt h, s u bject n u m ber or me dicati o n c o de n u m ber, nat ure of t he A E a n d i n vesti gat or's 
attri b uti o n.  
All oral re p orts of a n S A E m ust be c o nfir me d wit hi n 2 4 h o urs b y a writte n, m ore detaile d re p ort 
a n d si g ne d b y t he i n vesti gat or.  F or t his p ur p os e, t he s p o ns or will pr o vi de t he i n vesti gat or wit h 
t he Seri o us A d verse E ve nt F or m f or Cli nical Trials. 
All S A Es t hat ha ve n ot res ol ve d b y t he e n d of t h e st u d y, or t hat ha ve n ot res ol ve d u p o n 
disc o nti n uati o n of t he s u bject's p artici pati o n i n t he st u d y, m ust be f oll o we d u ntil eit her:  
 t he e ve nt res ol v es, 
 t he e ve nt sta bilizes, or  
 t he e ve nt bec o mes n o n-s eri o us 
T he i n vesti gat or s h o ul d r e p ort a n y f oll o w -u p i nf or mati o n as it bec o mes a vaila ble.  
9. 2. 3.   
Pre g n a ncies  
Pre g n a ncies o cc urri n g aft er t he first d ose of i n vesti gati o nal pr o d uct a n d d uri n g partici pati o n of 
t he st u d y are c o nsi dere d i m me diatel y re p orta ble e v e nts.  W hile n ot c o nsi dere d a S A E u nless a 
seri o us criteri o n is met, pre g na nci es occ urri n g i n s u bjects e nr olle d o n t he st u d y m ust be re p orte d 
a n d f oll o we d t o o utc o me.  T he i n vesti gat or s h o ul d c o m plete t he pre g n a nc y re p ort e C R F wit hi n 
o ne w or ki n g da y of k n o wle d ge of t he pre g na n c y.  F oll o wi n g d eli ver y or ter mi nati o n of 
pre g na nc y, t h e f oll o w -u p pre g na nc y re p ort f or m s h o ul d be c o m plete d o n t h e pre g na n c y C R F.  
S p o nta ne o us a b orti o ns s h o ul d al wa ys be re p orte d as S A Es.  F oll o w -u p i nf or mati o n re gar di n g t he 
o utc o me of t he pre g na nc y a n d a n y p ost natal se q u elae i n t he i nfa nt will be re q uire d.  
9. 3.   
C o nt acti n g S p o ns or Re g ar di n g S afet y  
A n y A E c o nsi dere d seri o us b y t he i n vesti gat or, or  t hat meets t he S A E criteria state d i n t his 
pr ot oc ol, m ust be re p orte d t o Pr o d uct Safet y wit hi n 2 4 h o urs fr o m t he ti me t hat st u d y site 
pers o n nel first lear ns of t he e ve nt.  T he st u d y site m ust e nter t he S A E i nt o t he E D C s yste m.  


 
 
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S o urce d oc u me nts will b e re q uest e d fr o m t he st u d y sites f or S A Es a n d s h o ul d be pr o vi de d t o 
Pr o d uct Safet y.  If t he s u bject is h os pitalize d d uri n g t he st u d y, a c o p y of t he h os pital disc har ge 
s u m mar y s h o ul d be pr o vi de d t o t he Pr o d uct Safet y as s o o n as it bec o mes a v aila 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 pl eti o n 
S t u d y su bj ect  partici p ati o n is c o m plete after Visit 5.   S u bject s w h o wit h dra w t heir c o nse nt t o be 
f oll o we d or are l ost-t o-f oll o w-u p bef ore c o m pleti o n of Visit 5 ( Wee k 1 2) will n ot be c o nsi dere d 
t o ha ve c o m plete d t he st u d y. 
1 0. 2.   
Wit h dr a w al  
All s u bjects ha v e t he ri g ht t o wit h dra w fr o m st u d y e val uati o ns at a n y ti me, f or a n y reas o n, 
wit h o ut prej u dice; n o net heless, i n vesti gat ors s h o ul d atte m pt t o e nc o ura ge s u bjects t o c o m plete 
t he pr ot oc ol s o t hat c o nti n ue d o bser vati o n a n d f oll o w-u p meas ure me nts ma y be o bt ai ne d .  T he 
i n vesti gat or ma y disc o nti n ue a s u bject’s p artici pati o n i n t he st u d y at his/ her discreti o n f or 
reas o ns i ncl u di n g, b ut n ot li mite d t o, t he f oll o wi n g: 
1.  S u bject e x perie nces a s eri o us or i nt olera ble A E t h at, i n t he o pi ni o n of t he i n vesti gat or, 
re q uires wit h dr a wal fr o m t he st u d y. 
2.  S u bject is i n vi olati o n of t he pr ot oc ol.  
3.  S u bject de vel o ps a c o n diti o n d uri n g t he c o urse of t he st u d y t hat ma kes it u n wise t o 
c o nti n ue wit h t he trial.  
4.  S u bject re q uires a m e dicati o n t hat is pr o hi bite d b y t he pr ot o c ol.  
5.  S u bject re q uests a n earl y disc o nti n uati o n f or a n y reas o n. 
At a n y p oi nt, t he i n vesti gat or ma y disc o nti n ue t he s u bject’s st u d y p artici pati o n at his/ her 
discreti o n a n d e ns ure t he s u bject recei ves a p pr o pri ate me dical care; t he i n vesti gat or ma y als o 
c o ns ult t he me dical  m o nit or t o disc uss o ut -of -ra n ge test res ults. 
1 0. 2. 1.   
H a n dli n g of Wit h dr a w als  
S u bjects will be free t o wit h dra w fr o m st u d y dr u g a d mi nistrati o n a n d f urt her f oll o w -u p t he st u d y 
at a n y ti me.  S u bject partici pati o n i n t he st u d y ma y be st o p p e d at a n y ti me at t he discr eti o n of t he 
i n vesti gat or or at t he re q uest of t he s p o ns or. 
W he ne ver p ossi ble, all s u bjects w h o wit h dra w fr o m st u d y dr u g a d mi nistrati o n s h o ul d be 
e nc o ura ge d t o re m ai n o n -st u d y f or f urt her f oll o w-u p t hr o u g h t he s u bject last sc he d ule d visit.  
H o we ver, s h o ul d  a re q u est f or earl y wit h dra wal fr o m t he st u d y wit h n o f urt her f oll o w -u p b e 


 
 
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ma de, t he s u bject s h o ul d be e nc o ura ge d t o ret ur n t o t he st u d y site f or a last f oll o w u p visit a n d  
u n der g o all e n d of st u d y/ earl y ter mi nati o n ass ess me nts.  
W he n a s u bject wit h dra ws  fr o m a d mi nistrati o n of st u d y dr u g or t he st u d y pri or t o c o m pleti n g 
Visit 5 ( Wee k 1 2), t he reas o n f or wit h dra wal is t o be d oc u me nte d o n t he e C R Fs a n d i n t he s o urce 
d oc u me nt.   
1 0. 2. 2.   
Re pl ace me nts  
S u bjects w h o disc o nti n ue partici pati o n i n t he st u d y f or a n y reas o n after d osi n g will n ot be 
re place d. 
1 1.   
S T A TI S TI C A L M E T H O D S  
T he pri mar y o bjecti ve of t his P hase 3  st u d y is t o test t he h y p ot hesis t hat s u bjects ra n d o mize d t o 
O T O -1 0 4 will de m o nstrate fe wer  defi niti ve verti g o da ys  ( D V D) t ha n s u bjects ra n d o mize d t o 
place b o at We e k 1 2 (t he 4 -wee k  ( 2 8-da y)  i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2).  T he 
sec o n dar y o bj ecti ve of t h e st u d y is t o descri be t he safet y pr ofile of a 1 2  m g d ose of O T O -1 0 4 
c o m pare d t o place b o w he n a d mi nistere d as a si n gle i ntrat y m pa ni c i njecti o n i n s u bjects wit h 
Me niere’s dis ease.  
T he f oll o wi n g statistical secti o ns descri be t h e ge n eral a nal ytic m et h o ds t o be i m ple me nte d t o 
assess t he o verall st u d y o bjecti ves.  M ore det aile d descri pti o ns of t he met h o d ol o g y will be 
pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P).  T he S A P will be pre pare d a n d fi nalize d bef ore 
u n bli n di n g t he s u bjects’ ra n d o mize d treat me nt assi g n me nts.  
1 1. 1.   
S a m ple Size  
T he tar get t otal sa m ple si ze f or t he st u d y is 1 6 0  ra n d o mize d wit h 1: 1 all ocati o n,  8 0  i n eac h 
treat me nt gr o u p stratifie d b y ge n d er.  T he sa m ple size esti mate was c h ose n t o ac hie ve m ore  t ha n 
9 0 % p o wer wit h si g nifica nce le vel of 0. 0 5 t w o -si de d t o reject t he n ull h y p ot hesis of n o treat me nt 
differe n ce f or t he pri mar y e n d p oi nt of D V D.  
T he p o wer esti mate was base d o n t he esti mate d treat me nt mea n s f or D V D at Wee k 1 2 (t he 4-
wee k ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2) fr o m t he rece ntl y c o m plete d P hase 2 b 
trial i n t his i n dicati o n.  T he O T O-1 0 4 a n d place b o treat me nt gr o u ps recei v e d a si n gle d ose of t he 
st u d y dr u g at D a y 1.  I n t he 2 b trial, the O T O -1 0 4 treat me nt gr o u p recei v e d t he sa me d ose as will 
be e val uat e d i n t his P hase 3 st u d y.   A P oiss o n ge neralize d li near re gressi o n m o del was use d t o 
esti mate t he mea n n u m ber of D V D f or t he O T O -1 0 4 a n d place b o gr o u ps d uri n g t he pri mar y 
e n d p oi nt 4 -wee k st u d y i nter val.  T he m o del i ncl u d e d treat me nt gr o u p as a fact or (cate g orical), 
a n d t he lea d-i n p eri o d as a c o vari ate.  A n offset f or t he n u m ber of diar y e ntries rec or de d f or t hat 
4 -wee k i nter val (i nter val fr o m Wee k 9 t hr o u g h 1 2) was i ncl u de d f or eac h s u bject t o acc o u nt f or 
missi n g diar y e ntries .  T h e n u m ber of lea d-i n peri o d D V D was a dj uste d t o 2 8 da ys.  T h e m o del 
was als o a dj uste d f or o ver -dis persi o n usi n g t h e Pears o n resi d uals as t he scale fact or.  T he 
esti mate d mea n n u m ber of D V D f or t he O T O -1 0 4 a n d  place b o gr o u ps were 4. 5 a n d 2. 1, 
res pecti vel y wit h a n esti mate d mea n differe n ce of (acti ve –  pl ace b o) -2. 4 da ys, a dj uste d f or lea d -
i n peri o d n u m ber of D V D.  T he m o del resi d ual v aria nce was 4. 7 9.  F or t he p ur p ose of t he sa m ple 
siz e calc ulati o n t he resi d ual varia nce a n d tr ue mea n differe nce was c o nsi dere d as 5. 0 a n d 2. 2, 
res pecti vel y. 


 
 
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1 1. 2.   
A n al ysis Sets  
T he f oll o wi n g d efi niti o ns will be use d t o deri ve t h e a nal ysis sets f or t his st u d y.    
F ull A n al ysis Set ( F A S):   T he f ull a nal ysis set will i ncl u de all s u bjects w h o are ra n d o mize d, 
recei v e st u d y dr u g, ha ve a baseli ne defi niti ve verti g o meas ure me nt  f or t he 4-wee k lea d -i n 
peri o d a n d at least o ne 4 -wee k defi niti ve verti g o meas ure me nt  p ost -b aseli ne.   T he pri mar y 
a nal ysis f or t he pri mar y e n d p oi nt of D V D  will be c o n d ucte d usi n g t he F A S.  S u bjects will be 
i ncl u de d i n t he treat me nt gr o u p t o w hi c h t he y were ra n d o mize d re gar dless of t he act ual st u d y 
dr u g recei ve d.  
C o m pleters A n al ysis Set:   T he c o m plet ers a n al ysis set will i ncl u de all s u bjects w h o are 
ra n d o mize d, receive st u d y dr u g, a n d ha v e all baseli ne a n d p ost -baseli ne d efi niti ve verti g o 
meas ure me nts f or eac h 4 -wee k st u d y i nter val.  S u bjects will be i ncl u de d i n t he treat me nt 
gr o u p t o w hi c h t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d.  
Per Pr ot oc o l A n al ysis Set:  T he p er pr ot o c ol a nal ysis set will i ncl u de all s u bjects w h o are 
ra n d o mize d, recei ve st u d y dr u g, m eet eli gi bilit y criteria, ha ve n o maj or pr ot oc ol de viati o ns,  
a n d ha ve a baseli ne a n d at least o ne 4 -wee k defi niti ve verti g o m eas ure me nt p ost -baseli ne.  
S u bjects will be i ncl u de d i n t he treat me nt gr o u p of t he act ual st u d y dr u g recei ve d.  
I nte nt-t o-Tre at A n al ysis Set (I T T):  T he I T T a n al ysis set will i ncl u de all ra n d o mize d 
s u bjects w h o recei ve st u d y dr u g.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p t o w hi c h 
t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d. 
S afet y A n al ysis Set:   T he safet y a nal ysis set will i ncl u de all s u bjects w h o recei ve st u d y 
dr u g.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p acc or di n g t o t he act ual tr eat me nt 
recei v e d re gar dless of t h eir ra n d o mize d assi g n me nt.  W he n t he ear is t he u nit of a nal ysis, t he 
safet y a n al ysis will cat e g orize a n ear b y w het her it was a treate d or a n u ntreate d ear, 
irres pecti ve of w het h er it was t he affect e d ear. 
1 1. 3.   
Descri pti o n of S u b gr o u ps t o be A n al yze d  
Descri pti ve a n al ys es will be perf or me d f or t h e pri mar y effi cac y e n d p oi nt f or t he f oll o wi n g 
s u b gr o u ps usi n g t he F A S wit h details pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P ): 
 S u bject De m o gra p hics  
 Ge n der  
 Race/ Et h nicit y  
 A ge (cate g ories:  1 8-3 0, 3 1 -4 0, 4 1 -6 0, > 6 1 yrs.)  
 Baseli ne Disease C haracteristics  
 D urati o n of Me niere’s Disease  
 Pre vi o us i ntrat y m pa nic st er oi d i njecti o n f or Me ni ere’s Disease  
 De gree of heari n g l oss  


 
 
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1 1. 4.   
S u bject De m o gr a p hics, B aseli ne Dise ase St at us, a n d Dis p ositi o n  
Descri pti ve statistics f or s u bject de m o gra p hics, baseli ne disease stat us, a n d s u bject dis p ositi o n 
will be pr o vi de d.   
1 1. 5.   
Effic ac y E v al u ati o ns  
1 1. 5. 1.   
Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt is t he n u m ber of  defi niti ve verti g o d a ys ( D V D) at Wee k 1 2  (t he 4-
wee k  ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2).  A D V D is defi ne d as eac h d a y t he 
s u bject rec or de d a v erti g o e pis o de lasti n g at least 2 0 mi n utes a n d c orres p o n ds t o a Verti g o Sc ore 
of 2 or m ore.  If m ulti ple e pis o des occ ur o n a gi ve n da y, o nl y t he w orst e pis o de i n ter ms of sc ore 
s h o ul d be rec or de d.   
1 1. 5. 2.   
Sec o n d ar y Effic ac y E n d p oi nts  
Sec o n dar y Efficac y E n d p oi nt:  
 T he n u m ber of defi niti ve verti g o d a ys ( D V D) at Wee k 8 [t he 4 -wee k ( 2 8 -da y) i nter val 
fr o m Wee k 5 t hr o u g h Wee k 8] 
 T he n u m ber of defi niti ve ver ti g o d a ys ( D V D) at Wee k 4 [t he 4-wee k ( 2 8 -da y) i nter val 
fr o m Wee k 1 t hr o u g h Wee k 4] 
 T he c ha n ge fr o m bas eli ne i n verti g o fre q u e nc y ( V F) d uri n g t he 4 -wee k st u d y i nter val 
(W ee k 9 t hr o u g h W ee k 1 2), w here verti g o fre q ue n c y is defi ne d as t he pr o p orti o n of da ys 
d uri n g t he 4 -wee k i nter val w here a defi niti ve verti g o e pis o de was rec or de d di vi de d b y t he 
n u m ber of n o n -missi n g diar y e ntries f or t he rele va nt i nter val  
 T he c ha n ge fr o m bas eli ne wit h res pect t o se verit y of verti g o e pis o des as m eas ure d b y t h e 
mea n Verti g o Sc o re d uri n g t he 4 -wee k st u d y i nter val ( Wee k 9 t hr o u g h Wee k 1 2 )  
 T he c ha n ge fr o m bas eli ne i n a vera ge dail y c o u nt of verti g o e pis o des, d uri n g t he 4 -wee k 
st u d y i nter val (W ee k 9 t hr o u g h W ee k 1 2)  
 Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d 
Be d ri d d e n e ve nts as a c o nse q ue nce of verti g o at W ee k 1 2  
 S F -3 6 at Wee k  1 2  
o  P h ysical H ealt h S u m mar y Meas ure  
o  Me ntal Healt h S u m mar y Meas ure  
o  8 Scales  
1 1. 5. 3.   
E x pl or at or y Effic ac y E n d p oi nts  
E x pl orat or y Effi cac y E n d p oi nt s are: 
 T he c ha n ge fr o m bas eli ne i n verti g o fre q u e nc y ( V F) d uri n g eac h 4 -wee k st u d y i nter val 
(W ee k 1 t hr o u g h W ee k 4) a n d ( W ee k 5 t hr o u g h W ee k 8), w here verti g o fre q ue nc y is 
defi ne d as t he pr o p orti o n of da ys d uri n g t he 4 -wee k i nter val w here a d efi niti ve verti g o 
e pis o de was rec or de d di vi de d b y t he n u m b er of n o n -missi n g diar y e ntri es f or t he rele va nt 
i nter val 


 
 
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 T he c ha n ge fr o m bas eli ne wit h res pect t o se verit y of verti g o e pis o des as m eas ure d b y t h e 
mea n Verti g o Sc ore d uri n g eac h 4 -wee k st u d y i nt er val ( Wee k 1 t hr o u g h  W ee k 4) a n d 
(W ee k 5 t hr o u g h 8)   
 T he c ha n ge fr o m bas eli ne i n a vera ge dail y c o u nt of verti g o e pis o des,  d uri n g eac h 4 -wee k 
st u d y i nter val (W ee k 1 t hr o u g h W ee k 4) a n d (W ee k 5 t hr o u g h W ee k 8)  
 Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d 
Be d ri d d e n e ve nts as a c o nse q ue nce of verti g o at W ee k 4 a n d W ee k 8  
 S F -3 6 at Wee ks 4 a n d 8  
o  P h ysical H ealt h S u m mar y Meas ure  
o  Me ntal Healt h S u m mar y Meas ure  
o  8 Scales  
 Ti n nit us F u ncti o nal I n d e x ( T FI)  at Wee ks 4, 8, a n d 1 2  
Details re gar di n g i m p utati o n of missi n g data, i ncl u di n g ite ms f or q uesti o n naires, will be 
pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P).  
1 1. 5. 4.   
A n al ytic Met h o ds f or Effic ac y  
T he pri mar y efficac y e n d p oi nt is t he n u m ber of D V D at Wee k 1 2 (t he 4 -wee k ( 2 8-d a y) i nter val 
fr o m Wee k 9 t hr o u g h Wee k 1 2).  P oiss o n re gressi o n m o del will be  use d t o esti mate a n d c o m pare 
t he mea n n u m ber of D V D f or O T O-1 0 4 a n d place b o gr o u ps d uri n g t he pri mar y e n d p oi nt 4 -wee k 
st u d y i nter val.  T h e m o del will i ncl u de  treat me nt gr o u p ( O T O-1 0 4 vs. pl ace b o) a n d ge n d er as 
fact ors (cate g orical), a n d t he lea d-i n peri o d as a c o variate.  A n offset f or t he n u m ber of diar y 
e ntries rec or de d f or t hat 4 -wee k i nter val (i nte r val fr o m Wee k 9 t hr o u g h 1 2) will be i ncl u de d f or 
eac h s u bj ect.  T he n u m ber of lea d -i n p eri o d D V D will be a djuste d t o 2 8 da ys.  T he m o d el will 
als o a dj ust  f or o ver-dis persi o n usi n g Pears o n resi d uals  as t he scale fact or.  
T he pri mar y a n al ysis p o p ulati o n f or t he c o m paris o n of t he pri mar y e n d p oi nt bet wee n t he 
treat me nt gr o u ps i n t his st u d y is f ull a nal ysis set ( F A S).   S u bjects will be i ncl u de d i n t he 
treat me nt gr o u p t o w hic h t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d. 
T he pri mar y e n d p oi nt a n al ysis als o will be c o n d u cte d usi n g p er -pr ot oc ol, I T T, a n d c o m pleters 
a nal ysis s ets as se nsiti vit y a n al ys es.   
If a s u bject h as n o rec or de d diar y data f or t he  Verti g o Se verit y Sc ore d uri n g  Wee k 1 2 i nter val 
t he n a n i m p utati o n met h o d w hic h will be s pecifie d i n t he S A P will be use d.  
T he sec o n d ar y efficac y e n d p oi nts of n u m ber of D V D  d uri n g 4 -wee k st u d y i nter val ( Wee k 1 
t hr o u g h Wee k 4) a n d (W ee k 5 t hr o u g h Wee k 8)  will be c o m pare d bet w ee n t he treat me nt gr o u ps  
se parat el y usi n g t he s a me P oiss o n re gressi o n m o del s pecifie d f or t he pri mar y e n d p oi nt.  
T he sec o n d ar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n verti g o fre q ue n c y ( V F) at Wee k 1 2 
(t he 4-wee k i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2), will be  c o m pare d bet wee n t he treat me nt 
gr o u ps usi n g a n al ysis of c o varia n ce ( A N C O V A) .  T he m o del will c o ntai n treat me nt gr o u p 
( O T O-1 0 4  vs. place b o)  a n d ge n d er as fact ors (cate g orical) a n d b aseli ne verti g o fre q ue n c y  as a 
c o variate.   


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
3 9   
 
T he sec o n d ar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n se verit y of verti g o d uri n g 4 -wee k 
st u d y i nter val (W ee k 9 t hr o u g h Wee k 1 2 ) will be c o m pare d bet w ee n  t he treat me nt gr o u ps usi n g 
A N C O V A  i ncl u di n g treat ment gr o u ps, ge n d er, a n d  se verit y sc ore at baseli ne as a c o v ariat e. 
T he sec o n d ar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n a vera ge d ail y c o u nt of verti g o 
e pis o des, d uri n g 4 -wee k st u d y i nter val ( W ee k 9 t hr o u g h W ee k 1 2) will be c o m pare d bet wee n t he 
treat me nt gr o u ps usi n g A N C O V A i ncl u di n g treat me nt gr o u ps, ge n der, a n d a vera ge dail y c o u nt of verti g o 
e pis o de  at baseli ne  as a c o variate .  
T he sec o n d ar y e n d p oi nt of o cc urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, 
Sic k at h o me, a n d Be d ri d de n e ve nts as a c o nse q u e nce of verti g o at W ee k 1 2 will be c o m pare d 
bet wee n t he treat me nt gr o u ps usi n g Ma ntel -Hae ns zel R o w Mea n Sc ores stratifie d b y ge n der.  
Alter nati ve m o dels will be pre -s p ecifie d i n t he S A P s h o ul d certai n ass u m pti o n s re gar di n g data 
a n d m o dels d o n ot h ol d .  I n a d diti o n, t he S A P will i ncl u de pre-s p ecifie d d at a tra nsf or m ati o ns 
s h o ul d e val uati o n of t he resi d uals s u g gest a data tra nsf or mati o n is m ore s uita ble. 
If t he pri mar y e n d p oi nt c o m paris o n bet wee n t h e t w o treat me nt gr o u ps is statisticall y si g nifica nt 
i n fa v or of O T O-1 0 4 t he n a cl ose d testi n g, gate -k ee pi n g pr oce d ure  will be use d t o c o m pare t h e 
f oll o wi n g sec o n dar y effi cac y e n d p oi nts se q ue ntiall y:  
1.  T he n u m ber of D V D at Wee k 8 [t he 4 -wee k ( 2 8 -da y) i nter val fr o m Wee k 5 t hr o u g h 
Wee k 8]  
2.  T he n u m ber of D V D at Wee k 4 [t he 4 -wee k ( 2 8 -da y) i nter val fr o m Wee k 1 t hr o u g h 
Wee k 4]  
I n t his pr oce d ure if t he first sec o n dar y e n d p oi nt c o m paris o n bet wee n t h e t w o treat me nt gr o u ps is 
statisticall y si g nifica nt i n fa v or of O T O-1 0 4 t he n t he sec o n d sec o n dar y  e n d p oi nt  will be 
c o m pare d a n d teste d.  If t he c o m paris o n of t he first sec o n dar y e n d p oi nt is n ot statisticall y 
si g nifica nt i n fa v or of O T O-1 0 4 t he n t he re p orte d p -val ue f or t h e sec o n d s ec o n dar y e n d p oi nt will 
be c o nsi dere d as a n o mi n al p -val ue.  
T he re mai ni n g sec o n dar y e n d p oi nts c o m paris o n will n ot f oll o w  t he gate kee pi n g pr oce d ure a n d 
t heref ore t he re p orte d p-val ues will be re p orte d as n o mi nal p -val ues.  T his pr oce d ure c o ntr ol s t he 
st u d y-wise T y p e I err or.  Si nce t he st u d y -wise err or is mai ntai ne d wit h t he a b o ve pr oce d ure, 
t here is n o α pe n alt y ass o ciate d wit h it.  All efficac y h y p ot hesis tests will be 2-si de d a n d 
perf or me d at α = 0. 0 5 si g nifica nce l e vel . 
1 1. 6.   
S afet y E v al u ati o ns  
Saf et y e n d p oi nts t o be e x a mi ne d i ncl u de:  
 Vital Si g ns, Hei g ht a n d Wei g ht Meas ure me nts  
 Cli nical La b orat or y Test  
 T y m pa n o metr y  
 A u di o metr y  
 Ot osc o p y  
 C -S S R S Assess me nt  


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
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 C o nc o mita nt Me dicati o ns  
 A d verse e ve nts  
Descri pti ve statistical ta b ulati o ns will be prese nte d f or  all s u bjects i ncl u de d i n t he Safet y 
A nal ysis Set.  
1 1. 6. 1.   
A d verse E ve nts  
T he c urre nt versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), as i n dicate d i n 
t he Data Ma n a ge me nt Pla n, will be use d t o c o de all A Es. 
T he pri mar y a n al ysis of A Es will c o nsi de r o nl y treat me nt-e mer ge nt A Es, e ve nts occ urri n g f or 
t he first ti me, or w orse ni n g d uri n g or after t he first d ose of st u d y dr u g.  S u bject i nci de nce of 
T E A Es a n d S A Es will be ta b ulate d b y preferre d ter ms a n d s yste m or ga n class.  Se verit y a n d 
relati o ns hi p t o st u d y dr u g will als o be prese nte d.  F or s u m mar y ta bles, a s u bject w h o e x perie nces 
t he sa me c o de d e ve nt m ore t ha n o nce is c o u nte d o nl y o ne ti me f or t hat c o de d e ve nt at t he hi g h est 
se verit y le vel.  A Es will be prese nt e d b y desce n di n g or der of fre q u e nc y i n Me d D R A s yste m 
or ga n class a n d preferre d ter m.  
S u b gr o u p a n al ys es f or a ge, race, a n d ge n der  will als o be e x a mi ne d pr o vi de d a reas o n a ble n u m ber 
of s u bjects i n eac h s u b gr o u p are a v aila ble f or a nal ysis.  Listi n gs of all S A Es, A Es lea di n g t o 
st u d y wit h dra wal, a n d deat hs o n -st u d y will als o be i ncl u de d.  D urati o n a n d o utc o me of eac h A E 
will be re p orte d i n s u bject listi n gs.   
A d verse e ve nts oc c urri n g d uri n g t he lea d -i n peri o d pri or t o e x p os ure t o st u d y dr u g will be 
re p orte d i n dat a listi n gs.  F urt her details will be pro vi de d i n t he S A P.  
1 1. 6. 2.   
Vit al Si g ns a n d L a b or at or y P ar a meters  
T he a nal ysis of vital si g ns a n d la b orat or y p ara m eters will i ncl u de descri pti ve statistics f or t he 
c ha n ge fr o m baseli ne t o t he e n d p oi nt visit, c ha n ge fr o m baseli ne f or eac h visit ( vital si g ns o nl y).  
W here a p pr o pri ate, a n al yses will als o i ncl u de s hifts fr o m baseli ne t o t he e n d p oi nt visit .  F or 
la b orat or y val u es, t he n or mal ra n ges will be use d t o deter mi ne t he cl assificati o ns. Val ues bel o w 
t he n or mal ra n ge will be classifie d as l o w, val u es a b o ve t he n or mal ra n ge will be classifie d as 
hi g h, a n d v al ues wit hi n t he n or mal ra n ge will be classifi e d as n or mal.  
1 1. 6. 3.   
Ot osc o pic E x a mi n ati o ns  
O bser vati o ns rec or de d d uri n g t he c o n d uct of ot os c o pic e x a ms will be descri pti ve i n nat ure.  T he 
n u m ber a n d perce nt of s u bjects prese nti n g wit h eac h Ot osc o pic classifi cati o n will be pr o vi de d b y 
treat me nt gr o u p a n d st u d y visit.  W here rel e va nt, t he n u m ber a n d pr o p orti o n of s u bjects wit h 
c ha n ges i n t heir o t osc o pi c classificati o n fr o m baseli ne t o t he e n d p oi nt visit will als o be pr o vi de d 
f or eac h treat me nt gr o u p.   
1 1. 6. 4.   
A u di o metr y Assess me nts  
Descri pti ve s u m mar y statistics f or a u d i o metric ass ess me nts of air a n d b o n e c o n d ucti o n 
t hres h ol ds at eac h fre q u e nc y will be pr o vi de d b y treat me nt gr o u p a n d st u d y visit.  I n a d diti o n, t he 
P T A c o m p ute d as t he a v era ge air c o n d u cti o n t hres h ol d f or t he 5 0 0, 1 0 0 0, a n d 2 0 0 0 Hz will als o 
be calc ul ate d.   


 
 
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Air -B o n e Ga p assess me nts at eac h fre q ue n c y f or treat me nt gr o u p a n d st u d y visit will be 
ta b ulate d as t he pr o p orti o n of s u bjects wit h air mi n us b o ne c o n d ucti o n t hres h ol ds of:   
1.  ≤ 1 0 d B or  
2.  > 1 0 d B.  
All a u di o metr y assess me nts will be ta b ulate d se paratel y f o r t he treate d a n d u ntreate d ear. 
1 1. 6. 5.   
T y m p a n o metr y  
S hift ta bles re prese nti n g t he pr o p orti o n of s u bjects wit h c ha n ges i n t heir t y m pa n o gra m fr o m 
baseli ne t o eac h p ost -bas eli ne st u d y visit will be calc ulate d f or eac h treat me nt gr o u p.  
T y m pa n o gra m c ha n ges will i ncl u de b ot h t he t y pe of t y m pa n o gra m ( A, B -s mall v ol u me a n d/ or 
n or mal, B -lar ge v ol u me, or C), as well as, w het her t he t y m pa n o gra m was j u d ge d t o b e n or mal or 
a b n or mal.  
1 1. 6. 6.   
C ol u m bi a - S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
T he C -S S R S  will be a d mi nistere d at eac h visi t usi n g t he a p pr o priat e versi o n i.e. Bas eli ne or 
Si nce Last Visit. A nal ysis of t his scale will be perf or me d o n t he Safet y A nal ysis Set.  
1 1. 6. 6. 1.  B aseli ne Versi o n  
T he Baseli ne versi o n of t he C -S S R S will be a d mi nistere d at t he Scree ni n g visit ( Visit 1). T his 
versi o n of t he scale ca pt ures b ot h s uici de i deati o n a n d s uici de be ha vi or (lifeti me). T here are 5 
s uici dal i deati o n q uesti o ns, eac h ca pt ure d as yes/ n o f or t he s u bject’s lifeti me. A d diti o nall y a 
si xt h s uici dal i deati o n varia ble will be create d t o i n dicate if t here was a n y i deati o n, re gar dless of 
t y pe. T h ere are 4 s ui ci dal be ha vi or q uesti o ns, eac h ca pt ure d as yes/ n o f or t h e s u bject’s lifeti me. 
A fift h s uici dal be ha vi or varia ble will be creat e d t o ca pt ure if t h ere was a n y s uici dal be ha vi or 
re gar dl ess of t y pe. A n a d ditio nal q uesti o n as ks if s uici dal be ha vi or is pres e nt d uri n g t he visit. All 
s uici dal i deati o n a n d be h a vi oral vari a bles as o utli ne d here will be ta b ulate d o verall a n d b y 
treat me nt gr o u p. All C-S S R S data will be i ncl u de d i n data listi n gs. T here is n o i ncl usi o n or 
e x cl usi o n criteri o n ass ociate d wit h t he Baseli ne C -S S R S sc ore.  S u bjects wit h a p ositi ve sc ore 
s h o ul d be referre d t o t heir pri mar y care pr o vi der f or f oll o w-u p.  
1 1. 6. 6. 2.  Si nce L ast Visit Versi o n  
T he Si nce Last Visit versi o n of t he C -S S R S will be a d mi nistere d at e ac h st u d y visit after t h e 
Scree ni n g visit ( Visit 1). T he sa me o verall i n di vi d ual varia bles f or s uici dal i deati o n a n d be ha vi or 
will be assesse d as i n t he Baseli ne v ersi o n. I n a d diti o n, o verall s uici dalit y ( yes/ n o) will be 
defi ne d as a n y s u bject ha vi n g a n y s uici dal i deati o n or be ha vi or si nce t he last visit. All s uici dal 
i deati o n a n d be ha vi or v aria bles will be ta b ulate d o verall a n d b y treat me nt gr o u p f or eac h st u d y 
visit. All C -S S R S data will be i ncl u de d i n data listi n gs.  
A n y s u bject wit h a n a p peara nce of a n y ne w s uici d al i deati o n or s uici de be h a vi or si nce Scree ni n g 
s h o ul d be referre d t o t heir pri mar y care pr o vi der f or f oll o w-u p.  
If a s u bject h as a n y p ost-Scree ni n g C -S S R S sc ore of 1 -3 f or I deati o n (i.e., a “ yes” a ns wer t o 
Q uesti o ns 1, 2, or 3) or a “ yes” res p o n se t o t he N o n-S uici dal Self -I nj uri o us Be ha vi or q uesti o n) 
a n d t he sc ore is hi g her t h a n t he Scree ni n g C -S S R S sc ore, t he n t his assess me nt s h o ul d be 


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
4 2   
 
rec or de d as a n A E . T his i nf or mati o n is re p orte d as i n dicate d i n Secti o n  9. 2. 1 .  ( P ossi ble A E 
ter ms: S uici dal pla ns, S uici dal i deati o n, S uici dal te n de nc y, S uici dal be ha vi or, S uici dal i nte nti o n, 
S uici dal de pressi o n, Acti ve s uici dal i deati o n, Passi ve s uici dal i d eati o n, Self-i nj uri o us be ha vi or 
wit h o ut s uici dal i nte nt).  
If a s u bject h as a n y p ost-Scree ni n g C -S S R S sc ore of 4 or 5 f or I deati o n (i.e., a “ yes” a ns wer t o 
q uesti o n 4 or 5) a n d/ or a n y q uesti o ns a ns were d yes f or S uici dal Be ha vi or ( wit h t he e x ce pti o n of 
a “ yes” res p o nse t o t he N o n-S uici dal Self -I nj uri o us Be ha vi or q uesti o n), a n d t his was n ot 
o bser ve d at Scree ni n g, t h e n t his assess me nt s h o ul d be rec or de d as a Seri o us A d verse E ve nt.  
T his i nf or mati o n is re p orte d as i n dicate d i n  Secti o n  9. 2. 2 . 
1 1. 7.   
H a n dli n g of Missi n g D at a, S u bject Wit h dr a w als, a n d Tre at me nt 
F ail ures  
I n a d diti o n t o t he pri mar y a n al ysis of t he  pri mar y e n d p oi nt , if nee de d s e veral se nsiti vit y a nal yses 
will als o be e val uate d.  T hese a nal ys es will be i ncl u de d i n t he S A P wit h a p pr o priate det ails pri or 
t o u n bli n di n g t he data bas e. 
T he S A P will i ncl u de greater detail r e gar di n g t he ha n dli n g of missi n g data as well as t he 
al g orit h ms f or s c ori n g t h e S F -3 6 , i ncl u di n g t he ha n dli n g of missi n g q u esti o n naire ite ms. 
E ver y eff ort will be ma d e t o f oll o w s u bjects f or st u d y o bser vati o n a n d e n c o ura ge c o m plia nce 
wit h st u d y meas ure me nts t o mi ni mize t he a m o u nt of missi n g data.  
E x ce pt f or partial dates, s afet y data will n ot be i m p ute d.  T he i m p utati o n al g orit h m f or p artial 
dates will be defi ne d i n t he S A P.  
1 1. 8.   
I nteri m A n al yses 
T here are n o f or mal i nteri m a nal yses pl a n ne d.  Bli n de d re vie w s of safet y data will be c o n d ucte d 
as descri be d i n Secti o n  1 4. 7 ; h o we ver, t he re vie w of s uc h data is n ot i nte n d e d t o i m pact t he st u d y 
c o n d uct u nless t here are safet y c o n cer ns.  As s u c h, it is e x pecte d t hat t he trial will c o nti n ue t o its 
sc he d ule d c o m pleti o n barri n g a n y u ne x pecte 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 Descri pti o n of St u d y Dr u g(s)  
T he i n vesti gati o nal dr u g pr o d uct a d mi nistere d t o s u bjects i n t his st u d y will be O T O -1 0 4 a n d 
place b o.  T he O T O -1 0 4 fi nal pr o d uct s us pe nsi o n f or  d osi n g will be pre pare d fr o m t w o se parate 
c o m p o ne nts, O T O -1 0 4 Dil ue nt ( o ne vial nee d e d) a n d O T O -1 0 4 Acti ve ( o ne vial nee de d). A n 
a p pr o priate v ol u me of O T O -1 0 4 Dil ue nt will be wit h dra w n a n d d eli vere d i nt o t he O T O -1 0 4 
Acti ve vial t o ac hie ve a vis uall y h o m o g e ne o us s us pe nsi o n of a tar get dr u g c o nce ntrati o n of 6 0 
m g/ m L.  Place b o will c o nsist of t he ve hicle use d t o f or m ulate O T O -1 0 4  a n d will be s u p plie d 
fr o m o ne vial ( O T O-1 0 4  Dil ue nt).  
T he f oll o wi n g dr u g s u p plies will be use d i n t he st u d y:  


 
 
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Pr o d uct  
S u p plie d as:  
O T O -1 0 4  
A kit c o ntai ni n g: o ne vial of O T O -1 0 4 Acti ve a n d o ne vial of O T O -1 0 4 
Dil ue nt.   
Place b o   
A kit c o ntai ni n g: o ne vial of O T O -1 0 4 Dil ue nt.  
1 2. 2.   
Directi o ns f or Use  
O T O -1 0 4 a n d place b o will  be pre pare d b y  a n u n bli n de d Q M P i n a clea n, sec ure l ocati o n wit h a 
r o o m te m perat ur e prefera bl y at or b el o w 2 3° C ( 7 3° F). T he l o cati o n will n ot be accesse d b y t he 
bli n de d pers o n nel d uri n g st u d y dr u g pre parati o n .  Please refer t o t he P har mac y Ma n ual f or 
detaile d st u d y dr u g pr e p arati o n i nstr ucti o ns.  
1 2. 3.   
P ac k a gi n g a n d L a beli n g  
1 2. 3. 1.   
P ac k a gi n g  
All st u d y dr u g kits will be la bele d wit h i nf or m ati o n t hat will meet t he a p plica ble re g ulat or y 
re q uire me nts.  
1 2. 3. 2.   
L a bels a n d L a beli n g I nstr ucti o ns  
A la bel will be affi x e d t o eac h kit b o x i n dicati n g kit n u m ber a n d st ora ge i nstr ucti o ns.  A la bel 
will be affi x e d t o t he O T O -1 0 4 Acti ve a n d Dil ue nt vials i n dicati n g c o nte nts a n d st ora ge 
i nstr ucti o ns.  A s yri n ge bli n di n g la bel will be pr o vi de d t o mas k t he s yri n ge c o nte nts f or i njecti o n. 
1 2. 4.   
M a n a ge me nt of Cli nic al S u p p lies  
T he cli nical s u p plies will be ma na ge d b y t h e I W R S.  T he I W R S will create s hi p me nt re q uests 
t hat will be ge n erat e d bas e d o n i n ve nt or y t hres h ol ds t hat are set f or eac h site.  A s hi p me nt 
re q uest will be ge n erate d b y t he I W R S s yste m a n d se nt t o t he cli nical s u p plies ve n d or.  U p o n 
s hi p me nt a n d recei pt of t he cli nical trial materi al, t he site pers o n nel (e. g., p har mac y) will 
ac k n o wle d ge t he s hi p me nt usi n g t he I W R S a n d i d e ntif y a n y da ma ge d, missi n g, or u n usa bl e kits 
s o t he y will n ot be dis pe nse d. 
1 2. 4. 1.   
St or a ge of K its 
All kits will be st ore d at 2 -8° C , wit h all o wa ble te m perat ure e x c ursi o ns as hi g h as 2 5° C f or u p t o 
7 2 h o urs.  All te m perat ur e e x c ursi o ns of t he st u d y dr u g m ust be d o c u me nte d i n t he st u d y dr u g 
acc o u nta bilit y l o g.  A n y e x c ursi o ns wit hi n t he all o wa ble te m p erat ure ra n ge a n d c o n diti o ns 
s h o ul d be d oc u me nte d, b ut t he st u d y dr u g is still acce pta bl e f or use a n d dis pe nsi n g t o s u bjects.  
If a n y e x c ursi o ns are o utsi de of t hese c o n diti o ns, t he st u d y dr u g s h o ul d n ot be use d t o treat 
s u bjects.  If t his occ urs, t he Q M P  pre pari n g t h e st u d y dr u g s h o ul d i m me di atel y q u ara nti ne t h e 
pr o d uct a n d re p ort t he kit(s) as u nacce pt a ble f or dis pe nsi n g t o t he I W R S t o re m o ve it fr o m 
i n ve nt or y. 


 
 
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1 2. 5.   
Dr u g Acc o u nt a bilit y  
It is t he res p o nsi bilit y of t he cli nical i n vesti gat or t o e ns ure t hat all stu d y dr u g recei v e d at t he site 
will be  i n ve nt orie d a n d acc o u nte d f or t hr o u g h o ut t he st u d y a n d t he res ult rec or de d o n t he dr u g 
acc o u nta bilit y f or m mai ntai ne d i n t he P har mac y Ma n ual.  T he Q M P  will  be i nstr ucte d t o ret ur n 
all ori gi nal c o nt ai ners, w het her e m pt y  or c o ntai ni n g st u d y dr u g, w he n i nstr ucte d b y t he st u d y 
m o nit or t o ret ur n.  St u d y dr u g ret ur ne d b y t he cli nical site staff will be st or e d a n d dis p ose d of 
acc or di n g t o t he s p o ns or's i nstr ucti o ns.  Dr u g acc o u nta bilit y will be verifie d b y t he s p o ns or's 
u n bli n de d st u d y m o nit or d uri n g t he c o urse of t he st u d y.  St u d y dr u g will be st ore d i n a li mite d 
access area or i n a l o c ke d refri gerat or u n d er a p pr o priate e n vir o n me nt al c o n diti o ns.  
T he i n vesti gat or a grees n ot t o s u p pl y t he st u d y dr u g t o a n y p ers o n ot her t ha n s u b-i n vesti gat ors, 
desi g nat e d staff a n d t he s u bjects partici pati n g i n t he st u d y.  St u d y dr u g ma y n ot be rela bel e d or 
reassi g ne d f or use b y ot h er s u bjects e xce pt u n der s pecial circ u msta nces a p pr o ve d b y Ot o n o m y. 
T he i n vesti gat or will retai n a n d st ore all ori gi nal c o ntai ners ret ur ne d b y t he cli nical site staff u ntil 
t hese c o ntai ners are i n ve nt orie d b y t he st u d y m o nit or.  U nless ot her wise i nstr ucte d b y t he 
s p o ns or, t he i n vesti gat or a grees at t he e n d of t h e st u d y t o ret ur n all ori gi nal c o ntai ners, w h et her 
e m pt y or c o ntai ni n g st u d y dr u g, t o t he s p o ns or as i nstr ucte d b y t h e st u d y m a na ger.  T he 
i n vesti gat or a grees t o neit her dis pe nse t he st u d y dr u g fr o m, n or st ore it at, a n y site ot her t h a n t he 
st u d y sites a gree d u p 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 ositi o n of ori gi nal c o ntai ners e m pt y or f ull wit h ret ur ne d or 
u n use d st u d y dr u g.  A p pr o priate d oc u me ntati o n will be mai ntai ne d.  Per missi o n ma y be gra nte d 
f or l ocal dis p ositi o n, wit h s u p p orti n g d oc u me nt ati o n. 
1 3.   
E T HI C A L A S P E C T S  
1 3. 1.   
I n vesti g at or Res p o nsi bilities 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he cli nical st u d y is p erf or me d i n acc or da nce 
wit h t he pr ot oc ol, t he Declarati o n of Helsi n ki, as well as wit h t he N ote f or G ui da nce o n G o o d 
Cli nical Practice (I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q u ire m e nts.  T hese d oc u me nts set 
f ort h t hat t he i nf or me d c o nse nt of t he s u bjects is a n esse ntial prec o n diti o n f or partici pati o n i n t he 
cli nical st u d y.  
1 3. 2.   
Rese arc h Et hics C o m mittee  (R E C ) 
T his trial will be u n derta ke n o nl y after f ull a p pr o val of t he pr ot oc ol a n d a d de n da has bee n 
o btai ne d fr o m a desi g n ate d R E C  a n d t he s p o ns or has recei ve d a c o p y of t his a p pr o val.  
T he R E C  m ust be i nf or me d of all s u bse q ue nt pr ot oc ol a me n d me nts iss ue d b y t he s p o ns or.  
Re p orts o n, a n d re vie ws of, t he trial a n d its pr o gress will be s u b mi tte d t o t he R E C  b y t he 
i n vesti gat or at i nter vals sti p ulate d i n t heir g ui deli n es. 


 
 
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1 3. 3.   
I nf or me d C o nse nt 
Eac h s u bject m ust gi ve writte n c o nse nt (a n d si g n ot her l ocall y re q uire d d oc u me nts) acc or di n g t o 
l ocal re q uir e me nts after t he nat ure of t he st u d y h as bee n f ully e x plai ne d.  T he c o nse nt f or m m ust 
be si g ne d pri or t o perf or ma nce of a n y st u d y -rel ate d acti vit y.  T he c o ns e nt f or m t hat is use d m ust 
be a p pr o ve d b ot h b y t he s p o ns or a n d b y t he re vi e wi n g R E C .  T he i nf or m e d c o nse nt s h o ul d be i n 
acc or da nce wit h t he c urre nt r e visi o n of t he Declarati o n of Helsi n ki, c urre nt I nter nati o nal 
C o nfere nce o n Har m o nizati o n (I C H) G o o d Cli nical Practice ( G C P) g ui d eli nes, a n d Ot o n o m y 
p olic y.  
T he i n vesti gat or m ust e x plai n t o p ote ntial s u bjects t he ai ms, met h o ds, reas o na bl y a ntici pate d 
be nef its a n d p ote ntial hazar ds of t he trial a n d a n y disc o mf ort it ma y e nt ail.  S u bjects will be 
i nf or me d t hat t he y are free n ot t o partici pate i n t he trial a n d t hat t he y ma y wit h dra w c o nse nt t o 
partici pate at a n y ti me.  T he y will be t ol d w hic h alter nati ve treat me nts are a vaila ble if t he y ref use 
t o ta ke part, a n d t hat s u c h ref usal will n ot prej u di ce f ut ure treat me nt.  Fi nall y, t he y will be t ol d 
t hat t heir rec or ds ma y be e x a mi ne d b y c o m pet e nt a ut h orities a n d a ut h orize d pers o ns, b ut t hat 
pers o nal i nf or mati o n will b e treate d as strictl y c o nfi de ntial a n d will n ot be p u blicl y a v aila ble.  
S u bjects m ust be gi ve n t he o p p ort u nit y t o as k q uesti o ns.  After t his e x pla nati o n a n d bef ore e ntr y 
i nt o t he trial, c o nse nt s h o ul d be a p pr o priat el y rec or de d b y mea ns of t he s u bject's d ate d si g nat ure.  
If a s u bject is u na bl e t o r ea d, a n i m partial wit ness m ust be prese nt d uri n g t h e e ntire i nf or m e d 
c o nse nt disc ussi o n.  T he si g nat ur e of t he i m partial wit ness will certif y t he s u bject's c o nse nt.  T he 
s u bject s h o ul d recei v e a si g ne d a n d date d c op y of t he i nf or me d c o ns e nt f or 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.   
Pr ot oc ol M o dific ati o ns  
All pr ot oc ol a me n d me nts m ust be iss ue d b y t he s p o ns or, si g ne d a n d date d b y t he i n vesti gat or, 
a n d s h o ul d n ot be i m ple me nte d wit h o ut pri or R E C  a p pr o val, e xce pt w here necessar y t o eli mi nate 
i m me diate hazar ds t o t he s u bjects or w he n t he c ha n ge(s) i n v ol ves o nl y l o gistical or 
a d mi nistrati ve as pects of t he trial (e. g., c h a n ge i n m o nit or, c ha n ge of tel e p h o ne n u m ber).  
Res p o nsi bilities f or re p orti n g pr ot oc ol a me n d m e nts t o a n y Re g ulat or y A ut h orit y (if a p plica ble) 
a n d/ or R E C  are f urt her descri be d i n t he Et hical As pects secti o n of t he pr ot oc ol.  
I n sit uati o ns re q uiri n g a de part ure fr o m t he pr ot oc ol, t he i n vesti gat or or ot her p h ysicia n i n 
atte n da nce will c o n tact 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 pres e ntati ve b y fa x, e mail or tele p h o ne (see S p o ns or C o ntact I nf or mati o n pa ge).  If p ossi ble, 
t his c o ntact will be ma de bef ore i m ple me nti n g a n y de p art ure fr o m pr ot oc ol.  I n all cases, co nt act 
wit h t he s p o ns or m ust be ma de as s o o n as p ossi bl e i n or der t o disc uss t he sit uati o n a n d a gree o n 
a n a p pr o pri ate c o urse of acti o n.  T he e C R F a n d s o urce d oc u m e nt will descri be a n y de part ure 
fr o m t he pr ot oc ol a n d t he circ u msta nces re q uiri n g it. 
1 4. 2.   
Re g ul at or y D oc u me nt ati o n  
D oc u me nts t hat m ust be pr o vi de d t o t he s p o ns or pri or t o st u d y dr u g s hi p me nt are as f oll o ws:  
 U p -t o-date c urric ul u m vitae f or eac h i n v esti gat or a n d s u b -i n vesti gat or. 


 
 
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 Si g ne d a n d d ate d I n vesti gat or A gree me nt.  
 A p plica ble l ocal r e g ulat or y d o c u m e ntati o n  
 A c o p y of t he f or mal writte n n otificati o n t o t he i n vesti gat or re gar di n g a p pr o val of t he 
pr ot oc ol b y a n R E C  t hat is i n c o m plia nce wit h re g ulat or y g ui deli nes.  T he writte n 
n otificati o n is t o be si g ne d b y t he c hair ma n or a ut h orize d desi g nee a n d m ust i de ntif y 
t he s pecific pr ot o c ol.  I n cases w here a n R E C  me m ber has a k n o w n c o nfli ct of 
i nterest, a bste nti o n of t hat i n di vi d ual fr o m v oti n g s h o ul d be d oc u me nte d; a n 
i n vesti gat or ( or s u b-i n vesti gat or) m a y be a m e m ber of t he R E C , b ut ma y n ot v ote o n 
a n y resear c h i n w hic h he or s he is i n v ol ve d.  
 Fi na ncial discl os ur e d oc u me ntati o n f or eac h i n vesti gat or a n d s u b -i n vesti gat or. 
 Na me a n d a d dress of t h e R E C  wit h a state me nt t hat it is or ga nize d a n d o perates 
acc or di n g t o G C P a n d t h e a p plica ble la ws a n d re g ulati o ns, a n d a  c urre nt list of t he 
R E C  me m bers.  T he R E C  Attestati o n f or m ca n b e use d t o ca pt ure t his i nf or mati o n.  
 A c o p y of t he R E C  a p pr o ve d i nf or me d c o ns e nt f or m a n d ot her a dj u ncti ve m aterials 
(e. g., a d vertisi n g) t o b e use d i n t he st u d y, i ncl u di n g writte n d oc u me ntati o n of R E C  
a p pr o val of t hes e ite ms.  
 Re q uire d fi na nci al a gree me nt.  
I n a d diti o n t o t he d oc u me nts re q uire d pri or t o t he st ud y, ot her d o c u me ntati o n ma y b e re q uire d 
d uri n g t he c o urse of t he st u d y.  
1 4. 3.   
S u bject I de ntific ati o n Re gister  
T he i n vesti gat or a grees t o c o m plete a s u bject i de ntificati o n re gister, w hic h will be use d f or t he 
p ur p ose of l o n g -ter m f oll o w-u p, if nee d e d.  T his f or m will be treate d as c o nfi de ntial, a n d will be 
file d b y t he i n v esti gat or i n t he Trial Site File.  Ot h er wise, all re p orts a n d c o m m u nicati o ns 
relati n g t o t he st u d y will i de ntif y s u bjects b y i nitials a n d assi g n e d n u m ber o nl y. 
1 4. 4.   
Rec or d Rete nti o n  
I n c o m plia nce wit h t he I C H/ G C P g ui deli nes t he i n vesti gat or/i nstit uti o n will mai ntai n all e C R Fs 
a n d all s o urce d o c u me nts t hat s u p p ort t he data c oll ecte d fr o m eac h s u bject, a n d all trial 
d oc u me nts as s pecifi e d i n Esse ntial D oc u me nts f or t he C o n d uct of a Cli nical Trial a n d as 
s pecifie d b y t he a p plica ble re g ulat or y re q uire m e nt(s).  T he i n vesti gat or/i nstit uti o n will ta ke 
meas ures t o pre ve nt acci de ntal or pre m at ure destr ucti o n of t hese d oc u me nts.  Esse ntial 
d oc u me nts m ust be retai ne d u ntil at least t w o years after t he last a p pr o va l of a mar k eti n g 
a p plicati o n i n a n I C H re gi o n or at least t w o years ha ve ela pse d si nce t he f or mal disc o nti n uati o n 
of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct.  T hese d oc u m e nts will be retai ne d f or a 
l o n ger peri o d if re q uire d b y t he a p plica ble reg ulat or y re q uire m e nts or b y a n a gree m e nt wit h t he 
s p o ns or.  It is t he res p o nsi bilit y of t he s p o ns or t o i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n 
t hese d oc u me nts n o l o n ger nee d t o b e ret ai ne d.  If t he res p o nsi ble i n vesti gat or retires, rel ocates, 
or f or  ot her reas o ns wit h dra ws fr o m t he res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o d y m ust 
be tra nsferre d t o a pers o n w h o will acce pt t he res p o nsi bilit y.  T he s p o ns or m ust be n otifie d i n 
writi n g of t he n a me a n d a d dress of t he ne w c ust o dia n.  


 
 
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1 4. 5.   
Electr o nic C as e Re p ort F or m  
Electr o nic Case Re p ort F or ms (e C R Fs) will be c o m plete d f or eac h s u bject.  Access f or data e ntr y 
will be pr o vi de d t o a p pr o priate site staff me m b ers.  All data m ust be e ntere d i nt o t he e C R Fs i n 
E n glis h a n d si g ne d a n d d ate d electr o nicall y b y t h e i n vesti gat or.   
T he e C R Fs s h o ul d be c o m plete d b y i n vesti gat or site staff at t he ti me of t he s u bject's visit, wit h 
t he e x ce pti o n of res ults of tests perf or me d o utsi de t he i n vesti gat or's office, s o t hat t he y al wa ys 
reflect t he latest o bser vati o ns o n t he s ubjects partici pati n g i n t he trial.  
As t he site staff e nters data, discre pa n cies will be a ut o maticall y ge nerate d wit hi n t he Electr o nic 
Data Ca pt ure ( E D C) s yst e m f or t he site staff t o res ol ve i m me diatel y.  I n a d diti o n, as a res ult of 
data re vie w b y t he S p o n s or or desi g nee, ma n ual q ueries will be rais e d electr o nicall y i n 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 dat a verifi cati o n b y t he cli nical m o nit or.  
All c orrecti o ns will be ma de wit hi n t he E D C s yst e m b y t he i n vesti gat or or ot her a ut h orize d st u d y 
site pers o n nel.  T he cli nical m o nit or a n d data ma n a ge me nt tea ms will e ns ure a p pr o priate 
res ol uti o n of q ueries.  T h e i n vesti gat or m ust a ut h orize c ha n ges t o t he rec or de d safet y a n d 
efficac y dat a.  
1 4. 6.   
Ter mi n ati o n  
A n i nitiati ve f or ce nter cl os ure or trial ter mi nati o n ca n be ta ke n at a n y ti me eit her b y t he s p o ns or 
or b y t he i n v esti gat or, pr o vi de d t here is reas o na bl e ca use a n d s uffi cie nt n otice is gi ve n i n 
a d va nce of t he i nte n de d t er mi nati o n.  Reas o ns f or s uc h acti o n ta ke n b y t he s p o ns or i ncl u de, b ut  
are n ot li mite d t o:  
 S uccessf ul c o m pleti o n of t he trial at t he ce nt er  
 T he ma xi m u m n u m ber of eli gi ble s u bjects f or t he trial has bee n e nr olle d  
 Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he s p o ns or's pr oce d ures, or 
G C P g ui deli nes  
 Safet y c o ncer ns  
 I n a de q uat e recr uit me nt of s u bjects b y t he i n vesti gat or 
 B usi ness reas o ns  
1 4. 7.   
D at a a n d S afet y M o nit ori n g Pl a n  
T he s p o ns or s hall pr o m ptl y re vi e w all i nf or mati o n rele va nt t o t he safet y of t he dr u g o btai ne d or 
ot her wise recei ve d fr o m f orei g n or d o mestic s o urces,  i ncl u di n g i nf or mati o n deri ve d fr o m t his 
cli nical st u d y a n d a n y ot her cli nical st u d y c o n d u cte d wit h O T O -1 0 4.  I n or der t o c o m pl y wit h 
t his, t he s p o ns or a n d C R O me dical pers o n n el will ha ve t he a bilit y t o re vie w bli n de d safet y 
i nf or mati o n as it is e ntere d a nd verifie d i n t he electr o nic data ca pt ure s yste m ( Secti o n  1 4. 5 ).  
De pe n di n g o n t he e nr oll me nt rate, all A Es i n t he ear a n d l a b yri nt h dis or ders S O C  w ill be 
re vie we d at least e v er y ot her m o nt h.  I n a d diti o n, reas o ns f or st u d y disc o nti n uati o n will be 
re vie we d t o s ee if a n y tre n ds i n st u d y dis c o nti n uati o n are i de ntifie d. 
I n v esti gat ors are i nstr uct e d t o c o ntact t he Pr o d uct Safet y wit hi n 2 4 h o urs f oll o wi n g t he 
i de ntificati o n of a S A E (Secti o n  9. 2. 2 ).  All S A Es will be re vie we d b y t h e s p o ns or a n d C R O 


 
 
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me dical pers o n n el wit hi n 1 -2 da ys after recei pt w het h er or n ot t he e ve nt was c o nsi dere d 
ass ociate d wit h st u d y dr u g. T he s p o ns or ass u mes res p o nsi bilit y f or a p pr o priate re p orti n g t o t he 
re g ulat or y a ut h orities. T he i n vesti gat or ass u mes res p o nsi bilit y f or re p orti n g e ve nts t o t he R E C  i n 
acc or da nce wit h t he R E C  req uire me nts.  All S A E’s will be part of t he C R O me dical 
pers o n nel/s p o ns or safet y re vie w.  
If, t hr o u g h t his o n g oi n g re vie w, t he s p o ns or d eter mi nes t hat O T O-1 0 4 pres e nts a n u nreas o na ble 
a n d si g nifica nt ris k t o s u bjects, t he s p o ns or s hall ta ke a p pr o priate ste ps  t o s us pe n d or disc o nti n ue 
t he st u d y a n d n otif y re g ulat or y a ut h orities, i n vesti gat ors a n d R E C s as a p pr o priate. 
1 4. 8.   
M o nit ori n g  
T he s p o ns or or its re pres e ntati ves will perf or m o n -site m o nit ori n g visits as fre q ue ntl y as 
necessar y base d o n site acti vit y t o re vie w pr ot oc ol c o m plia nce, c o m p are e C R Fs wit h i n di vi d ual 
s u bject’s me dical r ec or ds a n d cli nic c harts, a n d e ns ure t hat t he st u d y is b ei n g c o n d u cte d 
acc or di n g t o perti ne nt re g ulat or y re q uire m e nts.  T he dates of t he visits will be rec or de d b y t he 
m o nit or i n a trial  ce nter visit l o g t o be ke pt at t he site.  T he first p ost -i nitiati o n visit will us uall y 
be ma de as s o o n as p ossi ble after e nr oll me nt has be g u n.  At t hese visits, t he m o nit or will 
c o m pare t he data e nt ere d o nt o t he e C R Fs wit h t he h os pital or cli nic rec or ds ( s o urce d o c u me nts).  
T he re vie w of me dical rec or ds will be perf or me d i n a ma n ner t hat e ns ures s u bject c o nfi de ntialit y 
is mai ntai ne d.  At a mi ni m u m, s o urce d oc u me ntati o n m ust be a vaila ble t o s u bsta ntiate pr o per 
i nf or me d c o nse nt pr o ce d ures, a d here nce t o pr ot oc ol pr oce d ures, a de q u ate re p orti n g a n d f oll o w -
u p of A Es, a d mi nistrati o n of c o nc o mita nt me dicati o n, dr u g recei pt/ dis pe nsi n g/ret ur n rec or ds, a n d 
st u d y dr u g a d mi nistrati o n i nf or mati o 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 i n vesti gat or pri or t o t he st u d y.  Fi n di n gs fr o m t his re vie w of e C R Fs a n d s o urce 
d oc u me nts will be disc usse d wit h t he i n vesti gat or.  T he s p o ns or e x pects t hat, d uri n g m o nit ori n g 
visits, t he i n vesti gat or (a n d as a p pr o priate, t he st u d y c o or di nat or) will be a vaila ble, t he s o urce 
d oc u me ntati o n will be a v aila ble, a n d a s uita ble e n vir o n me nt will be pr o vi de d f or re vie w of 
st u d y-relate d d oc u m e nts. 
1 4. 9.   
D at a Q u alit y Ass ur a nce  
Ste ps t o be ta ke n t o ass ure t he acc urac y a n d relia bilit y of data i ncl u d e t he selecti o n of q ualifie d 
i n vesti gat ors a n d a p pr o priate st u d y ce nters, re vie w of pr ot oc ol pr oce d ures wit h t he i n vesti gat or 
a n d ass ociate d pers o n nel pri or t o st u d y i nitiati o n, a n d peri o dic m o nit ori n g visits b y t he s p o ns or 
or its re prese nt ati ves.  Case re p ort f or ms will be re vie we d f or acc urac y a n d c o m plete ness i n 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 uri n g a n d after o n -site m o nit ori n g 
visits, a n d a n y discre pa n cies will be res ol ve d wit h t he i n vesti gat or or desi g nees, as a p pr o priate, 
a n d d oc u me nte d i n t he E D C s yste m.  
1 4. 1 0.  
O n -Site A u dits  
Re prese ntati ves of t h e s p o ns or's Q u alit y Ass ura nce de part me nt ma y visit t he site t o carr y o ut a n 
a u dit of t he st u d y i n c o m plia nce wit h re g ulat or y g ui deli nes a n d c o m pa n y p olic y.  S uc h a u dits 
will re q uire access t o all st u d y rec or ds, i n cl u di n g s o urce d oc u m e nts, f or i ns pecti o n a n d 
c o m paris o n wit h t he e C R Fs. S u bject pri vac y m ust, h o we ver, be res p ecte d.  S ufficie nt pri or 
n otice will be pr o vi de d t o all o w t he i n vesti gat or t o pre pare pr o perl y f or t h e a u dit.  


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
4 9   
 
Si milar a u diti n g pr oce d ures ma y als o  be c o n d ucte d b y a ge nts of a n y re g ulat or y b o d y re vie wi n g 
t he res ults of t his st u d y i n s u p p ort of a Lice nsi n g A p plicati o n.  T he i n vesti gat or s h o ul d 
i m me diatel y n otif y t he s p o ns or if t he y ha ve b ee n c o ntacte d b y a re g ulat or y a ge nc y c o ncer ni n g a n 
u pc o mi n g i ns p ecti o n.  
1 4. 1 1.  
Use of I nf or m ati o n a n d P u blic ati o n  
All i nf or mati o n c o ncer ni n g O T O -1 0 4, Ot o n o m y o perati o ns, pate nt a p plicati o n, f or m ulas, 
ma n ufact uri n g pr ocesses, basic scie ntific dat a, a n d f or m ulati o n i nf or mati o n, s u p plie d b y t he 
s p o ns or t o t he i n vesti gat or a n d n ot pre vi o usl y p u blis he d, is c o nsi dere d c o nfi de ntial a n d re m ai ns 
t he s ole pr o pert y of Ot o n o m y.  T he i n vesti gat or a grees t o use t his i nf or mati o n o nl y t o 
acc o m plis h t his st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut t he s p o ns or's writte n c o nse nt.  
T he i n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o pe d i n t he cli nical st u d y will be use d b y 
Ot o n o m y i n c o n necti o n wit h t he c o nti n ue d de vel o p me nt of O T O -1 0 4, a n d t h us ma y be discl ose d 
as re q uire d t o ot her cli nical i n vesti gat ors or g o ver n me nt re g ulat or y a ge n cies.  T o per mit t he 
i nf or mati o n deri ve d fr o m t he cli nical st u dies t o be use d, t he i n vesti gat or is o bli gate d t o pr o vi de 
t he s p o ns or wit h all data o btai ne d i n t he st u d y. 
A n y p u blicati o n or ot her p u blic prese ntati o n of res ults fr o m t his st u d y re q uires pri or re vie w a n d 
writte n a p pr o val of Ot o n o m y.  Draft a bstr acts, ma n uscri pts, a n d materials f or prese ntati o n at 
scie ntific meeti n gs s h o ul d be pr o vi de d t o t he s p o ns or at least 3 0 w or ki n g d a ys pri or t o a bstract or 
ot her rele va nt s u b missi o n dea dli nes.  A ut h ors hi p of  p u blicati o ns res ulti n g fr o m t his st u d y will be 
base d o n ge nerall y acce pte d criteria f or maj or me dical j o ur nals.   


 
 
Ot o n o m y 1 0 4 -2 0 1 5 0 8 Pr ot oc ol V 3 . 0: 13  J a n uar y 2 0 1 6 
5 0   
 
1 5.   
R E F E R E N C E S  
A merica n S peec h La n g u a ge Heari n g Ass oci ati o n. " G ui deli nes f or Ma n ual P ure -T o ne T hres h ol d 
A u di o metr y." as ha. or g. 2 0 0 5. 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.  
Barritt, La ura. M e niere's Disease. Else vier I nc., 2 0 0 8.  
C o m mittee o n Heari n g a n d E q uili bri u m. " C o m mittee o n Heari n g a n d E q uili bri u m g ui deli nes f or 
t he dia g n osis a n d e val uati o n of t hera p y i n Me niere's diseas e." Ot olar y n g ol o g y - Hea d a n d 
Nec k S ur ger y 1 1 3 ( 1 9 9 5): 1 8 1 -1 8 5.  
Gates, G A, A M Verrall, J D Gree n, D L T ucci, a n d S A Telia n. " Me ni ett Cli nical Trial: L o n g -ter m 
F oll o w -u p." Arc hi v es of Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y 1 3 2 ( 2 0 0 6): 1 3 1 1 -
1 3 1 6.  
Gates, G A, a n d A M Verrall. " Val i dati o n of t he Mi niere's Disease Patie nt-Orie nte d S y m pt o m -
Se verit y I n de x." Arc hi ves of Ot olar y n g ol o g y - Hea d a n d nec k S ur ger y 1 3 1 ( 2 0 0 5): 8 6 3 -
8 6 7.  
Gates, G A, J D Gree n, D L T u cci, a n d S A Telia n. " T he Effects of Tra nst y m pa nic Micr o press ure 
Treat me nt i n Pe o ple  wit h U nilateral Me niere's Dis ease." Arc hi ves of Ot olar y n g ol o g y - 
Hea d a n d Nec k S ur ger y 1 3 0 ( 2 0 0 4): 7 1 8 -7 2 5.  
Gates, Ge or ge A. " Cli ni metrics of Me niere's Dis ease." T he Lar y n g osc o pe, 2 0 0 0: 8 -1 1.  
He nr y, J A, S Griest, E T hiel ma n, G Mc Milla n, C Kaeli n, a n d K F C arls o n. " Ti n nit us F u nct oi nal 
I n d e x: De vel o p me nt, Vali dati o n, O utc o mes Researc h, a n d Cli nical A p plicati o n." Heari n g 
Researc h, 2 0 1 5: 1 -7.  
Ki m, Har ol d, Ric har d Wiet, a n d R o bert Battista. " Tre n ds i n t he dia g n osis a n d t he ma na ge me nt of 
Me niere’s dis ease: Res ult s of a s ur ve y." Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y, 2 0 0 5: 
7 2 2 -7 2 6.  
Mei kle, M B, et al. " T h e Ti n nit us F u ncti o nal I n d e x: De vel o p me nt of a Ne w Cli nical Meas ure f or 
C hr o nic, I ntr usi ve Ti n nit us." Ear & Heari n g 3 3 ( 2 0 1 2): 1 5 2 -1 7 6.  
S hea, J o h n. " Classificati o n of Me niere's Disease." T he A merica n J o ur nal of Ot ol o g y 1 4, n o. 3 
( 1 9 9 3): 2 2 4-2 2 9.  
T h or nt o n, A, a n d M Raffi n. " S peec h Discri mi nati o n Sc ores M o dele d as a Bi n o mial Varia bl e." 
J o ur nal of S peec h a n d Heari n g Researc h 2 1 ( 1 9 7 8): 5 0 7-5 1 8.  
Ware, J E, K K S n o w, B K osi ns ki, a n d B Ga n d e k. S F -3 6 Healt h S ur ve y: M a n ual a n d 
I nter pret ati o n G ui de. T he Healt h I nstit ute, Ne w E n gla n d Me dical Ce nter, 1 9 9 3. 
Ware, J o h n E. S F -3 6 P h ysical & Me nt al Healt h S u m mar y Scales: A User's Ma n ual. Q ualit y 
Metric, 1 9 9 4.