Clinical trial NCT02768662
Conditions: Meniere's Disease
Sponsor: Otonomy, Inc.
Start date: 2016-08-01; Completion date: 2017-09-01
Enrollment: 142 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label extension study of a single intratympanic injection of OTO-104 given every 3 months for a total of 2 injections. Subjects must have completed either Otonomy study 104-201403 (1-Year, Phase 2, Safety Study of OTO-104) or 104-201508 (Phase 3 Study of OTO-104) in order to be eligible for this open-label extension study.

Detailed description:

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

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
  
 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A 6 -M O N T H , M U L TI C E N T E R, P H A S E 3 , O P E N -L A B E L  E X T E N SI O N S A F E T Y 
S T U D Y O F O T O -1 0 4  GI V E N A T 3 -M O N T H I N T E R V A L S B Y I N T R A T Y M P A NI C 
I N J E C TI O N I N S U B J E C T S WI T H U NI L A T E R A L M E NI E R E’ S DI S E A S E  
 
Pr ot oc ol N u m ber:  1 0 4 -2 0 1 6 1 0  
E u dr a C T N u m ber: 2 0 1 6 -0 0 0 7 6 6 -2 9  
 
 
 
S p o ns or C o ntact:  
 
 
 
 
 
 
 
 
 
 
Me dical M o nit or:  
 
 
 
 
 
 
  
   
 
 
 
 
 
Versi o n:  
2 . 0 
Date of Pr ot oc ol:  
2 6 A pril  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 pri etar 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 nc.  
 
 
 
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 ur e 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 ur e 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.  




 
 
 
                                                            3  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
P R O T O C O L A M E N D M E N T, V E R SI O N 2. 0  ................................................................................7  
S P O N S O R C O N T A C T I N F O R M A TI O N  .......................................................................................8  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................9  
A B B R E VI A TI O N S  .......................................................................................................................1 0  
S Y N O P SI S  ....................................................................................................................................1 1  
1.  
B A C K G R O U N D  ........................................................................................................1 5  
1. 1.  
Rati o nale f or Safet y St u d y  ..........................................................................................1 6  
2.  
O BJ E C TI V E S  .............................................................................................................1 6  
3.  
O V E R VI E W O F S T U D Y D E SI G N  ...........................................................................1 6  
4.  
S T U D Y P O P U L A TI O N  .............................................................................................1 7  
4. 1.  
Ge neral C o nsi derati o ns  ...............................................................................................1 7  
4. 2.  
I n cl usi o n Criteria ........................................................................................................1 7  
4. 3.  
E x cl usi o n Criteria  .......................................................................................................1 7  
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G ....................................................................1 8  
5. 1.  
E nr oll me nt Pr oce d u res ................................................................................................1 8  
5. 1. 1.  
Assi g n me nt of S u bject I d e ntificati o n N u m bers  ..........................................................1 8  
6.  
D O S A G E A N D A D MI NI S T R A TI O N  .......................................................................1 8  
6. 1.  
St u d y Dr u g A d mi nistrati o n .........................................................................................1 8  
6. 2.  
C o m plia nce  .................................................................................................................1 9  
7.  
P RI O R, C O N C O MI T A N T, A N D S U B S E Q U E N T T H E R A P Y  ................................1 9  
7. 1.  
Pr oscri be d T hera p y or Pr oce d ures D uri n g t he St u d y Peri o d  ......................................1 9  
7. 2.  
S y m pt o matic Relief Me dicati o ns  ...............................................................................2 0  
8.  
S T U D Y E V A L U A TI O N S  ..........................................................................................2 0  
8. 1.  
St u d y Pr oce d ures b y Visit  ..........................................................................................2 0  
8. 1. 1.  
Visit 1: Da y 1 ( Scree ni n g/ Baseli ne/ D ose N o. 1)  ........................................................2 0  
8. 1. 2.  
Visit 2: M o nt h 3 ( ± 2 wee ks) ( F oll o w U p a n d D os e N o. 2)  .......................................2 0  
8. 1. 3.  
Visit 3: M o nt h 6 ( ± 2 wee ks) ( E n d of St u d y/ Earl y Ter mi nati o n)  ...............................2 1  
8. 1. 4.  
U nsc he d ule d Visit  .......................................................................................................2 1  
8. 2.  
Safet y E val uati o ns  ......................................................................................................2 2  
8. 2. 1.  
Vital Si g n, Hei g ht a n d Wei g ht Me as ure me nts  ...........................................................2 2  


 
 
 
                                                            4  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
8. 2. 2.  
Uri ne Pre g na n c y Test  .................................................................................................2 2  
8. 2. 3.  
T y m pa n o metr y  ............................................................................................................2 2  
8. 2. 4.  
A u di o gra ms  .................................................................................................................2 2  
8. 2. 5.  
Ot osc o p y  .....................................................................................................................2 3  
8. 2. 6.  
C -S S R S Assess me nt  ...................................................................................................2 3  
8. 3.  
A d diti o nal E val uati o ns  ...............................................................................................2 3  
8. 3. 1.  
Me niere’s S y m pt o m Q uesti o n naire  ............................................................................2 3  
9.  
A D V E R S E E V E N T ( A E) R E P O R TI N G  ...................................................................2 4  
9. 1.  
A d verse E v e nt Classificati o n Defi niti o ns  ...................................................................2 4  
9. 1. 1.  
Assess me nt of Se verit y  ...............................................................................................2 5  
9. 1. 2.  
Assess me nt of Ca usalit y  .............................................................................................2 5  
9. 1. 3.  
F oll o w u p of A d verse E v e nts  .....................................................................................2 6  
9. 2.  
M o nit ori n g of A d v erse E ve nts  ....................................................................................2 6  
9. 2. 1.  
All A d verse E v e nts  .....................................................................................................2 6  
9. 2. 2.  
Seri o us A d verse E v e nts  ..............................................................................................2 7  
9. 2. 3.  
Pre g n a ncies  .................................................................................................................2 7  
9. 3.  
C o ntacti n g S p o ns or Re gar di n g Safet y  ........................................................................2 7  
1 0.  
S U BJ E C T C O M P L E TI O N  .........................................................................................2 8  
1 0. 1.  
C o m pleti o n  .................................................................................................................2 8  
1 0. 2.  
Wit h dra wal  .................................................................................................................2 8  
1 0. 2. 1.  
Ha n dli n g of Wit h dra wals  ............................................................................................2 8  
1 0. 2. 2.  
Re place me nts  ..............................................................................................................2 9  
1 1.  
S T A TI S TI C A L M E T H O D S  .......................................................................................2 9  
1 1. 1.  
Sa m ple Siz e  ................................................................................................................2 9  
1 1. 2.  
A nal ysis Sets  ...............................................................................................................2 9  
1 1. 3.  
Descri pti o n of S u b gr o u ps t o  be A nal yze d  ..................................................................2 9  
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  .............................2 9  
1 1. 5.  
Efficac y E val uati o ns  ...................................................................................................2 9  
1 1. 6.  
Ge neral A nal ytic Met h o ds  ..........................................................................................3 0  
1 1. 7.  
Safet y E val uati o n s ......................................................................................................3 0  
1 1. 7. 1.  
A d verse E v e nts  ...........................................................................................................3 0  
1 1. 7. 2.  
Vital Si g ns  ..................................................................................................................3 0  
1 1. 7. 3.  
Ot osc o pic E x a mi nati o ns  .............................................................................................3 0  


 
 
 
                                                            5  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
1 1. 7. 4.  
A u di o metr y Assess me nts  ............................................................................................3 1  
1 1. 7. 5.  
T y m pa n o metr y  ............................................................................................................3 1  
1 1. 7. 6.  
C o nc o mita nt Me dicati o ns  ...........................................................................................3 1  
1 1. 7. 7.  
C -S S R S  .......................................................................................................................3 1  
1 1. 7. 7. 1.  
C -S S R S: Baseli ne Versi o n  .........................................................................................3 1  
1 1. 7. 7. 2.  
C -S S R S: Si nce Last Visit Versi o n  ..............................................................................3 1  
1 1. 8.  
Ot her  E val uati o ns  .......................................................................................................3 2  
1 1. 8. 1.  
Me niere’s S y m pt o m Q uesti o n naire  ............................................................................3 2  
1 1. 9.  
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  ................3 2  
1 1. 1 0.  
I nteri m A nal yses .........................................................................................................3 2  
1 2.  
S T U D Y D R U G I N F O R M A TI O N  ..............................................................................3 2  
1 2. 1.  
P h ysical D escri pti o n of St u d y Dr u g(s)  .......................................................................3 2  
1 2. 2.  
Directi o ns f or Us e  .......................................................................................................3 3  
1 2. 3.  
Pac ka gi n g a n d La b eli n g  ..............................................................................................3 3  
1 2. 3. 1.  
Pac ka gi n g  ....................................................................................................................3 3  
1 2. 3. 2.  
La b els a n d La b eli n g I nstr ucti o ns  ................................................................................3 3  
1 2. 4.  
Ma na ge me nt of Cli nical S u p plies  ...............................................................................3 3  
1 2. 4. 1.  
St ora ge of Kits  ............................................................................................................3 3  
1 2. 5.  
Dr u g Acc o u nta bilit y  ...................................................................................................3 3  
1 3.  
E T HI C A L A S P E C T S  .................................................................................................3 4  
1 3. 1.  
I n v esti gat or Res p o nsi bilities .......................................................................................3 4  
1 3. 2.  
Researc h Et hics C o m mittee ( R E C)  ............................................................................3 4  
1 3. 3.  
I nf or me d C o nse nt  .......................................................................................................3 4  
1 4.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ..................................................................3 5  
1 4. 1.  
Pr ot oc ol M o dificati o ns  ...............................................................................................3 5  
1 4. 2.  
Re g ulat or y D oc u me ntati o n  .........................................................................................3 5  
1 4. 3.  
S u bject I d e ntific ati o n Re gister  ...................................................................................3 6  
1 4. 4.  
Rec or d Rete nti o n  ........................................................................................................3 6  
1 4. 5.  
Electr o nic Case Re p ort F or m  ......................................................................................3 6  
1 4. 6.  
Ter mi nati o n  .................................................................................................................3 7  
1 4. 7.  
Data a n d Safet y M o nit ori n g Pl a n  ...............................................................................3 7  
1 4. 8.  
M o nit ori n g  ..................................................................................................................3 7  
1 4. 9.  
Data Q ualit y Ass ura nce  ..............................................................................................3 8  


 
 
 
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Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
1 4. 1 0.  
O n -Site A u dits  ............................................................................................................3 8  
1 4. 1 1.  
Use of I nf or mati o n a n d P u blicati o n  ............................................................................3 8  
1 5.  
LI S T O F R E F E R E N C E S  ............................................................................................4 0  
 


 
 
 
                                                            7  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
P R O T O C O L A M E N D M E N T, V E R SI O N 2. 0  
T his pr ot oc ol a me n d me nt ser ves t o ma ke t he f oll o wi n g c 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 E u dra C T n u m ber t o title pa ge.  
Title pa ge, p g. 1  
 
3  
Re m o ve d me dical m o nit or ’s si g nat ure li ne f or 
pr ot oc ol a p pr o val.  
Pr ot oc ol a p pr o val pa ge , p g. 2  
4  
Re m o ve d tele p h o ne as a met h o d t o re p ort 
S A Es.  
Secti o n 9. 2. 2, Seri o us A d verse E ve nts, p g. 2 7  
5  
A d de d safet y fa x n u m ber as a bac k -u p c o ntact 
met h o d f or re p orti n g S A Es.  
Secti o n 9. 3 , C o ntacti n g S p o ns or Re gar di n g 
Safet y, p g. 2 7  
6  
Re m o ve d fa x as a met h o d t o c o ntact t he 
me dical m o nit or.  
Secti o n 1 4. 1, Pr ot oc ol M o dificati o ns, p g. 3 5  


 
 
 
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Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
S P O N S O R C O N T A C T I N F O R M A TI O N  
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.  


 
 
 
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Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
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 b le 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 a n 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 versi 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 ur e 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 pri or 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) 
I nstit uti o n Na me  
 
 
 


 
 
 
                                                            1 0  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
A B B R E VI A TI O N S  
A b bre vi ati o n  
E x pl a n ati o n  
A A O -H N S  
A 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 E  
A d verse E ve nt  
B C A  
B o ne C o n d ucti o n A vera ge  
C  
Celsi us  
C R F/e C R F  
Case Re p ort F or m/electr o nic Case Re p ort F or m  
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 B  
Deci bel  
E D C  
Electr o nic Data Ca pt ure S yste m  
F  
Fa hre n heit  
F A X  
Facsi mile  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
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 ntrat y m pa nic 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m L  
Milliliter  
m g  
Milli gra m  
m m  
Milli meter  
O T O -1 0 4  
I n vesti gati o nal Pr o d uct 
P T A  
P ure T o ne A vera ge  
R E C  
Researc h Et hics C o m mittee  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt  
 


 
 
 
                                                            1 1  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
S Y N O P SI S  
N A M E O F S P O N S O R/ C O M P A N Y:  
 
Ot o n o m y, I nc.  
N A M E O F I N V E S TI G A TI O N A L P R O D U C T:  
 
O T O -1 0 4  
N A M E O F A C TI V E I N G R E DI E N T:  
 
De xa met has o ne  
Title of St u d y: A 6 -m o nt h , m ultice nter, P hase 3,  o pe n -la bel e xte nsi o n safet y st u d y of O T O-1 0 4 gi ve n 
at 3-m o nt h i nter vals b y i ntrat y m pa nic  i njecti o n i n s u bjects wit h u nilateral Me niere’s disease. 
St u d y C e nter(s ): T his st u d y will be c o n d ucte d at a p pr o xi matel y 6 0 -7 0 sites i n si x 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, P ola n d, Ital y, Bel gi u m a n d Fra nce . 
St u die d Peri o d : 1 8  m o nt hs  
P h ase of D e vel o p me nt: P hase 3  
St u d y Desi g n:  
T his is a 6 -m o nt h, m ultice nter, P hase 3 , o pe n-la bel e xte nsi o n safet y st u d y i n s u bjects wit h u nilateral 
Me niere’s disease.  S u bjects will recei ve 1 i ntrat y m pa nic (I T) i njecti o n of 1 2 m g O T O -1 0 4 at 3-m o nt h 
i nter vals f or a t otal of 2 i njecti o ns.  Safet y data t o be c ollecte d i ncl u de a d verse e ve nts, c o nc o mita nt 
me dicati o ns, ot osc o p y, vital si g ns, a u di ol o g y, t y m pa n o metr y, C ol u m bia -S uici de Se verit y Rati n g Scale 
( C-S S R S) q uesti o n naire a n d a Me niere’s di sease s y m pt o m q uesti o n naire. 
O bjecti ve:  
T he o bjecti ve is t o assess t he safet y of re peat I T i njecti o ns of 1 2 m g O T O -1 0 4 at 3 -m o nt h i nter vals i n 
a n o pe n -la bel st u d y. 
Met h o d ol o g y:  
T he d urati o n of t he st u d y f or eac h s u bj ect will be 6 m o nt hs.   
O nce s u bjects meet all eli gi bilit y criteria, t he y will be e nr olle d a n d ma y recei ve u p t o 2 I T i njecti o ns of 
O T O -1 0 4 at  3 -m o nt h i nter vals.  All s u bjects will re mai n o n sta n dar d of care treat me nt f or u nilateral 
Me niere’s disease.  S u bjects will ret ur n t o t he st u d y sites at M o nt h 3 f or safet y assess me nts a n d a n ot her 
I T i nj ecti o n of O T O-1 0 4.   Safet y assess me nts will be c o m plete d at t he e n d of t he st u d y ( M o nt h 6) or 
u p o n earl y wit h dra wal fr o m t he st u d y.  
N u m ber of S u bjects :  
U p t o 3 0 0 s u bjects will  be e nr olle d . 
Di a g n osis a n d M ai n C riteri 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, eac 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 years or ol der.  
2.  S u bj ect has c o m plete d t he P hase 2 ( 1 0 4 -2 0 1 4 0 3 ) or P hase 3 ( 1 0 4-2 0 1 5 0 8 ) cli nical st u d y. 
3.  Fe male s u bjects of c hil d bea ri n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-


 
 
 
                                                            1 2  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
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 test 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 ntere 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, 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 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 de).   
4.  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 visi ts. 
5.  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 
la 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 proce d ures.  
 
Di a g n osis a n d M ai n Criteri a f or E xcl usi o n:  
T o be eli gi ble f or t his st u d y, eac 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. 
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 deficie 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 dia, 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 njecti o n i ncl u di n g b ut n ot li mite d t o a m o n o meric, 
atelectatic or atr o p hic t y m pa nic me m bra ne. 
6.  S u bj ect has a hist or y of t y m pa n ost o m y t u bes t hat i ncl u des e vi de nce of perf orati o n or lac k of 
cl os ure. 
7.  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.  
8.  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.  
9.  S u bj ect has hist or y of dr o p attac ks.  
1 0.  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 Visit 1.  
1 1.  S u bj ect has ha d i ntrat y m pa nic ster oi ds wit hi n 1 m o nt h pri or t o Visit 1.  
1 2.  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 nic i njecti o n of ster oi ds. 
1 3.  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 4.  S u bj ect has a n y ot her cli nicall y si g nifica nt ill ness or me dical c o n diti o n t hat, i n t he 
i n vesti gat or’s a n d t he me dical m o nit or’s o pi ni on, 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. 
1 5.  S u bj ect has partici pate d i n a cli nical trial wit hi n 3 0 da ys of Visit 1, n ot i ncl u di n g t he O T O -1 0 4 
P hase  3 st u d y ( 1 0 4 -2 0 1 5 0 8 ). 


 
 
 
                                                            1 3  
 
 
  
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6  
Criteri a f or E v al u ati o n:  
 
Safet y E val uati o ns :  
Ke y safet 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)  
 
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 her E val uati o n s: 
 Me niere’s s y m pt o m q uesti o n naire 
St atistic al Met h o ds:  
T his is a n o pe n la bel safet y st u d y wit h o ne treat me nt gr o u p.  All statistical a nal yses will be descri pti ve 
i n nat ure. 
I n vesti g ati o n al Pr o d uct, D os a ge a n d M o de of A d mi nistr ati o n:  
O T O -1 0 4 1 2 m g, si n gle, i ntrat y m pa nic i njecti o n, 0. 2 m L 
D ur ati o n of T re at me nt:  
Si n gle I T  i njecti o n gi ve n  at Da y 1  a n d M o nt h 3  
Ref ere nce T her a p y, D os a ge a n d M o de of A d mi nistr ati o n:  
N o ne  
Ti me a n d E ve nts Sc he d ule: See  T a ble  1 . 
 


 
 
 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            1 4  
 
 
T a ble  1 : 
Ti me a n d E ve nts T a ble  
Pr o ce d ure  
Scree ni n g/ 
B aseli ne/ D ose   
N o. 1  
F oll o w -u p/ D ose 
N o. 2  
E n d -of -St u d y/  
E arl y Ter m.  
U nsc he d ule d 
Visit  
Visit 1
1 
Visit 2  
Visit 3
2 
U nsc he d ule d  
D a y 1  
M o nt h 3              
( ± 2 w ee ks) 
M o nt h 6               
( ± 2 w ee ks) 
N/ A  
I nf or me d c o nse nt (i ncl u di ng 
pri vac y la n g ua ge/d oc u me nts)  
X  
 
 
 
Eli gi bilit y criteria  
X  
 
 
 
Me dical hist or y
3 
X  
 
 
 
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
Vital si g n meas ure me nts
4 
X  
X  
X  
X  
Hei g ht a n d wei g ht meas ure me nts  
X  
 
X
5 
 
Uri ne Pre g na nc y test
6 
X  
X  
X  
 
T y m pa n o metr y  
X  
X  
X  
X as i n dicate d  
A u di o metr y  
X  
X  
X  
X as i n dicate d  
Ot osc o p y  
X  
X  
X  
X  
C -S S R S assess me nt
7 
X  
X  
X  
X  
Me niere’s s y m pt o m 
q uesti o n naire  
X  
X  
X  
 
A d mi nister st u d y dr u g  
X  
X  
 
 
A d verse e ve nt m o nit ori n g  
X  
X  
X  
X  
1 Visit 1 ma y als o be t he last st u d y visit f or 1 0 4 -2 0 1 5 0 8 . 
2 Pr oce d ures  sc he d ule d f or Visit 3 will be perf or me d at t he e n d of t he f oll o w -u p peri o d ( ± 2 wee ks) or u p o n earl y 
disc o nti n uati o n fr o m t he st u d y.  
3 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.  
4 Vital si g n meas ure me nts i ncl u de bl o o d press ure a n d p ulse rate.  
5 O nl y wei g ht will be ta ke n at St u d y Visit 3.  
6 Fe male s u bj ects of c hil d beari n g p ote ntial will ha ve a uri ne pre g na nc y test via di pstic k at e ver y sc he d ule d visit.  O n 
Visit 1 a n d 2, t he pre g na nc y test m ust b e c o m plete d a n d c o nfir me d ne gati ve pr i or t o d osi n g.  If a s u bj ect is f o u n d 
t o be pre g na nt after d osi n g wit h O T O-1 0 4, t he y will c o m plet e t he f oll o w -u p peri o d b ut will n ot be d ose d f urt her 
wit h O T O -1 0 4.  
7 At Visit 1, t he Si nce  Last Visit versi o n of t he C -S S R S will be use d f or s u bj ects e nr olli n g fr o m St u d y 1 0 4 -2 0 1 5 0 8  
w hile t he B aseli ne versi o n will b e use d f or all s u bj ects e nr olli n g fr o m St u d y 1 0 4 -2 0 1 4 0 3 .  T he Si nce Last Visit 
versi o n of t he C -S S R S will b e use d at all s u bse q ue nt  visits.


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            1 5  
 
 
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 m e 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 lasti 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 h e dia g nosis 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 versi 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 ds; h o we 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 Meniere’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 dis ease.  H o w e ver, t he d e vice is n ot wi del y use 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 nsatisfact 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 oa 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 o l uti o n 
 
.  S o me p ol o x a mers, 
, ha ve t her m ore versi ble pr o perties 
a n d f u ncti o n as li q ui d p har mace utical ve hicl es t hat gel at b o d y te m p erat ur e.  Ot o n o m y ha s 
f or m ulate d de x a met has o ne, a s y nt hetic me m ber of t he gl u c oc ortic oi d class of ster oi d h or m o nes, 
i n 
 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. S i 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 v e  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 n cti onal 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.  


 
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1. 1.  
R ati o n ale f or S afet y  St u d y  
T w o cli nical st u dies ha ve bee n c o m plete d  i n t he U nite d States: a P hase 1 b st u d y a n d a P hase 2 b 
st u d y.  I n a d diti o n, t hree st u dies ha ve bee n i nitiate d i n eit her t he U nite d States or t he U nite d 
Ki n g d o m : P hase 2 re peat d ose safet y st u d y, P hase 3 st u d y a n d P hase 3 e xte nsi o n st u d y.  T he  
ra n d o mize d, place b o-c o ntr olle d, d o u ble -bli n d, m ulti -ce nter P hase 2 b  st u d y i n 1 5 4 u nilateral 
Me niere’s dis ease p atie nts de m o nstrate d t hat a si n gle I T a d mi nistrati o n of O T O -1 0 4 res ulte d i n  
i m pr o ve me nts i n verti g o c o ntr ol.  T he c o m plete d a n d o n g oi n g cli nical st u dies ha ve bee n eit her 
si n gle-d os e wit h a 3 -m o nt h or 4 -m o nt h f oll o w-u p peri o d  or a re peat -d ose wit h 4 d oses 
a d mi nistere d o ver o ne year .  Beca use Me niere’s disease is c hr oni c a n d i nter mitte nt, t he safet y of 
re peat a d mi nistrati o n nee ds t o be e val uate d.  T his st u d y was d esi g n e d wit h a t w o i njecti o n desi g n 
t o l o o k at re peat d oses o v er t he c o urse of si x m o nt hs.  T hree  m o nt hs was c h ose n as t he d ose 
i nter val d ue t o  i nf or mati o n gai n e d d uri n g t he f oll o w-u p peri o d i n r e gar d t o effect a n d safet y i n 
t he c o m pleted  P hase 1 b  a n d P hase 2 b st u dies .  
2.  
O B J E C TI V E S  
T he o bjecti ve is t o assess t he safet y of re peat I T i njecti o ns of 1 2 m g O T O-1 0 4 at 3 -m o nt h 
i nter vals i n a n o pe n-la b el st u d y i n s u bjects wit h u nilateral Me niere’s disease. 
3.  
O V E R VI E W O F S T U D Y D E SI G N  
T his is a 6 -m o nt h, m ultice nter, P hase 3 , o p e n-la bel e xte nsi o n safet y st u d y i n s u bjects wit h 
u nilateral Me niere’s disease.  S u bjects will recei ve 1 I T i njecti o n of 1 2 m g O T O -1 0 4 at 3 -m o nt h 
i ntervals f or a t otal of 2 i njecti o ns.  Safet y data t o be c ollecte d i ncl u d e a d verse e ve nts, 
c o nc o mita nt me dicati o ns, ot osc o p y, vital si g ns, a u di ol o g y, t y m p a n o metr y, C ol u m bia -S uici de 
Se verit y Rati n g Scal e ( C -S S R S) q uesti o n naire a n d a Me niere’s diseas e s y m pt o m q u esti o n naire.  
O nce s u bjects meet all eli gi bilit y criteria, t he y will be e nr olle d a n d ma y recei ve u p t o 2 I T 
i njecti o ns of O T O-1 0 4 at 3 -m o nt h i nter vals.  All s u bjects will re mai n o n sta n dar d of care 
treat me nt f or u nilateral Me niere’s dis ease.  S u bjects will ret ur n t o t he st u d y sites at M o nt h 3 f or 
safet y assess me nts a n d a n ot her I T i njecti o n of O T O -1 0 4.  Safet y ass ess me nts will be c o m plete d 
at t he e n d of t he st u d y ( M o nt h 6) or u p o n earl y wit h dra wal fr o m t he st u d y.


 
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4.  
S T U D Y P O P U L A TI O N  
4. 1.  
Ge ner al C o nsi der ati o ns  
U p t o 3 0 0  s u bjects will be e nr olle d  at a p pr o xi matel y 6 0 -7 0 sites i n si x c o u ntries, i ncl u di n g 
U nite d Ki n g d o m, G er ma n y, P ola n d, Ital y, Bel gi u m a n d Fra nce .  S u bjects will be e nr olle d o nl y if 
t he y me et 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 w er 
( u nless n ot a p plica ble): 
1.  S u bject is a male or fe m ale a ge d 1 8 years or ol der.  
2.  S u bject has c o m plete d t h e P hase 2 ( 1 0 4 -2 0 1 4 0 3 ) or P hase 3 (1 0 4 -2 0 1 5 0 8 ) cli nical st u d y. 
3.  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 e nr oll me nt. W o me n of c hil d beari n g p ot e ntial 
w h o are n ot a bsti ne nt fr o m se x wit h male part ners ma y b e e ntere 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, c o ntrace pti ve i m pla nt 
or i nject i 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 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 de).   
4.  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.  
5.  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. 
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 per res pir at or y s yste m.  
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 dise ase.  
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 nic 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.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            1 8  
 
 
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 h at 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 n ot li mite d t o a 
m o n o meric, atelectatic or atr o p hic t y m p a nic me m bra ne.  
6.  S u bject has a hist or y of t y m pa n ost o m y t u bes t hat i ncl u des e vi de nce of perf orati o n or lac k 
of cl os ure.  
7.  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.  
8.  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.  
9.  S u bject has hist or y of dr o p attac ks.  
1 0.  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 Visit 1.  
1 1.  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 Visit 1.  
1 2.  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 d s. 
1 3.  S u bject has a h y pers e 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 4.  S u bject has a n y ot her cli nicall y si g nifica nt ill ness or me dical c o n diti o n t hat, i n t he 
i n vesti gat or's a n d t h e 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.  
1 5.  S u bject has partici pate d i n a cli nical trial wit hi n 3 0 da ys of Visit 1, n ot i ncl u di n g t he 
O T O -1 0 4 P hase 3 st u d y ( 1 0 4 -2 0 1 5 0 8 ). 
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G 
T his st u d y is a n o pe n -la b el st u d y wit h all s u bjects recei vi n g O T O-1 0 4; t heref ore, n o 
ra n d o mizati o n or bli n di n g is re q uire d. 
5. 1.  
E nr oll me nt Pr oce d ures  
5. 1. 1.  
Assi g n me nt of S u bject I de ntific ati o n N u m bers  
All s u bjects will retai n t he sa me u ni q ue s u bject i de ntificati o n n u m ber as t h e o ne assi g ne d in 
cli nical st u d y 1 0 4 -2 0 1 4 0 3  or 1 0 4 -2 0 1 5 0 8  pl us a 3 -di git n u m ber t o i n dicate w hic h st u d y t he 
s u bject partici pate d i n pr e vi o usl y.  T he s u bject i de ntificati o n 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 a n d will re mai n wit h t he s u bject t hr o u g h o ut t he d urati o n of t he 
st u d y.  All s u bjects wit h a si g ne d i nf or me d c o ns e nt f or t he st u d y, w het her e nr olle d or n ot (scree n 
fail ures, s u bject r ef usal, etc.), will be d oc u me nt e d. 
6.  
D O S A G E A N D A D MI NI S T R A TI O N  
6. 1.  
St u d y 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 diseas e s u bjects is as f oll o ws:   


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            1 9  
 
 
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 hetiz e 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 h e p osteri or i nf eri or q ua dra nt 
wit h t o pical li d ocai ne/ pril ocai ne crea m (i.e., 
) u ntil t he t y m pa 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 t he 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 pers o n nel as a si n gle, i ntrat y m pa ni c i njecti o n  at Visit 1 
a n d 2 e x ce pt  w he n wit h h el d d ue t o p ote ntial safet y c o n cer ns .  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 o c u me nts a n d t he e C R F.  
T he site will mai ntai 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 ntorie 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 dic ati 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 
e nr oll me nt , w hic h will be c o nsi dere d pri or t hera p y.  A n y c o nc 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 or Pr oce d ures 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 ar e 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 p pr essi ve me dicati o ns 
 P he n ol f or use i n a nest h etizi n g t he t y m pa nic me m bra ne  
 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 
 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 os cri be d t hera pi es will be c o nsi dere d a pr ot o c ol de viati o n . 


 
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7. 2.  
S y m pt o m atic Relief Me dic ati o ns  
It is rec o g niz e 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.  I nter mitte nt use of vesti b ular s u p pressa nts 
a n d a nti -e metics is all o w e d as s y m pt o matic relief me dicati o ns.  T he use of ge nt a mici n , 
c ortic oster oi ds  or s ur ger y at a n y ti me d uri n g t h e st u d y will be c o nsi de re d a pr ot oc ol de viati o n .  
A n y c ha n ges re p ort e 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: D a y 1 ( Scree ni n g/ B aseli ne/ D ose N o. 1)  
T he f oll o wi n g assess me nts will b e perf or me d at Visit 1.  F or s u bjects e nr olli n g directl y ( wit hi n 1 
m o nt h) fr o m St u d y 1 0 4 -2 0 1 5 0 8 , t he t y m pa n o metr y, a u di o metr y, ot osc o p y a n d C-S S R S 
assess me nt data c ollecte d at t he fi nal visit of St u d y 1 0 4 -2 0 1 5 0 8  will ser ve as t he Bas eli ne data 
f or Visit 1. 
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  
 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 n l y) 
 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 or Si nce Last Visit versi o n  
 Me niere’s s y m pt o m q uesti o n naire  
 A d mi nister O T O -1 0 4 (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 a d mi nistrati o n)  
 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. 2.  
Visit 2: M o nt h 3  ( ± 2 wee ks) ( F oll o w U p a n d D ose N o. 2) 
T he f oll o wi n g assess me nts will be perf or me d at Visit 2 . 


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 1  
 
 
 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)  
 A u di o metr y  
 T y m pa n o metr y  
 Ot osc o p y  
 C -S S R S assess me nt, Si nce Last Visit versi o n  
 Me niere’s s y m pt o m q uesti o n naire  
 A d mi nister O T O -1 0 4 (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 a d mi nistrati o n)  
 A d verse e ve n ts (t o be collecte d d uri n g or  after O T O -1 0 4 a d mi nistrati o n)  
8. 1. 3.  
Visit 3 : M o nt h 6  ( ± 2 wee ks) ( 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 3 . 
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 Wei g ht  meas ur e me nt  
 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)  
 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, Si nce Last Visit versi o n  
 Me niere’s s y m pt o m  q uesti o n naire  
 A d verse e ve nts  
8. 1. 4.  
U nsc he d ule d Visit  
T he f oll o wi n g assess me nts will be perf or me d at a n u nsc he d ule d visit . 
 C o nc o mita nt me dicati o ns  
 Vital si g ns  
 T y m pa n o metr y , as i n dicate d 
 A u di o metr y , as i n dicate d 
 Ot osc o p y  
 C -S S R S assess me nt, Si nce Last Visit versi o n  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 2  
 
 
 A d verse e ve nts  
8. 2.  
S afet y E v al u ati o ns  
Safet y assess me nts i ncl u de:  
 Vital Si g ns, Hei g ht a n d Wei g ht Meas ure me nts  
 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. 2. 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 ur e me nts (i ncl u di n g s yst olic a n d di ast 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.  Bl o o d press ur e a n d  p ulse rate will be meas ure d after s u bjects ha ve 
bee n seat e 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  3 . 
8. 2. 2.  
Uri ne Pre g n a nc y Test  
A uri ne pre g n a nc y tes t vi a di pstic k will be c o n d ucte d o nl y o n w o me n of c hil d beari n g p ot e ntial at 
all st u d y visits .  T he uri ne pre g na n c y test m ust be c o n d ucte d a n d c o nfir me d ne gati ve pri or t o 
a d mi nistrati o n of O T O -1 0 4  at St u d y Visits 1 a n d 2 . 
8. 2. 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 a t 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 heir h eari n g ai ds d uri n g t he 
t y m pa n o metr y assess me nt. 
8. 2. 4.  
A u di o gr a ms  
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 ncie s.  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 h eari 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 


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 3  
 
 
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. 2. 5.  
Ot osc o p y  
Ot osc o pic e x a ms will be 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 y sici a n.  Prese nce a n d size 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 d v erse e v e nts ( A Es ) o nl y if t he perf orati o n i ncreases 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.  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 ot osc o pic e x a m.  
8. 2. 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 Si nce Last Visit versi o n of 
t he C-S S R S will be use d f or s u bjects e nr olli n g fr o m St u d y 1 0 4 -2 0 1 5 0 8  w hile t he Bas eli ne 
versi o n will be use d f or all s u bjects  e nr olli n g fr o m St u d y 1 0 4 -2 0 1 4 0 3 .  T he Si nce Last Visit 
versi o n of t he C -S S R S will be use d at all s u bse q ue nt visits.  A n y s u bject wit h a p ositi ve sc ore o n 
t he Bas eli 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 ha vi or si nce t he 
Baseli ne v ersi o n ( w h et her a d mi nistere d i n t his st u d y or St u d y 1 0 4 -2 0 1 5 0 8 ) 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-Baseli ne  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 Baseli ne  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 ad verse e v e nt ( 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. 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 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-Baseli ne  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 w ere 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 Bas eli ne , t he n t his assess me nt s h o ul d be rec or de d as a seri o us ad verse eve 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 . 
8. 3.  
A d diti o n al E v al u ati o ns  
8. 3. 1.  
Me niere’s S y m pt o m  Q uesti o n n aire  
T he Me niere’s s y m pt o m q uesti o n naire is a set of  q uest i o ns t hat will be a d mi nistere d at St u d y 
Visits 1, 2,  a n d 3 .  Eac h q uesti o n has 5 p ossi ble res p o nses:  1) N o Verti g o/ N o Ti n nit us/ N o Ear 
F ull ness/ N o Heari n g Diffic ult y ( de p e n di n g o n t he q uesti o n  a d mi nistere d), 2) Mil d , 3) M o derate , 
4) Se vere , a n d 5) E xtre mel y Se v ere.   T his ass ess me nt is c o nsi dere d a n a d diti o nal e n d p oi nt.  


 
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9.  
A D V E R S E E V E N T ( A E) R E P O R TI N G  
Ti mel y, acc urate, a n d c o m plete 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 S A Es re p orte d or o bser 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 p a ge of t he e C R F f or all e nr oll e d s u bjects.  I nf or mati o n t o be c ollecte d 
i ncl u des descri pti on of e ve nt, date of o nset, i n vesti gat or -s pecifi e d assess me nt of t he se verit y a n d 
relati o ns hi p t o st u d y dr u g, dat e of res ol uti o n of t he e ve nt, seri o us ness, a n y re q uire d tr eat me nt or 
e val 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 ness es, 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 disease states m ust 
als o be re p ort e d.  Perf orati o ns of t he t y m pa nic me m bra ne will be ca pt ure d as A Es o nl y if t h e 
perf orati o n i ncreases i n siz e a n d d oes n ot res ol v e 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 mpt 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 his 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 w ar 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 hr eate 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 hetic all y mi g ht ha v e 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 gat i 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 
 is a c o n ge nital a n o mal y/ birt h defect.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 5  
 
 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x erc ise 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 vesti 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 cr iteria: 
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 vities.  
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 ui re 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 uire c o m ple x 
me dicati o n/treat me nt or h os pitaliz ati 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 ere . 
Gr a de 5 –  D e 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 b e 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 vesti 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 wil l 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 v e 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 o ns (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 pea r t o e x plai n t he e ve nt. 
Pr o b a ble : A d verse e v e 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 relate 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  
 the 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 ca 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  
 the 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.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 6  
 
 
P ossi ble : A d vers e e ve nts t hat, after caref ul me dical e val uati o n, d o n ot meet t he criteria 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:  
 the e ve nt oc c urs aft er e x p os ure t o t he st u d y dr u g, a n d  
 there 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  
 in t he a bse nce of a reas o na ble te m p oral r elati 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 nati 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: 
 the e ve nt d oes n ot ha ve a reas o na bl e te m p oral r elati 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 ca 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 biliz es, 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 defi 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 AEs i n res p o nse t o ge n eral, 
n o n -directe d q u esti 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 ea c h A E 
v ol u nteere d b y t he s u bject , 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 eC 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 eC 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 ort e d 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 eC 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 uir e 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 o ns 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 ort e 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 V isit.  
T he descri pti o n of t he A E will i ncl u de descri pti o n of e ve nt, date of o nset, date of res ol uti o n, 
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 uir e d 
treat me nt or e v al uati o ns, a n d o utc o me.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 7  
 
 
T he s p o ns or ass u mes r es p o nsi bilit y f or a p pr o pri ate re p orti n g of A Es t o t he 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 
I nstit uti o nal Re vie w B oar d (R E C ) in 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 nic al 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 e-m ail  or facsi mi le (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, n at ur e 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 n fir 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 biliz es, or 
 t he e ve nt be c 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 o r 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 u ct  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 b e 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.  
  
 
 


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 8  
 
 
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 h e 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 pleti o n  
S u bjects w h o wit h dra w  fr o m f urt her a d mi nistrati o n of st u d y dr u g or 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 3  ( M o nt h 6 ) will n ot be 
c o nsi dere d t o ha v e 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 ve t he ri g ht t o wit h dra w f r o m st u d y dr u g a d mi nistrati o n a n d/ or st u d y e v al 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 e ve n if t he s u bject has wit h dra w n fr o m st u d y dr u g 
s o t hat c o nti nue d o bser vati o n a n d f oll o w -u p meas ure me nts ma y be o btai n e d.  T he i n vesti gat or 
ma y disc o nti n ue a s u bject’s partici 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 bl e 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 di cati 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 ur e 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 f urt her 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 participati o n i n t he st u d y ma y be st o p pe d at a n y ti me at t he 
discreti 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 f urt her 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 foll 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 dr a 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 
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.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            2 9  
 
 
W he n a s u bject wi t h dra ws fr o m f urt her 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 3  ( M o nt h 6 ), t he reas o n f or wit h dra wal is t o be d oc u m e nte d o n t he eC R Fs a n d 
i n t he s o urce d oc u m e nt.   
1 0. 2. 2.  
Re pl ac e 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 e m p hasis of t he a nal ysis will be wit h res pect t o descri pti o n a n d esti mati o n rat her t ha n 
h y p ot hesis testi n g .  T he f oll o wi n g statistical secti o ns descri be t he ge neral a nal ytic met 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 detaile 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).   
1 1. 1.  
S a m ple Siz e 
It is e x pecte d t hat up t o 3 0 0 s u bject s fr o m P hase 2 (1 0 4 -2 0 1 4 0 3 ) or P has e 3 ( 1 0 4 -2 0 1 5 0 8 ) 
cli nical trials will be e nr olle d i nt o t his st u d y.  T he sa m ple siz e was n ot base d o n a n y p o wer 
calc ulati o n.   
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.    
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 at least o ne 
d ose of st u d y dr u g.   
1 1. 3.  
Descri pti o n of S u b gr o u ps t o be A n al yze d  
Ke y safet y d ata will be d escri be d  f or t he f oll o wi n g s u b gr o u ps usi n g t he safet y a nal ysis set : 
 S u bject De m o gra p hics  
 Ge n der  
A d diti o nal de m o gra p hic a n d baseli ne c h aracteristi c s u b gr o u ps will be c o nsi dere d a n d i d e ntifie d 
i n detail i n t he S A P. 
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, b aseli ne disease stat us, a n d s u bject dis p ositi o n 
will be pr o vi de d.  If feasi ble, a Ka pla n -Meier pl ot of ti me -t o-st u d y wit h dr a wal will als o be 
esti mate d.  Pr ot oc ol de viati o n s will be a nal yze d b y a g gre gat e s u m mar y a n d/ or li ne listi n gs if t he 
n u m ber of de viati o n s is s mall. 
1 1. 5.  
Effic ac y E v al u ati o ns  
N ot a p plica ble  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 0  
 
 
1 1. 6.  
Ge ner al A n al ytic Met h o ds  
T he pri mar y a n al yti c a p pr oac h f or t his trial will be descri pti ve.  S u m mar y statistics will be 
calc ulate d a n d w here rele va nt , 9 5 % c o nfi de n ce i nt er vals pres e nte d.  Details of t he a nal ysis will 
be descri b e d i n t he S A P.  
1 1. 7.  
S afet y E v al u ati o ns  
Safet y e val uati o ns i ncl u d e : 
 Vital Si g ns, Hei g ht a n d Wei g ht Meas ure me nts  
 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  
1 1. 7. 1.  
A d verse E ve nts  
V ersi o n 1 8. 1  of Me dic al Dicti o nar y f or Re g ul at or y Acti vities  ( Me d D R A) 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 der o nl y tr eat me nt e mer ge nt A Es (T E A Es ), e ve nts 
occ urri n g f or t he first ti me, or w ors e 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 t er ms a n d s yste m or ga n class.  
T hese a n al ys es ma y als o be ta b ulate d b y visit , ti me of o nset a n d/ or c u m ulati ve e x p os ure.  I n 
a d diti o n, se verit y a n d rel ati o ns hi p t o st u d y dr u g will als o be prese nte d.   A d verse e v e nts  will be 
prese nte d b y d esce 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 of A Es b y  ge n d er will be e x a mi ne d.   Listi n gs of all S A Es, A Es lea di n g t o 
st u d y wit h dra w al, 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.   
1 1. 7. 2.  
Vit al Si g ns  
T he a nal ysis of vital si g ns will i ncl u de descri pti ve statistics f or t he c ha n ge fr o m baseli ne t o  eac h 
p ost -baseli ne visit  w here v ital si g ns are c ollecte d.  T he c ha n ge fr o m bas eli ne t o t he w orst p ost -
baseli ne val ue (i ncrease/ decrease) m a y als o be e x a mi ne d.   W ei g ht meas ure me nts f or baseli ne 
a n d p ost -baseli ne visits will be ta b ulate d  as will hei g ht meas ure me nts f or baseli ne . 
1 1. 7. 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.  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 classificati o n will be pr o vi de d b y st u d y 
visit  usi n g s hift ta bles w here a p pr o priate .  Data will be ta b ulate d se paratel y f or t he treate d a n d 
u n treate d ear.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 1  
 
 
1 1. 7. 4.  
A u di o metr y Assess me nts  
Descri pti ve s u m mar y statistics a n d/ or s hift ta bles f or a u di o metric ass ess me nts of air a n d b o ne 
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 st u d y visit.  I n a d diti o n, t he p ure 
t o ne a vera ge (P T A ) a n d b o ne c o n d ucti o n a v era ge ( B C A) will be calc ulat e d as t he a vera ge air  or 
b o ne  c o n d ucti o n t hres h ol d f or fre q ue nci es of 5 0 0, 1 0 0 0, a n d 2 0 0 0 .  
Air -B o n e Ga p assess me nts at eac h fre q ue n c y 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 0 d B or  
 > 1 0 d B.  
All a u di o metr y assess me nts will be ta b ulate d se paratel y f or t he treate d a n d u ntreate d ear.  
1 1. 7. 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 .  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).   
1 1. 7. 6.  
C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt me dicati o ns will be c o de d b y W H O Dr u g a n d will be ta b ulate d b y dr u g class a n d 
preferre d dr u g na me.  
1 1. 7. 7.  
C -S S R S  
T he C -S S R S will be a d mi nistere d at eac h visit 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. 7. 7. 1.  C -S S R S: B aseli ne Versi o n  
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 Si nce Last Visit versi o n of 
t he C-S S R S will be use d f or s u bjects e nr olli n g dir ectl y ( wit hi n 1 m o nt h) fr o m St u d y 1 0 4 -2 0 1 5 0 8  
w hile t he Bas eli ne versi o n will be use d f or all ot her s u bjects.  T he Si nce Last Visit versi o n of t he 
C -S S R S will be use d at all s u bse q ue nt visits.  T he Baseli ne v ersi o n of t he s cale 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 h e 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 w as a n y i deati o n, re gar dless of t y pe.  T h ere are 4 s uici dal be h a vi or 
q uesti o ns, ea c h ca pt ure d as yes/ n o f or t he 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 ur e if t here w as a n y s uici dal be ha vi or re gar dless of t y pe.  A n a d diti o 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 uic i dal i deati o n a n d be h a vi oral 
varia bles as o utli ne d here will be ta b ulate d o verall a n d b y tr eat 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.  
1 1. 7. 7. 2.  C -S S R S: Si nce L ast Visit V ersi 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 eac h st u d y visit i ncl u di n g 
Visit 1 or after Visit 1  de pe n di n g o n w het her t he s u bject was a p artici pa nt fr o m St u d y 1 0 4 -


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 2  
 
 
2 0 1 4 0 3  or 1 0 4 -2 0 1 5 0 8 .  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 an d be ha vi or v aria bles will be ta b ulate d o verall a n d b y tr eat 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.  
1 1. 8.  
Ot her E v al u ati o ns  
A d diti o nal e n d p oi nts i ncl u de:  
 Me niere’s s y m pt o m q uesti o n naire  
1 1. 8. 1.  
Me niere’s S y m pt o m Q uesti o n n aire  
Descri pti ve s u m mar y statistics de n oti n g t he c h a n ge fr o m baseli ne a n d/ or s hift ta bles f or t he 
verti g o, ti n nit us, a ural f ull ness a n d s u bjecti ve heari n g will be pr o vi de d.  F or t he Gl o bal 
Me niere’s Disease q u esti o n, n ot meas ure d at b aseli ne, s u m mar y statistic s f or eac h visit will be 
pr o vi de d.  
1 1. 9.  
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  
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 ur e me nts t o mi ni mize t he a m o u nt of missi n g d ata.  
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. 1 0.  
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 .  Re vie w of safet y data will b e 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 de 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.  T h e 
O T O -1 0 4 fi nal pr o d u ct 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 de d) a n d O T O -1 0 4 Acti ve ( o ne vial n ee de d). A n a p pr o priat e 
v ol u me of O T O -1 0 4 Dil ue nt will be wit h dra w n a n d deli 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 ge ne o us s us pe nsi o n of a t ar get dr u g c o n ce ntrati o n of 6 0 m g/ m L.  
T he pr o d uct will be s u p plies as a kit c o ntai ni n g o n e vial of O T O -1 0 4 Acti v e a n d o ne vial of 
O T O -1 0 4 Dil ue nt.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 3  
 
 
1 2. 2.  
Directi o ns f or Use  
O T O -1 0 4 is t o be pre p are d in a cle a n  l ocati o n wit h a r o o m te m perat ure prefera bl y at or bel o w 
2 3° C ( 7 3° F).  Please refer t o t he P har mac y Ma n u al f or detaile d st u d y dr u g pre parati 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 , O T O-1 0 4 Acti ve a n d O T O -1 0 4 Dil ue nt vials  i n dicati n g 
c o nte nts a n d st ora ge i nstr ucti o ns. 
1 2. 4.  
M a n a ge me nt of Cli nic al S u p plies  
T he cli nical s u p plies will be ma na ge d b y t h e C R O .  T he S p o ns or  will creat e s hi p me nt re q uests 
t hat will be ge n erat e d o n i n ve nt or y t hr es h ol ds t hat are set f or eac h site.  A s hi p me nt re q uest will 
be ge nerate d a n d  s e 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 material, t he site pers o n nel will ac k n o wle d ge t he s hi p me nt a n d i de ntif y a n y d a ma ge d, 
missi n g, or u n usa ble kits s o t he y will n ot be dis pe nse d.   
1 2. 4. 1.  
St or a ge of Kits  
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 perat 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 st u d y dr u g s h o ul d i m me diatel y b e q uara nti ne d  a n d re m o ved  fr o m 
i n ve nt or y. 
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 st u 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 r ec 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  site m ust  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, 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 n e d b y t h e cli nical site staff will be st ore 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 st u d y m o nit or 
d uri n g o n -site m o nit ori n g visits.  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 oc ke d 
ca bi net u n der a p pr o pri ate e n vir o n me ntal 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 by ot h er s u bjects e x ce pt u n der s pecial cir c u msta nces a p pr o ve d b y Ot o n o m y.  


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 4  
 
 
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 n e 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 nstructe 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  H elsi 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 uire 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 d esi 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 b se 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 mitte 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. 
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 uir e 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 ull y 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 h e 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 re 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 nefits a n d p ote ntial ha zar 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 
that 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 be 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 u esti o ns.  After t his e x pla nati o n a n d bef ore e ntr y 


 
Ot o n o m y 1 0 4 -2 0 1 6 1 0 Pr ot oc ol V 2. 0 : 2 6 A pril  2 0 1 6                                                            3 5  
 
 
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 s i 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 o p 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  ap 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 pect s 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 o c ol, t he i n vesti gat or or ot her p h ysicia n i n 
atte n da nce will c o ntact t he site ma na ger , Me dical M o nit or or ot her a p pr o priate s p o ns or 
re pres e ntati ve b y 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 b ef ore i m ple me nti n g a n y de part ure fr o m pr ot oc ol.  I n all cases, c o 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 urs e of acti o n.  T he eC 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 m e 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. 
 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 me 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 h ere 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 researc 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 o r 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 ur e t his i n f or mati o n. 


 
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 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 u d y, ot her d o c u me ntati o n ma y b e re q uir e 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 -term 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 a cci 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 lea st t w o years after t h e last a p pr o val 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 ps e 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 perio d if re q uire d b y t he a p plica ble re g 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 o f t he n e w c ust o dia n. 
1 4. 5.  
Electr o nic C ase 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  ele ctr o nicall y b y t he 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 m e 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 u bjects 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 ns 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 y st 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 pri ate 


 
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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 
effic ac 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 safet y i nf or m ati o n as 
it is e ntere d a n d verifie d i n t he electr o nic d ata 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 la b yri nt h dis or ders S O C will be re vi e we d at least e ver 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 see if a n y tre n ds 
i n st u d y disc 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 
me dical pers o n n el w it hi n 1-2 da ys after recei pt w het her 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 pri ate re p orti n g t o t he 
re g ulat or y a ut h orities. T h e 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  re q 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 


 
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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 b e g u n.  At t hese visits, t he m o nit or will 
c o m pare t he d ata e nt ere d o nt o t he eC 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 E s, 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 m e 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 eC 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 pri ate, 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 n cl 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 p ers 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 .  Cas e re p ort f or m s 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 b ase 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 ncl 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 eC 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 d it. 
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 pecti 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 nic al i n v esti gat ors or g o ver n me nt re g ulat or y a ge ncies.  T o per mit t he 


 
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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 v a 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.   
 


 
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1 5.  
LI S T O F R E F E R E N C E S  
A merica n S peec h -La n g u a ge -H eari n g Ass o ciati o n. ( 2 0 0 5). G ui deli nes f or ma n ual p ure -to ne 
t hres h ol d a u di o metr y [ G ui deli nes]. A vaila ble fr o m w w w.as ha. or g/ p olic y. - See m ore at: 
htt p:// w w w.as ha. or g/ p olic y/ G L 2 0 0 5 -0 0 0 1 4. ht m #st has h. 0 X g 5 w h C S. d p uf  
Barritt L. Me ni ere’s Dise ase . X P h ar m 2 0 0 8 ( 1 -6).  
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 disease.  Ot o -l ary n g ol He a d Neck S ur g.  
1 9 9 5;  1 1 3( 3): 1 8 1 -1 8 5.  
Ki m H H, Wiet RJ,  Batista R A. Tre n ds i n t he dia g n osis a n d ma na ge me nt of Me niere’s dis ease: 
res ults of a s ur ve y. Ot ol ary n g ol He a d Neck S ur g.  2 0 0 5; 1 3 2: 7 2 2 -6.  
S hea JJ: Classificati o n of Me niere’s Disease. A m J Ot ol  1 9 9 3: 1 4: 2 2 4 -2 2 9.