Conditions: Meniere Disease
Keywords: Meniere's Disease Vertigo Endolymphatic Hydrops Labyrinth Diseases Ear Diseases Otorhinolaryngologic Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 148
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: None arm 2: None

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

Protocol document:
Prot_SAP_000.pdf: 




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


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4   
1 0.  
S U BJ E C T C O M P L E TI O N  ......................................................................................... 4 3 
1 0. 1.  
C o m pleti o n ................................................................................................................. 4 3  
1 0. 2.  
Wit h dra wal  ................................................................................................................. 4 3 
1 1.  
S T A TI S TI C A L M E T H O D S  ....................................................................................... 4 4 
1 1. 1.  
Sa m ple Size  ................................................................................................................ 4 4 
1 1. 2.  
A nal ysis S ets ............................................................................................................... 4 4 
1 1. 3.  
Descri pti o n of S u b gr o u ps t o be A nal yze d .................................................................. 4 5  
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  ............................. 4 5 
1 1. 5.  
Efficac y E val uati o ns  ................................................................................................... 4 5 
1 1. 6.  
Safet y E val uati o ns ...................................................................................................... 4 8  
1 1. 7.  
Ha n dli n g of Missi n g Data, S u bject Wit h dra wals, a n d Treat me nt Fail ures ................ 5 1  
1 1. 8.  
I nteri m A nal yses ......................................................................................................... 5 1 
1 2.  
S T U D Y  D R U G I N F O R M A TI O N  .............................................................................. 5 1 
1 2. 1.  
P h ysical Descri pti o n of St u d y Dr u g(s) ....................................................................... 5 1  
1 2. 2.  
Directi o ns f or Use  ....................................................................................................... 5 1 
1 2. 3.  
Pac ka gi n g a n d La beli n g .............................................................................................. 5 2  
1 2. 4.  
Ma na ge me nt of Cli nical S u p plies  ............................................................................... 5 2 
1 2. 5.  
Dr u g Acc o u nta bilit y ................................................................................................... 5 2  
1 3.  
E T HI C A L A S P E C T S  ................................................................................................. 5 3 
1 3. 1.  
I n vesti gat or Res p o nsi bilities ....................................................................................... 5 3 
1 3. 2.  
I nstit uti o nal Re vie w B oar d (I R B) a n d Researc h Et hics C o m mittee ( R E C) ............... 5 3 
1 3. 3.  
I nf or me d C o nse nt ....................................................................................................... 5 3 
1 4.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  .................................................................. 5 4 
1 4. 1.  
Pr ot oc ol M o dificati o ns ............................................................................................... 5 4  
1 4. 2.  
Re g ulat or y D oc u me ntati o n  ......................................................................................... 5 4 
1 4. 3.  
Rec or d Rete nti o n ........................................................................................................ 5 4  
1 4. 4.  
Electr o nic Case Re p ort F or m  ...................................................................................... 5 5 
1 4. 5.  
Ter mi nati o n  ................................................................................................................. 5 5 
1 4. 6.  
Data a n d Safet y M o nit ori n g Pla n  ............................................................................... 5 6 
1 4. 7.  
M o nit ori n g .................................................................................................................. 5 6  
1 4. 8.  
Data Q ualit y Ass ura nce  .............................................................................................. 5 6 
1 4. 9.  
O n -Site A u dits  ............................................................................................................ 5 7 
1 4. 1 0.  
Use of I nf or mati o n a n d P u blicati o n ............................................................................ 5 7  


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
5   
1 5.  
R E F E R E N C E S  ........................................................................................................... 5 8 
 
LI S T O F T A B L E S  
Ta ble  1: 
Ti me a n d E ve nts Sc he d ule .......................................................................................... 2 2  
 
 




Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
7 
Secti o n(s)  
Descri pti o n of C h a n ges  
R ati o n ale 
F ull A n al ysis Set ( F A S):   T he f ull a nal ysis set will 
i ncl u de all s u bjects w h o are ra n d o mize d, recei ve st u d y 
dr u g, ha ve a baseli ne defi niti ve verti g o meas ure me nt 
f or t he 4-wee k lea d -i n peri o d a n d at least o ne p ost-
baseli ne dail y diar y e ntr y.  T he pri mar y a nal ysis f or t he 
pri mar y e n d p oi nt of D V D will be c o n d ucte d usi n g t he 
F A S.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p 
t o w hic h t he y were ra n d o mize d re gar dless of t he act ual 
st u d y dr u g recei ve d. 
Is: 
F ull A n al ysis Set ( F A S) :  T he f ull a nal ysis set will 
i ncl u de all s u bjects w h o are ra n d o mize d, recei ve st u d y 
dr u g, ha ve a baseli ne defi niti ve verti g o meas ure me nt 
f or t he 4-wee k lea d -i n peri o d a n d at least o ne p ost-
baseli ne dail y diar y e n tr y f or Wee k 1 2.  All effic ac y 
a n al yses  will be c o n d ucte d usi n g t he F A S.  S u bjects 
will be i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y 
were ra n d o mize d re gar dless of t he act ual st u d y dr u g 
recei ve d. 
Per Pr ot oc ol A n al ysis Set  defi niti o n  
Was:  
Per Pr ot oc ol A n al ysis Set:   T he per pr ot oc ol a nal ysis 
set will i ncl u de all s u bjects w h o are ra n d o mize d, 
recei ve st u d y dr u g, meet eli gi bilit y criteria, ha ve n o 
maj or pr ot oc ol de viati o ns,  a n d ha ve a baseli ne a n d at 
least o ne 4-wee k defi niti ve verti g o meas ure me n t p ost-
baseli ne, i.e. at least o ne p ost -baseli ne dail y diar y 
e ntr y.   
Is: 
Per Pr ot oc ol A n al ysis Set:   T he per pr ot oc ol a nal ysis 
set will i ncl u de all s u bjects w h o are ra n d o mize d, 
recei ve st u d y dr u g, meet eli gi bilit y criteria, ha ve n o 
maj or pr ot oc ol de viati o ns,  a n d ha ve a baseli ne 
defi niti ve verti g o me as ure me nt  a n d at least o ne p ost -
baseli ne d ail y di ar y e ntr y wit hi n Wee k 9 t hr o u g h 1 2 . 
I nte nt t o Tre at A n al ysis Set: 
Was:  
I nte nt-t o-Treat A nal ysis Set (I T T):  T he I T T a nal ysis 
set will i ncl u de all ra n d o mize d s u bjects w h o recei ve 
st u d y dr u g.  S u bjects will be i ncl u de d i n t he treat me nt 
reflecti n g pri mar y 
a nal ysis is at Wee k 
1 2 [t he 4- wee k ( 2 8 
da y) i nter val fr o m 
Wee k 9 t hr o u g h 
Wee k 1 2 ] a n d 
clarificati o n o n 
w he n t he I T T 
p o p ulati o n will be 
use d.   






Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 0 
Secti o n(s)  
Descri pti o n of C h a n ges  
R ati o n ale 
w here a defi niti ve verti g o e pis o de was rec or de d 
di vi de d b y t he n u m ber of n o n- missi n g diar y e ntries 
f or t he rele va nt i nter val 
•
Se verit y of verti g o e pis o des as meas ure d b y t he
mea n Verti g o Sc ore d uri n g eac h 4- wee k st u d y
i nter val ( Wee k 1 t hr o u g h Wee k 4) a n d ( Wee k 5
t hr o u g h 8).
•
A vera ge dail y c o u nt of verti g o e pis o des d uri n g
eac h 4- wee k st u d y i nter val ( Wee k 1 t hr o u g h Wee k
4) a n d ( Wee k 5 t hr o u g h Wee k 8)
•
T he n u m ber of da ys Sic k at h o me or Be dri d de n as a
c o nse q ue nce of verti g o d uri n g eac h 4- wee k st u d y
i nter val ( Wee k 1 t hr o u g h Wee k 4) a n d ( Wee k 5
t hr o u g h Wee k 8)
•
T he n u m ber of defi niti ve verti g o da ys ( D V D)
d uri n g eac h 4 - wee k st u d y i nter val ( Wee k 1 t hr o u g h
Wee k 4) a n d ( Wee k 5 t hr o u g h Wee k 8)
Is: 
•
T he c ha n ge fr o m baseli ne i n verti g o fre q ue nc y
( V F) at Wee k 8, w here verti g o fre q ue nc y is defi ne d
as t he n u m ber of D V Ds rec or de d d uri n g t he 4-
wee k i nter val di vi de d b y t he n u m ber of n o n-
missi n g diar y e ntries f or t he rele va nt i nter val
•
Se verit y of verti g o e pis o des as meas ure d b y t he
Me a n Se verit y  Verti g o Sc ore ( M S V S ) at Wee k 8
•
A vera ge dail y c o u nt of verti g o e pis o des at  Wee k 8
•
T he 2 8- d a y a ver a ge  of n u m ber of da ys Sic k at
h o me or Be dri d de n as a c o nse q ue nce of verti g o
d uri n g eac h 4 - wee k st u d y i nter val  (i.e., Wee k 4,
Wee k 8, Wee k 1 2 )
•
T he 2 8- d a y a ver a ge  defi niti ve verti g o da ys ( D V D)
at  Wee k 8
Ne w Te xt:  
•
Occ urre nce of N or m al acti vit y, Sli g ht li mit ati o n,
M o der ate li mit ati o n, Sic k at h o me, a n d
Be dri d de n e ve nts as a c o nse q ue nce of verti g o at
Wee k 4, Wee k 8, a n d Wee k 1 2
e x pl orat or y  
e n d p oi nts. 


Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 1 
Secti o n(s)  
Descri pti o n of C h a n ges  
R ati o n ale 
1 1. 5. 4 A nal ytic 
met h o ds f or 
Efficac y 
Re vise d Secti o n ( mi x of pre vi o us a n d ne w te xt). 
T he pri m ar y effic ac y e n d p oi nt, t he 2 8 - d a y a ver a ge 
D V D at Wee k 1 2 (t he 4- wee k i nter v al fr o m Wee k 9 
t hr o u g h Wee k 1 2), will be c o m p are d bet wee n O T O-
1 0 4 a n d pl ace b o at t he 2-t aile d, 0. 0 5 al p h a le vel 
usi n g a Ne g ati ve Bi n o mi al m o del. T his m o del will 
i ncl u de fi xed effects f or r a n d o mize d tre at me nt 
gr o u p ( O T O - 1 0 4 vs. pl ace b o) a n d se x ( m ale vs. 
fe m ale), wit h t he 2 8- d a y a ver a ge D V D fr o m t he 
le a d-i n peri o d as a c o v ari ate.   
T he pri mar y a nal ysis p o p ulati o n f or t he c o m paris o n of 
t he pri mar y e n d p oi nt bet wee n t he treat me nt gr o u ps i n 
t his st u d y is f ull a nal ysis set ( F A S).  S u bjects will be 
i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y were 
ra n d o mize d re gar dless of t he act ual st u d y dr u g 
recei ve d. 
T he pri mar y e n d p oi nt a nal ysis als o will be c o n d ucte d 
usi n g per- pr ot oc ol a n d I T T a nal ysis sets as se nsiti vit y 
a nal yses.   
T he ke y  sec o n dar y efficac y e n d p oi nt of t he Me a n 
Se verit y Verti g o Sc ore ( M S V S) f or Wee k 1 2  ( Wee k 
9 t hr o u g h Wee k 1 2) will be a n al yze d usi n g a n 
A N C O V A m o del wit h fi xe d effects of r a n d o mize d 
tre at me nt, gr o u p ( O T O- 1 0 4 vs. pl ace b o) a n d se x 
( m ale vs. fe m ale), wit h t he s u bject’s a ver a ge me a n 
se verit y verti g o sc ore at le a d-i n peri o d as a 
c o v ari ate. 
T he ke y  sec o n dar y e n d p oi nt of t he 2 8- d a y a ver a ge of 
n u m ber of da ys Sic k at h o me or Be dri d de n ( D S B ) as a 
c o nse q ue nce of verti g o at Wee k 1 2 will be c o m pare d 
bet wee n t he treat me nt gr o u ps usi n g usi n g t he s a me 
Ne g ati ve Bi n o mi al m o del as s pecifie d f or t he 
pri m ar y a n al ysis a n d usi n g t he 2 8- d a y a ver a ge 
Le a d -i n D S B as a c o v ari ate.  T he m o del will i ncl u de 
fi xe d effects f or ra n d o mize d treat me nt gr o u p ( O T O-
1 0 4 vs. place b o) a n d  se x ( male vs. fe male).   
T he ke y sec o n d ar y e n d p oi nts of perce nt of s u bjects 
ac hie vi n g a 7 5 % a n d a 1 0 0 % (i.e., c o u nt of zer o) 
re d ucti o n fr o m b ase li ne i n 2 8-d a y a ver a ge of D V D 
will be c o m p are d bet wee n t he tre at me nt gr o u ps 
usi n g a c hi -s q u are test. T he ris k differe nce a n d t he 
Re vise d t his 
secti o n t o reflect 
t he pri mar y 
a nal yses, 
sec o n dar y 
a nal yses, 
e x pl orat pr y 
a nal yses a n d t he 
gate- kee pi n g 
pr oce d ure t hat is 
pr o vi de d i n t he 
S A P Versi o n 2. 0. 


Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 2 
Secti o n(s)  
Descri pti o n of C h a n ges  
R ati o n ale 
9 5 % CI ar o u n d t he ris k differe nce will als o be 
pr o vi de d.  
T he sec o n dar y efficac y e n d p oi nt of c ha n ge fr o m 
baseli ne i n verti g o fre q ue nc y ( V F) at Wee k 1 2 (t he 4-
wee k i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2), will be 
a nal yze d usi n g a n A N C O V A m o del wit h tre at me nt 
as a fi xe d effect a n d se x as fi xe d effects wit h t he 
le a d-i n peri o d V F as a c o v ari ate.   
T he sec o n dar y efficac y e n d p oi nt of a vera ge dail y c o u nt 
of verti g o e pis o des d uri n g 4- wee k st u d y i nter val ( Wee k 
9 t hr o u g h Wee k 1 2) will be usi n g t he A N C O V A 
m o del s pecifie d f or t he sec o n d ar y effic ac y e n d p oi nt 
of c h a n ge fr o m b aseli ne i n V F at Wee k 1 2,  usi n g 
t he s u bject’s A ver a ge D ail y Verti g o C o u nt ( A D V C) 
at le a d-i n peri o d as a c o v ari ate .    
Alter nati ve m o dels will be pre -s pecifie d i n t he S A P 
s h o ul d certai n ass u m pti o ns re gar di n g data a n d m o dels 
d o n ot h ol d.  I n a d diti o n, t he S A P will i ncl u de pre-
s pecifie d data tra nsf or mati o ns s h o ul d e val uati o n of t he 
resi d uals s u g gest a data tra nsf or mati o n is m ore 
s uita ble. 
If t he pri mar y e n d p oi nt c o m paris o n bet wee n t he t w o 
treat me nt gr o u ps is statisticall y si g nifica nt i n fa v or of 
O T O - 1 0 4 t he n a cl ose d testi n g, gate- kee pi n g pr oce d ure 
will be use d t o c o m pare t he f oll o wi n g sec o n dar y 
efficac y e n d p oi nts se q ue ntiall y:  
1. Se verit y of verti g o e pis o des as meas ure d b y t he
mea n Verti g o Sc ore at Wee k 1 2 (t he 4 -wee k ( 2 8 -
da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2)
2.
T he 2 8- d a y a ver a ge  n u m ber of da ys Sic k at h o me
or Be dri d de n as a c o nse q ue nce of verti g o at Wee k
1 2 (t he 4- wee k ( 2 8- da y) i nter val fr o m Wee k 9
t hr o u g h Wee k 1 2)
3.
Perce nt of s u bjects ac hie vi n g a 7 5 % re d ucti o n
fr o m b aseli ne i n 2 8- d a y a ver a ge D V D at Wee k
1 2 .
4.
Perce nt of s u bjects ac hie vi n g a 1 0 0 % re d ucti o n
fr o m b aseli ne (i.e., c o u nt of zer o) i n 2 8 - d a y
a ver a ge D V D at Wee k 1 2.


Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 3 
Secti o n(s)  
Descri pti o n of C h a n ges  
R ati o n ale 
I n t his pr oce d ure, if t he first sec o n dar y e n d p oi nt 
c o m paris o n bet wee n t he t w o treat me nt gr o u ps is 
statisticall y si g nifica nt i n fa v or of O T O- 1 0 4 t he n t he 
sec o n d sec o n dar y e n d p oi nt will be c o m pare d a n d 
teste d.  If t he sec o n d ke y sec o n d ar y e n d p oi nt 
c o m p aris o n bet wee n t he t w o tre at me nt gr o u ps is 
teste d a n d t he res ult is st atistic all y si g nific a nt i n 
f a v or of O T O- 1 0 4, t he n t he t hir d ke y sec o n d ar y 
e n d p oi nt will be c o m p are d a n d teste d. If t he t hir d 
ke y sec o n d ar y e n d p oi nt c o m p aris o n bet wee n t he 
t w o tre at me nt gr o u ps is teste d a n d t he res ult is 
st atistic all y si g nific a nt i n f a v or of O T O- 1 0 4, t he n 
t he f o urt h ke y sec o n d ar y e n d p oi nt will be c o m p are d 
a n d teste d. If t he c o m p aris o n bet wee n tre at me nt 
gr o u ps is st atistic all y si g nific a nt f or t he f o urt h ke y 
sec o n d ar y e n d p oi nt, t he n it c a n be cl ai me d t h at all 
ke y sec o n d ar y e n d p oi nts are st atistic all y si g nific a nt 
i n f a v or of O T O- 1 0 4. 
At t he first ke y sec o n d ar y e n d p oi nt t h at d oes n ot 
de m o nstr ate a st atistic all y si g nific a nt differe nce 
bet wee n gr o u ps i n f a v or of O T O- 1 0 4, t he g ate-
kee pi n g pr oce d ure e n ds a n d a n y s u bse q ue nt ke y 
sec o n d ar y e n d p oi nt p-v al ues will be c o nsi dere d as a 
n o mi n al p - v al ue(s).  
T he g ate- kee pi n g pr oce d ure c o ntr ols t he T y pe I 
err or f or t he f o ur pl a n ne d c o m p aris o ns  a n d, 
t heref ore, t here will be n o α s pe n di n g pe n alt y 
ass oci ate d wit h t he pl a n ne d ke y  sec o n d ar y 
c o m p aris o ns.  
T he re m ai ni n g sec o n d ar y e n d p oi nts c o m p aris o ns 
will n ot f oll o w t he g ate -kee pi n g pr oce d ure a n d, 
t heref ore, t he re p orte d p-v al ues will be re p orte d as 
n o mi n al p - v al ues.  T hese a n al yses will be c o n d ucte d 
usi n g t he F A S o nl y.  
All effic ac y h y p ot hesis tests will be 2 -si de d a n d 
perf or me d at α = 0. 0 5 si g nific a nce le vel, u nless 
ot her wise s pecifi d i n t he S A P.  




 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 5   
I N V E S TI G A T O R A G R E E M E N T 
I ha 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 nate d a n d will a bi de b y all a p plica ble l ocal a n d nati o nal re g ulat or y o bli gati o ns. 
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y. I will disc uss t his material wit h t he m t o e ns ure t he y 
are f ull y i nf or me d re gar di n g t he dr u g a n d t he c o n d uct o f 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 Ot o n o m y, I nc. ( hereafter, “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 I nstit uti o nal Re vie w B oar d (I R B) or Researc 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 I R B or 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 he a p pr o priate versi o n of t he i nf or me d c o nse nt. I a gree t hat t he S p o ns or or its re prese ntati ves 
s hall ha ve access t o a n y ori gi nal s o urce d oc u me nts t o verif y data ca pt ure d f or t his cli nical trial. 
I f urt her a gree n ot t o ori gi nate or use t he na me of t he S p o ns or 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 release 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 nce here u n der, wit h o ut t he pri or writte n c o nse nt of t he S p o ns or. 
 
 
 
 
 
I n vesti gat or's Si g nat ure 
 
Date  
Na me of I n vesti gat or (ty pe d or pri nte d) 
 
 
 
 
 
 
 
 
 
 
 


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 6   
A B B R E VI A TI O N S  
A D V C  
A vera ge Dail y Verti g o C o u nt  
A E  
A d verse E ve nt  
A N C O V A  
A nal ysis of C o varia nce  
A A O -H N S   
A merica n Aca de m y of Ot olar y n g ol o g y - Hea d a n d Nec k S ur ger y   
C  
Celsi us  
C R O  
C o ntract Researc h Or ga nizati o n  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
D S B  
D a ys Sic k at H o me or Be dri d de n  
D V D  
Defi niti ve Verti g o Da y  
e C R F  
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
F A S  
F ull A nal ysis Set  
G C P  
G o o d Cli nical Practice  
Hz  
Hertz  
I C H 
I nter nati o nal C o u ncil  f or Har m o ni sati o n 
I C H D-III 
I nter nati o nal Classificati o n of Hea dac he Dis or ders III 
I T 
I ntrat y m pa nic 
I T T 
I nte nt t o Treat 
IV R S  
I nteracti ve V oice  Res p o nse  S yste m  
I W R S 
Me d D R A  
I nteracti ve We b Ra n d o mizati o n S yste m 
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  
m L  
Milliliter  
M S V S  
Mea n Se verit y Verti g o Sc ore  
O T O -1 0 4  
I n vesti gati o nal Pr o d uct ( St u d y Dr u g) 
P T A  
P ure T o ne A vera ge  
P GI C  
Q M P  
Patie nt Gl o bal I m pressi o n of C ha n ge  
Q ualifie d Me dical Pr ofessi o nal  
R E C  
Researc h Et hics C o m mittee  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S F -3 6  
S h ort F or m  3 6 Healt h S ur ve y  
S O C  
S yste m Or ga n Class   
V F  
Verti g o Fre q ue nc y  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 


Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 7 
S Y N O P SI S  
N A M E O F S P O N S O R/ C O M P A N Y : 
Ot o n o m y, I nc.  
N A M E O F FI NI S H E D P R O D U C T : 
N A M E O F A C TI V E I N G R E DI E N T( S) : 
O T O- 1 0 4  
De x a met has o ne  
Pr ot oc ol N o.:  1 0 4 -2 0 1 8 1 1  
Title of St u d y:  A pr os pecti ve, ra n d o mize d, d o u ble bli n d, place b o -c o ntr olle d, m ultice nter, P hase 3 efficac y a n d 
safet y st u d y of O T O-1 0 4 gi ve n as a si n gle i ntrat y m pa nic i njecti o n i n s u bjects wit h u nilateral Me niere’s disease.  
St u d y Ce nter(s):   T his st u d y wi ll be c o n d ucte d at a p pr o xi matel y 6 0 sites gl o ball y.  
St u d y Peri o d:  A p pr o xi matel y 1. 5 years  
P h ase of De vel o p me nt:  3 
St u d y Desi g n:  
T his is a ra n d o mize d, d o u ble bli n d, place b o -c o ntr olle d, m ultice nter 1 6 -wee k P hase 3 st u d y.  F oll o wi n g a n 
i nitial 4-wee k lea d -i n peri o d, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o eit her 1 2 m g O T O-1 0 4 or place b o 
usi n g a 1: 1 all ocati o n  rati o stratifie d by ge n der.  S u bjects will be o bser ve d f or 1 2 wee ks f oll o wi n g a si n gle 
i ntrat y m pa nic i njecti o n of eit her 1 2 m g O T O-1 0 4 or place b o.  
St u d y O bjecti ve s: 
Pri mar y : T o i n vesti gate t he efficac y of O T O-1 0 4 i n s u bjects wit h Me niere’s disease, as meas ure d b y t he 
n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 1 2 (t he 4 -wee k i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2).  
Sec o n dar y :  T o i n vesti gate t he safet y pr ofile of O T O-1 0 4 i n s u bjects wit h Me niere’s disease.  
Met h o d s: 
T he d urati o n of t he st u d y f or eac h s u bject will be a p pr o xi matel y 1 6  wee ks, i ncl u di n g a 4 -wee k lea d -i n peri o d 
bef ore d osi n g (a si n gle  i njecti o n), f oll o we d b y a 12- wee k f oll o w -u p peri o d.  
After scree ni n g ( Visit 1), all eli gi ble s u bjects will e nter i nt o a 4-wee k lea d -i n peri o d.  D uri n g t he lea d -i n 
peri o d, s u bjects will rec or d t heir dail y verti g o e x perie nce t o all o w f or a baseli ne assess me nt of t hese e ve nts.  
A n y da y wit h a rec or de d defi niti ve verti g o e pis o de, w hic h is a n e pis o de lasti n g at least 2 0 mi n utes 
(c orres p o n di n g t o a Verti g o Se verit y Sc ore of 2 or m ore), will be defi ne d as a defi niti ve verti g o da y ( D V D).  
F oll o wi n g t he lea d -i n peri o d, eli gi ble s u bjects will be ra n d o mize d t o 1 2 m g O T O-1 0 4 or place b o usi n g a 1: 1 
all ocati o n rati o. T he ra n d o mizati o n is stratifie d b y ge n der.  
After a si n gle i ntrat y m pa nic i njecti o n of  O T O -1 0 4  or place b o o n Da y 1, s u bjects will c o nti n ue t o rec or d t heir 
dail y verti g o e x perie nce  d uri n g t he 1 2 -wee k f oll o w -u p per i o d.  S u bjects will visit t he st u d y site at Wee ks 4 a n d 
8 f or a d diti o nal efficac y a n d safet y assess me nts.  Efficac y a n d safet y assess me nts will als o be c o m plete d at t he 
e n d of st u d y ( Wee k 1 2 ) or u p o n earl y disc o nti n uati o n  fr o m t he st u d y. 
N u m ber of S u bject s: 
T he pla n ne d sa m ple size f or t his st u d y is 1 4 2  s u bjects (7 1  assi g ne d t o 1 2 m g O T O -1 0 4 a n d 7 1  t o place b o). 
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
S u bjects 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 bject is a male or fe male a ge d 1 8 t o  8 5 years, i ncl usi ve.
2.
S u bject has a dia g n osis of defi nite u nilateral Me niere’s disease b y 1 9 9 5  A A O -H N S criteria.


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 8   
N A M E O F S P O N S O R/ C O M P A N Y : 
 
Ot o n o m y, I nc.  
 
N A M E O F FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O- 1 0 4  
 
De xa met has o ne  
 
3.  S u bject self -re p orts acti ve, defi niti ve verti g o  e pis o des f or t he 2 m o nt hs pri or t o t he st u d y lea d-i n 
peri o d.  
4.  S u bject has d oc u me nte d as y m metric se ns ori ne ural heari n g l oss at scree ni n g or wit hi n t he past 1 2 
m o nt hs acc or di n g t o 1 9 9 5  A A O -H N S criteria defi ne d as o ne of t he f oll o wi n g:   
a. 
T he arit h metic mea n of heari n g t hres h ol ds ( p ure t o ne a vera ge, P T A) at 2 5 0, 5 0 0 a n d 
1 0 0 0  Hz of 1 5 d B or m ore hi g her t ha n t he P T A of 1 0 0 0, 2 0 0 0, a n d 3 0 0 0 Hz , 
b.  T he arit h metic mea n of  P T A at 5 0 0, 1 0 0 0, 2 0 0 0 a n d 3 0 0 0 Hz is 2 0 d B or m ore p o orer i n t he 
ear i n q uesti o n t ha n o n t he o p p osite si de, 
c. 
It is t he j u d g me nt of t he In vesti gat or t hat t he s u bject’s heari n g l oss meets reas o na ble 
a u di o metric criteria f or heari n g l oss c haracteristic of Me niere’s disease, a n d if  so, it m ust  be 
j ustifie d a n d d oc u me nte d , a n d disc usse d wit h  t he me dical m o nit or. 
5.  If ta ki n g me dicati o n  f or Me niere’s disease (e. g., di uretics, vesti b ular s u p pressa nts, beta histi ne, 
a nti de pressa nts, or a n xi ol ytics), s u bject m ust be o n sta ble d oses of t he me dicati o n  f or at least 2 wee ks 
pri or t o Scree ni n g a n d a gre es t o re mai n o n sta ble d oses of t he me dicati o n f or t he d urati o n of t he 
st u d y.    
6.  Fe male s u bjects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-me n o pa usal 
( ≥1 2 m o nt hs si nce last me nstr ual peri o d a n d 4 5 years of a ge or ol der) ] m ust ha ve a ne gati ve uri n e 
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 ut i 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 njecti 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).   
7.  S u bject is willi n g t o c o m pl y wit h t he pr ot oc ol a n d atte n d all st u d y visits.  
8.  S u bject is a ble t o use t he tele p h o ne  t o c o m plete t heir dail y diar y. 
9.  S u bject 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 pri vac y la n g ua ge 
c o m plia nt wit h c o u ntr y a n d/ or l ocal re q uire me nts, bef ore t he i nitiati o n of a n y st u d y -relate d 
pr oce d ures.  
At t he c o m pleti o n of t he first 2 8 da ys of t he lea d -i n perio d:  
1 0.  S u bject has e x perie nce d a n d rec or de d at least 4 a n d a ma xi m u m of 2 2 defi niti ve verti g o  da y s d uri n g 
t he 4-wee k lea d -i n peri o d. 
1 1.  S u bject c o m plete d at least 2 2 of 2 8 diar y e ntries d uri n g t he 4-wee k lea d -i n peri o d. 
 
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 bject has a n i nfecti o n i n t he ear, si n uses, or u p per res pirat or y s yste m  at t he ti me of ra n d o mizati o n . 
2.  S u bject is pre g na nt or lactati n g.  
3.  S u bject has a hist or y of i m m u n o deficie nc y disease.  
4.  S u bject has acti ve or rece nt ( < 1 m o nt h pri or t o scree ni n g) mi d dle ear 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.  


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
1 9   
N A M E O F S P O N S O R/ C O M P A N Y : 
 
Ot o n o m y, I nc.  
 
N A M E O F FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O- 1 0 4  
 
De xa met has o ne  
 
5.  S u bject 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 m o n o meric t y m pa nic me m bra ne. 
6.  S u bject has a hist or y of si g nifica nt mi d dle ear or i n ner ear s ur ger y, or e n d ol y m p hatic sac s ur ger y   i n 
t he affecte d ear. 
7.  S u bject has a hist or y of pre vi o us use of i ntrat y m pa nic ge nta mici n i n t he affecte d ear.  
8.  S u bject has a hist or y of t y m p a n ost o m y t u bes wit h e vi de nce of perf orati o n or lac k of cl os ure  i n t he 
affecte d ear . 
9.  S u bject has use d s yste mic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea d -i n peri o d. 
1 0.  S u bject has a hist or y of pre vi o us  use of i ntrat y m pa nic ster oi ds i n t he affecte d ear. 
1 1.  S u bject has e x perie nce d a n a d verse react o n t o de xa met has o ne.  
1 2.  S u bject has a hist or y of vesti b ular mi grai n e. I nter nati o nal Classificati o n of Hea dac he Dis or ders III 
criteria f or vesti b ular mi grai ne i ncl u des a c urre nt or past histo r y of mi grai ne wit h or wit h o ut a ura, 
v esti b ular s y m pt o ms of m o derate or se vere i nte nsit y  lasti n g bet wee n 5 mi n utes a n d 7 2 h o urs, a n d at 
least half of e pis o des are ass ociate d wit hat least 1 of t he 4 f oll o wi n g mi grai ne o us feat u res: u nilateral 
hea dac he, p ulsati n g  q ualit y , ph ot o p h o bia , a n d vis ual a ura. 
1 3.  S u bject has hist or y of dr o p attac ks.  
1 4.  S u bject is n ot a ble t o acc uratel y i de ntif y a n d re p ort e pis o des of verti g o.  
1 5.  S u bject has a n y ot her cli nicall y si g nifica nt ill ness , me dical c o n diti o n or me dical hi st or y t hat, i n t he 
In vesti gat or’s or t he me dical m o nit or’s o pi ni o n, w o ul d pr o hi bit t he s u bject fr o m partici pati n g i n t he 
st u d y at scree ni n g or at t he ti me of ra n d o mizati o n . 
1 6.  S u bject has use d a n i n vesti gati o nal dr u g or de vice i n t he 3 m o nt hs pri or t o scree ni n g.  
1 7.  S u bject has a hist or y of seri o us s u bsta nce a b use (e. g. c ocai ne, her oi n) wit hi n t he prece di n g 6 m o nt hs 
pri or t o scree ni n g.  
1 8.  S u bject has pre vi o usl y bee n ra n d o mize d t o a cli nical st u d y of O T O -1 0 4.  
Test Pr o d uct, D ose a n d M o de of A d mi nistr ati o n:  
1 2  m g O T O -1 0 4 , si n gle 0. 2 m L i ntrat y m pa nic i njecti o n t o t he affecte d ear  
D ur ati o n of Tre at me nt:    
Si n gle 0. 2 m L i ntrat y m pa nic i njecti o n t o t he affecte d ear  
Refere nce T her a p y, D ose a n d M o de of A d mi nistr ati o n:  
1 6 % p ol o xa mer s ol uti o n ( place b o), si n gle 0. 2 m L i ntrat y m pa nic i njecti o n t o t he affecte d ear 
O utc o me Me as ures f or E v al u ati o n:  
Pri mar y Efficac y E n d p oi nt:  
T he pri mar y efficac y e n d p oi nt is t he 2 8 -da y a vera ge  defi niti ve verti g o da ys ( D V D) at Wee k 1 2 [t he 4-wee k  
( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2].  A D V D is defi ne d as a da y w here t he s u bject rec or de d at 
least o ne verti g o e pis o de lasti n g at least 2 0 mi n utes a n d c orres p o n ds t o a Verti g o Se verit y Sc ore of 2 or m ore.  
If m ulti ple e pis o des occ ur o n a gi ve n da y, s u bjects will be i nstr ucte d t o rec or d t he Verti g o Se verit y Sc ore f or 
t he w orst e pis o de e x perie nce d d uri n g t he da y.  
Sec o n dar y Efficac y E n d p oi nt s: 
•  
S e verit y of verti g o e pis o des as meas ure d b y t he M ea n Se verit y Verti g o Sc ore  ( M S V S) at Wee k 1 2 
[t he 4-wee k  ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] 


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 0   
N A M E O F S P O N S O R/ C O M P A N Y : 
 
Ot o n o m y, I nc.  
 
N A M E O F FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O- 1 0 4  
 
De xa met has o ne  
 
•  
T he t he 2 8-da y a vera ge  of n u m ber of da ys Sic k at h o me or  Be dri d de n  as a c o nse q ue nce of verti g o at 
Wee k 1 2 [ t he 4-wee k  ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] 
•  
T he c ha n ge fr o m  baseli ne i n verti g o fre q ue nc y ( V F) at Wee k 1 2 [ t he 4-wee k  ( 2 8-da y) i nter val fr o m 
Wee k 9 t hr o u g h Wee k 1 2 ], w here verti g o fre q ue nc y is defi ne d as t he n u m ber of D V Ds rec or de d  
d uri n g t he 4 -wee k i nter val di vi de d b y t he n u m ber of n o n -missi n g diar y e ntr ies f or the rele va nt 
i nter val 
•  
A vera ge  dail y c o u nt of verti g o e pis o des at Wee k 1 2 [ t he 4-wee k  ( 2 8-da y) i nter val fr o m Wee k 9 
t hr o u g h Wee k 1 2] 
E x pl orat or y Efficac y E n d p oi nts:  
•  
T he c ha n ge  fr o m baseli ne i n verti g o fre q ue nc y ( V F) at W ee k 8, w here verti g o fre q ue nc y is defi ne d as 
t he n u m ber  of D V Ds  rec or de d d uri n g t he 4 -wee k i nter val di vi de d b y t he n u m ber of n o n -missi n g diar y 
e ntries f or t he rele va nt i nter val  
•  
S e verit y of verti g o e pis o des as meas ure d b y t he  Mea n Se verit y Verti g o Sc ore  ( M S V S)  at W ee k 8   
•  
A vera ge dail y c o u nt of verti g o e pis o des  at Wee k 8  
•  
T he 2 8 -da y a vera ge  n u m ber of da ys Sic k at h o me or  Be d ri d de n as a c o nse q ue nce of verti g o d uri n g 
eac h  4-wee k st u d y i nter val ( i.e., at Wee k 4, Wee k 8 a n d Wee k 1 2)  
•  
T he n u m ber of 2 8 -da y a vera ge defi niti ve verti g o da ys ( D V D) d uri n g eac h 4-wee k st u d y i nter val 
( Wee k 1 t hr o u g h Wee k 4) a n d ( Wee k 5 t hr o u g h W ee k 8) 
•  
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) at Wee ks 8 a n d 1 2  
•  
S F -3 6 S ocial F u ncti o ni n g S u bscale  assess me nt at Wee ks 8 a n d 1 2  
•  
Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d Be dri d de n 
e ve nts as a c o nse q ue nce of verti g o at Wee k 4, Wee k 8, a n d Wee k 1 2  
Safet y Assess me nts : 
S afet y assess me nts  i ncl u de: 
•  
A d verse e ve nts  
•  
A u di o metr y assess me nts  
•  
T y m pa n o metr y  
•  
O t osc o pic e xa mi nati o ns 
•  
Cli nical la b ora t or y meas ure me nts 
•  
Vital si g n meas ure me nts  
•  
C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S): Baseli ne a n d Si nce Last Visit versi o ns  
St atistic al Met h o ds:  
T he pri mar y efficac y e n d p oi nt is t he  2 8 -da y a vera ge  D V D at Wee k 1 2 [t he 4-wee k ( 2 8-da y) i nter val fr o m 
Wee k 9 t hr o u g h Wee k 1 2 ].   T he tar get t otal sa m ple size f or t he st u d y is 1 4 2 ra n d o mize d wit h 1: 1 all ocati o n, 
7 1 i n eac h treat me nt gr o u p 
T he pri mar y a nal ysis will be c o n d ucte d usi n g a Ne gati ve Bi n o mial m o del at Wee k 1 2.  F or t he Ne gati ve 
Bi n o mial a nal y sis, a sa m ple size of 1 4 2 s u bjects will pr o vi de a p pr o xi matel y 9 0 % p o wer t o detect a differe nce 
bet wee n gr o u ps i n t he 2 8 -da y a vera ge D V D. It is ass u me d t hat t he 2 8 -da y a vera ge D V D will be 2. 4 7 a n d 4. 6 6 
f or O T O-1 0 4 a n d place b o, res pecti vel y, f or a n esti mate d  rati o of 0. 5 3. It is als o ass u me d t hat t he distri b uti o n 
s ha pe para meter is 1. 0 4.  T he ass u m pti o ns use d f or t he Ne gati ve Bi n o mial m o del were base d o n t he pre vi o usl y 


 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 1   
N A M E O F S P O N S O R/ C O M P A N Y : 
 
Ot o n o m y, I nc.  
 
N A M E O F FI NI S H E D P R O D U C T : 
 
N A M E O F A C TI V E I N G R E DI E N T( S) :                
 
O T O- 1 0 4  
 
De xa met has o ne  
 
c o n d ucte d st u d y 1 0 4 -2 0 1 5 0 8 ( data o n file). T he calc ulati o ns were c o n d ucte d usi n g E A S T v 6. 5 fr o m C ytel, I nc. 
T he pri mar y a nal ysis p o p ulati o n f or t his st u d y is t he f ull a nal ysis set ( F A S).  T he F A S  will i ncl u de all s u bjects 
w h o are ra n d o mize d, recei ve st u d y dr u g, ha ve a baseli ne D V D meas ure me nt f or t he 4 -wee k lea d -i n peri o d, a n d 
ha ve at least o ne da y of D V D meas ure me nt at Wee k 1 2 [t he 4 -wee k ( 2 8 da y) i nter val fr o m Wee k 9 t hr o u g h 
Wee k 1 2 ].    
I n t he pri mar y efficac y a nal ysis if a s u bject is missi n g t heir Wee k 1 2, 2 8-da y a vera ge D V D i n F A S, t he s u bject 
will e nter t he a nal ysis ha vi n g a missi n g val ue. It is ass u me d t hat data will be missi n g at ra n d o m . Se nsiti vit y 
a nal yses will be u n derta ke n t o e xa mi ne t he effect of missi n g dail y diar y ( D D) data o n t he res ults of t he 
pri mar y e n d p oi nt a nal ysis f or t he F A S a n d f or s u bjects w h o m disc o nti n ue d t he st u d y pri or  t o e nteri n g t he 
Wee k 1 2 i nter val . w hic h i ncl u de vari o us i m p utati o n met h o ds as s pecifie d i n t he Statistical A nal ysis Pla n 
(S A P).  S u bjects will be i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d re gar dless of t he 
act ual st u d y dr u g recei ve d.   
If t he pri mar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is statisticall y si g nifica nt i n fa v or of 
O T O- 1 0 4 t he n a cl ose d testi n g, gate -kee pi n g pr oce d ure, will be use d t o c o m pare t he f oll o wi n g sec o n dar y 
efficac y e n d p oi nts se q ue ntiall y :  
1.  S e verit y of verti g o e pis o des as meas ure d b y t he M ea n Verti g o Se verit y Sc ore  ( M S V S) at Wee k 
1 2 [ t he 4-wee k  ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] 
2.  T he 2 8 -da y a vera ge  of n u m ber of da ys Sic k at h o me or  Be dri d de n  as a c o nse q ue nce of verti g o at 
Wee k 1 2 [ the 4 -wee k  ( 2 8-da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] 
3.  Perce nt of s u bjects ac hie vi n g a 7 5 % re d ucti o n fr o m baseli ne i n 2 8 -da y a vera ge  D V D at Wee k 1 2  
4.  Perce nt of s u bjects ac hie vi n g a 1 0 0 % re d ucti o n fr o m baseli ne (i.e., c o u nt of zer o)  i n 2 8-da y 
a vera ge D V D a t Wee k 1 2. 
I n t his pr oce d ure if t he first sec o n dar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is statisticall y 
si g nifica nt i n fa v or of O T O-1 0 4 t he n t he sec o n d sec o n dar y e n d p oi nt will be c o m pare d a n d teste d .  If t he 
sec o n d ke y sec o n dar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is teste d a n d t he res ult is 
statisticall y si g nifica nt i n fa v or of O T O-1 0 4, t he n t he t hir d ke y sec o n dar y e n d p oi nt will be c o m pare d a n d 
teste d. If t he t hir d ke y sec o n dar y e n d p oi nt c o m paris o n bet wee n t he t wo treat me nt gr o u ps is teste d a n d t he 
res ult is statisticall y si g nifica nt i n fa v or of O T O-1 0 4, t he n t he f o urt h ke y sec o n dar y e n d p oi nt will be c o m pare d 
a n d teste d. If t he c o m paris o n bet wee n treat me nt gr o u ps is statisticall y si g nifica nt f or t he f o urt h ke y sec o n dar y 
e n d p oi nt, t he n it  ca n be clai me d t hat all ke y sec o n dar y e n d p oi nts are statisticall y si g nifica nt i n fa v or of  
O T O- 1 0 4.  
At t he first ke y sec o n dar y e n d p oi nt t hat d oes n ot de m o nstrate a statisticall y si g nifica nt differe nce bet wee n 
gr o u ps i n fa v or of O T O -1 0 4, t he gate -kee pi n g pr oce d ure e n ds a n d a n y s u bse q ue nt ke y sec o n dar y e n d p oi nt p -
val ues will be c o nsi dere d as a n o mi nal p val ue(s).  
T he gate -kee pi n g pr oce d ure c o ntr ols t he T y pe I err or f or t he f o ur pla n ne d c o m paris o ns a n d, t heref ore, t here 
will be n o α s pe n di n g pe nalt y ass ociate d wit h t he pla n ne d ke y sec o n dar y c o m paris o ns.  
T he re mai ni n g sec o n dar y e n d p oi nts c o m paris o n will n ot g o t hr o u g h t he gate kee pi n g pr oce d ure a n d t heref ore 
t he re p orte d p-val ues will be re p orte d as n o mi nal p -val ues.    All efficac y h y p ot h esis tests will be 2 -si de d a n d 
perf or me d at α = 0. 0 5 si g nifica nce le vel  u nless ot her wise s pecifie d i n t he S A P.   
Ti me a n d E ve nts Sc he d ule:  See  Ta ble  1. 


 
 
 
 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 2   
T a ble  1: 
Ti me a n d E ve nts Sc he d ule  
Pr oce d ure  
Scree ni n g  
Le a d -I n 
B aseli ne 1/ 
Tre at me nt 
Visit  
F oll o w -u p 
Visit  
F oll o w -u p 
Visit  
E n d -of -St u d y/  
E arl y 
Ter mi n ati o n  
U nsc he d ule d 
Visit  
Visit 1  
–  
Visit 2  
Visit 3  
Visit 4  
Visit 5 2 
U nsc he d ule d  
–  
–  
–  
Wee k 4  
Wee k 8  
Wee k 1 2  
N/ A  
U p t o 1 4 d a ys 
pri or t o st art 
of le a d -i n 
D a y -2 8 t o -1 
( + 3 d a ys) 
D a y 1  
D a y 2 8  
( ± 2 d a ys)  
D a y 5 6  
( ± 2 d a ys)  
D a y 8 4  
(+ 4  d a ys)  
N/ A  
I nf or me d c o nse nt (i ncl u di n g 
pri vac y la n g ua ge/ d oc u me nts)  
X 
 
 
 
 
 
 
Eli gi bilit y criteria  
X 
X 3 
X 
 
 
 
 
Me dical hist or y
4 
X 
 
X 
 
 
 
 
C o nc o mita nt me dicati o ns  
X 
 
X 
X 
X 
X 
X 
Vital si g n meas ure me nts 5 
X 
 
X 
X 
X 
X 
X 
Hei g ht a n d wei g ht meas ure me nts  
X 
 
 
 
 
X 6 
 
Pre g na nc y test 7 
X 
 
X 
 
 
X 
 
Cli nical la b orat or y test 8 
X 
 
X 
 
 
X 
X as i n dicate d  
T y m pa n o metr y  
X 
 
X 
X 
X 
X 
X as i n dicate d  
A u di o metr y  
X 
 
X 
X 
X 
X 
X as i n dicate d  
Ot osc o p y 
X 
 
X 
X 
X 
X 
X 
P GI C  
 
 
 
 
X 
X 
 
S F -3 6 S ocial F u ncti o ni n g 
S u bscale assess me nt  
 
 
X 
 
X 
X 
 
C- S S R S assess me nt 9 
X 
 
X 
X 
X 
X 
X 
Instr uct s u bject o n I V R S diar y 
use a n d re vie w a n y c o m plia nce 
iss ues1 0     
X 
 
X 
X 
X 
 
 
Ra n d o mizati o n 1 1 ,1 2 
 
 
X 
 
 
 
 


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




 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 5   
 
1. 1.  
R ati o n ale f or St u d y  a n d D ose Selecti o n  
Ot o n o m y has c o m plete d 4 place b o -c o ntr olle d, d o u ble-bli n d, m ulti -ce nter cli nical st u dies wit h 
O T O -1 0 4 i n Me niere’s disease: a n e x pl orat or y P hase 1 b st u d y, 1 0 4- 2 0 0 9 0 1, a P hase 2 b st u d y, 
1 0 4- 2 0 1 1 0 2, a n d t w o P hase 3 st u di es, 1 0 4- 2 0 1 5 0 6 a n d 1 0 4- 2 0 1 5 0 8.  T he P hase 1 b st u d y 
de m o nstrate d t hat a si n gle i ntrat y m pa nic i njecti o n of O T O- 1 0 4 at d oses of 3 m g or 1 2 m g was  
safe a n d well t olerate d i n s u bjects wit h Me niere’s disease.  I n a d diti o n, t he tre n ds i n t he data 
s u g gest treat me nt wit h 1 2 m g O T O- 1 0 4 was ass ociate d wit h a cli nicall y mea ni n gf ul re d ucti o n i n 
verti g o fre q ue nc y at 3 m o nt hs after treat me nt  c o m pare d t o 3 m g O T O - 1 0 4 or place b o.  T he 
P hase 2 b st u d y t heref ore ra n d o mize d 1 5 4 s u bjects wit h u nilateral Me niere’s disease t o treat me nt 
wit h 1 2 m g O T O- 1 0 4 or place b o.  T his st u d y de m o nstrate d i m pr o ve me nt i n n u m ber of defi niti ve 
verti g o da ys c o m pare d t o t he lea d-i n peri o d wit h a si n gle I T i njecti o n of O T O- 1 0 4 c o m pare d t o 
place b o  d uri n g t he Wee k 1 2 i nter val wit h a s maller i m pr o ve me nt o bser ve d at Wee k 1 6.  
T heref ore, t he fi nal d ose selecte d a n d pri mar y o bser vati o n p oi nt f or t he t w o P hase 3 st u dies wa s 
1 2 m g O T O- 1 0 4 a n d t he Wee k 1 2 i nter val , res pecti vel y.   
T he 1 0 4- 2 0 1 5 0 8 P hase 3 st u d y de m o nstrate d a si g nifica nt effect o n t he pri mar y e n d p oi nt at 
Wee k 1 2 wit h O T O- 1 0 4 s u bjects e x perie nci n g a greater decrease i n t he c o u nt of defi niti ve 
verti g o da ys c o m pare d t o place b o s u bjects.  O T O - 1 0 4 treat me nt als o met ke y Wee k 1 2 
sec o n dar y e n d p oi nts i n t his st u d y i ncl u di n g si g nifica nt decreases i n t he mea n verti g o se verit y 
sc ore, decreases fr o m baseli ne i n verti g o fre q ue nc y, a n d re d ucti o ns i n n u m ber of da ys at h o me 
sic k or be dri d de n.  T he 1 0 4- 2 0 1 5 0 6 P hase 3 st u d y , i n c o ntrast, di d n ot de m o nstrate a statistical 
differe nce  bet wee n O T O - 1 0 4 a n d place b o s u bjects i n defi niti ve verti g o da ys at Wee k 1 2 or f or 
a n y of t he sec o n dar y e n d p oi nts.  O n a nal ysis of t he differe nces bet wee n t he t w o P hase 3 st u dies , 
a ke y fi n di n g was t hat t he place b o res p o nse i n 1 0 4- 2 0 1 5 0 6 was greater t ha n t hat o bser ve d i n 
st u d y 1 0 4- 2 0 1 5 0 8 as well t he place b o res p o nse i n all ot her O T O-1 0 4 cli nical trials i n Me niere’s 
disease patie nts.  T he p ur p ose of t he c urre nt P hase 3 st u d y, 1 0 4- 2 0 1 8 1 1, t heref ore, is t o f urt her 
i n vesti gate t he efficac y of O T O - 1 0 4 i n s u bjects wit h Me niere’s disease, i nf or me d b y t he res ults 
of st u dies 1 0 4- 2 0 1 5 0 6 a n d 1 0 4- 2 0 1 5 0 8.   
2.  
O B J E C TI V E S  
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o  i n vesti gate t he efficac y of O T O- 1 0 4 i n s u bjects wit h Me niere’s 
disease, as meas ure d b y t he n u m ber of defi niti ve verti g o da ys ( D V D) at Wee k 1 2 (t he 4 -wee k 
i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2). 
2. 2.  
Sec o n d ar y O bjecti ve  
T he sec o n dar y o bjecti ve is t o  i n vesti gate t he safet y pr ofile of O T O- 1 0 4 i n s u bjects wit h 
Me niere’s disease.  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 6   
 
3.  
O V E R VI E W O F S T U D Y D E SI G N  
T his is a ra n d o mize d, d o u ble bli n d, place b o- c o ntr olle d, m ultice nter 1 6 -wee k P hase 3 st u d y.  
F oll o wi n g a n i nitial 4 -wee k lea d -i n peri o d, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o eit her 
1 2 m g O T O- 1 0 4 or place b o usi n g a 1: 1 all ocati o n rati o.  Ra n d o mizati o n will be stratifie d base d 
o n ge n der. S u bjects will be o bser ve d f or 1 2 wee ks f oll o wi n g a si n gle i ntrat y m pa nic i njecti o n of 
eit her 1 2 m g O T O - 1 0 4 or place b o. 
T he d urati o n of t he st u d y f or eac h s u bject will be a p pr o xi matel y 1 6 wee ks, i ncl u di n g a 4- wee k 
lea d-i n peri o d bef ore d osi n g (a si n gle i njecti o n), f oll o we d b y a 1 2- wee k f oll o w- u p peri o d. 
After scree ni n g ( Visit 1), all eli gi ble s u bjects will e nter i nt o a 4 -wee k lea d -i n peri o d.  D uri n g t he 
lea d-i n peri o d, s u bjects will rec or d t heir dail y verti g o e x perie nce t o all o w f or a baseli ne 
assess me nt of t hese e ve nts.  A n y da y wit h a rec or de d defi ni ti ve verti g o e pis o de, a n e pis o de 
lasti n g at least 2 0 mi n utes (c orres p o n di n g t o a Verti g o Se verit y Sc ore of 2 or m ore), will be 
defi ne d as a defi niti ve verti g o da y ( D V D).  F oll o wi n g t he lea d -i n peri o d, eli gi ble s u bjects will be 
ra n d o mize d t o 1 2 m g O T O- 1 0 4 or place b o usi n g a 1: 1 all ocati o n rati o.   
After a si n gle i ntrat y m pa nic i njecti o n wit h O T O - 1 0 4 or place b o o n Da y 1, s u bjects will c o nti n ue 
t o rec or d t heir dail y verti g o e x perie nce d uri n g t he 1 2 - wee k f oll o w- u p peri o d. S u bjects will visit 
t he st u d y site at Wee ks 4 a n d 8 f or a d diti o nal efficac y a n d/ or safet y assess me nts. Efficac y a n d 
safet y assess me nts will als o be c o m plete d at t he e n d of st u d y ( Wee k 1 2) or u p o n earl y 
disc o nti n uati o n fr o m t he st u d y. 
4.  
S T U D Y P O P U L A TI O N  
4. 1.  
Ge ner al C o nsi der ati o ns  
A p pr o xi matel y 1 4 2 s u bjects will be e nr olle d at a p pr o xi matel y 6 0 sites gl o ball y.  S u bjects will be 
ra n d o mize d o nl y if t he y meet all of t he i ncl usi o n criteria a n d n o ne of t he e xcl 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 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 b ri 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 bject is a male or fe male a ge d 1 8 t o 8 5 years, i ncl usi ve.  
2.  S u bject has a dia g n osis of defi nite u nilateral Me niere's disease b y 1 9 9 5 A A O -H N S 
criteria. 
3.  S u bject self -re p orts acti ve, defi niti ve verti g o epis o des f or t he 2 m o nt hs pri or t o t he st u d y 
lea d-i n peri o d. 
4.  S u bject has d oc u me nte d as y m metric se ns ori ne ural heari n g l oss at scree ni n g or wit hi n t he 
past 1 2 m o nt hs acc or di n g t o 1 9 9 5 A A O -H N S criteria defi ne d as o ne of t he f oll o wi n g:  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 7   
 
a. T he arit h metic mea n of h eari n g t hres h ol ds ( p ure t o ne a vera ge, P T A) at 2 5 0, 5 0 0 a n d 
1 0 0 0 Hz of 1 5 d B or m ore hi g her t ha n t he P T A of 1 0 0 0, 2 0 0 0, a n d 3 0 0 0 Hz, 
b.  T he arit h metic mea n of  P T A at 5 0 0, 1 0 0 0, 2 0 0 0 a n d 3 0 0 0 Hz is 2 0 d B or m ore 
p o orer i n t he ear i n q uesti o n t ha n o n t he o p p osite si de,  
c. It is t he j u d g me nt of the I n vesti gat or t hat t he s u bject 's heari n g l oss meets reas o na ble 
a u di o metric criteria f or heari n g l oss c haracteristic of Me niere's disease, a n d if s o, it 
m ust be j ustifie d a n d d oc u me nte d,  a n d disc usse d wit h  t he me dical m o nit or. 
5.  If ta ki n g me dicati o n f or Me niere’s disease (e. g. , di uretics, vesti b ular s u p pressa nts, 
beta histi ne, a nti de pressa nts, or a n xi ol ytics), s u bject m ust be o n s ta ble d oses of t he 
me dicati o n  f or at least 2 wee ks pri or t o Scree ni n g a n d a grees t o re mai n o n sta ble d oses of 
t he me dicati o n f or t he d urati o n of t he st u d y.   
6.  Fe male s u bjects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-
me n o pa usal ( ≥1 2 m o nt hs si nce last me nst r 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 ra n d o mizati o n. W o me n of c hil d beari n g 
p ote ntial w h o are n ot a bsti ne nt fr o m se x wit h male part ners ma y be e 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 njecti o n, i ntra uteri ne de vice, “ d o u ble barrier” met h o ds 
i ncl u di n g male c o n d o m wit h dia p hra g m, mal e 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).  
7.  S u bject is willi n g t o c o m pl y wit h t he pr ot oc ol a n d atte n d all st u d y visits.  
8.  S u bject is a ble t o use t he tele p h o ne  t o c o m plete t heir dail y diar y . 
9.  S u bject 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 pri vac y 
la n g ua ge c o m plia nt wit h c o u ntr y a n d/ or l ocal re q uire me nts, bef ore t he i nitiati o n of a n y 
st u d y-relate d pr oce d ures. 
At t he c o m pleti o n of t he first 2 8 da ys of t he lea d-i n peri o d: 
1 0.  S u bject has e x perie n ce d a n d rec or de d at least 4 a n d a ma xi m u m of 2 2 defi niti ve verti g o 
da ys d uri n g t he 4- wee k lea d -i n peri o d. 
1 1.  S u bject c o m plete d at least 2 2 of 2 8 diar y e ntries d uri n g t he 4- wee k lea d -i n peri o d. 
4. 3.  
E xcl usi o n Criteri a  
T o be eli gi ble f or t his st u d y, eac h of t 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 bject has a n i nfecti o n i n t he ear, si n uses, or u p per res pirat or y s yste m at t he ti me of 
ra n d o mizati o n. 
2.  S u bject is pre g na nt or lactati n g.  
3.  S u bject has a hist or y of i m m u n o deficie nc y disease.  
4.  S u bject has acti ve or rece nt ( < 1 m o nt h pri or t o scree ni n g) mi d dle ear 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.  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 8   
 
5.  S u bject 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 
m o n o meric t y m pa nic me m bra ne.  
6.  S u bject has a hist or y of si g nifica nt mi d dle ear or i n ner ear s ur ger y, or e n d ol y m p hatic sac 
s ur ger y i n t he affecte d ear. 
7.  S u bject has a hist or y of pre vi o us use of i ntrat y m pa nic ge nta mici n i n t he affecte d ear.  
8.  S u bject has a hist or y of t y m pa n ost o m y t u bes wit h e vi de nce of perf orati o n or lac k of 
cl os ure i n t he affecte d ear. 
9.  S u bject has use d s yste mic ster oi ds wit hi n 1 m o nt h pri or t o e nteri n g t he lea d -i n peri o d. 
1 0.  S u bject has a hist or y of pre vi o us use of  i ntrat y m pa nic ster oi ds i n t he affecte d ear. 
1 1.  S u bject has e x perie nce d a n a d verse reacti o n t o de xa met has o ne .  
1 2.  S u bject has a hist or y of vesti b ular mi grai n e. I nter nati o nal Classificati o n of Hea dac he 
Dis or ders III criteria f or vesti b ular mi grai ne i ncl u des a c urre nt or past histo r y of mi grai ne 
wit h or wit h o ut a ura, vesti b ular s y m pt o ms of m o derate or se vere i nte nsit y l asti n g 
bet wee n 5 mi n utes a n d 7 2 h o urs, a n d at least half of e pis o des are ass ociate d wit hat least 1 
of t he 4 f oll o wi n g mi grai ne o us featires: u nilateral hea dac he, p ulsati n g q ualit y, 
p h ot o p h o bia, a n d vis ual a ura. 
1 3.  S u bject has hist or y of dr o p attac ks. 
1 4.  S u bject i s n ot a ble t o acc uratel y i de ntif y a n d re p ort e pis o des of verti g o. 
1 5.  S u bject has a n y ot her cli nicall y si g nifica nt ill ness , me dical c o n diti o n, or me dical hist or y  
t hat, i n t he I n vesti gat or’s or t he me dical m o nit or’s o pi ni o n, w o ul d pr o hi bit t he s u bject 
fr o m partici pati n g i n t he st u d y at scree ni n g or at t he ti me of ra n d o mizati o n . 
1 6.  S u bject has use d a n i n vesti gati o nal dr u g or de vice i n t he 3 m o nt hs pri or t o scree ni n g.  
1 7.  S u bject has a hist or y of seri o us s u bsta nce a b use (e. g. c ocai ne, her oi n) wit hi n t he 
prece di n g 6 m o nt hs pri or t o scree ni n g.  
1 8.  S u bject has pre vi o usl y bee n ra n d o mize d t o a cli nical st u d y  of O T O - 1 0 4. 
5.  
R A N D O MI Z A TI O N A N D B LI N DI N G  
5. 1.  
O ver vie w  
At t he c o ncl usi o n of t he scree ni n g/lea d- i n peri o d, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o 
eit her O T O- 1 0 4 or place b o i n a 1: 1 all ocati o n rati o , base d o n a c o m p uter- ge nerate d 
ra n d o mizati o n sc he d ule.   
•  1 2 m g O T O- 1 0 4; si n gle, i ntrat y m pa nic i njecti o n  
•  Place b o; si n gle, i ntrat y m pa nic i njecti o n  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
2 9   
 
5. 2.  
E nr oll me nt Pr oce d ures  
5. 2. 1.  
Assi g n me nt of S u bject I de ntific ati o n N u m bers  
At t he scree ni n g visit, Visit 1, s u bjects si g ni n g t he i nf or me d c o nse nt will be assi g ne d a u ni q ue 
s u bject i de ntificati o n n u m ber.  O nce assi g ne d, t he s u bject i de ntificati o n n u m ber will n ot be re-
assi g ne d a n d s h o ul d n ot be c ha n ge d.  T his n u m ber will be use d t o i de ntif y t he s u bject t hr o u g h o ut 
t he st u d y, i ncl u di n g t he scree ni n g a n d lea d-i n peri o ds. 
5. 2. 2.  
Tre at me nt Assi g n me nt  
St u d y sites will l o g i n t o t he I W R S t o e xec ute eac h ra n d o mizati o n after a s u bject has met all 
prere q uisites f or ra n d o mizati o n a n d has c o m plete d all sc he d ule d pr oce d ures f or Da y 1 ( Visit 2).   
St u d y site pers o n nel, w h o are bli n de d t o treat me nt assi g n me nt, will recei ve a ra n d o mizati o n 
n otificati o n i n dicati n g t he kit n u m ber  ( pac ka ge d st u d y dr u g), a n d t he date a n d ti me of 
ra n d o mizati o n f or eac h s u bject.  O nce assi g ne d, kit n u m bers ca n n ot be re -assi g ne d.  S u bjects 
will be c o nsi dere d e nr olle d i nt o t he st u d y o nce t he y are ra n d o mize d a n d assi g ne d a u ni q ue 
ra n d o mizati o n n u m ber. 
St u d y sites will pr o vi de t he i nf or mati o n c o ntai ne d i n t he I W R S ra n d o mizati o n n otificati o n  t o t he 
u n bli n de d q ualifie d me dical pr ofessi o nal ( Q M P) res p o nsi ble f or pre parati o n of t he s yri n ge 
c o ntai ni n g st u d y dr u g.  T he u ni q ue kit n u m ber pr o vi de d b y t he I W R S will c orres p o n d t o a kit of 
pac ka ge d st u d y dr u g la bele d wit h t he i de ntical kit n u m ber.  T he Q M P  will pre pare t he s yri n ge 
fr o m t he c o nte nts of t he st u d y dr u g pac ka ge c orres p o n di n g t o t he I W R S kit n u m ber acc or di n g t o 
t he i nstr ucti o ns i n t he st u d y P har mac y Ma n ual.   T he s u bject i de ntificati o n n u m ber a n d kit 
n u m ber m ust b ot h be rec or de d i n t he s u bject’s rec or d at t he Baseli ne visit . 
5. 2. 3.  
R a n d o miz ati o n Al g orit h m 
S u bjects will be ra n d o mize d i n a 1: 1 rati o treat me nt gr o u ps, stratifie d b y ge n der, usi n g a 
per m ute d bl oc k ra n d o mizati o n al g orit h m.  T he ra n d o mizati o n pr ocess will be de pl o ye d via a n 
i nter net- base d IW R S w hic h is accessi ble 2 4 h o urs a da y t o a ut h orize d users.  T he s u bject’s 
ra n d o mizati o n n u m ber will deter mi ne t he ra n d o mize d treat me nt assi g n me nt.  N u m bere d kits will 
be dis pe nse d b y t he Q M P  base d o n t he treat me nt assi g n me nt.  St u d y dr u g kits will be la bele d 
wit h a u ni q ue kit n u m ber usi n g a se parate a n d i n de pe n de nt ra n d o mizati o n al g orit h m. 
5. 3.  
Bli n di n g  
T he st u d y will be d o u ble- bli n de d.  T o mai ntai n t he bli n d f or site pers o n nel i n v ol ve d i n st u d y 
assess me nts, bli n di n g pr oce d ures m ust be f oll o we d acc or di n g t o t he Site Bli n di n g Pla n a n d 
briefl y descri be d bel o w: 
Treat me nt s yri n ges will be pre -l oa de d b y a n u n bli n de d Q M P .  Eac h s yri n ge will be pre pare d 
acc or di n g t o t he detaile d i nstr ucti o ns i n t he P har mac y Ma n ual i n a ma n ner t hat pre ve nts 
vis ualizati o n of s yri n ge c o nte nts b y all ot her st u d y staff t hr o u g h t he use of a s yri n ge o verla bel.  
I n a d diti o n, a n y i nteracti o n wit h s u bjects wit h re gar d t o t he c ollecti o n, re vie w or disc ussi o n of 
st u d y assess me nts, wit h t he e xce pti o n of ot osc o pic e xa ms, will be d o ne b y t he st u d y c o or di nat or, 
a u di ol o gist or s o me o ne ot her t ha n t he Q M P  w h o pre pare d t he s yri n ge a n d t he p h ysicia n w h o 
a d mi nistere d t he i ntrat y m pa nic i njecti o n of st u d y dr u g.  E ver y eff ort s h o ul d be ma de t o e ns ure 


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
3 0   
 
t hat ot osc o pic e xa ms are c o n d ucte d b y t he p h ysicia n w h o a d mi nistere d t he st u d y dr u g or a n ot her 
p h ysicia n i n v ol ve d i n t he st u d y, b ut n ot res p o nsi ble f or ot her assess me nts f or t he s pecific s u bject .  
P h ysicia ns a d mi nisteri n g st u d y dr u g a n d c o n d ucti n g t he ot osc o pic e xa ms will be i nstr ucte d n ot 
t o disc uss a n y p ote ntial vis ual differe nces o bser ve d i n st u d y material wit h s u bjects or st u d y staff. 
T he bli n d s h o ul d be br o ke n o nl y if k n o wi n g t he s u bject’s treat me nt all ocati o n w o ul d facilitate 
s pecific e mer ge nc y treat me nt.  T he p h ysicia n w h o a d mi nistere d t he st u d y dr u g is u n bli n d e d at 
t he ti me of i njecti o n.  If t he p h ysicia n w h o a d mi nistere d t he st u d y dr u g is n ot a vaila ble or d oes 
n ot rec ollect t he treat me nt a d mi nistere d, t he I n vesti gat or ca n access t he u n bli n de d dr u g 
acc o u nta bilit y rec or ds c o m plete d a n d retai ne d b y t he Q M P w he n pre pari n g O T O- 1 0 4 or place b o.  
I n vesti gat ors ma y  als o u n bli n d via t he I nteracti ve Res p o nse Tec h n ol o g y (I R T) ra n d o mizati o n 
s yste m f or t he st u d y, w hic h per mits ra pi d u n bli n di n g.  I n all cases, t he In vesti gat or m us t c o ntact 
t he me dical m o nit or as s o o n as is pr actical after u n bli n di n g has occ urre d a n d e mer ge nc y 
treat me nt i nitiate d. 
If t he bli n d is br o ke n, t he s u bject will c o nti n ue t o be f oll o we d a n d e val uate d per- pr ot oc ol.  T he 
date, ti me, a n d reas o n f or t he u n bli n di n g m ust be d oc u me nte d o n t he a p pr o priate pa ge of t he 
e C R F.  
T he ra n d o mizati o n sc he d ule or bl oc ki n g fact or(s) will n ot b e re veale d t o st u d y s u bjects, 
In vesti gat ors, cli nical staff, site ma na gers or S p o ns or re prese ntati ves u ntil all s u bjects ha ve 
c o m plete d t he trial a n d t he data base has bee n fi nalize d b y t he S p o ns or. 
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 a n d place b o are pr o vi de d i n a St u d y Dr u g Kit a n d pre pare d b y a Q M P i n a clea n 
l ocati o n at r o o m te m perat ure.  T o mai ntai n st u d y bli n d, pre parati o n s h o ul d be c o n d ucte d i n a 
l ocati o n se parate fr o m bli n de d st u d y pers o n nel.  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 njecti o n of 6 0 m g/ m L O T O- 1 0 4.  Refer t o t he P har mac y Ma n ual  
f or i nstr ucti o ns o n pre pari n g o ne s yri n ge wit h O T O- 1 0 4 or place b o.   
O T O - 1 0 4 or place b o s h o ul d be pre pare d wit h a 1 m L l uer-l oc k sterile s yri n ge o nl y.  L uer sli p ti p 
s yri n ges are n ot acce pta ble f or use d ue t o t he visc osit y of O T O- 1 0 4.  A d mi nistrati o n n ee dles ca n 
be 2 5, 2 6, or 2 7 ga u ge a n d t y picall y ra n ge fr o m 1. 5 t o 3. 5 i nc hes i n le n gt h.   N ote, O T O - 1 0 4 a n d 
place b o are t her m ose nsiti ve a n d will gel w he n war me d, t heref ore ha n dli n g of t he secti o n of t he 
s yri n ge barrel c o ntai ni n g t he st u d y dr u g a n d a n y l ocati o n o n t he nee dle s h o ul d be li mite d.  If 
O T O - 1 0 4 or place b o gels pri or t o a d mi nistrati o n, it ca n be c o ole d t o a li q ui d b y eit her placi n g t he 
s yri n ge o n a n ice pac k c o vere d b y a sterile dra pe or i n t he refri gerat or f or se veral mi n utes.    
T he rec o m me n de d i njecti o n pr oce d ure f or i ntrat y m pa nic a d mi nistrati o n of O T O- 1 0 4 i n 
Me niere’s disease s u bjects is as f oll o ws .  A ve ntilati o n h ole i n t he t y m pa nic me m bra ne is n ot 
nee de d  d ue t o t he s mall i njecti o n v ol u me.     
1.  Place t he s u bject i n a rec u m be nt p ositi o n wit h t he st u d y dr u g ear u p war ds.   
2.  Pri or t o a d mi nistrati o n, c o nfir m t he ear t o be treate d is t he affecte d st u d y dr u g ear.  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
3 1   
 
3.  A nest hetize t he t y m pa nic me m bra ne b y c o veri n g t he e x ter nal s urface of t he i nferi or-
p osteri or q ua dra nt wit h a t o pical pre parati o n c o ntai ni n g li d ocai ne, pril ocai ne, or ot her 
relate d a nest hetic  (e. g.  
  
or li d ocai ne s pra y) 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 l i d ocai ne or li d ocai ne/ pril ocai ne crea m.  
P he n ol s h o ul d n ot be use d t o a nest hetize t he t y m pa nic me m bra ne.  
4.  Usi n g t he pre pare d s yri n ge, i nsert t he nee dle i nt o t he i nferi or - p osteri or q ua dra nt of t he 
t y m pa nic me m bra ne at t he le vel of t he r o u n d wi n d o w, ta ki n g care n ot t o i nsert t he nee dle 
f urt her t ha n necessar y.   
5.  Wit h t he nee dle be vel faci n g i n t he i nferi or - p osteri or directi o n, i nject 0. 2 m L of O T O-
1 0 4 or place b o t o war ds t he r o u n d wi n d o w. 
6. 2.  
C o m pli a nce  
O T O - 1 0 4 or place b o will be a d mi nistere d b y site me dical pr ofessi o nals  as a si n gle, 
i ntrat y m pa nic i njecti o n at Visit 2.  A n y de viati o ns i n a d mi nistrati o n will be d oc u me nte d i n t he 
s o urce d oc u me nts a n d t 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 nt orie d a n d acc o u nte d f or t hr o u g h o ut t he trial. 
7.  
P RI O R, C O N C O MI T A N T A N D S U B S E Q U E N T T H E R A P Y  
Use of all c o 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.  T his will i ncl u de all 
s y m pt o matic relief me dicati o ns f or Me niere’s disease s ym pt o ms, prescri pti o n dr u gs, her bal 
pr o d ucts, vita mi ns, mi nerals, a n d o ver-t he-c o u nter me dicati o ns ta ke n wit hi n 3 0 da ys bef ore 
Scree ni n g , w hic h will be c o nsi dere d pri or t hera p y.  O nl y sta ble d oses (at least 2 wee ks pri or t o 
Scree ni n g  a n d c o nti n ui n g f or t he d urati o n of t he st u d y) of me dicati o ns f or Me niere’s disease 
s y m pt o ms (e. g. di uretics, vesti b ular s u p pressa nts, beta histi ne, a nti de pressa nts, or a n xi ol ytics) are 
all o we d.  A n y c o nc o mita nt me dicati o n dee me d necessar y f or t he welfare 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 vesti gat or e xce pt f or t h ose liste d i n Secti o n  7. 1.  
T he me dical m o nit or s h o ul d be alerte d t o a n y c ha n ges i n c o nc o mita nt me dicati o ns.  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 o hi bite d T her a p y D uri n g t he St u d y Peri o d  
T he f oll o wi n g t hera pies are pr o hi bite d d uri n g t he st u d y: 
•  S yste mic c ortic oster oi ds  
•  I m m u n os u p pressi ve me dicati o ns 
•  I ntrat y m pa 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 treat me nt of Me niere’s disease  
•  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 o hi bite d t hera pies will be c o nsi dere d a pr ot oc 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 nize d t hat s u bjects ma y at ti mes use certai n me dicati o ns f or relief of s y m pt o ms relate d 
t o Me niere’s disease d uri n g t he c o urse of t he st u d y.  Use of vesti b ular s u p pressa nts a n d a nti-
e metics is all o we d as s y m pt o matic relief me dicati o ns.  Me dicati o ns ta ke n f or t he ac ute treat me nt 
of a verti g o attac k m ust be rec or de d as s uc h i n t he e C R F.  T he use of i ntrat y mpa nic ster oi ds, 
i ntrat y m pa nic ge nta mici n, or ear s ur ger y at a n y ti me d uri n g t he st u d y will be c o nsi dere d a 
pr ot oc ol de viati o n.  A n y c ha n ges re p orte d b y t he s u bjects i n c o nc o mita nt me dicati o ns s h o ul d be 
rec or de d i n t he s u bject’s e C R F. 
8.  
S T U D Y E V A L U A TI O N S  
8. 1.  
St u d y Pr oce d ures b y Visit  
8. 1. 1.  
Visit 1: U p t o 1 4 d a ys pri or t o i niti ati o n of le a d- i n peri o d ( Scree ni n g) 
Beca use a u di ol o g y, t y m pa n o metr y a n d ot osc o pic e xa ms are c o nsi dere d r o uti ne f or t his patie nt 
p o p ulati o n, data o btai ne d fr o m assess me nts perf or me d pri or t o d oc u me ntati o n of i nf or me d 
c o nse nt ca n be use d as scree ni n g data.  I n t hese cases, t he data s h o ul d ha ve bee n c ollecte d wit hi n 
1 4 d a ys of i nitiati o n of t he lea d -i n peri o d. 
T he f oll o wi n g assess me nts will be perf or me d at Visit 1.  
•  I nf or me d c o nse nt 
•  C o nfir m eli gi bilit y criteria  
•  Me dical hist or y  
•  C o nc o m ita nt me dicati o ns 
•  Vital si g ns  
•  Hei g ht a n d wei g ht meas ure me nts  
•  Ser u m  pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y)  
•  Cli nical la b orat or y test  
•  T y m pa n o metr y 
•  A u di o metr y  
•  Ot osc o p y 
•  C- S S R S assess me nt: Baseli ne versi o n  
•  Re vie w I V R S diar y i nstr uc ti o ns wit h s u bject 
8. 1. 2.  
Le a d -I n Peri o d ( D a y - 2 8 t hr o u g h - 1 ( + 3 d a ys)) 
T he s u bject will rec or d t heir dail y verti g o e x perie nce d uri n g t he e ntire lea d-i n peri o d u ntil 
ra n d o mizati o n, i neli gi bilit y or wit h dra wal of c o nse nt.  T he deter mi nati o n of w het her s u bjects 


 
 
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3 3   
 
mee t I ncl usi o n Criteria N o. 1 0 a n d 1 1 will be c o n d ucte d 2 8 da ys after i nitiati o n of t he lea d-i n 
peri o d. 
8. 1. 3.  
Visit 2: D a y 1 ( B aseli ne/ D ose A d mi nistr ati o n)  
T he f oll o wi n g assess me nts will be perf or me d at Visit 2.  
•  C o nfir m eli gi bilit y criteria  
•  Me dical hist or y  
•  C o nc o mita nt me dicati o ns  
•  Vital si g ns  
•  Uri ne pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y)  
•  Cli nical la b orat or y test  
•  T y m pa n o metr y 
•  A u di o metr y 
•  Ot osc o p y 
•  S F - 3 6 S ocial F u ncti o ni n g S u bscale assess me nt 
•  C- S S R S assess me nt, Si nce Last Visit versi o n  
•  Ra n d o mize a n d a d mi nister O T O - 1 0 4 or place b o (all assess me nts i n t he a b o ve list 
m ust be c o n d ucte d pri or t o O T O- 1 0 4 or place b o a d mi nistrati o n)  
•  Re vie w s u bject I V R S diar y i nstr ucti o ns 
•  A d verse e ve nts (t o be c ollecte d d uri n g or after O T O - 1 0 4 a d mi nistrati o n) 
8. 1. 4.  
Vis it 3, 4: Wee k 4 a n d 8 ( ± 2 d a ys) ( F oll o w U p) 
T he f oll o wi n g assess me nts will be perf or me d at Visit 3 a n d 4.  
•  C o nc o mita nt me dicati o ns  
•  Vital si g ns  
•  T y m pa n o metr y 
•  A u di o metr y  
•  Ot osc o p y 
•  Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C)  – Wee k 8 o nl y  
•  S F - 3 6 S ocial F u ncti o ni n g S u bscale assess me nt – Wee k 8 o nl y 
•  C- S S R S assess me nt, Si nce Last Visit versi o n  
•  Re vie w s u bject I V R S diar y i nstr ucti o ns 
•  A d verse e ve nts  


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


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
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Usi n g t he dail y verti g o scales  de vel o pe d b y Gates (Gates, 2 0 0 0 ; Gates, 2 0 0 4 ; Gates 2 0 0 5 ; Gates, 
2 0 0 6 ) a n d a da pte d t o a n I V R S, s u bjects are i nstr ucte d t o rec or d t he sc ore t hat best c orres p o n ds t o 
t he w orst verti g o e pis o de e x perie nce d eac h da y , a n d t he effect o n t heir dail y acti vities of t heir 
t otal verti g o e x perie nce t hat da y usi n g a 5- p oi nt sc ori n g s yste m: 
Verti g o Se verit y Sc ore  
0 = Verti g o -free da y 
1 = Mil d - a n attac k lasti n g less t ha n 2 0 mi n utes  
2 = M o derate - a n attac k lasti n g m ore t ha n 2 0 mi n utes 
3 = Se vere - a n attac k lasti n g m ore t ha n 2 0 mi n utes a n d acc o m pa nie d b y na usea a n d/ or 
v o miti n g 
4 = T he w orst attac k e x perie nce d t o date  
Effect of Verti g o  o n Acti vit y Le vel 
0 = N or mal Acti vit y  
1 = Sli g ht li mitati o n  
2 = M o derate li mitati o n  
3 = Sic k at h o me 
4 = Be d ri d de n 
T he occ urre nce of a defi niti ve verti g o e pis o de f or a gi ve n da y is defi ne d as a rec or de d Verti g o 
Se verit y Sc ore of 2 or m ore f or t hat da y.  If m ulti ple attac ks occ ur o n t he sa me da y, o nl y t he 
w orst attac k s h o ul d be sc ore d. 
8. 2. 2.  
P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C)  
T he P GI C is  a patie nt -re p orte d o utc o me t hat e val uates t he c ha n ge i n o verall “ gl o bal” Me niere’s 
disease stat us as percei ve d b y t he s u bject.  T he s u bject is as ke d: “ Si nce t he be gi n ni n g of t he 
cli nical st u d y, h o w w o ul d y o u rate y o ur Me niere’s disease?”.  T he be gi n ni n g o f t he cli nical st u d y 
i n t his c o nte xt is t he ti me pri or t o st u d y dr u g a d mi nistrati o n.  T he 7 res p o nse cate g ories (a n d 
p oi nt sc ores) f or t he P GI C are:  
•  Ver y m uc h w orse = - 3 
•  M uc h w orse = - 2 
•  Mi ni mall y w orse = - 1 
•  U nc ha n ge d = 0 
•  Mi ni mall y i m pr o ve d = + 1 
•  M uc h i m pr o v e d = + 2 
•  Ver y m uc h i m pr o ve d = + 3  


 
 
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8. 2. 3.  
S h ort F or m 3 6 ( S F -3 6) He alt h S ur ve y – S oci al F u ncti o ni n g S u bsc ale  
T he S F - 3 6 is a vali date d, 3 6-ite m, m ulti- p ur p ose, s h ort-f or m healt h s ur ve y ( Ware et al., 1 9 9 3; 
Ware et al., 1 9 9 4).  It c o nsists of 8 s u bscales, b ut o nl y t he S ocial F u ncti o ni n g S u bscale 
c o nsisti n g of 2 q uesti o ns will be a d mi nistere d. 
T he 2 q uesti o ns of t he S ocial F u ncti o ni n g S u bscale are: 
1)  D uri n g t he past 4 wee ks, t o w hat e xte nt has y o ur p h ysical healt h or e m oti o nal pr o ble ms 
i nterfere d wit h y o ur n or mal s ocial acti vities wit h fa mil y, frie n ds, nei g h b ors, or gr o u ps? 
o  1 – N ot at all 
o  2 – Sli g htl y  
o  3 – M o deratel y  
o  4 – Q uite a bit  
o  5 – E xtre mel y  
2)  D uri n g t he past 4 wee ks, h o w m uc h of t he ti me has y o ur p h ysical healt h or e m oti o nal 
pr o ble ms i nterfere d wit h y o ur s ocial acti vities (li ke visiti n g wit h frie n ds, relati ves, etc.)?  
o  1 – All of t he ti me  
o  2 – M ost of t he ti me  
o  3 – S o me of t he ti me  
o  4 – A little of t he ti me  
o  5 – N o ne of t he ti me 
8. 3.  
S afet y E v al u ati o ns  
Safet y assess me nts i ncl u de : 
•  Vital S i g ns a n d Wei g ht M eas ure me nts 
•  Cli nical La b orat or y Test s 
•  T y m pa n o metr y 
•  A u di o metr y 
•  Ot osc o p y  
•  C- S S R S Assess me nt  
•  C o nc o mita nt Me dicati o ns  
•  A d verse e ve nts (see Secti o n  9) 
8. 3. 1.  
Vit al Si g n s, Hei g ht a n d Wei g ht Me as ure me nts 
Vital si g n meas ure me nts (i ncl u di n g s yst olic a n d diast olic bl o o d press ure a n d p ulse rate) will be 
c ollecte d at all st u d y visits.  Vital si g ns  will be meas ure d after s u bjects ha ve bee n seate d f or 5 


 
 
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3 7   
 
mi n utes a n d w hile s u bjects are i n a sitti n g p ositi o n.  Hei g ht a n d wei g ht will be meas ure d at Visit 
1 a n d wei g ht will be meas ure d a gai n at Visit 5. 
8. 3. 2.  
Cli nic al L a b or at or y Test 
All cli nical la b orat or y tests will  be pr ocesse d b y a Ce ntral La b orat or y. 
Bl o o d a n d uri ne sa m ples f or he mat ol o g y, ser u m c he mistr y, uri nal ysis, a n d pre g na nc y tests will 
be pre pare d usi n g sta n dar d pr oce d ures.  Cli nical la b orat or y testi n g will be c o m plete d at Visits 1, 
2 a n d 5.  I n a d diti o n, fe male s u bjects of c hil d beari n g p ote ntial will ha ve ser u m pre g na nc y test at 
Visit 1 a n d a uri ne pre g na nc y test at Visits 2 a n d 5. 
T he bl o o d a n d uri ne sa m ples will be use d f or t he f oll o wi n g tests: 
He mat ol o g y: w hite bl o o d cell c o u nt wit h differe ntial, he m o gl o bi n, he mat ocrit, platelet c o u nt, 
re d bl o o d cell c o u nt, mea n c or p usc ular v ol u me, mea n c or p usc ular he m o gl o bi n, a n d mea n 
c or p usc ular he m o gl o bi n c o nce ntrati o n.  
Ser u m C he mistr y:  al b u mi n, al kali ne p h os p hatase, ala ni ne a mi n otra nsferase ( A L T), as partate 
a mi n otra nsferase ( A S T), bl o o d urea nitr o ge n, car b o n di o xi de, calci u m, c hl ori de, creati ni ne, 
gl uc ose, lactate de h y dr o ge nase, p h os p h or us, p otassi u m, s o di u m, t otal bilir u bi n, t otal pr otei n. 
Uri nal ysis:  a p peara nce, c ol or, gl uc ose, ket o nes, nitrite, p H, pr otei n, s pecific gra vit y, occ ult 
bl o o d, le u k oc yte esterase, a n d ur o bili n o ge n. 
8. 3. 3.  
T y m p a n o metr y 
T y m pa n o metr y assess me nts will be use d t o assess t he m o bilit y a n d c o m plia nce of t he t y m pa nic 
me m bra ne, press ure a n d v ol u me i n t he mi d dle ear, a n d f u ncti o n of t he t y m pa nic me m bra ne, 
o ssicles a n d e ustac hia n t u be.  T y m pa n o gra ms will be c o m plete d i n b ot h ears at all st u d y visits , 
u nless t he e xa mi ner deter mi nes t hat t here is a c o ntrai n dicati o n t o perf or mi n g t he pr oce d ure .  
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 
t y m pa n o metr y assess me nt. 
8. 3. 4.  
A u di o metr y  
A u di o metric assess me nts will be use d t o assess heari n g f u ncti o n i n b ot h ears.  A u di o gra ms 
s h o ul d be c o n d ucte d at 2 5 0, 5 0 0, 1 0 0 0, 2 0 0 0, 3 0 0 0, 4 0 0 0 a n d 8 0 0 0 Hz at Scree ni n g a n 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 all ot her st u d y visits ( Baseli ne, Wee k 4, Wee k 8, a n d Wee k 
1 2) f or air c o n d ucti o n a n d at 1 0 0 0, 2 0 0 0, a n d 4 0 0 0 Hz f or 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 ucti o n t hres h ol ds will be assesse d.  P ure t o ne a vera gi n g f or air c o n d ucti o n 
testi n g will be d o ne at 5 0 0, 1 0 0 0, a n d 2 0 0 0 Hz fre q ue ncies.  S u bjects weari n g heari n g ai ds 
s h o ul d be i nstr ucte d n ot t o wear t heir heari n g ai ds d uri n g t he a u di o gra m. 
A u di o metric assess me nts m ust be c o n d ucte d i n acc or da nce wit h A merica n -S peec h - La n g ua ge-
Heari n g Ass ociati 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 nse d or certifie d 
a u di ol o gist or a q ualifie d assista nt wit h a p pr o priate trai ni n g u n der t he direct s u per visi o n of a 
lice nse d or certifie d  a u di ol o gist. 


 
 
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8. 3. 5.  
Ot osc o p y 
Ot osc o pic e xa ms will be use d t o assess t he a u dit or y ca nal, t he a p peara n ce of t he t y m pa nic 
me m bra ne, a n d t he heali n g of t he i ntrat y m pa nic i njecti o n site.  Ot osc o pic e xa 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 he st u d y b y t he p h ysicia n or q ualifie d healt hcare 
pr ofessi o nal.  Prese nce a n d size of t y m pa nic me m bra ne perf orati o ns will be rec or de 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 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.   
8. 3. 6.  
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)  Assess me nt  
T he C -S S R S is a scale t hat ca pt ures t he occ urre nce, se verit y, a n d fre q ue nc y of s uici de-relate d 
t h o u g hts a n d be ha vi ors d uri n g t he assess me nt peri o d (P os ner 2 0 1 1 ).  T he U. S. F o o d a n d Dr u g 
A d mi nistrati o n re q uires t hat a pr os pecti ve assess me nt f or s uici dal i de ati o n a n d be ha vi or be 
i ncl u de d i n cli nical trials i n v ol vi n g all dr u gs a n d bi ol o gical pr o d ucts f or ne ur ol o gical i n dicati o ns.  
T his is tr ue w het her or n ot a partic ular pr o d uct is k n o w n or s us pecte d t o be ass ociate d wit h 
treat me nt-e mer ge nt s uici dal i deati o n a n d be ha vi or.  T he C- S S R S assess me nt f ulfills t his 
re q uire 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 Baseli ne 
versi o n will be use d at Visit 1 f or all s u bjects.  F or Visits 2 t hr o u g h 5 , t he Si nce Last Visit 
versi o n will be use d.  A n y s u bject wit h a p ositi ve sc ore at Baseli ne ( Scree ni n g) or a n a p peara nce 
of a n y ne w s uici dal i deati o n or s uici de be ha vi or si nce Baseli ne 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 has a n y p ost-Scree ni n g C -S S R S sc or e 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 ha n t he Scree ni n g C- S S R S sc ore, t he n t his assess me nt s h o ul d be 
rec or de d as a n A E.  T his i nf or mati o n is re p orte d as i n dicate d i n Secti o n  9. ( P ossi ble A E ter ms: 
S uici dal pla ns, S uici dal i deati o n, S uici dal te n 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 has a n y p ost-Scree ni n g C - S S R S sc ore of 4 or 5 f or I deati o n (i.e., a “ yes” a ns wer t o 
q uesti o n 4 or 5) a n d/ or a n y q uesti o ns a ns were d yes f or S uici dal Be ha vi or ( wit h t he e xce pti o n of 
a “ yes” res p o nse t o t he N o n -S uici dal Self -I nj uri o us Be ha vi or q uesti o n), a n d t his was n ot 
o bser ve d at Scree ni n g, t he n t his assess me nt s h o ul d be rec or de d as a Seri o us A d verse E ve nt 
( S A E).  T his i nf or mati o n is re p orte d as i n dicate d i n Secti o n  9. 2. 2. 
9.  
A D V E R S E E V E N T 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 seri o us a d verse e ve nts ( 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 pa ge of t he e C R F  f or all e nr olle d s u bjects.  
I nf or mati o n t o be c ollecte d i ncl u des descri pti o n  of e ve nt, date of o nset, I n vesti gat or- s pecifie 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, date of res ol uti o n of t he e ve nt, 
seri o us ness, a n y req uire d treat 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 nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt me dicati o ns, or 


 
 
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pr o gressi o n of disease states m ust als o be re p orte d.  Perf orati o ns of t he t y m pa nic  me m bra ne will 
be ca pt ure d as 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. 
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 ble a n d u ni nte n de d dia g n osis, s y m pt o m, si g n, s y n dr o me or disease w hic h 
occ urs d uri n g t he st u d y, ha vi n g bee n a bse nt at baseli ne, or, if prese nt at baseli ne, a p pears t o 
w orse n. 
T his i ncl u des a n y occ urre nce t hat is ne w i n o nset or a g gra vate d i n se verit y or fre q ue 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 oce 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 treat me nt or a n y ot her t hera pe utic i nter ve nti o n 
•  re q uire f urt her dia g n ostic e val uati o n (e xcl u di n g a re petiti o n of t he sa me pr oce d ure t o 
c o nfir m t he a b n or malit y)  
•  are ass ociate d wit h cli nical si g ns or s y m pt o ms j u d ge d b y t he In vesti gat or t o ha v e a 
si g nifica nt cli nical i m pact 
Seri o us A d verse E ve nt ( S A E):  
A n S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat: 
•  res ults i n deat h, 
•  is life-t hreate ni n g ( N ote: t he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e ve nt rat her t ha n t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere.),  
•  re q uires i n-patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacity, or 
•  is a c o n ge nital a n o mal y/ birt h defect. 
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise 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 hreate 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 utc 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 seri o us. 
9. 1. 1.  
Assess me nt of Se verit y  
T he In vesti gat or will assess t he i nte nsit y of t he A E a n d rate t he A E as mil d, m o derate, or se vere 
usi n g t he f oll o wi n g criteria:  


 
 
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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 ufficie nt disc o mf ort t o i nterfere wit h dail y 
acti vit y a n d/ or re q uire 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 vere:  T hese e ve nts i nca pacitate 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 pitalizati o n.  
Gr a de 4 – Life T hre ate ni n g:  T hese e ve nts are t h ose f or w hic h t he s u bject was at ris k of 
deat h at t he ti me of t he e ve nt rat her t ha n a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca use d 
deat h if it were m ore se vere.  
Gr a de 5 – De at h : T he 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 se verit y of a n A E s h o ul d be d oc 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 ve nt at eac h le vel of i nte nsit y t o be perf or me d.  
9. 1. 2.  
Assess me nt of C a us alit y  
T he In 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 will n ot be a fact or i n deter mi ni n g w hat is or is n ot re p orte d i n t he 
st u d y.   
T he In vesti gat or will assess t he relati o ns hi p or ass ociati o n of t he  st u d y dr u g i n ca usi n g or 
c o ntri b uti n g t o t he A E, w hic h will be c haracterize d usi n g t he f oll o wi n g classificati o n a n d 
criteria: 
Defi nite:  A d verse e ve nts t hat, after caref ul me dical e val uati o n, are c o nsi dere d defi nitel y 
relate d t o t he st u d y dr u g; ot her c o n diti 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 pear t o e x plai n t he e ve nt. 
Pr o b a ble:  A d verse e ve nts t hat, after caref ul me dical e val uati o n, are c o nsi dere d wit h a hi g h 
de gree of certai nt y t o be  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 na ble te m p oral relati o ns hi p e xists bet wee n t he e ve nt a n d e x p os ure t o t he st u d y 
dr u g, a n d 
•  t he e ve nt is a k n o w n reacti o n t o t he st u d y dr u g t hat ca n n ot be e x plai ne d b y a n 
alter nati ve 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 
•  t he e ve nt is n ot a k n o w n reacti o n t o t he st u d y dr u g b ut ca n n ot be reas o na bl y 
e x plai ne d b y a n alter nati ve ca use.  
P ossi ble:  A d verse e 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 ble relati 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 haracteristics will a p pl y:  
•  t he e ve nt occ urs after e x p os ure t o t he st u d y dr u g, a n d 
•  t here is a reas o na ble 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  


 
 
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•  i n t he a bse nce of a reas o na ble te m p oral relati o ns hi p, t he e ve nt ca n n ot be e x plai ne d b y 
a n alter nati ve ca use.  
N ot rel ate d:  A d verse e ve nts i n t his cate g or y will ha ve eit her of t he f oll o wi n g c haracteristics:  
•  t he e ve nt d oes n ot ha ve a reas o na ble te m p oral relati o ns hi p t o st u d y dr u g 
a d mi nistrati o n a n d/ or ca n be e x plai ne d b y a c o m m o nl y occ urri n g alter nati ve ca use. 
9. 1. 3.  
F oll o w u p of A d verse E ve nts  
T he In 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 In 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 bilize s, 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 Dr u g Safet y acc or di n g t o t he 
re p ortin 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 A Es i n res p o nse t o ge neral, 
n o n- directe d q uesti o ni n g (e. g., " H o w has y o ur healt h bee n si nce t he last visit?").  F or eac h A E 
v ol u nteere d b y t he s u 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 e C R F, i n acc or da nce wit h t he g ui deli nes t hat acc o m pa n y it.  
All A Es, re gar dless 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 ter mi n ol o g y i n t he s o urce d oc u me nt a n d o n t he e C R F.  W he ne ver 
p ossi ble, dia g n oses s h o ul d be gi ve n w he n si g ns a n d s y m pt o ms are d ue 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 ose, 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 orte d as " u p per 
res pirat or y i nfecti o n").  I n vesti gat ors m ust rec or d o n t he e C R F t heir o pi ni o n c o ncer ni n g t he 
relati o ns hi p of t he A E t o st u d y t hera p y.  All meas ures re q uire d f or A E ma na ge me nt m ust be 
rec or de d i n t he s o urce d oc u me nt a n d re p orte d acc or di n g t o s p o nsor i nstr ucti o ns.  
A n y n o n-seri o us A E t hat occ urs after t he d ose of st u d y dr u g m ust be re p orte d i n detail o n t he 
a p pr o priate e C R F pa ge a n d f oll o we d u ntil res ol uti o n, sta bilizati o n, or t he E n d of St u d y Visit.  
T he descri pti o n of t he A E will i ncl u de descri 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 ness, a n y re q uire d 
treat me nt or e val uati o ns, a n d o utc o me.  
T he S p o ns or ass u mes res p o nsi bilit y f or a p pr o priate re p orti n g of A Es t o t 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 In 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 (I R B) or Researc h Et hics C o m mittee  (R E C ) i n acc or da nce wit h l ocal 
re g ulati o ns. 




 
 
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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  
St u d y s u bject partici pati o n is c o m plete after Visit 5  a n d c o m pleti o n of t he Da y 8 4 diar y of t heir 
verti g o e x perie nce.  S u bject s w h o wit h dra w t heir c o nse nt t o be f oll o we d or are l ost-t o-f oll o w- u p 
bef ore c o m pleti o n of Visit 5 ( Wee k 1 2) will n ot be c o nsi dere d t o ha ve c o m plete d t he st u d y. 
1 0. 2.  
Wit h dr a w al  
All s u bjects ha ve t he ri g ht t o wit h dra w fr o m st u d y e val uati o ns at a n y ti me, f or a n y reas o n , 
wit h o ut prej u dice; n o net heless, I n vesti gat ors s h o ul d atte m pt t o e nc o ura ge s u bjects t o c o m plete 
t he pr ot oc ol s o t hat c o nti n ue d o bser vati o n a n d f oll o w- u p meas ure me nts ma y be o btai ne d.   
S u bjects m ust be wit h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g:  
•  Wi t h dra wal of c o nse nt 
•  T he s u bject is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol 
Ot her reas o ns f or wit h dra wal of s u bjects fr o m t he st u d y mi g ht i ncl u de:  
•  At t he discreti o n of t he I n vesti gat or f or me dical reas o ns  
•  At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce 
•  Si g nifica nt pr ot oc ol de viati o n  
•  Decisi o n b y t he I n vesti gat or or S p o ns or 
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 partici pati o n 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 u bject, a n d e ns ure t he s u bject recei ves a p pr o priate 
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 t he st u d y, i ncl u di n g disc o nti n ui n g 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 of t he st u d y at a n y ti me.  S u bject partici pati o n i n t he st u d y 
ma y be st o p 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 
wit h rati o nale d oc u me nte d. 
S h o ul d a re q ues t f or earl y wit h dra wal fr o m t he st u d y wit h n o f urt her f oll o w- u p be 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 assess me nts.  
W he n a s u bject wit h dra ws fr o m t he st u d y pri or t o c o m pleti n g t he E n d- of- St u d y Visit, t he reas o n 
f or wit h dra wal is t o be d oc u me nte d o n t he e C R Fs a n d i n t he s o urce d oc u me nt. 
1 0. 2. 2.  
Re pl ace me nts  
S u bjects w h o disc o nti n ue partici pati o n i n t he st u d y f or a n y reas o n after d osi n g will n ot be 
re place d. 


 
 
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1 1.  
S T A T I S TI C A L M E T H O D S 
T he pri mar y o bjecti ve of t his P hase 3 st u d y is t o test t he h y p ot hesis t hat s u bjects ra n d o mize d t o 
O T O -1 0 4 will de m o nstrate fe wer defi niti ve verti g o da ys ( D V D) t ha n s u bjects ra n d o mize d t o 
place b o at Wee k 1 2 (t he 4 -wee k  ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2).  T he mai n 
sec o n dar y o bjecti ve of t he st u d y is t o i n vesti gate t he safet y pr ofile of a 1 2 m g d ose of O T O- 1 0 4 
c o m pare d t o place b o w he n a d mi nistere d as a si n gle i ntrat y m pa nic i njecti o n i n s u bjects wit h 
Me niere’s disease.  
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).  T he S A P will be pre pare d a n d fi na lize d bef ore 
u n bli n di n g t he s u bjects’ ra n d o mize d treat me nt assi g n me nts.  
1 1. 1.  
S a m ple Size  
T he tar get t otal sa m ple size f or t he st u d y is 1 4 2 s u bjects ra n d o mize d wit h 1: 1 all ocati o n, 
dr u g: place b o, wit h 7 1 i n eac h gr o u p.   
T he p o wer esti mate was base d o n t he esti mate d treat me nt gr o u p mea ns f or D V D at Wee k 1 2 [t he 
4- wee k ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2] fr o m pre vi o usl y c o n d ucte d trials b y t he 
S p o ns or i n t his i n dicati o n.  T he pri mar y a nal ysis will  be c o n d ucte d usi n g a Ne gati ve Bi n o mial 
m o del at Wee k 1 2.  F or t he Ne gati ve Bi n o mial a nal ysis, a sa m ple size of 1 4 2  s u bjects will 
pr o vi de a p pr o xi matel y 9 0 % p o wer t o detect a differe nce bet wee n gr o u ps i n t he 2 8- da y a vera ge 
D V D. It is ass u me d t hat t he 2 8 - da y a vera ge D V D will be 2. 4 7 a n d 4. 6 6 f or O T O- 1 0 4 a n d 
p lace b o, res pecti vel y, f or a n esti mate d rati o of 0. 5 3. It is als o ass u me d t hat t he distri b uti o n s ha pe 
para meter is 1. 0 4.  T he ass u m pti o ns use d f or t he Ne gati ve Bi n o mial m o del were base d o n t he 
pre vi o usl y c o n d ucte d st u d y O T O- 1 0 4- 2 0 1 5 0 8 ( data o n file). T he calc ulati o ns were c o n d ucte d 
usi n g E A S T v 6. 5 fr o m C ytel, I nc. 
1 1. 2.  
A n al ysis Sets  
T he f oll o wi n g defi niti o ns will be use d t o deri ve t he a nal ysis sets f or t his st u d y.    
F ull A n al ysis Set ( F A S):   T he f ull a nal ysis set will i ncl u de all s u bjects w h o are ra n d o mize d, 
recei ve st u d y dr u g, ha ve a baseli ne defi niti ve verti g o meas ure me nt  f or t he 4-wee k lea d -i n 
peri o d a n d at least o ne p ost - baseli ne dail y diar y e ntr y  f or Wee k 1 2.  All efficac y a nal yses  
will be c o n d ucte d usi n g t he F A S.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p t o w hic h 
t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d. 
Per Pr ot oc ol A n al ysis Set:   T he per pr ot oc ol a nal ysis set will i ncl u de all s u bjects w h o are 
ra n d o mize d, recei ve st u d y dr u g, meet eli gi bilit y criteria, ha ve n o maj or pr ot oc ol de viati o ns,  
a n d ha ve a baseli ne defi niti ve verti g o meas ure me nt a n d at least o ne p ost- baseli ne  dail y diar y 
e ntr y wit hi n Wee k 9  t hr o u g h 1 2.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p of t he 
act ual st u d y dr u g recei ve d. 
I nte nt-t o-Tre at A n al ysis Set (I T T):  T he I T T a nal ysis set will i ncl u de all ra n d o mize d 
s u bjects w h o recei ve st u d y dr u g.  S u bjects will be i ncl u de d i n t he treat me nt gr o u p t o w hic h 
t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d. T he I T T set will be use d 
t o assess se nsiti vit y t o missi n g data.  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4 5   
 
Safet y A nal ysis Set:  T he safet y a nal ysis set will i ncl u de all  s u bjects w h o recei ve st u d y dr u g.  
S u bjects will be i ncl u de d i n t he treat me nt gr o u p acc or di n g t o t he act ual treat me nt recei ve d 
re gar dless of t heir ra n d o mize d assi g n me nt.  W he n t he ear is t he u nit of a nal ysis, t he safet y 
a nal ysis will cate g orize a n ear b y w het her it was a treate d or a n u ntreate d ear, irres pecti ve of 
w het her it was t he affecte d ear.  
1 1. 3.  
Descri pti o n of S u b gr o u ps t o be A n al yze d  
Des cri pti ve a nal yses will be perf or me d f or t he pri mar y efficac y e n d p oi nt f or t he f oll o wi n g 
s u b gr o u ps usi n g t he F A S wit h details pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P ): 
•  S u bject De m o gra p hics 
− Ge n der 
− Race/ Et h nicit y  
− A ge (cate g ories:  1 8 -3 0, 3 1 - 4 0, 4 1- 6 0, 6 1- 6 4, 6 5- 7 4, 7 5- 8 4, ≥8 5 yrs.) 
•  Baseli ne Disease C haracteristics  
− D urati o n of Me niere’s Disease  
− De gree of heari n g l oss  
− Beta histi ne use  
1 1. 4.  
S u bject De m o gr a p hics, B aseli ne Dise ase St at us, a n d Dis p ositi o n  
Descri pti ve statistics f or s u bject de m o gra p hics, baseli ne disease stat us, a n d s u bject dis p ositi o n 
will be pr o vi de d.   
1 1. 5.  
Effic ac y E v al u ati o ns  
1 1. 5. 1.  
Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt is t he 2 8- da y a vera ge defi niti ve verti g o da ys ( D V D) at Wee k 1 2 
(t he 4-wee k  ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2).  A D V D is defi ne d as eac h da y 
t he s u bject rec or de d a verti g o e pis o de lasti n g at least 2 0 mi n utes a n d c orres p o n ds t o a Verti g o 
Sc ore of 2 or m ore.  If m ulti ple e pis o des occ ur o n a gi ve n da y, o nl y t he w orst e pis o de i n ter ms of 
sc ore s h o ul d be rec or de d.   
1 1. 5. 2.  
Sec o n d ar y Effic ac y E n d p oi nts  
Sec o n dar y Efficac y E n d p oi nt: 
•  Se verit y of verti g o e pis o des as meas ure d b y t he M ea n Se verit y Verti g o Sc ore  ( M S V S) at 
Wee k 1 2 (t he 4 -wee k ( 2 8 - da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2) 
•  T he 2 8- da y a vera ge of n u m ber of da ys Sic k at h o me or Be dri d de n ( D S B) as a 
c o nse q ue nce of verti g o at Wee k 1 2 (t he 4- wee k ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h 
Wee k 1 2) 


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4 6   
 
•  Perce nt of s u bjects ac hie vi n g a 7 5 % re d ucti o n fr o m baseli ne i n 2 8- da y a vera ge D V D at 
Wee k 1 2  
•  Perce nt of s u bject s ac hie vi n g a 1 0 0 % re d ucti o n fr o m baseli ne (i.e., c o u nt of zer o) i n 2 8-
da y a vera ge D V D at Wee k 1 2  
•  T he c ha n ge fr o m baseli ne i n verti g o fre q ue nc y ( V F) at Wee k 1 2 (t he 4- wee k st u d y 
i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2), w here verti g o fre q ue nc y is defi ne d as t he 
n u m ber of D V Ds rec or de d d uri n g t he 4 - wee k i nter val di vi de d b y t he n u m ber of n o n-
missi n g diar y e ntries f or t he rele va nt i nter val  
•  A vera ge dail y c o u nt of verti g o e pis o des at Wee k 1 2 (t he 4 -wee k ( 2 8- da y) i nter val fr o m 
Wee k 9 t hr o u g h Wee k 1 2) 
1 1. 5. 3.  
E x pl or at or y Effic ac y E n d p oi nts  
E x pl orat or y Efficac y E n d p oi nt s are: 
•  T he c ha n ge fr o m baseli ne i n verti g o fre q ue nc y ( V F) at Wee k 8, w here verti g o fre q ue nc y 
is defi ne d as t he n u m ber of D V Ds  rec or de d d uri n g t he 4- wee k i nter val di vi de d b y t he 
n u m ber of n o n- missi n g diar y e ntries f or t he rele va nt i nter val  
•  Se verit y of verti g o e pis o des as meas ure d b y t he M ea n Se verit y Verti g o Sc ore  ( M S V S) at 
Wee k  8  
•  A vera ge dail y c o u nt of verti g o e pis o des at Wee k 8  
•  T he 2 8- da y a vera ge  of n u m ber of da ys Sic k at h o me or Be dri d de n as a c o nse q ue nce of 
verti g o d uri n g eac h 4-wee k st u d y i nter val  (i.e., Wee k 4 , Wee k 8 , Wee k 1 2) 
•  T he n u m ber of 2 8- da y a vera ge defi niti ve verti g o d a ys ( D V D) at Wee k 8  
•  Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) at Wee ks 8 a n d 1 2 
•  S F - 3 6 S ocial F u ncti o ni n g S u bscale at Wee ks 8 a n d 1 2 
Occ urre nce of N or mal acti vit y, Sli g ht li mitati o n, M o derate li mitati o n, Sic k at h o me, a n d Be dri d de n 
e ve nts as a c o nse q ue nce of verti g o at Wee k 4, Wee k 8, a n d Wee k 1 2  Details re gar di n g i m p utati o n 
of missi n g data, i ncl u di n g ite ms f or q uesti o n naires, will be pr o vi de d i n t he Statistical 
A nal ysis Pla n ( S A P).  
1 1. 5. 4.  
A n al ytic Met h o ds f or Effi c ac y 
T he pri mar y efficac y e n d p oi nt, t h e 2 8-da y a vera ge D V D at Wee k 1 2 (t he 4 -wee k i nter val  fr o m 
Wee k 9 t hr o u g h Wee k 1 2), will be c o m pare d bet wee n O T O- 1 0 4 a n d place b o at t he 2-taile d, 0. 0 5 
al p ha le vel usi n g a Ne gati ve Bi n o mial m o del. T his m o del will i ncl u de fi xe d effects f or 
ra n d o mize d treat me nt gr o u p ( O T O- 1 0 4 vs. place b o) a n d se x ( male vs. fe male), wit h t he 2 8 - da y 
a vera ge D V D fr o m t he lea d-i n peri o d as a c o variate.   
T he pri mar y a nal ysis p o p ulati o n f or t he c o m paris o n of t he pri mar y e n d p oi nt bet wee n t he 
treat me nt gr o u ps i n t his st u d y is f ull a nal ysis set ( F A S).  S u bjects will be i ncl u de d i n t he 
treat me nt gr o u p t o w hic h t he y were ra n d o mize d re gar dless of t he act ual st u d y dr u g recei ve d. 
T he pri mar y e n d p oi nt a nal ysis als o will be c o n d ucte d usi n g per- pr ot oc ol  a n d I T T  a nal ysis sets 
as se nsiti vit y a nal yses .   


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4 7   
 
T he ke y sec o n dar y efficac y e n d p oi nt of t he Mea n Se verit y Verti g o Sc ore ( M S V S) f or Wee k 1 2 
( Wee k 9 t hr o u g h Wee k 1 2) will be a nal yze d usi n g a n A N C O V A m o del wit h fi xe d effects of 
ra n d o mize d treat me nt, gr o u p ( O T O- 1 0 4 vs. place b o) a n d se x ( male vs. fe male), wit h t he 
s u bject’s a vera ge mea n se verit y verti g o sc ore at lea d -i n peri o d as a c o variate. 
T he ke y sec o n dar y e n d p oi nt of t he 2 8- da y a vera ge of n u m ber of da ys Sic k at h o me or Be dri d de n 
( D S B) as a c o nse q ue nce of verti g o at Wee k 1 2 will be c o m pare d bet wee n t he treat me nt gr o u ps 
usi n g usi n g t he sa me Ne gati ve Bi n o mial m o del as s pecifie d f or t he pri mar y a nal ysis a n d usi n g 
t he 2 8-da y a vera ge Lea d -i n D S B  as a c o variate.   T he m o del will i ncl u de fi xe d effects f or 
ra n d o mize d treat me nt gr o u p ( O T O- 1 0 4 vs. place b o) a n d se x ( male vs. fe male).   
T he ke y sec o n dar y e n d p oi nts of perce nt of s u bjects ac hie vi n g a 7 5 % a n d a 1 0 0 % (i.e., c o u nt of 
zer o)  re d ucti o n fr o m baseli ne i n 2 8-da y a vera ge of D V D will be c o m pare d bet wee n t he treat me nt 
gr o u ps usi n g a c hi-s q uare test. T he ris k differe nce a n d t he 9 5 % CI ar o u n d t he ris k differe nce will 
als o be pr o vi de d. 
T he sec o n dar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n verti g o fre q ue nc y ( V F) at Wee k 1 2 
(t he 4- wee k i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2), will be a n al yze d usi n g a n A N C O V A 
m o del wit h treat me nt as a fi xe d effect a n d  se x as fi xe d effects wit h t he lea d-i n peri o d V F as a 
c o variate .   
T he sec o n dar y efficac y e n d p oi nt of a vera ge dail y c o u nt of verti g o e pis o des d uri n g 4- wee k st u d y 
i nter val (Wee k 9 t hr o u g h Wee k 1 2) will be usi n g t he A N C O V A m o del s pecifie d f or t he 
sec o n dar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n V F  at Wee k 1 2,  usi n g t he s u bject’s 
A vera ge Dail y Verti g o C o u nt ( A D V C ) at lea d-i n peri o d as a c o variate.    
Alter nati ve m o dels will be pre -s pecifie d i n t he S A P s h o ul d certai n ass u m pti o n s re gar di n g data 
a n d m o dels d o n ot h ol d.  I n a d diti o n, t he S A P will i ncl u de pre- s pecifie d data tra nsf or mati o ns 
s h o ul d e val uati o n of t he resi duals s u g gest a data tra nsf or mati o n is m ore s uita ble.  
If t he pri mar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is statisticall y si g nifica nt 
i n fa v or of O T O- 1 0 4 t he n a cl ose d testi n g, gate- kee pi n g pr oce d ure will be use d t o c o m pare t he 
f oll o wi n g sec o n dar y efficac y e n d p oi nts se q ue ntiall y:  
1.  Se verit y of verti g o e pis o des as meas ure d b y t he mea n Verti g o Sc ore at Wee k 1 2 (t he 4-
wee k ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2) 
2.  T he  2 8-da y a vera ge  n u m ber of da ys Sic k at h o me or Be dri d de n as a c o nse q ue nce of 
verti g o at Wee k 1 2 (t he 4 - wee k ( 2 8- da y) i nter val fr o m Wee k 9 t hr o u g h Wee k 1 2) 
3.  Perce nt of s u bjects ac hie vi n g a 7 5 % re d ucti o n fr o m baseli ne i n 2 8- da y a vera ge  D V D at 
Wee k 1 2.  
4.  Perce nt of s u bjects ac hie vi n g a 1 0 0 % re d ucti o n fr o m baseli ne (i.e., c o u nt of zer o)  i n 2 8-
da y a vera ge D V D at Wee k 1 2.  
I n t his pr oce d ure, if t he first sec o n dar y e n d p oi nt c o m paris o n bet wee n t he t w o treat me nt gr o u ps is 
statisticall y si g nifica nt i n fa v or of O T O- 1 0 4 t he n t he sec o n d sec o n dar y e n d p oi nt will be 
c o m pare d a n d teste d.  If t he sec o n d ke y sec o n dar y e n d p oi nt c o m paris o n bet wee n t he t w o 
treat me nt gr o u ps is teste d a n d t he res ult is statisticall y si g nifica nt i n fa v or of O T O- 1 0 4, t he n t he 
t hir d ke y sec o n dar y e n d p oi nt will be c o m pare d a n d teste d. If t he t hir d ke y sec o n dar y e n d p oi nt 
c o m paris o n bet wee n t he t w o treat me nt gr o u ps is teste d a n d t he res ult is statisticall y si g nifica nt i n 


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4 8   
 
fa v or of O T O- 1 0 4, t he n t he f o urt h ke y sec o n dar y e n d p oi nt will be c o m pare d a n d teste d. If t he 
c o m paris o n bet wee n  treat me nt gr o u ps is statisticall y si g nifica nt f or t he f o urt h ke y sec o n dar y 
e n d p oi nt, t he n it ca n be clai m e d t hat all ke y sec o n dar y e n d p oi nts are statisticall y si g nifica nt i n 
fa v or of O T O- 1 0 4. 
At t he first ke y sec o n dar y e n d p oi nt t hat d oes n ot de m o nstrate a statisticall y si g nifica nt differe nce 
bet wee n gr o u ps i n fa v or of O T O- 1 0 4, t he gate- kee pi n g pr oce d ure e n ds a n d a n y s u bse q ue nt ke y 
sec o n dar y e n d p oi nt p-val ues will be c o nsi dere d as a n o mi nal p - val ue(s).  
T he gate- kee pi n g pr oce d ure c o ntr ols t he T y pe I err or f or t he f o ur pla n ne d c o m paris o ns a n d, 
t heref ore, t here will be n o α s pe n di n g pe nalt y ass ociate d wit h t he pla n ne d ke y sec o n dar y 
c o m paris o ns. 
T he re mai ni n g sec o n dar y e n d p oi nts c o m paris o ns will n ot f oll o w t he gate- kee pi n g pr oce d ure a n d, 
t heref ore, t he re p orte d p- val ues will be re p orte d as n o mi nal p-val ues.   T hese a nal yses will be 
c o n d ucte d usi n g t he F A S o nl y. 
All efficac y h y p ot hesis tests will be 2 -si de d a n d perf or me d at α = 0. 0 5 si g nifica nce le vel, u nless 
ot her wise s pecifi d i n t he S A P . 
1 1. 6.  
S afet y E v al u ati o ns  
Safet y e n d p oi nts t o be e xa mi ne d i ncl u de: 
•  Vital Si g ns a n d Wei g ht Meas ure me nts  
•  Cli nical La b orat or y Test  
•  T y m pa n o me tr 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  
Descri pti ve statistical ta b ulati o ns will be prese nte d f or all s u bjects i ncl u de d i n t he Safet y 
A nal ysis Set.  
1 1. 6. 1.  
A d verse E ve nts  
T he c urre nt versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), as i n dicate d i n 
t he Data Ma na ge me nt Pla n, will be use d t o c o de all A Es. 
T he pri mar y a nal ysis of A Es will c o nsi der o nl y treat me nt -e mer ge nt A Es, e ve nts occ urri n g f or 
t he first ti me, or w orse ni n g d uri n g or after t he first d ose of st u d y dr u g.  S u bject i nci de nce of 
T E A Es a n d S A Es will be ta b ulate d b y preferre d ter ms a n d s yste m or ga n class.  Se verit y a n d 
relati o ns hi p t o st u d y dr u g will als o be prese nte d.  F or s u m mar y ta bles, a s u bject w h o e x perie nces 
t he sa me c o de d eve nt m ore t ha n o nce is c o u nte d o nl y o ne ti me f or t hat c o de d e ve nt at t he hi g hest 


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
4 9   
 
se verit y le vel.  A Es will be prese nte d b y desce n di n g or der of fre q ue 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 nal yses f or a ge, race, a n d ge n der will als o be e xa mi ne d pr o vi de d a reas o na ble n u m ber 
of s u bjects i n eac h s u b gr o u p are a vaila ble f or a nal ysis.  Listi n gs of all S A Es, A Es lea di n g t o 
st u d y wit h dra wal, a n d deat hs o n-st u d y will als o be i ncl u de d.  D urati o n a n d o utc o me of eac h A E 
will be re p orte d i n s u bject listi n gs.   
A d verse e ve nts occ urri n g d uri n g t he lea d-i n peri o d pri or t o e x p os ure t o st u d y dr u g will be 
re p orte d i n data listi n gs.  F urt her details will be pr o vi de d i n t he S A P. 
1 1. 6. 2.  
Vit al Si g ns a n d L a b or at or y P ar a meters 
T he a nal ysis of vital si g ns a n d la b orat o r y para meters will i ncl u de descri pti ve statistics f or t he 
c ha n ge fr o m baseli ne t o t he e n d p oi nt visit, c ha n ge fr o m baseli ne f or eac h visit ( vital si g ns o nl y).  
W here a p pr o priate, a nal yses will als o i ncl u de s hifts fr o m baseli ne t o t he e n d p oi nt visit.  F or 
la b orat or y val ues, t he n or mal ra n ges will be use d t o deter mi ne t he classificati o ns. Val ues bel o w 
t he n or mal ra n ge will be classifie d as l o w, val ues a b o ve t he n or mal ra n ge will be classifie d as 
hi g h, a n d val ues wit hi n t he n or mal ra n ge will be classifie d as n o r mal. 
1 1. 6. 3.  
Ot osc o pic E x a mi n ati o ns  
O bser vati o ns rec or de d d uri n g t he c o n d uct of ot osc o pic e xa ms will be descri pti ve i n nat ure.  T he 
n u m ber a n d perce nt of s u bjects prese nti n g wit h eac h Ot osc o pic classificati o n will be pr o vi de d b y 
treat me nt gr o u p, i ncl u di n g o verall, a n d st u d y visit.  W here rele va nt, t he n u m ber a n d pr o p orti o n of 
s u bjects wit h c ha n ges i n t heir o t osc o pic classificati o n fr o m baseli ne t o t he e n d p oi nt visit will 
als o be pr o vi de d f or eac h treat me nt gr o u p a n d o verall.   
1 1. 6. 4.  
A u di o metr y Assess me nts  
Descri pti ve s u m mar y statistics f or a u di o metric assess 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 ue nc y will be pr o vi de d b y treat me nt gr o u p a n d st u d y visit.  I n a d diti o n, t he 
P T A f or air c o n d ucti o n testi n g will be calc ulate d as t he a vera ge t hresh ol d f or t he 5 0 0, 1 0 0 0, a n d 
2 0 0 0 Hz fre q ue ncies.  
Air -B o ne Ga p assess me nts at eac h fre q ue nc y f or treat me nt gr o u p a n d st u d y visit will be 
ta b ulate d as t he pr o p orti o n of s u bjects wit h air mi n us b o ne c o n d ucti o n t hres h ol ds of:   
•  ≤ 1 0 d B or  
•  > 1 0 d B. 
All a u di o m etr 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. 6. 5.  
T y m p a n o metr y 
S hift ta bles re prese nti n g t he pr o p orti o n of s u bjects wit h c ha n ges i n t heir t y m pa n o gra m fr o m 
baseli ne t o eac h p ost -baseli ne st u d y visit will be calc ulate d f or eac h  treat me nt gr o u p.  
T y m pa n o gra m c ha n ges will i ncl u de b ot h t he t y pe of t y m pa n o gra m ( A, B- s mall v ol u me a n d/ or 
n or mal, B- lar ge v ol u me, or C).  


 
 
Ot o n o m y 1 0 4- 2 0 1 8 1 1 Pr ot oc ol V 3. 0: 3 0 J ul y 2 0 2 0 
5 0   
 
1 1. 6. 6.  
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
T he C- S S R S  will be a d mi nistere d at eac h visit usi n g t he a p pr o priate v ersi o n i.e., Baseli ne or 
Si nce Last Visit. A nal ysis of t his scale will be perf or me d o n t he Safet y A nal ysis Set.  
1 1. 6. 6. 1.  B aseli ne Versi o n  
T he Baseli ne versi o n of t he C -S S R S will be a d mi nistere d at t he Scree ni n g visit ( Visit 1). T his 
versi o n of t he scale ca pt ures b o t h s uici de i deati o n a n d s uici de be ha vi or (lifeti me). T here are 5 
s uici dal i deati o n q uesti o ns, eac h ca pt ure d as yes/ n o f or t he s u bject’s lifeti me. A d diti o nall y a 
si xt h s uici dal i deati o n varia ble will be create d t o i n dicate if t here was a n y i deati o n, re gar dless of 
t y pe. T here are 4 s uici dal be ha vi or q uesti o ns, eac h ca pt ure d as yes/ n o f or t he s u bject’s lifeti me. 
A fift h s uici dal be ha vi or varia ble will be create d t o ca pt ure if t here was 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 prese nt d uri n g t he visit. All 
s uici dal i deati o n a n d be ha vi oral varia bles as o utli ne d here will be ta b ulate d o verall a n d b y 
treat me nt gr o u p. All C- S S R S data will be i ncl u de d i n data listi n gs. T here is n o i ncl usi o n or 
e xcl usi o n criteri o n a ss ociate d wit h t he Baseli ne C-S S R S sc ore.  S u bjects wit h a p ositi ve sc ore 
s h o ul d be referre d t o t heir pri mar y care pr o vi der f or f oll o w-u p.  
1 1. 6. 6. 2.  Si nce L ast Visit Versi o n  
T he Si nce Last Visit versi o n of t he C -S S R S will be a d mi nistere d at eac h st u d y visit after t he 
Scree ni n g visit ( Visit 1).  T he sa me o verall i n di vi d ual varia bles f or s uici dal i deati o n a n d 
be ha vi or will be assesse d as i n t he Baseli ne versi o n.  I n a d diti o n, o verall s uici dalit y ( yes/ n o) will 
be defi ne d as a n y s u bject ha vi n g a n y s uici dal i deati o n or be ha vi or si nce t he last visit.  All 
s uici dal i deati o n a n d be ha vi or varia bles will be ta b ulate d o verall a n d b y treat me nt gr o u p f or eac h 
st u d y visit, as well as s hift ta bles dis pla ys s u bjects w h o m o ve fr o m ‘ N o’ t o ‘ Yes’ at eac h st u d y 
visit .  All C -S S R S data will be i ncl u de d i n data listi n gs  . 
A n y s u bject wit h a n a p peara nce of a n y ne w s uici dal i deati o n or s uici de be ha vi or si nce Scree ni n g 
s h o ul d be referre d t o t heir pri mar y care pr o vi der f or f oll o w-u p.  
If a s u bject has a n y p ost-Scree ni n g C -S S R S sc ore of 1 -3 f or I deati o n (i.e., a “ yes” a ns wer t o 
Q uesti o ns 1, 2, or 3) or a “ yes” res p o nse t o t he N o n- S uici dal Self -I nj uri o us Be ha vi or q uesti o n) 
a n d t he sc ore is hi g her t ha n t he Sc ree ni n g C-S S R S sc ore, t he n t his assess me nt s h o ul d be 
rec or de d as a n A E .  T his i nf or mati o n is re p orte d as i n dicate d i n  Secti o n  9. 2. 1.  ( P ossi ble A E 
ter ms: S uici dal pla ns, S uici dal i deati o n, S uici dal te n de nc y, S uici dal be ha vi or, S uici dal i nte nti o n, 
S uici dal de pressi o n, Acti ve s uici dal i deati o n, Passi ve s uici dal i 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 has a n y p ost-Scree ni n g C - S S R S sc ore of 4 or 5 f or I deati o n (i.e., a “ yes” a ns wer t o 
q uesti o n 4 or 5) a n d/ or a n y q uesti o ns a ns were d yes f or S uici dal Be ha vi or ( wit h t he e xce pti o n of 
a “ yes” res p o nse t o t he N o n -S uici dal Self -I nj uri o us Be ha vi or q uesti o n), a n d t his was n ot 
o bser ve d at Scree ni n g, t he n t his assess me nt s h o ul d be rec or de d as a Seri o us A d verse E ve nt.  
T his i nf or mati o n is re p orte d as i n dicate d i n  Secti o n  9. 2. 2. 


 
 
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1 1. 7.  
H a n d li n g of Missi n g D at a, S u bject Wit h dr a w als, a n d Tre at me nt 
F ail ures  
I n a d diti o n t o t he pri mar y a nal ysis of t he pri mar y e n d p oi nt, se veral se nsiti vit y a nal yses will als o 
be e val uate d.  T hese a nal yses will be i ncl u de d i n t he S A P wit h a p pr o priate details pri or t o 
u n bli n di n g t he data base.  
T he S A P will i ncl u de greater detail re gar di n g t he ha n dli n g of missi n g data as well as a n y 
al g orit h ms f or sc ori n g, i ncl u di n g t he ha n dli n g of missi n g q uesti o n naire ite ms. 
E ver y eff ort will be ma de t o f oll o w s u bjects f or st u d y o bser vati o n a n d e nc o ura ge c o m plia nce 
wit h st u d y meas ure me nts t o mi ni mize t he a m o u nt of missi n g data.  
E xce pt f or partial dates, safet 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 partial 
dates will be defi ne d i n t he S A P. 
1 1. 8.  
I nteri m A n al yses 
T here  are n o f or mal i nteri m a nal yses pla n ne d.  Bli n de d re vie w s of safet y data will be c o n d ucte d 
as descri be d i n Secti o n  1 4. 6; 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 ncer ns.  As s uc h, it is e x pecte d t hat t he trial will c o nti n ue t o its 
sc he d ule d c o m pleti o n barri n g a n y u ne x pecte d safet y iss ues. 
1 2.  
S T U D Y D R U G I N F O R M A TI O N  
1 2. 1.  
P h ysic al Descri pti o n of St u d y Dr u g(s)  
T he i n vesti gati o nal dr u g pr o d uct a d mi nistere d t o s u bjects i n t his st u d y will be O T O- 1 0 4 a n d 
place b o.  T he O T O- 1 0 4 fi nal pr o d uct s us pe nsi o n f or d osi n g will be pre pare d fr o m t w o se parate 
c o m p o ne nts, 
 ( o ne vial nee de d) a n d O T O- 1 0 4 Acti ve ( o ne vial nee de d).   
A n a p pr o priate v ol u me of 
 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 tar get dr u g 
c o nce ntrati o n of 6 0 m g/ m L.  Place b o will c o nsist of t he  ve hicle use d t o f or m ulate O T O- 1 0 4 a n d 
will be s u p plie d fr o m o ne vial 
). 
T he f oll o wi n g dr u g s u p plies will be use d i n t he st u d y: 
Pr o d uct  
S u p plie d as:  
O T O -1 0 4  
A kit c o ntai ni n g: o ne vial of O T O -1 0 4 Acti ve a n d o ne vial of 
 
s ol uti o n.  
Place b o   
A kit c o ntai ni n g: o ne vial of 
 s ol uti o n.  
1 2. 2.  
Directi o ns f or Use  
O T O - 1 0 4 a n d place b o will  be pre pare d b y a n u n bli n de d Q M P i n a clea n, sec ure l ocati o n wit h a 
r o o m te m perat ure prefera bl y at or bel o w 2 3° C ( 7 3° F).  T he l ocati o n will n ot be accesse d b y t he 
bli n de d pers o n nel d uri n g st u d y dr u g pre parati o n.  Please refer t o t he P har mac y Ma n ual f or 
detaile d st u d y dr u g p re parati o n i nstr ucti o ns. 


 
 
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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 mati 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 xe d t o eac h kit b o x i n dicati n g kit n u m ber a n d st ora ge i nstr ucti o ns.  A la bel 
will be affi xe d t o t he O T O - 1 0 4 Acti ve a n d 1 6 % p ol o xa mer s ol uti o n vials i n dicati n g c o nte nts a n d 
st ora ge i nstr ucti o ns.  A s yri n ge bli n di n g la bel will be pr o vi de d t o mas k t he s yri n ge c o nte nts f or 
i njecti o n. 
1 2. 4.  
M a n a ge me nt of Cli nic al S u p plies  
T he cli nical s u p plies will be ma na ge d b y t he I W R S.  T he I W R S will create s hi p me nt re q uests 
t hat will be ge nerate d base d o n i n ve nt or y t hres h ol ds t hat are set f or eac h site.  A s hi p me nt 
re q uest will be ge nerate d b y t he I W R S s yste m a n d se nt t o t he cli nical s u p plies ve n d or.  U p o n 
s hi p me nt a n d recei pt of t he cli nical trial material, t he site pers o n nel (e. g., p har mac y) will 
ac k n o wle d ge t he s hi p me nt usi n g t he I W R S a n d i de ntif y a n y da 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 i n acc or da nce wit h i nstr ucti o ns o n t he pr o d uct la bel.  All te m perat ure 
e xc ursi o ns of t he st u d y dr u g m ust be d oc 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 xc 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 ble f or use a n d dis pe nsi n g t o s u bjects.  If a n y e xc ursi o ns are o utsi de of 
t hese c o n diti o ns, t he st u d y dr u g s h o ul d n ot be use d t o treat s u bjects.  If t his occ urs, t he Q M P  
pre pari n g t he st u d y dr u g s h o ul d i m me diatel y q uara nti ne t he pr o d uct a n d re p ort t he kit(s) as 
u nacce pta ble f or dis pe nsi n g t o t he I W R S t o re m o ve it fr o m i n ve nt or y. 
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 receive d at t he site 
will be  i n ve nt orie d a n d acc o u nte d f or t hr o u g h o ut t he st u d y a n d t he res ult rec or de d o n t he dr u g 
acc o u nta bilit y f or m mai ntai ne d i n t he P har mac y Ma n ual.  T he Q M P will  be i nstr ucte d t o ret ur n 
all ori gi nal c o ntai ners, w het her e m pt y or c o ntai ni n g  st u d y dr u g, w he n i nstr ucte d b y t he st u d y 
m o nit or t o ret ur n.  St u d y dr u g ret ur ne d b y t he cli nical site staff will be st 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 
u n bli n de d st u d y m o nit or d uri n g t he c o urse of t he st u d y.  St u d y dr u g will be st ore d i n a li mite d 
access area or i n a l oc ke d refri gerat or u n der a p pr o priate 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 pers o n ot her t ha n s u b-I n vesti gat ors, 
desi g nate 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 bele d or 
reassi g ne d f or use b y ot her s u bjects e xce pt u n der s pecial circ u msta nces a p pr o ve d b y t he 
S p o ns or. 


 
 
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T he In vesti gat or will retai n a n d st ore all ori gi nal c o ntai n ers ret ur ne d b y t he cli nical site staff 
u ntil t hese c o ntai ners are i n ve nt orie d b y t he st u d y m o nit or.  U nless ot her wise i nstr ucte d b y t he 
s p o ns or, t he In vesti gat or a grees at t he e n d of t he st u d y t o ret ur n all ori gi nal c o ntai ners, w het 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 he st u d y ma 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 ha 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 ntati 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 perf or me d i n acc or da nce 
wit h t he pr ot oc ol, t he Declarati o n of Helsi n ki, as well as wit h t he N ote f or G ui da nce o n G o o d 
Cli nical Practice (I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire me nts.  T h ese 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.  
I nstit uti o n al Re vie w B o ar d (I R B) a n d Rese arc h Et hics C o m mittee  
(R E C ) 
T his trial will be u n derta ke n o nl y after f ull a p pr o val of t he pr ot oc ol a n d a d de n da has bee n 
o btai ne d fr o m a desi g nate d I R B or 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 I R B or R E C m ust be i nf or me d of all s u bse q ue nt pr ot oc ol a me n d me nts iss ue d b y t he 
s p o ns or. 
Re p orts o n, a n d re vie ws of, t he trial a n d its pr o gress will be s u b mitte d t o t he I R B or R E C b y t he 
In vesti gat or at i nter vals sti p ulate d i n t heir g ui deli nes.  
1 3. 3.  
I nf or me d C o nse nt 
Eac h s u bject m ust gi ve writte n c o nse nt a n d si g n ot her l ocall y re q uire d d oc u me nts acc or di n g t o 
l ocal re q uire me nts after t he nat ure of t he st u d y has bee n f ull y e x plai ne d.  T he c o nse nt f or m is 
t y picall y si g ne d at t he Scree ni n g Visit ( Visit 1) a n d m ust be si g ne d pri or t o perf or ma nce of a n y 
st u d y-relate d acti vit y.  T he c onse 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 vie wi n g I R B or R E C.  T he i nf or me 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 nisati o n 
(I C H) G oo d Cli nical Practice ( G C P) g ui deli nes, a n d S p o ns or 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 hazar ds of t he trial a n d a n y disc o mf ort it ma y e ntail.  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 uc h ref usal will n ot prej u dice f ut ure treat me nt.  Fi nall y, t he y will be t ol d 


 
 
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t hat t heir rec or ds ma y be e xa mi ne d b y c o m pete 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 vaila ble.  
S u bjects m ust be gi ve n t he o p p ort u nit y t o as k q uesti o ns.  After t his e x pla nati o n a n d bef ore e ntr y 
i nt o t he trial, c o nse nt s h o ul d be a p pr o priatel y rec or de d b y mea ns of t he s u bject's date d si g nat ure.  
If a s u bject is u na ble t o rea d, a n i m partial wit ness m ust be prese nt d uri n g t he e ntire i nf or me d 
c o nse nt disc ussi o n.  T he si g nat ure 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 ve a si g ne d a n d date d c o p y of t he i nf or me d c o nse 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 I R B or R E C  a p pr o val, e xce pt w here necessar y t o 
eli mi nate i m me diate hazar ds t o t he s u bjects or w he n t he c ha n ge(s) i n v ol v es o nl y l o gistical or 
a d mi nistrati ve as pects of t he trial (e. g., c ha n ge i n m o nit or, c ha n ge of tele 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 me 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 I R B or R E C  are f urt her descri be d i n t he Et hical As pects secti o n of t he pr ot oc ol.  
I n sit uati o ns re q uiri n g a de part ure fr o m t he pr ot oc ol, t he I n vesti gat or or ot her p h ysicia n i n 
atte n da nce will c o ntact t he site ma na ger, Me dical M o nit or , or ot her a p pr o priate S p o ns or 
re prese ntati ve b y e mail or tele p ho ne (see S p o ns or C o ntact I nf or mati o n pa ge).  If p ossi ble, t his 
c o ntact will be ma de bef ore i m ple me nti n g a n y de part ure fr o m pr ot oc ol.  I n all cases, c o ntact 
wit h t he S p o ns or m ust be ma de as s o o n as p ossi ble 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 priate c o urse of acti o n.  T he e C R F a n d s o urce d oc u me 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  
T here are esse ntial d oc u me nts t hat m ust be pr o vi de d t o t he S p o ns or at t he be gi n ni n g of t he st u d y 
t hat will e na ble t he site t o be i nitiate d a n d t o recei ve st u d y dr u g.  I n s o me cases, t here ma y be 
ne w d oc u me nts re q uire d or t he i nitial esse ntial d oc u me nts will be u p date d d uri n g t he c o urse of 
t he st u d y.   
Esse ntial d oc u me nts i ncl u de, b ut are n ot l i mite d t o:  c urric ul u m vitae f or eac h I n vesti gat or a n d 
s u b-I n vesti gat or, d oc u me ntati o n of I R B/ E C/ R E C pr ot oc ol a p pr o val a n d ass ociate d s u bject 
c o nse nt d oc u me nts, si g ne d cli nical trial a gree me nt, a n d si g ne d pr ot oc ol.  T he S p o ns or or its 
re prese ntati ves will w or k wit h t he sites t o i de ntif y, c ollect, re vie w, a n d a p pr o ve t he a p pr o priate 
d oc u me ntati o n pac ka ge.   
1 4. 3.  
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 In 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 oc u me nts t hat s u p p ort t he data c ollecte d fr o m eac h s u bject, a n d all trial 
d oc u me nts as s pecifie 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 me nt(s).  T he In vesti gat or/i nstit uti o n will ta ke 
meas ures t o pre ve nt acc i de ntal or pre mat ure destr ucti o n of t hese d oc u me nts.  Esse ntial 


 
 
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d oc u me nts m ust be retai ne d u ntil at least t w o years after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n or at least t w o years ha ve ela pse d si nce t he f or mal disc o nti n uati o n 
of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct.  T hese d oc u me nts will be retai ne d f or a 
l o n ger peri o d if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he 
s p o ns or.  It is t he res p o 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 be retai ne d.  If t he res p o nsi ble In 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 na me a n d a d dress of t he ne w c ust o dia n.  
1 4. 4.  
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 bers.  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 date d electr 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 xce pti o n of res ults of tests perf or me d o utsi de t he I n vesti gat or's office, s o t hat t he y al wa ys 
reflect t he latest o bser vati o ns o n t he s u bjects partici pati n g i n t he trial.  
As t he site staff e nters data, discre pa ncies will be a ut o maticall y ge nerate d wit hi n t he Electr o nic 
Data Ca pt ure ( E D C) s yste 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 raise 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 data verificati 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 yste 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 na ge me nt tea ms will e ns ure a p pr o priate 
res ol uti o n of q ueries.  T he I n vesti gat or m ust a ut h orize c ha n ges t o t he rec or de d safet y a n d 
efficac y data.  
1 4. 5.  
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 vesti gat or, pr o vi de d t here is reas o na b le ca use a n d s ufficie nt n otice is gi ve n i n 
a d va nce of t he i nte n de d ter 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 nter  
•  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 na de q uate recr uit me nt of s u bjects b y t he I n vesti gat or 
•  B usi ness reas o ns  


 
 
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1 4. 6.  
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 vie 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 ucte 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 nel will ha ve t he a bilit y t o re vie w bli n de d safet y 
i nf or mati o n as it is e ntere d a n d verifie d i n t he electr o nic data ca pt ure s yste m (Secti o n  1 4. 4).  
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 vie 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 vesti gat ors are i nstr ucte d t o c o ntact Dr u g  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 he S p o ns or a n d C R O me dical pers o n nel 
wit 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 re s p o nsi bilit y f or a p pr o priate re p orti n g t o t he re g ulat or y a ut h orities.  T he 
In 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 I R B or R E C i n acc or da nce wit h 
t he I R B or 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 deter mi nes t hat O T O-1 0 4 prese 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, In vesti gat ors a n d I R Bs or R E Cs as a p pr o priate. 
1 4. 7.  
M o nit ori n g  
T he S p o ns or or its re prese 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 pare e C R Fs wit h i n di vi d ual 
s u bject’s me dical rec or ds a n d cli nic c harts, a n d e ns ure t hat t he st u d y is bei n g c o n d ucte d 
acc or di n g t o perti ne nt re g ulat or y re q uire me nts.  T he dates of t he visits will be rec or de d b y t he 
m o nit or i n a trial ce nter visit l o g t o be ke pt at t he site.  T he first p ost -i nitiati o n visit will us uall y 
be ma de as s o o n as p ossi ble after e nr oll me nt has be g u n.  At t hese visits, t he m o nit or will 
c o m pare t he data e ntere d o nt o t he e C R Fs wit h t he h os pital or cli nic rec or ds (s o urce d oc 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 oce d ures, a d here nce t o pr ot oc ol pr oce d ures, a de q uate re p orti n g a n d f oll o w-
u p of A Es, a d mi n istrati o n of c o nc o mita nt me dicati o n, dr u g recei pt/ dis pe nsi n g/ret ur n rec or ds, a n d 
st u d y dr u g a d mi nistrati o n i nf or mati o n.  S pecific ite ms re q uire d as s o urce d oc u me nts will be 
re vie we d wit h t he I n vesti gat or pri or t o t he st u d y.  Fi n di n gs fr o m t his re vie w of e C R Fs a n d 
s o urce d oc u me nts will be disc usse d wit h t he I n vesti gat or.  T he Sp o ns or e x pects t hat, d uri n g 
m o nit ori n g visits, t he In vesti gat or (a n d as a p pr o priate, t he st u d y c o or di nat or) will be a vaila ble, 
t he s o urce d oc u me ntati o n will be a vaila 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 me nts. 
1 4. 8.  
D at a Q u alit y Ass ur a nce  
Ste ps t o be ta ke n t o ass ure t he acc urac y a n d relia bilit y of data i ncl u de 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 In vesti gat or 
a n d ass ociate d pers o n nel pri or t o st u d y i nitiati o n, a n d peri o dic m o nit ori n g visits b y t he S p o ns or 


 
 
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or its re prese ntati ves.  Case re p ort f or ms will be re vie we d f or acc urac y a n d c o m plete ness i n t he 
E D C s yste m data base b y t he S p o ns or or its re prese ntati ves d uri n g a n d after o n- site m o nit ori n g 
visits, a n d a n y discre pa ncies 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. 9.  
O n -Site A u dits  
Re prese ntati ves of t he S p o ns or's Q ualit y Ass ura nce de part me nt ma y visit t he site t o carr y o ut a n 
a 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 me nts, f or i ns pecti o n a n d 
c o m paris o n wit h t he e C R Fs. S u bject pri vac y m ust, h o we ver, be res pecte 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 he a u dit.  
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 bee 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 0.  
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, S p o ns or 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 data, a n d f or m ulati o n i n f 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 mai ns 
t he s ole pr o pert y of t he S p o ns or.  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 
t he S p o ns or 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 r e q uire d t o ot her cli nical I n vesti gat ors or g o ver n me nt re g ulat or y a ge ncies.  T o 
per mit t he i nf or mati o n deri ve d fr o m t he cli nical st u dies t o be use d, t he In 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 t he S p o ns or .  Draft a bstracts, 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 da ys pri or t o a bstract or 
ot her rele va nt s u b missi o n dea dli nes.  A ut h ors hi p of p u blicati o ns res ulti n g fr o m t his st u d y will be 
base d o n ge nerall y acce pte d criteria f or maj or me dical j o ur nals.    


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