Conditions: Tinnitus, Subjective
Keywords: tinnitus, intratympanic injection, gacyclidine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, plasma pharmacokinetics (PK), and exploratory efficacy of OTO-313 administered as an intratympanic injection for the treatment of subjective tinnitus.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: OTO-313 intervention 2: Placebo
Intervention descriptions: intervention 1: single intratympanic injection of gacyclidine intervention 2: single intratympanic injection of placebo

Protocol document:
Prot_SAP_000.pdf: 




 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................... 1 
T A B L E O F C O N T E N T S  ................................................................................................................. 3 
LI S T O F T A B L E S  ........................................................................................................................... 5 
LI S T O F FI G U R E S  ......................................................................................................................... 5 
P R O T O C O L A M E N D M E N T, V E R SI O N 3. 0  ................................................................................ 6 
S P O N S O R C O N T A C T I N F O R M A TI O N  ....................................................................................... 7 
I N V E S TI G A T O R A G R E E M E N T................................................................................................... 8 
A B B R E VI A TI O N S  ......................................................................................................................... 9 
1.  
B A C K G R O U N D  ........................................................................................................ 2 0 
1. 1.  
Rati o nale  ..................................................................................................................... 2 0 
2.  
O BJ E C TI V E S  ............................................................................................................. 2 1 
2. 1.  
Part A  .......................................................................................................................... 2 1 
2. 2.  
Part B  .......................................................................................................................... 2 2 
3.  
O V E R VI E W O F S T U D Y D E SI G N  ........................................................................... 2 2 
3. 1.  
Part A  .......................................................................................................................... 2 2 
3. 2.  
Part B  .......................................................................................................................... 2 3 
4.  
S T U D Y P O P U L A TI O N  ............................................................................................. 2 5 
4. 1.  
Ge ner al C o nsi derati o ns ............................................................................................... 2 5 
4. 2.  
I n cl usi o n Criteria ........................................................................................................ 2 5 
4. 3.  
E x cl usi o n Criteria  ....................................................................................................... 2 6 
5.  
R A N D O MI Z A TI O N A N D B L I N DI N G .................................................................... 2 8 
5. 1.  
O ver vie w  ..................................................................................................................... 2 8 
5. 2.  
E nr oll me nt Pr oce d ur es  ................................................................................................2 8  
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  ....................................................................... 2 9 
6. 1.  
I n v esti gati o nal Pr o d uct A d mi nistrati o n ...................................................................... 2 9 
6. 2.  
C o m plia nce ................................................................................................................. 3 0 
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 0 
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 0 
7. 2.  
S y m pt o matic Relief Me dicati o ns a n d T hera pies  ........................................................ 3 1 
8.  
S T U D Y E V A L U A TI O N S  .......................................................................................... 3 1 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
8. 1.  
St u d y Pr o ce d ur es b y Visit – Part A  ............................................................................ 3 1 
8. 2.  
St u d y Pr o ce d ur es b y Visit – Part B  ............................................................................ 3 3 
8. 3.  
Me dical Hist or y a n d D e m o gra p hi cs ........................................................................... 3 5 
8. 4.  
Vi de o f or S u bjects o n Cli nical Researc h Partici pati o n  ............................................... 3 5 
8. 5.  
Efficac y E val uati o ns ................................................................................................... 3 5 
8. 6.  
Bl o o d Sa m pli n g f or Plas ma P K E val uati o ns .............................................................. 3 7 
8. 7.  
Safet y E val uati o ns  ...................................................................................................... 3 8 
9.  
A D V E R S E E V E N T R E P O R T I N G ............................................................................ 4 1 
9. 1.  
A d verse E v e nt Classificati o n Defi niti o ns  ................................................................... 4 1 
9. 2.  
M o nit ori n g of A d v erse E ve nts .................................................................................... 4 3 
9. 3.  
C o ntacti n g S p o ns or Re gar di n g Safet y ........................................................................ 4 5 
1 0.  
S U BJ E C T C O M P L E TI O N  ......................................................................................... 4 5 
1 0. 1.  
C o m pleti o n  ................................................................................................................. 4 5 
1 0. 2.  
Wit h dra wal  ................................................................................................................. 4 5 
1 1.  
S T A TI S TI C A L M E T H O D S  ....................................................................................... 4 6 
1 1. 1.  
Sa m ple Size  ................................................................................................................ 4 6 
1 1. 2.  
A nal ysis Sets  ............................................................................................................... 4 6 
1 1. 3.  
S u bject De m o gra p hics, Baseli ne Disease Stat us, a n d Dis p ositi o n ............................. 4 6  
1 1. 4.  
St u d y E n d p oi nts  .......................................................................................................... 4 7 
1 1. 5.  
Safet y E val uati o ns  ...................................................................................................... 4 8 
1 1. 6.  
Ha n dli n g of Missi n g Dat a, S u bject Wit h dra wals, a n d Treat me nt Fail ures  ................ 5 0 
1 1. 7.  
I nteri m A nal yses ......................................................................................................... 5 0 
1 2.  
I N V E S TI G A TI O N A L P R O DU C T I N F O R M A TI O N  ............................................... 5 0 
1 2. 1.  
P h ysical D escri pti o n of I n vesti gati o nal Pr o d uct ......................................................... 5 0 
1 2. 2.  
Directi o ns f or Us e  ....................................................................................................... 5 1 
1 2. 3.  
Pac ka gi n g a n d La b eli n g  .............................................................................................. 5 1 
1 2. 4.  
Ma na ge me nt of Cli nical S u p plies  ............................................................................... 5 1 
1 2. 5.  
I n v esti gati o nal Pr o d uct Acc o u nta bilit y ...................................................................... 5 1 
1 3.  
E T HI C A L A S P E C T S  ................................................................................................. 5 2 
1 3. 1.  
I n v esti gat or Res p o nsi bilities ....................................................................................... 5 2 
1 3. 2.  
I nstit uti o nal Re vie w B oar d (I R B) ............................................................................... 5 2 
1 3. 3.  
I nf or me d C o nse nt ....................................................................................................... 5 2 
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 3 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
1 4. 1.  
Pr ot oc ol M o dificati o ns ............................................................................................... 5 3 
1 4. 2.  
Re g ulat or y D oc u me ntati o n  ......................................................................................... 5 3 
1 4. 3.  
Re c or d Rete nti o n ........................................................................................................ 5 3 
1 4. 4.  
Electr o nic Case Re p ort F or m (e C R F)  ......................................................................... 5 4 
1 4. 5.  
Ter mi nati o n  ................................................................................................................. 5 4 
1 4. 6.  
Data a n d Saf et y M o nit ori n g Pla n  ............................................................................... 5 5 
1 4. 7.  
M o nit ori n g .................................................................................................................. 5 5 
1 4. 8.  
Data Q ualit y Ass ur a nce  .............................................................................................. 5 6 
1 4. 9.  
O n -Site A u dits  ............................................................................................................ 5 6 
1 4. 1 0.  
P u blicati o n P olic y  ....................................................................................................... 5 6 
1 5.  
R E F E R E N C E S  ........................................................................................................... 5 7 
 
 
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 Part A .................................................................................. 1 6 
Ta ble 2:  Ti me a n d E ve nts Sc he d ule Part B  .................................................................................. 1 8 
 
 
LI S T O F FI G U R E S  
Fi g ure 1.  St u d y Desi g n Sc he matic – Part A  ................................................................................. 2 4 
Fi g ure 2.  St u d y Desi g n Sc he matic – Part B  .................................................................................. 2 5 
 
 
 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
P R O T O C O L A M E N D M E N T, V E R SI O N 3 . 0 
T his pr ot oc ol a me n d me nt ser ves t o ma ke t he f oll o wi n g c h a n ges. 
Ite m N o. 
C ha n ge 
Secti o n  
1 
Re vise d e x cl usi o n criteria 1 5 t o 
e x cl u de t he use of s yste mic ster oi ds 
(i ncl u di n g de x a met has o n e), wit hi n 6 
wee ks pri or t o t he Scree ni n g visit.  
T he use of i ntrat y m pa ni c ster oi ds ha d 
alrea d y b ee n e x cl u de d  f or 6 wee ks 
pri or t o t he Scree ni n g visit , t heref ore 
t he re visi o n a d ds s yste mic ster oi ds t o 
t he e x cl usi o n.  S yste mic ster oi ds ma y 
be use d f or tr eati n g se ns ori ne ural 
heari n g l oss  a n d t he 6-wee k  
e x cl usi o nar y peri o d pri or t o 
Scree ni n g will all o w f or a n y resi d ual 
effects of t he s yste mic st er oi d, if a n y, 
t o sta bilize pri or t o ra n d o mizati o n. 
T he use of s yste mic ster oi ds is als o 
pr o hi bite d d uri n g t he st u d y a n d t h e 
pr o hi bite d t hera pies secti o n has bee n 
re vise d acc or di n gl y. 
S y n o psis 
Secti o n 4. 3,  E x cl usi o n Criteria 
Secti o n 7. 1 
 
 
 




 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
I N V E S TI G A T O R A G R E E M EN T  
I h a ve r ea d t his pr ot oc ol a n d a gree t hat it c o ntai ns all necessar y details f or carr yi n g o ut t his 
st u d y.  I will c o n d uct t he st u d y as o utli ne d herei n a n d will c o m plete t he st u d y wit hi n t he ti me 
desi g nat e d a n d will a bi de b y all a p plica ble l ocal a n d nati o nal re g ulat or y o bli gati o ns. 
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y.  I will disc uss t his material wit h t he m t o e ns ure t he y 
are f ull y i nf or m e d re gar di n g t h e dr u g a n d t he c o n d uct of t he st u d y. 
I will use o nl y t he i nf or med c o nse nt f or m a p pr o ve d b y Ot o n o m y, I n c. ( hereafter, “t he S p o ns or ”) 
or its re prese nt ati ve a n d a p pr o ve d b y t he I nstit uti o nal Re vie w B o ar d (I R B) res p o nsi ble f or t his 
st u d y a n d will f ulfill all r es p o nsi bilities f or s u b mitti n g perti ne nt i nf or m ati o n t o t he I R B 
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 st u d y, or le gall y 
a ut h orize d re pres e ntati ve, rea ds, u n dersta n ds, a n d si g ns t he a p pr o priate v ersi o n of t he i nf or me d 
c o nse nt.  I a gr ee t hat t he S p o ns or or its re prese nt ati ves s hall ha ve access t o a n y ori gi n al s o urce 
d oc u me nts t o verif y data ca pt ure d f or t his cli nical st u d y. 
I f urt her a gree n ot t o ori gi nate or use t he n a me of t he S p o ns or a n d/ or O T O- 3 1 3, or a n y of its 
e mpl o yees, i n a n y p u blicit y, ne ws r eleas e or ot her p u blic a n n o u nce me nt, writte n or oral, w het h er 
t o t he p u blic, press or ot h er wise, r elati n g t o t his pr ot oc ol, t o a n y a me n d me nt heret o, or t o t he 
perf or ma n ce h ere u n d er, 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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
                                                    9  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
A B B R E VI A TI O N S  
A E  
A d verse E ve nt  
A S H A  
A merica n S peec h a n d La n g ua ge Heari n g Ass ociati o n  
C R O  
Cli nical Researc h Or ga nizati o n  
C -S S R S  
C Y P 2 B 6  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C yt oc hr o me P 4 5 0 Is of or m 2 B 6  
d B  
e C R F 
Deci bel  
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
G C P  
G o o d Cli nical Practice  
Hz  
I C H 
Hertz  
I nter nati o nal C o nfere nce o n Har m o ni sati o n 
I R B 
I nstit uti o nal Re vie w B oar d  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  
m L  
Milliliter  
N  
N M D A  
N R S  
N u m ber  
N- Met h yl - D-As partic Aci d  
N u meric Rati n g Scale  
O T O -3 1 1  
O T O - 3 1 3 
 
P K  
Ot o n o m y I n vesti gati o nal Pr o d uct  i n p ol o xa mer, Gac ycli di ne  ( Acti ve I n gre die nt) 
Ot o n o m y I n vesti gati o nal Pr o d uct i n me di u m- c hai n tri gl yceri de, Gac ycli di ne ( Acti ve 
I n gre die nt) 
P har mac o ki netics  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P T  
Preferre d T er m  
S A E  
S A P  
Seri o us A d verse E ve nt  
Statistical A nal ysis Pla n  
S D  
Sta n dar d  De viati o n  
S O C  
S yste m Or ga n Class  
T E A E  
T FI  
T S C H Q  
Treat me nt E mer ge nt A d ver se E ve nt 
Ti n nit us F u ncti o nal I n de x  
Ti n nit us Sa m ple Case Hist or y Q uesti o n naire  
 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
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 -3 1 3  
 
Gac ycli di ne  
 
Pr ot oc ol N o.:  3 1 3 -2 0 1 9 0 1  
Title of St u d y:  A ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d P hase 1/ 2  st u d y of O TO- 3 1 3  gi ve n as a si n gle 
i ntrat y m pa nic i nj ecti o n i n s u bj ects wit h s u bj ecti ve ti n nit us 
St u d y Ce nter(s):   P art A of t his st u d y wi ll be c o n d ucte d at 1 site  i n t he U nite d States a n d P art B will be 
c o n d ucte d at a p pr o xi matel y 2 0 sites i n t he U nite d States  
St u d y Peri o d:  a p pr o xi matel y 1 2 m o nt hs  
P h ase of De vel o p me nt:  1/ 2  
St u d y Desi g n:  
T his  is t he first st u d y of i ntrat y m pa nic O T O-3 1 3  i n s u bj ects wit h ti n nit us a n d is c o m p ose d of 2 pa rts.  P art A is 
a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d P hase 1 c o h ort t o e val uate t he safet y a n d plas ma 
p har mac o ki netics ( P K) of o ne d ose le vel ( 0. 1 1 m g) of O T O -3 1 3 i n s u bj ects wit h u nilateral  or bilateral  
s u bj ecti ve ti n nit us.  Ei g ht eli gi ble s u bj ects will be ra n d o ml y assi g ne d t o eit her O T O -3 1 3 ( 6 s u bj ects) or 
place b o ( 2 s u bj ects) f or i ntrat y m pa nic i nj ecti o n t o a si n gle (st u d y) ear.  S u bj ects i n P art A will u n der g o bl o o d 
sa m pli n g f or plas ma c o nce ntr ati o n testi n g of gac ycli di ne i ncl u di n g ( +) a n d (-) e na nti o mers of gac ycli di ne (a n d 
p ossi bl y its meta b olites)  o n D a ys 1, 2, a n d 8 a n d will be o bser ve d f or safet y a n d e x pl orat or y efficac y f or 2 8 
da ys.  
 
If acce pta ble safet y a n d t olera bilit y is o bser ve d i n P art A (as deter mi ne d b y re vie w of data t hr o u g h Da y 8 f or 
all s u bj ects b y t he Safet y Re vi e w C o m mittee ), P art B of t he st u d y will be i nitiate d.  P art B is a ra n d o mize d, 
d o u ble -bli n d, place b o -c o ntr oll e d c o h ort of s u bj ects wit h u nil ateral s u bj ecti ve ti n nit us t o e val uate t he safet y a n d 
preli mi nar y  efficac y of O T O -3 1 3.  Fift y s u bj ects will be ra n d o ml y assi g ne d , usi n g a 1: 1 all ocati o n rati o, t o 
i ntrat y m pa nic i nj ecti o n of eit her 0. 3 2 m g O T O -3 1 3  or place b o  t o t he affecte d (st u d y) ear.  If acce pta ble safet y 
a n d t olera bilit y is o bser ve d for t he first 1 2 s u bj ects d ose d i n P art B (as deter mi ne d b y re vie w of data t hr o u g h 
Da y 8 b y t he Safet y Re vie w C o m mittee), t he re mai ni n g s u bjects i n P art B will be e nr olle d.  I n t he e ve nt t hat 
a d verse safet y fi n di n gs occ ur wit h 0. 3 2 m g O T O -3 1 3 i n t he first 1 2 s u bj ects, P art B s u bj ects ma y be e nr olle d 
usi n g  t he 0. 1 1 m g d ose le vel  of O T O -3 1 3 , a n d e nr oll me nt e x pa n de d  s o t hat 5 0 s u bj ects are ra n d o mize d t o t hat 
d ose le vel  or  t o place b o .  All s u bj ects i n P art B will be o bser ve d f or  safet y a n d preli mi nar y  efficac y f or  8 
wee ks  f oll o wi n g d osi n g .  Bl o o d sa m ples f or P K a nal ysis will be o btai ne d o n Da y 1 a n d o n Da y 8 i n a s u bset of 
a p pr o xi matel y 1 6 s u bj ects at s electe d sites i n P art B.  
St u d y O bjecti ve s: 
P art A  
Pri mar y : 
•  
T o e val uate t he safet y a n d t olera bilit y of O T O -3 1 3 i n s u bj ects wit h u nilateral or bilateral ti n nit us. 
Sec o n dar y :  
•  
T o assess t he plas ma P K  of ga c ycli di ne i ncl u di n g ( +) a n d (-) e na nti o mers of gac ycli di ne (a n d 
p ossi bl y its meta b olites).  
P art B  
Pri mar y : 
•  
T o e val uate t he safet y a n d t olera bilit y of O T O -3 1 3 i n s u bj ects wit h u nilateral ti n nit us.  
Sec o n dar y :  
•  
T o e xa mi ne t he preli mi nar y efficac y of O T O -3 1 3  i n s u bj ects wit h u nilateral ti n nit us , as me as ure d b y 
t he c ha n ge fr o m B aseli ne i n t he Ti n nit us F u ncti o nal I n d e x ( T FI).  


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  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 -3 1 3  
 
Gac ycli di ne  
 
•  
T o assess, i n a s u bset of s u bj ects, t he plas ma P K of gac ycli di ne i ncl u di n g ( +) a n d (-) e na nti o mers of 
gac ycli di ne (a n d p ossi bl y its meta b olites).  
E x pl orat or y : 
•  
T o e x pl ore t he preli mi na r y efficac y of O T O -3 1 3 o n ti n nit us a n n o ya nce usi n g a s u bj ect-re p orte d 
N u meric Rati n g Scale ( N R S).  
•  
T o e x pl ore t he preli mi nar y  efficac y of O T O -3 1 3 o n ti n nit us l o u d ness usi n g a s u bj ect-re p orte d N R S. 
•  
T o e x pl ore  t he preli mi nar y efficac y of O T O -3 1 3 o n ti n nit us se verit y usi n g t he P atie nt Gl o bal 
I m pressi o n of C ha n ge ( P GI C). 
 
M et h o d s: 
P art A  
P art A will be c o n d ucte d at 1 site i n t he U nite d States a n d will i n v ol ve 1 o ver ni g ht sta y i n t he researc h u nit.  
T h e d urati o n of P art A f or eac h s u bj ect will be a p pr o xi matel y 4- 6 wee ks , i ncl u di n g a n u p t o  2-wee k  Scree ni n g 
peri o d a n d a 4- wee k  f oll o w-u p peri o d.    
After i nf or me d c o nse nt a n d Scree ni n g, eli gi ble s u bj ects will be ra n d o mize d t o O T O -3 1 3 or place b o at t he 
B aseli ne visit ( Da y 1).  Ei g ht s u bj ects will recei ve eit her 0. 1 1 m g O T O -3 1 3 ( N = 6) or place b o ( N = 2).  Plas ma 
sa m ples f or p har mac o ki netic ( P K) a nal ysis will be o btai ne d o n Da y 1 ( pre-d ose, 0. 5, 1, 2, 4, 8, a n d 1 2 h o urs 
p ost -a d mi nistrati o n), Da y 2 ( 2 4 h o urs p ost -a d mi nistrati o n), a n d Da y 8.  S u bj ects will re mai n o ver ni g ht i n t he 
researc h u nit o n Da y 1 a n d will be disc har ge d o n Da y 2.  A d diti o nal f oll o w-u p visits f or safet y a n d efficac y 
assess me nts will be c o n d ucte d o n Da y 8, Da y 1 5, a n d Da y 2 9 (e n d of st u d y) or u p o n earl y ter mi nati o n fr o m 
t he st u d y.   
If acce pta ble safet y a n d t olera bilit y is o bser ve d f or 8 da ys p ost-a d mi nistrati o n i n P art A i n all s u bj ects, P art B 
will be i nitiate d wit h t he 0. 3 2 m g d ose le vel of O T O -3 1 3  (see Safet y Data Re vie w) .   
P art B  
P art B will be c o n d ucte d at a p pr o xi matel y 2 0 sites i n t he U nite d States.  T he d urati o n of P art B f or eac h 
s u bj ect will be a p pr o xi matel y 1 0 -1 2 wee ks, i ncl u di n g a n u p t o  2-wee k Scree ni n g peri o d, a 2 -wee k Lea d -i n 
assess me nt  peri o d, a n d a n 8- wee k  F oll o w -U p peri o d.  If acce pta ble safet y a n d t olera bilit y is o bser ve d f or 8 
da ys f or t he first 1 2 s u bj ects d ose d (see Safet y Data Re vie w) , t he re mai ni n g s u bj ects i n P art B will be e nr olle d.  
I n t he e ve nt t hat a d verse safet y fi n di n gs occ ur wit h 0. 3 2 m g O T O-3 1 3 i n t he first 1 2 s u bj ects, P art B s u bj ects 
ma y be e nr olle d usi n g 0. 1 1 m g O T O -3 1 3, a n d e nr oll me nt e x pa n de d s o t hat 5 0 s u bj ects are  ra n d o mize d t o t his 
(l o wer) d ose le vel  or t o place b o  i n or der t o reac h t he tar get n u m ber of s u bj ects f or P art B. 
After i nf or me d c o nse nt a n d Scree ni n g, p ote ntial  s u bj ects will be gi n a 2 -wee k lea d -i n assess me nt peri o d.  
D uri n g t his ti me, s u bj ects will e nter  dail y ti n nit us a n n o ya nce a n d ti n nit us l o u d ness se verit y i nt o a n electr o nic 
diar y usi n g t he a p pr o priate N u meric Rati n g Scales ( N R S) f or eac h s y m pt o m.  S u bj ects m ust ha ve c o m plete d 
t he ti n nit us electr o nic  diar y  o n  4 of t he last 7 da ys of t he Lea d -i n peri o d f or eli gi bilit y.  S u bj ects will als o 
c o m plete t he Ti n nit us F u ncti o nal I n de x ( T FI) at b ot h t he Scree ni n g visit a n d t he B aseli ne visit ( Da y 1) .  
S u bj ects  m ust ha ve a sc ore of ≥ 2 5 at eac h T FI assess me nt f or eli gi bilit y.  At t he B aseli ne visit ( Da y 1) , 
eli gi b le su bj ects will be ra n d o mize d t o O T O -3 1 3 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 nj ecti o n wit h O T O -3 1 3  or place b o t o t he affecte d (st u d y) ear o n Da y 1, s u bj ects 
will c o nti n ue t o rec or d t heir ti n nit us a n n o ya nce a n d ti n nit us l o u d ness o n a dail y basis usi n g t he electr o nic diar y 
d uri n g t he 8- wee k  f oll o w-u p peri o d .  S u bj ects will c o m plete t he T FI at st u d y visits o n Da y 1 ( B aseli ne), Da y 1 5, 
Da y 2 9, a n d Da y 5 7 (e n d of st u d y).  A d diti o nal safet y a n d/ or e x pl orat or y assess me nts will a ls o be c o m plete d at 
Da y 1 ( B aseli ne), Da y 8, Da y 1 5, Da y 2 9, a n d Da y 5 7  (e n d of st u d y) or u p o n earl y ter mi nati o n fr o m t he st u d y.  


 
                                                    1 2  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  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 -3 1 3  
 
Gac ycli di ne  
 
I n a s u bset of 1 6 s u bj ects at selecte d sites, b l o o d sa m ples f or P K a nal ysis will be o btai ne d o n Da y 1 ( pre-d ose 
a n d 1- h o ur  p ost -a d mi nistrati o n) a n d o n Da y 8.  
Safet y Data Re vie w  
T he decisi o n t o pr ocee d wit h i nitiat i o n of d osi n g i n P art B , a n d s u bse q ue nt d osi n g decisi o ns, will be ma de b y a 
Safet y Re vie w C o m mittee .  T he Safet y Re vie w C o m mittee will i ncl u de at a mi ni m u m t he Me dical M o nit or, 
t he I n vesti gat or at t he P hase 1 researc h u nit, a n d t he Cli nical Re prese ntati ve of t he S p o ns or.  Safet y data, 
i ncl u di n g a d verse e ve nts, cli ni cal safet y la b orat or y meas ure me nts, a u di o metr y, ot osc o p y, t y m pa n o metr y, a n d 
C- S S R S data t hr o u g h Da y 8, will be e val uate d a n d t he decisi o n t o pr ocee d will be base d o n t he cli nical 
si g nifica nce of a n y a d verse e ve nts or s us pecte d i n vesti gati o nal pr o d uct-relate d fi n di n gs.  I nitiall y, all data will 
be re vie we d i n a bli n de d ma n ner wit h re gar d t o treat me nt assi g n me nt.  T he treat me nt assi g n me nt f or a n 
i n di vi d ual s u bj ect ma y be u n bli n de d, if dee me d necessar y t o e na ble  me dical care or st u d y  decisi o n -ma ki n g  b y 
t he Safet y Re vie w C o m mittee. 
N u m ber of S u bjects:  
T he pla n ne d sa m ple size f or t his st u d y is 5 8 t o 7 0 s u bj ects (8 s u bj ects i n P art A a n d 5 0 t o 6 2 s u bj ects i n P art 
B ). 
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
T o be eli gi ble f or t his st u d y, e ac h of t he f oll o wi n g criteria m ust be satisfie d wit h a “ Y E S” a ns wer ( u nless n ot 
a p plica ble): 
P art A o nl y  
1.  S u bj ect has s u bj ecti ve u nilater al or bilateral ti n nit us a n d is c o nsiste ntl y a ware of t heir ti n nit us 
t hr o u g h o ut m uc h of t he wa ki n g da y. 
P art B o nl y  
2.  S u bj ect has s u bj ecti ve u nilater al ti n nit us a n d is c o nsiste ntl y a ware of t heir ti n nit us t hr o u g h o ut m uc h 
of t he wa ki n g da y.  
3.  S u bj ect’s self -re p orte d d urati o n of ti n nit us is bet wee n 1 m o nt h a n d 6 m o nt hs ( 3 0 t o 1 8 0 da ys) pri or t o 
si g ni n g i nf or me d c o nse nt. 
4.  S u bj ect has a n o verall sc ore of ≥ 2 5 o n t he T FI at Scree ni n g a n d B aseli ne ( Da y 1 ) visits . 
5.  S u bj ect is a ble t o use t he electr o nic diar y t o c o m plete t heir dail y ti n nit us rati n gs a n d has c o m plete d at 
least 4 of t he last 7 da ys of diar y e ntries d uri n g t he 2-wee k L ea d -i n peri o d. 
P art A a n d B  
6.  S u bj ect i s a male or fe male a ge d 1 8 t o 7 5  years, i ncl usi ve.  
7.  S u bj ect’s ti n nit us is li kel y of c oc hlear ori gi n, e. g., ass ociate d wit h se ns ori ne ural heari n g l oss; ac ute 
heari n g l oss fr o m n oise tra u ma, bar otra u ma, or tra u matic c oc hlear i nj ur y  (ac ute ac o ustic tr a u ma, blast 
tra u ma, mi d dle ear s ur ger y, i n ner ear bar otra u ma); a ge-relat e d heari n g l oss; res ol ve d otitis me dia; 
ot ot o xic dr u g e x p os ure .  
8.  Fe male s u bj ects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost -me n o pa usal 
( ≥1 2 m o nt hs si nce last me nstr ual peri o d a n d 4 5 years of a ge or ol der)] m ust ha ve a ne gati ve uri ne 
pre g na nc y test at B aseli ne  ( Da y 1).  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 m ust use  effecti ve met h o ds of c o ntrace pti o n f or t he d urati o n of t he st u d y 
i ncl u di n g: esta blis he d use of oral, i nj ecte d, or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n; 
place me nt of a n i ntra uteri ne d e vice or i ntra uteri ne s yste m; or “ d o u ble barrier” met h o ds i ncl u di n g a 
c o m bi nati o n of male c o n d o m wit h eit her dia p hra g m  or cer vi cal ca p  wit h s per mici de.  Fe male s u bj ects 
of c hil d beari n g p ote ntial m ust als o refrai n fr o m e g g d o nati o n or retrie val f or t he d urati o n of t he st u d y.   


 
                                                    1 3  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  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 -3 1 3  
 
Gac ycli di ne  
 
9.  Male s u bj ects ( u nless s ur gicall y sterile) w h o are n ot a bsti ne nt fr o m se x wit h fe male part ners of 
c hil d beari n g p ote ntial m ust a gree t o use a n effecti ve c o ntrac e pti ve met h o d (as detaile d f or I ncl usi o n 
Criteria 8 ) f or t he d urati o n of t he st u d y.  Male s u bj ects m ust refrai n fr o m s per m d o nati o n f or t he 
d urati o n of t he st u d y.  
1 0.  S u bj ect is willi n g t o c o m pl y wit h t he pr ot oc ol a n d atte n d all st u d y visits.  
1 1.  S u bj ect is a ble t o pr o vi de writte n i nf or me d c o nse nt  after t he sc o pe a n d nat ure  of t he i n vesti gati o n 
ha ve bee n e x plai ne d , a n d bef ore t he i nitiati o n of a n y st u d y -r elate d pr oce d ures. 
Di a g n osis a n d M ai n Criteri a f or E xcl usi o n:  
T o be eli gi ble f or t his st u d y, e ac h of t he f oll o wi n g criteria m ust be satisfie d wit h a “ N O” a ns wer  ( u nless n ot 
a p plica ble): 
P art A a n d B  
1.  S u bj ect has p ulsatile ti n nit us, ti n nit us res ulti n g fr o m tra u mati c hea d or nec k i nj ur y, or ti n nit us 
res ulti n g fr o m a t u mor or str o ke.  
2.  S u bj ect has acti ve 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 ol esteat o ma), 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 Ne c k S ur ger y E q uili bri u m C o m mittee i n 
2 0 1 5 ( G oe bel 2 0 1 6 ), or vesti b ular sc h wa n n o ma. 
3.  S u bj ect has rece ntl y ( < 1 m o nt h of Scree ni n g) i nitiate d ne w treat me nt f or ti n nit us (e. g. n ois e or s o u n d 
ge nerat ors, heari n g ai ds, be ha vi oral t hera p y ; me dicat i o ns or o ver -t he-c o u nter s u p ple me nts ); o nl y 
sta ble ti n nit us treat me nts are all o we d d uri n g t he st u d y a n d n o ne w treat me nts s h o ul d be i ntr o d uce d .  
4.  S u bj ect is n ot a ble t o acc uratel y i de ntif y a n d re p ort t heir ti n nit us per I n vesti gat or’s o pi ni o n . 
5.  S u bj ect has a n a b n or malit y of t he t y m pa nic me m bra ne i n t he affecte d (st u d y) ear t hat w o ul d i ncrease 
t he ris k ass ociate d wit h i ntrat y m pa nic i nj ecti o n, i ncl u di n g b ut n ot li mite d t o m o n o meric t y m pa nic 
me m bra ne.  
6.  S u bj ect has e vi de nc e of perf or ati o n or lac k of cl os ure  of t he t y m pa nic me m bra ne at Scree ni n g or 
B aseli ne  ( Da y 1) visits. 
7.  S u bj ect is recei vi n g a n y o n g oi n g t hera p y k n o w n as p ote ntiall y ti n nit us -i n d uci n g (e. g. 
a mi n o gl yc osi des, ot ot o xic c he m ot hera pe ut ic dr u gs, l o o p di uretics,  q ui ni ne, hi g h d oses of  as piri n or 
ot her n o nster oi dal a nti -i nfla m mat or y dr u gs).  Usa ge of l o w d oses of as piri n or ot her n o n -ster oi dal 
a nti -i nfla m mat or y dr u gs ma y be per mitte d at t he I n vesti gat or’s discreti o n. 
8.  S u bj ect a ns were d “ Yes” t o Q uesti o n 4 or 5 re gar di n g acti ve s uici dal i deati o n o n t he C -S S R S 
a d mi nistere d at Scree ni n g or B aseli ne ( Da y 1 ) visits.   I n a d diti o n, s u bj ects dee me d b y t he In vesti gat or 
t o be at si g nifica nt ris k of s uici dal be ha vi or s h o ul d be e xcl u d e d.  
9.  S u bj ect has se vere or u ntreate d  de pr essi o n or a n xiet y t hat, i n t he I n vesti gat or’s o pi ni o n, w o ul d li kel y 
re d uce t he safet y of st u d y partici pati o n or c o m plia nce wit h st u d y pr oce d ures .  O nl y s ta ble d oses 
(ta ke n f or ≥ 1 m o nt h  pri or t o Scree ni n g) of a nti de pressa nt a n d a nti -a n xiet y me dicati o n s are all o we d 
d uri n g t he st u d y.    
1 0.  S u bj ect is pre g na nt or lactati n g.  
1 1.  S u bj ect has a hist or y of i m m u n o deficie nc y disease.   
1 2.  S u bj ect has a hist or y of s u bsta nce or alc o h ol a b use wit hi n t he prece di n g 6 m o nt hs pri or t o Scree ni n g.  
1 3.  S u bj ect is recei vi n g c o nc o mit a nt  treat me nt wit h a n y ot her N M D A rece pt or a nta g o nist (e. g. 
me ma nti ne, de xtr o met h or p ha n).  


 
                                                    1 4  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  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 -3 1 3  
 
Gac ycli di ne  
 
1 4.  S u bj ect has a hist or y of pre vi o us use of i ntrat y m pa nic ge nta mici n i n t he affecte d ear.  
1 5.  S u bj ect has recei ve d s yste mic or i ntrat y m pa nic ster oi ds (i ncl u di n g de xa met has o ne) wit hi n 6 wee ks  
pri or t o t he Scree ni n g visit. 
1 6.  S u bj ect has a k n o w n h y perse nsiti vit y t o gac ycli di ne or a n y of t he e xci pie nts i n O T O -3 1 3.  
1 7.  S u bj ect has use d m o derate or str o n g i n d ucers of C Y P 2 B 6 (e. g. car ba maze pi ne, efa vire nz, rifa m pi n, or 
rit o na vir) wit hi n 3 0 da ys pri or t o Scree ni n g .  
1 8.  S u bj ect has 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 at Scree ni n g or 
B aseli ne ( Da y 1 ) t hat, i n t he I n vesti gat or’s o pi ni o n, w o ul d li kel y re d uce t he safet y of st u d y 
partici pati o n or c o m plia nce wit h st u d y pr oce d ures . 
Test  Pr o d uct, D ose , a n d M o de of A d mi nistr ati o n:  
0. 1 1 m g O T O -3 1 3 or 0. 3 2  m g O T O -3 1 3  (s ol uti o n of gac ycli d i ne i n me di u m -c hai n tri gl yceri de s), si n gle (0. 2 
m L  v ol u me)  i ntrat y m pa nic i nj ecti o n t o t he affecte d (st u d y) e ar  
Refere nce Pr o d uct , D ose, a n d M o de of A d mi nistr ati o n:  
Place b o ( 1 0 0 % me di u m -c hai n tri gl yceri des s ol uti o n), si n gle ( 0. 2 m L v ol u me) i ntrat y m pa nic i nj ecti o n t o t he 
affecte d (st u d y) ear  
D ur ati o n of Tre at me nt:    
Si n gle (0. 2 m L v ol u me) i ntrat y m pa nic i nj ecti o n t o t he affect e d (st u d y) ear  
E n d p oi nts  f or E v al u ati o n: 
P art A  
Safet y E n d p oi nts : 
•  
Assess me nt of  treat me nt-e mer ge nt a d verse e ve nts  ( T E A Es). 
•  
Cli nicall y si g nifica nt a d verse c ha n ge fr o m B aseli ne i n a u di o metr y assess me nts, t y m pa n o metr y, a n d 
ot osc o pic e xa mi nati o ns.  
•  
Cli nicall y si g nifica nt a d verse c ha n ge fr o m B aseli ne i n cli nic al la b orat or y meas ure me nts ( he mat ol o g y, 
ser u m c he mistr y, a n d uri nal ysis) or  vital si g ns meas ure me nts (s yst olic a n d diast olic bl o o d press ure,  
p ulse rate).  
•  
Assess me nt of s uici dalit y via C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S) . 
P K E n d p oi nts :  
•  
Plas ma c o nce ntrati o ns of gac ycli di ne i ncl u di n g ( +) a n d ( -) e na nti o mers of gac ycli di ne (a n d p ossi bl y 
its meta b olites). 
E x pl orat or y Efficac y E n d p oi nts :  
•  
C ha n ge i n T FI o verall sc ore fr o m B aseli ne at Da y 8, 1 5, a n d 2 9.  
•  
P GI C sc ore s at Da ys 8, 1 5, a n d 2 9.  
P art B  
Safet y E n d p oi nts : 
•  
Assess me nt  of T E A Es.  
•  
Cli nicall y si g nifica nt a d verse c ha n ge fr o m B aseli ne i n a u di o metr y assess me nts , t y m pa n o metr y, a n d 
ot osc o pic e xa mi nati o ns.  


 
                                                    1 5  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  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 -3 1 3  
 
Gac ycli di ne  
 
•  
Cli nicall y si g nifica nt a d verse c ha n ge fr o m B aseli ne i n cli nic al la b orat or y meas ure me nts ( he mat ol o g y, 
ser u m c he mistr y, a n d uri nal ysis) or  vital si g ns meas ure me nts (s yst olic a n d diast olic bl o o d press ure, 
p ulse rate).  
•  
Assess me nt of s uici dalit y via C- S S R S . 
P K E n d p oi nts :  
•  
Plas ma c o nce ntrati o ns of gac ycli di ne i ncl u di n g ( +) a n d ( -) e na nti o mers of gac ycli di ne a n d (p ossi bl y 
its meta b olites). 
Pri mar y  Efficac y E n d p oi nt:  
•  
C ha n ge i n T FI o verall sc ore fr o m B aseli ne at Da y 5 7.  
E x pl orat or y Efficac y E n d p oi nts : 
•  
C ha n ge fr o m B aseli ne i n t he 7- da y a vera ge N R S rati n gs of ti n nit us a n n o ya nce  at W ee ks 2, 4, a n d  8.  
•  
C ha n ge fr o m B aseli ne i n t he 7- da y a vera ge N R S rati n gs of ti n nit us l o u d ness  at W ee ks 2, 4, a n d 8 . 
•  
C ha n ge fr o m B aseli ne i n T FI o ver all sc ore fr o m B aseli ne at Da ys 1 5 a n d 2 9.  
•  
T he occ urre nce of at least a 1 3 -p oi nt re d ucti o n i n t he o verall T FI sc ore fr o m B aseli ne at Da y s 1 5, 2 9, 
a n d 5 7. 
•  
C ha n ge i n T FI s u bscale (I ntr usi ve ness, Se nse of C o ntr ol, C o g niti ve, Slee p, A u dit or y, Rela xati o n, 
Q ualit y of Life, E m oti o nal) sc ores fr o m B aseli ne at Da ys 1 5, 2 9, a n d 5 7.  
•  
P GI C sc ore s at Da y 8, 1 5, 2 9, a n d 5 7. 
St atistic al M et h o ds:  
S a m ple Size J ustific ati o n:  
T he sa m ple size f or P art A ( 8 s u bj ects) was selecte d base d o n cli nical j u d g me nt a n d is n ot base d o n statistical 
c o nsi derati o ns.  F or P art B, t he ass u me d tr ue sta n dar d de viati o n ( S D) of t he c ha n ge fr o m B aseli ne t o Da y 5 7 i n 
t he T FI o verall sc ore is 1 7 p oi nts.  B ase d o n t he use of a o ne-si de d t w o-sa m ple t test at t he α = 0. 0 5 le vel of 
si g nifica nce, a sa m ple size of 5 0 s u bj ects ( 2 5 s u bj ects per ar m)  will pr o vi d e 8 0 % p o wer t o detect a mea n 
differe nce bet wee n gr o u ps of 1 2 p oi nts.  
P art A a n al yses:  
Safet y a n d P K data will be s u m marize d descri pti vel y.  T he a nal yses of t he P K data will be c o n d ucte d b y a n 
i n de pe n de nt ve n d or wit h e x perie nce i n P K a nal yses. 
P art B a n al yses:  
F or P art B, t he ke y sec o n dar y e n d p oi nt (c ha n ge fr o m B aseli ne t o Da y 5 7 i n t he T FI o verall sc ore) a n d all 
e x pl orat or y e n d p oi nts t hat are defi ne d i n ter ms of t he c ha n ge fr o m baseli ne wi ll be a nal yze d usi n g a nal ysis of 
c o varia nce ( A N C O V A) m o dels wit h treat me nt gr o u p as a fact or a n d t he baseli ne val ue of t he c orres p o n di n g 
e n d p oi nt as a c o variate.  All pr o p orti o n e n d p oi nts will be a nal yze d usi n g P ears o n’s c hi -s q uare test, pr o vi de d 
t hat t he mi ni m u m e x pecte d cell c o u nt is at least 5.  Ot her wis e, Fis her’s e xact test will be use d.  C orrelati o ns 
bet wee n e n d p oi nts will be ass esse d usi n g t he P ears o n a n d S pear ma n c orrelati o n c oefficie nts.  All statistical 
a nal yses will be c o n d ucte d usi n g o ne -si de d tests at t he α = 0. 0 5 le vel of si g nifica nce, wit h n o a dj ust me nts f or 
m ulti plicit y.  
 
Safet y a n d P K data will be s u m marize d descri pti vel y.  


 
                                                                                                              1 6  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
T a ble 1:  Ti me a n d E ve nts Sc he d ule P art A  
Pr oce d ure  
Scree ni n g  
C hec k -i n/ B aseli ne1/ I P 
A d mi nistr ati o n  
Disc h ar ge  
F oll o w U p  
Visit 1  
Visit 2  
[ o ver ni g ht st a y] 
Visit 3  
 
Visit 4  
 
Visit 5 / E T 2 
U p t o 1 4 d a ys pri or 
t o st art of B aseli ne 
D a y 1  
D a y 2 
D a y 8  
( ± 2 d a ys)  
D a y 1 5  
( ± 2 d a ys)  
D a y 2 9  
( ± 2 d a ys)  
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 
 
 
 
 
Me dical hist or y
3 
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 4 
X 
X 
X 
X 
X 
X 
Hei g ht a n d wei g ht 
meas ure me nts  
X 
 
 
 
 
X 5 
Pre g na nc y test 6 
X 
X 
 
 
 
X 
Cli nical la b orat or y tes ts7  
X 
X 
 
X 
 
X 
S u bj ect vi de o 8 
X 
 
 
 
 
 
T y m pa n o metr y  
X 
 
 
X 
X 
X 
A u di o metr y  
X 
 
 
X 
X 
X 
Ot osc o p y 
X 
X 
 
X 
X 
X 
T FI  
X 
X 
 
X 
X 
X 
P GI C  
 
 
 
X 
X 
X 
C- S S R S assess me nt 9 
X 
X 
 
X 
X 
X 
Ra n d o mizati o n 1 0 
 
X 
 
 
 
 
A d mi nister i n vesti gati o nal 
pr o d uct 1 1 
 
X 
 
 
 
 
A d verse e ve nt m o nit ori n g  
 
X 
X 
X 
X  
X 
Plas ma P K Sa m pli n g 1 2 
 
X 
X 
X 
 
 


 
                                                                                                              1 7  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
 
1 B aseli 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 i n vesti gati o nal pr o d uct.  Res ults fr o m t he c o nc o mita nt me dicati o ns re vie w , uri ne 
pre g na nc y test  (f or fe males of c hil d beari n g p ote ntial), a n d C-S S R S  (“ Si nce Last Visit” versi o n)  must be a vaila ble a n d re vie we d b y t he I n vesti gat or t o c o nfir m 
t he s u bj ect’s eli gi bilit y bef ore ra n d o mizati o n.   
2 E n d -of -st u d y pr oce d ures will be perf or me d at Visit 5 ( Da y 29 ± 2 da ys) or u p o n earl y ter mi nati o n ( E T) fr o m t he st u d y.  
3 Me dical hist or y t o i ncl u de i nf or mati o n o n de m o gra p hics.  Me dical hist or y als o i ncl u des c o m pleti o n of t he m o difie d Ti n nit us Sa m ple Case Hist or y 
Q uesti o n naire ( T S C H Q) t o ca pt ure ti n nit us a n d relate d me di cal hist or y i nf or mati o n.  O nl y c ha n ges i n me dical hist or y si nce t he Scree ni n g visit will be rec or de d 
at t he B aseli ne ( Da y 1) visit.  
4 Vital si g ns meas ure me nts i ncl u de s yst olic a n d diast olic bl o o d press ure a n d p ulse rate.  
5 O nl y wei g ht is t o be meas u re d at Da y 2 9 . 
6 Fe male s u bj ects 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 uri ne pre g na nc y test at B aseli ne ( pri or t o ra n d o mizati o n), a n d a uri ne 
pre g na nc y test at Da y 2 9.  If t he Scree ni n g or B aseli ne pre g na nc y test res ult  is p ositi ve, t he s u bj ect is n ot eli gi ble f or e nr oll me nt i nt o t he st u d y.  If a s u bj ect is 
f o u n d t o be pre g na nt after d osi n g wit h i n vesti gati o nal pr o d uct, t he y will c o m plete t he 4-wee k F oll o w -U p peri o d.  Ser u m pre g na nc y test res ults fr o m S cree ni n g 
as well as t he uri ne pre g na nc y test at B aseli 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.  
7 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.  S u bj ects will be ra n d o mize d usi n g la b orat o r y res ults fr o m Scree nin g.  
La b orat or y res ults fr o m B aseli ne ( Da y 1 ) are n ot re q uire d f or ra n d o mizati o n.  
8 S u bj ects vie w a s h ort e d ucati o nal vi de o o n cli nical researc h partici pati o n e ntitle d “ W hat it Mea ns t o T a ke P art i n Cli nical R esearc h St u dies”.   Vie wi n g of t he 
vi de o will be  c o m plete d after i nf or me d c o nse nt b ut pri or t o  a n y efficac y assess me nts  (e. g. T FI) d uri n g t he scree ni n g visit. 
9 C ol u m bia -S uici de Se verit y R ati n g Scale: “B aseli ne ” versi o n will be use d at t he Scree ni n g visit a n d t he “Si nce Last Visit ” versi o n will be use d at all s u bse q ue nt 
visits.  
1 0 Ra n d o mizati o n m ust occ ur pri or t o a d mi nistrati o n of i n vesti gati o nal pr o d uct.  T he st u d y site will e xec ute eac h ra n d o mizati o n after a s u bj ect has met all 
prere q uisites f or ra n d o mizati o n.  
1 1 I n vesti gati o nal pr o d uct ( O T O -3 1 3 or place b o) is a d mi nist ere d b y intrat y m pa nic i nj ecti o n t o t he affecte d (st u d y) ear.  
1 2 Plas ma sa m ples f or P K a nal ysis will be o btai ne d pre -d ose o n Da y 1 ( a n y ti me pri or t o i ntrat y m pa nic i nj ecti o n), at 0. 5, 1, 2, 4, 8, a n d 1 2 h o urs p ost -d ose o n Da y 
1 ( ± 1 5 mi n utes at eac h p ost -d ose ti me p oi nt o n Da y 1), 2 4 h o urs ( ± 1 h o ur) p ost -d ose o n Da y 2, a n d o n Da y 8 (si n gle s a m ple o btai ne d at a n y ti me d uri n g st u d y 
visit o n Da y 8)  
 


 
                                                                                                              1 8  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
T a ble 2 :  Ti me a n d E ve nts Sc he d ule P art B  
Pr oce d ure  
Scree ni n g  
Le a d -I n 
B aseli ne 1/ I P 
A d mi nistr ati o n  
F oll o w U p 
Visit 1  
 
Visit 2  
Visit 3  
Visit 4  
Visit 5  
Visit 6 / E T 2 
U p t o 1 4 d a ys pri or 
t o st art of Le a d -I n 
D a y -1 4 t o  
D a y -1  
( + 3 d a ys) 
D a y 1  
D a y 8 
( ± 2 d a ys)  
D a y 1 5  
( ± 2 d a ys)  
D a y 2 9  
( ± 2 d a ys)  
D a y 5 7  
(+ 3  d a ys)  
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 
 
 
 
 
Me dical hist or y
3 
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 4 
X 
 
X 
X 
X 
X 
X 
Hei g ht a n d wei g ht meas ure me nts  
X 
 
 
 
 
 
X 5 
Pre g na nc y test 6 
X 
 
X 
 
 
 
X 
Cli nical la b orat or y tes ts7  
X 
 
X 
X 
 
 
X 
S u bj ect vi de o 8 
X 
 
 
 
 
 
 
T y m pa n o metr y  
X 
 
X 
X 
X 
X 
X 
A u di o metr y  
X 
 
X 
X 
X 
X 
X 
Ot osc o p y 
X 
 
X 
X 
X 
X 
X 
Dail y N R S ti n nit us electr o nic diar y 
a n d c o m plia nce re vie w 9 
X 
X 
X 
X 
X 
X 
X 
T FI  
X 
 
X 
 
X 
X 
X 
P GI C  
 
 
 
X 
X 
X 
X 
C- S S R S assess me nt 1 0 
X 
 
X 
X 
X 
X 
X 
Ra n d o mizati o n 1 1 
 
 
X 
 
 
 
 
A d mi nister i n vesti gati o nal pr o d uct1 2 
 
 
X 
 
 
 
 
A d verse e ve nt m o nit ori n g  
 
 
X 
X 
X 
X  
X 
Plas ma P K sa m pli n g 1 3 
 
 
X 
X 
 
 
 


 
                                                                                                              1 9  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
1 B aseli 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 i n vesti gati o nal pr o d uct.  Res ults fr o m t he c o nc o mita nt me dicati o ns re vie w, uri ne 
pre g na nc y test  (f or fe males of c hil d beari n g p ote ntial), a n d C -S S R S (“ Si nce Last Visit” versi o n) m ust be a vaila ble a n d re vie we d b y t he I n vesti gat or t o c o nfir m t he 
s u bj ect’s eli gi bilit y bef ore ra n d o mizati o n.   
2 E n d -of -st u d y pr oce d ures will be perf or me d at Visit 6 ( Da y 5 7 ± 2 da ys) or u p o n earl y ter mi nati o n ( E T) fr o m t he st u d y.  
3 Me dical hist or y t o i ncl u de i nf or mati o n o n de m o gra p hics.  Me dical hist or y als o i ncl u des c o m pleti o n of t he m o difie d Ti n nit us Sa m ple Case Hist or y 
Q uesti o n naire ( T S C H Q) t o ca pt ure ti n nit us a n d relate d  me di cal hist or y i nf or mati o n.  O nl y c ha n ges i n me dical hist or y si nce t he Scree ni n g visit will be rec or de d 
at t he B aseli ne ( Da y 1) visit.  
4 Vital si g ns meas ure me nts i ncl u de s yst olic a n d diast olic bl o o d press ure a n d p ulse rate.  
5 O nl y wei g ht is t o be meas ure d at Da y 5 7 . 
6 Fe male s u bj ects 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 uri ne pre g na nc y test at B aseli n e ( pri or t o ra n d o mizati o n), a n d a uri ne 
pre g na nc y test at Da y 5 7.  If t he Scree ni n g or B aseli ne pre g na nc y test res ult is p ositi ve, t he s u bj ect is n ot eli gi ble f or e n r 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 i n vesti gati o nal pr o d uct, t he y will c o m plete t he 8-wee k 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, w hile t he uri ne pre g na nc y test is c o n d ucte d l ocall y.  Ser u m pre g na nc y test res ults fr o m Scree ni n g as we ll as t he uri ne pre g na nc y test at 
B aseli 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.  
7 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 bj ects will be ra n d o mi ze d usi n g 
la b orat or y res ults fr o m Scree ni n g.  La b orat or y res ults fr o m t he B aseli ne visit (Da y 1 ) are n o t re q uire d f or ra n d o mizati o n. 
8 S u bj ects  vie w a s h ort e d ucati o nal vi de o o n cli nical researc h  partici pati o n e ntitle d “W hat it Mea ns t o T a ke P art i n Cli nical Researc h  St u dies” .  Vie wi n g of t he 
vi de o will be c o m plete d after i nf or me d c o nse nt b ut pri or t o a n y e fficac y assess me nts (e. g. T FI) d uri n g t he scree ni n g visit. 
9 O nce t he s u bj ect has met t he i ncl usi o n/e xcl usi o n criteria at Scree ni n g, t he s u bj ect will e nt er a 2 -wee k lea d-i n assess me nt peri o d .  S u bj ects ma y be e nt ere d i nt o 
t he lea d-i n peri o d bef ore l a b orat o r y res ults fr o m Scree ni n g are a vaila ble.  D uri n g t his peri o d , t he s u bj ect will rec or d t heir ti n nit us a n n o ya nce a n d ti n nit us 
l o u d ness dail y usi n g t he N R S electr o nic diar y .  S u bj ects m ust c o m plete  t heir ti n nit us rati n gs f or at least 4 of last 7 da ys of lea d-i n testi n g t o be eli gi ble f or 
ra n d o mizati o n.  Re mi n der alerts t o s u bj ects a n d site staff will hel p t o e ns ure c o m plia nce.   After ra n d o mizati o n, s u bj ects will c o nti n ue t o rec or d t heir dail y 
ti n nit us a n n o ya nce a n d ti n nit us l o u d ness f or t he 56- da y f oll o w -u p pe ri o d.  Re vie w of diar y c o m plia nce will be c o n d ucte d t hr o u g h o ut t he lea d-i n a n d f oll o w-u p 
peri o ds  a n d a d diti o nal i nstr ucti o ns a n d trai ni n g will be pr o vi de d t o e ns ure c o m plia nce .   
1 0 C ol u m bia -S uici de Se verit y Rati n g Scale “B aseli ne ” versi o n will be use d at t he Scree ni n g visit a n d t he “Si nce Last Visit versi o n ” will be use d at all s u bse q ue nt 
visits.  
1 1 Ra n d o mizati o n m ust occ ur pri or t o a d mi nistrati o n of i n vesti gati o nal pr o d uct.  St u d y s ites will e xec ute eac h ra n d o mizati o n after a s u bj ect has met all 
prere q uisites f or ra n d o mizati o n.  
1 2I n vesti gati o nal pr o d uct ( O T O-3 1 3 or place b o , res pecti vel y) is a d mi nistere d b y intrat y m pa nic i nj ecti o n t o t he affecte d (st u d y) ear.  
1 3Plas ma sa m ples f or P K a nal ysis will be o btai ne d i n a s u bs et of a p pr o xi matel y 1 6 s u bj ects at select sites o n Da y 1 ( pre -d ose a n y ti me  pri or t o i ntrat y m pa nic 
i nj ecti o n a n d 1 h o ur ± 1 5 mi n utes p ost -a d mi nistrati o n) a n d o n Da y 8 (si n gle sa m ple o btai ne d at a n y ti me d uri n g st u d y visit o n Da y 8).  


 
                                                  2 0  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
1.  
B A C K G R O U N D  
Ti n nit us or “ri n gi n g i n t h e ears ”,  is defi ne d  as a perce pti o n of s o u n ds wit h o ut a c orrelate d 
e xter nal a u dit or y sti m ul us.  Esti mates i n dicate  t hat a p pr o xi matel y 1 0 % of t h e U S  a d ult 
p o p ulati o n, or 2 1. 4 milli o n pe o ple, s uffer fr o m ti n nit us (B hatt et al 2 0 1 6) .  T he pre v ale nce of 
ti n nit us i ncreases wit h a ge, pea ki n g bet w ee n 6 0 t o 6 9 years of a ge.  E x p os ure t o recreati o nal, 
firear m, a n d occ u p ati o nal n oise i ncreases t h e o d ds of e x perie nci n g ti n nit us (S har g or o ds k y et al 
2 0 1 0) , a n d ti n nit us is t he lea di n g s er vice-relate d ca use of disa bilit y a m o n g U S militar y v etera ns 
(U S Veter a ns Be nefits A d mi nistrati o n ).  Ti n nit us is ofte n a l o n g-ter m c o n diti o n.  Base d o n a 
2 0 0 7 U S Nati o nal Healt h I nter vie w s ur v e y , 5 6 % of i n di vi d uals wit h ti n nit us ha d s y m pt o ms 
l o n ger t h a n 5 years a n d 3 6 % ha d nearl y c o nsta nt s y m pt o ms (B h att et al 2 0 1 6 ).   
Ti n nit us ca n be d istressf ul, ne gati vel y i m pacti n g  q ualit y of life  ( N o n da hl et al 2 0 0 7) as affect e d 
patie nts re p ort ass oci ate d  s y m pt o ms of i ns o m nia, a n xiet y, d e pressi o n , a n d c o g niti ve diffic ulties 
(Sc hec kl ma n n  et al 2 0 15 ; Ze m a n et al 2 0 1 4; B hatt et al 2 0 1 7 ; Te g g- Q ui n n et al 2 0 1 6).  W hile 
s o me ha bit uate t o t he s o u n d, a p pr o xi matel y 1 i n 4 pe o ple wit h ti n nit us belie ve  it t o be a m o derat e 
t o se vere pr o bl e m a n d nearl y h alf  will see k me di cal treat me nt (B hatt et al 2 0 1 6 ).  At prese nt , 
h o we ver, t here is n o c ure or a p pr o ve d m e dicati o n.  C urre nt ma na ge m e nt of ti n nit us lar gel y 
f oc uses o n m o d ulati o n of t he patie nt’s atte nti o n a n d res p o nses t o t he se nsati o n.  A ppr oac h es 
i ncl u de e d ucati o n a n d c o u nseli n g, s o u n d t hera p y, use of heari n g ai ds, a n d c o g niti ve be h a vi oral 
t hera p y (T u n k el et al  2 0 1 4).    
Ca uses a n d c o n diti o ns ass ociate d wit h ti n nit us i ncl u de se ns ori ne ural heari n g l oss, ac ut e heari n g 
l oss fr o m n oise tra u ma, b ar otra u ma, or tra u matic c oc hlear i nj ur y (ac ute ac o ustic tra u ma, blast 
tra u ma, mi d dle ear s ur ger y, i n ner ear bar otra u ma), a ge-relate d h eari n g l oss, Me niere’s dis ease, 
otitis me dia, ot ot o xic dr u g use, a n d hea d a n d nec k i nj uries ( La n g g ut h et al 2 0 1 3) .  I n ma n y cases, 
ti n nit us arises as a c o nse q ue nce of c oc hlear i ns ults a n d theref ore  o n e p har mac ot hera p y a p pr o ac h 
t o t he treat me nt of ti n nit us is directe d at n or malizi n g altere d ne ural acti vit y wit hi n t he c oc hlea.  
E x cessi ve acti vati o n of N M D A rece pt ors at t he l e vel  of t he i n ner hair cell s y na ps es wit h  
s u bse q ue nt deaffere ntati o n ma y b e a ke y m ec ha nis m  of a b n or mal se ns or y si g nali n g i n ti n nit us 
(Bi n g et al. 2 0 1 5 ).   
A n u m ber of s yste micall y a d mi nister e d a ge nts ha ve bee n teste d  i n cli nical st u dies i n ti n nit us, 
ai me d at i nfl ue nci n g t he p utati ve  i m bala nce i n a u dit or y firi n g rates pr o d u ce d b y c oc hlear i ns ults 
(Sa va ge a n d Wa d d ell 2 0 1 3; H oare  et al 2 0 1 1).  H o we ver, efficac y of s yst e mic 
p har mac ot hera pies a n d ot her i nter ve nti o ns f or ti n nit us has yet t o be pr o v e n.  I nt rat y m p a nic 
deli ver y of dr u gs p er mits de p ositi o n of dr u gs o v er t he r o u n d wi n d o w me m bra ne.  T his  e n a bles 
access t o t he i n ner ear f or m ore l ocalize d deli ver y t o t he c oc hlea a n d less s yste mic dr u g e x p os ure 
(Bir d et al. 2 0 0 7 ).  Es ket a mi ne  ( A M- 1 0 1), a n o nc o m petiti ve N M D A-rece pt or a nta g o nist, has 
be e n a d mi nistere d as 3 se parate i ntr at y m pa nic  i njecti o ns o ver a peri o d of a fe w da ys.  I n a P hase 
2 st u d y, es ket a mi ne re d u ce d ti n nit us se verit y a m o n g s o me s u bjects (va n de He y ni n g et al. 2 0 1 4) , 
alt ho u g h efficac y w as n ot de m o nstrate d  i n t w o P hase 3  st u dies ( u n p u blis he d res ults).    
1. 1.  
R ati o n ale  
Gac ycli di ne, t he acti ve a ge nt i n O T O - 3 1 3, is a n o nc o m petiti ve N M D A-rece pt or a nta g o nist t hat 
is c o nsi dere d t o ha ve greater p ote nc y, faster o n-rate, a n d sl o wer off-rece pt or rate t ha n ot h er 


 
                                                  2 1  
 
Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
N M D A -r ece pt or a nta g o nists, i ncl u di n g es keta mi n e (Mit ha a n d Ma y n ar d 2 0 0 1; Pi u et al 2 0 1 8) .  
Gac ycli di ne w as ori gi nall y f or m ulat e d  as O T O - 3 1 1, a s ol uti o n of gac ycli di ne i n a li q ui d 
t her m ore versi ble h y dr o gel p ol y mer, t o pr o vi de s ustai ne d e x p os ure of gac ycli di ne  t o c oc hlear 
tiss ues f oll o wi n g a si n gle i ntrat y m pa nic a d mi nistrati o n.  A d diti o nal precli nical st u dies s h o we d 
t hat gac ycli di ne f or m ulate d i n a li pi d- base d, me di u m-c hai n tri gl yceri d e s s ol uti o n ( O T O- 3 1 3) 
pr o vi de d greater a n d l o n ger lasti n g i n n er ear e x p os ures of gac ycli di ne c o m pare d t o O T O- 3 1 1 
a n d es keta mi ne w h e n i njecte d i ntrat y m pa nicall y.       
T he p har mac ol o g y, saf et y, a n d t o xicit y of gac ycli di ne, O T O - 3 1 1, a n d O T O- 3 1 3 ha ve b ee n 
e val uate d  pr ecli nicall y  a n d pr o vi de s ufficie nt rati o nale f or a d va nci n g O T O- 3 1 3 i nt o cli nical 
testi n g.  Gac ycli di ne was  ori gi nall y st u die d usi n g i ntra ve n o us a d mi nistrati o n i n cli nical st u dies i n 
s pi nal c or d a n d br ai n tra u ma patie nts a n d n o c o ncer ni n g safet y iss ues were i de ntifie d.  
Gac ycli di ne h as als o bee n a d mi nistere d t o t he otic c o m part me nt i n a n o pe n la bel case -seri es i n 
patie nts wit h c hr o nic ti n nit us .  T he dr u g was ge n erall y safe a n d well -t olerate d a n d re d u ced 
s u bjecti ve ti n nit us rati n gs i n 4 of t he 6 s u bjects e v al uate d (We nzel, et al. 2 0 1 0 ).  I n a rece ntl y 
c o m plete d P hase 1 st u d y i n healt h y s u bjects (St u d y 3 1 1 - 2 0 1 5 0 1), O T O- 3 1 1, place b o or s h a m 
was a d mi nistere d as a si n gle i ntrat y m pa ni c i njecti o n .  All  O T O - 3 1 1 d ose le vels teste d ( 0. 1 5 m g, 
0. 3 m g, a n d 0. 6 m g) w er e well -t oler ate d a n d n o s afet y c o n cer ns w ere i de ntifie d .  T he precli nical 
a n d cli nical data o btai n e d t o date are d escri b e d i n m ore detail i n t he I n vesti g ator’s  Br oc h ure. 
T h e c urr e nt st u d y ( 3 1 3- 2 0 1 9 0 1) is t he first cli nical st u d y of i ntrat y m pa nic O T O- 3 1 3 i n s u bjects 
wit h ti n nit us a n d is c o m p ose d of 2 parts.  Part A is a ra n d o mize d, d o u ble- bli n d, place b o-
c o ntr olle d c o h ort t o e v al uate t he saf et y, t olera bilit y, a n d pl as ma p har m ac o ki netics ( P K) of 0. 1 1 
m g O T O - 3 1 3, f oll o wi n g i ntrat y m pa nic a d mi nistrati o n, i n s u bjects wit h s u bjecti ve u nilateral or 
bilateral ti n nit us.  If acce pta ble safet y a n d t olera bilit y is o bser ve d f or 8 da ys i n Part A, as 
deter mi ne d b y t he Saf et y Re vie w C o m mittee, Part B will be  i nitiate d.  Part B is a ra n d o mize d, 
d o u ble- bli n d, place b o- c o ntr olle d st u d y t o i n vesti gate t he safet y, plas ma P K , a n d preli mi nar y 
efficac y of 0. 3 2 m g O T O - 3 1 3 i n s u bjects wit h s u bjecti ve u nilateral ti n nit us.  If acce pta bl e safet y 
a n d t olera bilit y is o bser v e d f or 8 da ys i n t he first 1 2 s u bjects i n Part B, as deter mi ne d b y t he 
Safet y R e vie w C o m mittee, t he re mai ni n g s u bjects i n Part B will be e nr olle d.  T he 0. 1 1 m g a n d 
0. 3 2 m g d oses of O T O -3 1 3 t o be teste d i n t his st u d y are e x pecte d t o b e safe a n d well -t olerated 
base d o n precli nical st u dies a n d o n t he cli nical St u d y 3 1 1- 2 0 1 5 0 1 c o n d ucte d wit h O T O- 3 1 1 i n 
healt h y s u bjects .  Precli nical data s u g gest t hat t he t w o d ose le vels of O T O - 3 1 3 will pr o d uce 
s ufficie nt i n ner ear e x p os ures of gac ycli di ne  i n h u ma ns.  I n a d diti o n, t he li pi d f or m ulati o n of 
O T O - 3 1 3 is e x pecte d t o mai ntai n  s ustai ne d e x p os ures t o t he c oc hl ea o ver ti me (at least 7 t o 1 4 
da ys i n pr ecli nical testi n g).  T a ke n t o get h er, t he precli nical a n d cli nical dat a s u p p ort t he 
e val uati o n of t he t w o d os e le vels of O T O - 3 1 3 i n t his P hase 1/ 2 st u d y i n s u bjects wit h ti n nit us. 
2.  
O B J E C TI V E S 
2. 1.  
P art A  
2. 1. 1.  
Pri m ar y O bjecti ve  
•  T o e val uate t he s afet y a n d t olera bilit y of O T O - 3 1 3 i n s u bjects wit h u nilateral or bilateral 
ti n nit us. 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
2. 1. 2.  
Sec o n d ar y O bjecti ve  
•  T o assess t he plas ma P K of gac ycli di ne i ncl u di n g ( +) a n d (- ) e na nti o mers of gac ycli di ne 
(a n d p ossi bl y its meta b olites). 
2. 2.  
P art B  
2. 2. 1.  
Pri m ar y o bjecti ve 
•  T o e val uate t he s afet y a n d t olera bilit y of O T O - 3 1 3 i n s u bjects wit h u nilateral ti n nit us.  
2. 2. 2.  
Sec o n d ar y O bjecti ve s 
•  T o e x a mi ne t he preli mi nar y efficac y of O T O - 3 1 3 i n s u bjects wit h u nilateral ti n nit us, as 
meas ure d b y t he c ha n ge fr o m Baseli ne i n t he Ti n nit us F u ncti o nal I n de x ( T FI). 
•  T o assess t he plas ma P K of gac ycli di ne i ncl u di n g ( +) a n d (- ) e na nti o mers of gac ycli di ne 
(a n d p ossi bl y its meta b olites).  
2. 2. 3.  
E x pl or at or y O bjecti ves 
•  T o e val uate t he e x pl orat or y efficac y of O T O - 3 1 3 o n ti n nit us a n n o ya nce usi n g s u bject-
re p orte d N u m eric Rati n g Scales ( N R S). 
•  T o e val uate t he e x pl orat or y efficac y of O T O - 3 1 3 o n ti n nit us l o u d ness usi n g s u bject-
re p orte d N R S. 
•  T o deter mi ne t he e x pl orat or y efficac y of O T O- 3 1 3 o n t he Patie nt Gl o bal I m pressi o n of 
C ha n ge ( P GI C) wit h res p ect t o ti n nit us se verit y.  
3.  
O V E R VI E W O F S T U D Y D E SI G N  
3. 1.  
P art A  
Part A will be c o n d ucte d at 1 site i n t he U nite d States a n d will i n v ol ve 1 o ver ni g ht sta y i n t he 
researc h u nit.  T he d ur ati o n of Part A f or eac h of t he 8 s u bjects will be a p pr o xi matel y 4- 6 w ee ks, 
i ncl u di n g a n u p t o 2- w ee k Scree ni n g peri o d a n d a 4-wee k f oll o w- u p peri o d.   
After i nf or m e d c o nse nt a n d Scree ni n g, eli gi ble s u bjects will be ra n d o mize d t o O T O - 3 1 3 or 
place b o at t he Bas eli ne visit ( Da y 1).  Ei g ht s u bjects will recei ve eit her 0. 1 1 m g O T O- 3 1 3 ( N = 6) 
or place b o ( N = 2).  Plas ma sa m ples f or P K a n al ysis will  be o btai ne d o n Da y 1 ( pre- d os e, 0. 5, 1, 
2, 4, 8, a n d 1 2 h o urs p ost-a d mi nistrati o n), Da y 2 ( 2 4 h o urs p ost-a d mi nistrati o n), a n d Da y 8.  
S u bjects will re mai n o ver ni g ht i n t he r esearc h u nit o n Da y 1 a n d will be disc har ge d o n Da y 2.  
A d diti o nal f oll o w- u p visits f or safet y a n d efficac y assess me nts will be c o n d ucte d o n Da y 8, D a y 
1 5, a n d Da y 2 9 ( e n d of st u d y) or u p o n earl y ter mi nati o n fr o m t he st u d y.   
If acce pta bl e saf et y a n d t olera bilit y is o bser v e d f or 8 da ys p ost-a d mi nistrati o n i n Part A, Part B 
will be i niti ate d wit h t he 0. 3 2 m g d ose le v el of O T O- 3 1 3 (see Safet y D ata Re vie w i n Secti o n 
1 4. 6. 1 ). 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
3. 2.  
P art B  
Part B will be c o n d u cte d at a p pr o xi matel y 2 0 sites i n t he U nite d States.  T he d urati o n of Part B 
f or eac h s u bject will be a p pr o xi matel y 1 0- 1 2 wee ks, i ncl u di n g a n u p t o 2- wee k Scree ni n g peri o d, 
a 2-wee k Lea d -I n assess me nt peri o d, a n d a n 8- wee k F oll o w- U p p eri o d.  If acce pta ble safet y a n d 
t olera bilit y is o bser v e d f or 8 da ys f or t he first 1 2 s u bjects d ose d (see Safet y D ata Re vie w i n 
Secti o n 1 4. 6. 1 ), t he remai ni n g s u bjects i n Part B will be e nr olle d.  I n t he e ve nt t hat a d vers e 
safet y fi n di n gs occ ur wit h 0. 3 2 m g O T O- 3 1 3 i n t he first 1 2 s u bjects, Part B s u bjects ma y b e 
e nr olle d usi n g 0. 1 1 m g O T O- 3 1 3, a n d e nr oll me nt e x pa n de d s o t hat 5 0 s u bjects are ra n d o mize d 
t o t his (l o wer) d ose le vel  or place b o  t o reac h t he tar get n u m ber of s u bjects f or Part B. 
After i nf or m e d c o nse nt a n d Scree ni n g, p ote ntial s u bjects will be gi n a 2 -wee k Lea d -i n assess me nt 
peri o d.  D uri n g t his ti me, s u bjects will e nter  dail y ti n nit us a n n o ya nce a n d ti n nit us l o u d ness i nt o 
a n electr o ni c diar y usi n g a N u meric Rati n g Scal e ( N R S) .  S u bjects m ust ha ve c o m pleted t he 
ti n nit us electr o nic diar y o n 4 of t he last 7 da ys of t he Lea d-i n p eri o d f or eli gi bilit y.  S u bjects will 
als o c o m plete t he Ti n nit us F u ncti o nal I n de x ( T FI) at b ot h t he Scree ni n g visit a n d t he Bas eli ne 
visit ( Da y 1) .  S u bjects m ust ha ve a sc ore of ≥ 2 5 at eac h T FI ass ess me nt f or eli gi bilit y.  At t he 
Baseli ne visit ( D a y 1), eli gi ble s u bjects will be ra n d o mize d t o O T O - 3 1 3 or place b o usi n g a 1: 1 
all ocati o n rati o.   
After a si n gle i ntr at y m p a nic i njecti o n wit h O T O - 3 1 3 or place b o t o t he affecte d (st u d y) ear o n 
Da y 1, s u bjects will c o nti n ue t o rec or d t heir ti n nit us a n n o ya nce a n d ti n nit us l o u d ness o n a dail y 
basis usi n g t he electr o nic diar y d uri n g t he 8 -w ee k f oll o w - u p peri o d.  S u bjects will c o m plete t he 
T FI at st u d y visits o n Da y 1 ( Bas eli ne), D a y 1 5, Da y 2 9, a n d D a y 5 7 (e n d of st u d y).  A d diti o nal 
safet y a n d/ or e x pl orat or y assess me nts will als o be c o m plete d at Da y 1 ( Bas eli ne), Da y 8, Da y 1 5, 
Da y 2 9, a n d D a y 5 7 (e n d of st u d y) or u p o n earl y ter mi nati o n fr o m t he st u d y.  I n a s u bset of 
a p pr o xi matel y 1 6 s u bjects i n Part B, bl o o d sa m ples f or P K a nal ysis will be o btai ne d o n Da y 1 
( pre- d os e a n d 1- h o ur p ost-a d mi nistrati o n) a n d o n Da y 8. 
 
 
 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
Fi g ure 1 .  St u d y Desi g n Sc he m atic – P art A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S C R E E NI N G   
U p  t o 1 4 da ys pri or t o B aseli ne 
C H E C K -I N T O U NI T / B A S E LI N E /  
I P A D MI NI S T R A TI O N 
Serial P K  sa m pli n g 
Da y 1 ( o ver ni g ht sta y)  
DI S C H A R G E F R O M U NI T  
P K sa m pli n g  
Da y 2  
F O L L O W -U P E V A L U A TI O N S   
Da y 8 (i ncl u des P K sa m pli n g ) a n d Da y 1 5 
E N D -O F -S T U D Y /  
E A R L Y -T E R MI N A TI O N  E V A L U A TI O N S  
Da y 2 9 ( or Earl y T er mi nati o n ) 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
Fi g ure 2.  St u d y Desi g n Sc he m atic – P art B  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 5 8 t o 7 0 s u bjects ( 8 s u bjects i n Part A a n d 5 0 t o 6 2 s u bjects i n Part B) will be 
e nr olle d at a p pr o xi matel y 2 0 st u d y sites i n t he U nite d States.  S u bjects will be eli gi ble if t h e y 
meet all of t he f oll o wi n g i ncl usi o n criteria a n d n o n e of t he e x cl usi o n criteria.  
4. 2.  
I ncl usi o n Criteri a 
T o be eli gi ble f or t his st u d y , eac h of t h e f oll o wi n g criteria m ust be satisfie d wit h a “ Y E S” a ns w er 
( u nless n ot a p plica ble): 
P art A o nl y 
1.  S u bject has s u bjecti ve u nilateral or bilateral ti n nit us a n d is c o nsiste ntl y a w are of t h eir 
ti n nit us t hr o u g h o ut m uc h of t he wa ki n g da y. 
P art B o nl y 
2.  S u bject has s u bjecti ve u nilateral ti n nit us a n d is c o nsiste ntl y a ware of t h eir ti n nit us 
t hr o u g h o ut m uc h of t h e wa ki n g d a y. 
3.  S u bject’s self -r e p orte d d urati o n of ti n nit us is bet wee n 1 m o nt h a n d 6 m o nt hs ( 3 0 t o 1 8 0 
da ys) pri or t o si g ni n g i nf or me d c o nse nt. 
S C R E E NI N G   
U p t o 1 4 da ys pri or t o B aseli ne  
B A S E LI N E L E A D -I N P E RI O D 
2 wee ks  
Da y -1 4 t o Da y -1  
B A S E LI N E / I P A D MI NI S T R A TI O N  
P K Sa m pli n g at Selecte d Sites  
Da y 1  
F O L L O W -U P E V A L U A TI O N S  
Da y 8 ( P K sa m pli n g  at Select e d Sites), Da y 1 5, 
a n d Da y 2 9  
E N D -O F -S T U D Y /  
E A R L Y -T E R MI N A TI O N  E V A L U A TI O N S  
Da y 5 7 ( or Earl y T er mi nati o n ) 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
4.  S u bje ct has a n o ver all sc ore of ≥ 2 5 o n t he T FI at Scree ni n g a n d Bas eli ne ( Da y 1) visits.  
5.  S u bject is a ble t o use t he electr o nic diar y t o c o m plete t heir dail y ti n nit us rati n gs a n d h as 
c o m plete d at least 4 of t h e last 7 da ys of diar y e ntries d uri n g t he 2- wee k Lea d-i n peri o d. 
P art A a n d B 
6.  S u bject is a male or fe m ale a ge d 1 8 t o 7 5 years, i n cl usi ve. 
7.  S u bject’s ti n nit us is li kel y of c oc hlear ori gi n, e. g., ass ociate d wit h se ns ori n e ural heari n g 
l oss; ac ute heari n g l oss fr o m n oise tra u ma, bar otra u ma, or tra u matic c oc hlear i nj ur y 
(ac ute ac o ustic tra u m a, blast tra u ma, mi d dle ear s ur ger y, i n ner ear bar otra u ma); a ge-
relate d heari n g l oss; res ol ve d otitis me dia; ot ot o xic dr u g e x p os ure.  
8.  Fe male s u bjects of c hil d beari n g p ote ntial [i.e., n ot s ur gicall y sterile a n d/ or n ot p ost-
me n o pa usal ( ≥1 2  m o nt hs si nce last me nstr ual peri o d a n d 4 5 years of a ge or ol der)] m ust 
ha ve a n e gati ve uri ne pre g na n c y test at Baseli ne ( Da y 1).  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 m ust use effecti ve met h o ds 
of c o ntrace pti o n f or t he d urati o n of t he st u d y i n cl u di n g: esta blis he d use of oral, i njecte d, 
or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n; place me nt of a n i ntra uteri ne de vice or 
i ntra uteri ne s yste m; or “ d o u ble barrier” met h o ds i ncl u di n g a c o m bi nati o n of male 
c o n d o m wit h eit her dia p hra g m or cer vical ca p wit h s per mici de.  Fe male s u bjects of 
c hil dbeari n g p ote ntial m ust als o refrai n fr o m e g g d o nati o n or retrie v al f or t he d urati o n of 
t he st u d y.  
9.  Male s u bjects ( u nless s ur gicall y sterile) w h o are n ot a bsti ne nt fr o m se x wit h fe male 
part ners of c hil d beari n g p ote ntial m ust a gree t o use a n effecti ve c o ntrace pti ve met h o d (as 
detaile d f or I n cl usi o n Criteria 8) f or t he d urati o n of t he st u d y.  M ale s u bjects m ust refrai n 
fr o m s per m d o nati o n f or t he d urati o n of t he st u d y. 
1 0.  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.  
1 1.  S u bject is a ble t o pr o vi de writte n i nf or me d c o ns e nt after t he sc o p e a n d n at ure of t he 
i n vesti gati o n ha ve b ee n e x plai ne d, a n d bef ore t he i nitiati o n of a n y st u d y-rel ate d 
pr oce d ur es. 
4. 3.  
E xcl usi o n Criteri a  
T o be eli gi ble f or t his st u d y, eac h of t h e f oll o wi n g criteria m ust be sat isfie d wit h a “ N O” a ns wer: 
( u nless n ot a p plica ble): 
P art A a n d B 
1.  S u bject has p ulsatile ti n nit us, ti n nit us res ulti n g fr o m tra u matic hea d or nec k i nj ur y, or 
ti n nit us res ulti n g fr o m a t u m or or str o ke. 
2.  S u bject has acti ve mi d dle ear dis ease (i ncl u di n g b ut n ot l i 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 olest eat o ma), 
Me niere’s dis ease  as o utli ne d b y t he A merica n Aca de m y of Ot olar y n g ol o g y- H ea d a n d 
Nec k S ur ger y E q uili bri u m C o m mittee i n 2 0 1 5 ( G oe bel 2 0 1 6),  or v esti b ular sc h wa n n o ma. 
3.  S u bject has rece ntl y ( < 1 m o nt h of Scree ni n g) i nitiate d ne w treat me nt f or ti n nit us (e. g. 
n oise or s o u n d ge ner at ors, heari n g ai ds, be h a vi oral t hera p y; m e dicati o ns or o ver-t he-
c o u nter s u p ple me nts ); o nl y sta ble ti n nit us treat me nts are all o we d d uri n g t h e st u d y a n d n o 
ne w treat me nts s h o ul d be i ntr o d uce d.  


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
4.  S u bject is n ot a ble t o acc uratel y i de ntif y a n d re p ort t heir ti n nit us per I n v esti gat or’s 
o pi ni o n. 
5.  S u bject has a n a b n or m alit y of t he t y m pa nic m e m bra ne i n t he affecte d (st u d y) ear t h at 
w o ul d i ncreas e t he ris k ass ociate d wit h i ntrat y m p a 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 e vi de nce of p erf or ati o n or lac k of cl os ure of t he t y m pa nic m e m bra ne at 
Scree ni n g or Bas eli ne ( D a y 1) visits.  
7.  S u bject is re cei vi n g a n y o n g oi n g t hera p y k n o w n as p ote ntiall y ti n nit us-i n d uci n g (e. g. 
a mi n o gl yc osi des, ot ot o xic c he m ot hera p e utic dr u gs, l o o p di uretics, q ui ni ne, hi g h d oses of 
as piri n or ot her n o nster oi dal a nti- i nfla m mat or y dr u gs).  Us a ge of l o w d os es of as piri n or 
ot her n o n- ster oi dal a nti-i nfla m mat or y dr u gs ma y be per mitte d at t he I n v esti gat or’s 
discreti o n . 
8.  S u bject a ns wer e d “ Y es” t o Q uesti o n 4 or 5 re gar di n g acti ve s uici dal i deati o n o n t he C-
S S R S a d mi nistere d at Scree ni n g or Bas eli ne ( Da y 1) visits.  I n a d diti o n, s u bjects dee me d 
b y t he I n vesti gat or t o be at si g nifica nt ris k of s uici dal be ha vi or s h o ul d be e x cl u de d. 
9.  S u bject has se ver e or u ntreate d d e pressi o n or a n xiet y t hat, i n t he I n v esti gat or’s o pi ni o n, 
w o ul d li kel y re d u ce t he s afet y of st u d y partici pati o n or c o m plia nce wit h st u d y 
pr oce d ur es.  O nl y sta ble d oses (ta ke n f or ≥ 1 m o nt h pri or t o Scree ni n g) of a nti d e pressa nt 
a n d a nti-a n xiet y me dicati o ns are all o w e d d uri n g t he st u d y.    
1 0.  S u bject is pre g n a nt or lactati n g.  
1 1.  S u bject has a hist or y of i m m u n o deficie nc y disease.  
1 2.  S u bject has a hist or y of s u bsta nce or alc o h ol a b us e wit hi n t he prece di n g 6 m o nt hs pri or t o 
Scree ni n g.  
1 3.  S u bject is recei vi n g c o n c o mita nt treat me nt wit h a n y ot her N M D A rece pt or a nta g o nist 
(e. g. me ma nti ne, de xtr o met h or p ha n). 
1 4.  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.  
1 5.  S u bject has recei ve d s yst e mic or i ntrat y m pa nic ster oi ds (i ncl u di n g de x a met has o ne) 
wit hi n 6 wee ks  pri or t o t he Scree ni n g visit.  
1 6.  S u bject has a k n o w n h y p erse nsiti vit y t o gac ycli di ne or a n y of t h e e x ci pie nts  i n O T O- 3 1 3. 
1 7.  S u bject has use d m o derat e or str o n g i n d ucers of C Y P 2 B 6 (e. g. car b a maze pi ne, efa vire nz, 
rifa m pi n, or rit o na vir) wit hi n 3 0 da ys pri or t o Scree ni n g.  
1 8.  S u bject has 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 at 
Scree n i n g or Bas eli ne ( D a y 1) t hat, i n t he I n vesti gat or’s o pi ni o n, w o ul d li kel y re d uce t he 
safet y of st u d y partici pati o n or c o m plia nce wit h st u d y pr o ce d ures. 
 


 
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5.  
R A N D O MI Z A TI O N A N D B L I N DI N G 
5. 1.  
O ver vie w  
I n Part A, 8 e nr olle d s u bj ects will be assi g n e d ra n d o ml y t o 0. 1 1 m g  O T O - 3 1 3 or place b o usi n g a 
6: 2 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. 
•  0. 1 1 m g O T O - 3 1 3; si n gl e ( 0. 2 m L v ol u me) i ntrat y m pa nic i njecti o n t o t he affecte d (st u d y) 
ear  
•  Place b o  ( ve hicl e); si n gl e ( 0. 2 m L v ol u me) i ntrat y m pa nic i njecti o n t o t he affecte d (st u d y) 
ear  
I n Part B, 5 0 e nr olle d s u bjects will be assi g n e d ra n d o ml y t o 0. 3 2 m g O T O- 3 1 3 ( or 0. 1 1 m g 
O T O -3 1 3 after Saf et y Data Re vie w; see Secti o n 1 4. 6. 1 ) or place b o usi n g a 1: 1 all ocati o n rati o, 
base d o n a c o m p uter- ge n erate d ra n d o mizati o n sc he d ule.  
•  0. 3 2 m g O T O- 3 1 3; si n gl e ( 0. 2 m L v ol u me) i ntrat y m pa nic i njecti o n t o a si n gle, affecte d  
(st u d y) ear 
•  Place b o ( ve hicl e); si n gl e  ( 0. 2 m L v ol u me) i ntrat y m pa nic i njecti o n t o a si n gle, affecte d  
(st u d y) ear 
I n t he e ve nt t hat a d v erse safet y fi n di n gs occ ur wit h 0. 3 2 m g O T O- 3 1 3 i n t he first 1 2 s u bjects, 
Part B s u bjects ma y b e e nr olle d usi n g 0. 1 1 m g O T O- 3 1 3, a n d e nr oll me nt e x pa n de d s o t hat 5 0 
s u bjects are ra n d o mize d t o t his (l o wer) d ose le v el  or place b o t o reac h t he tar get n u m ber of 
s u bjects f or Part B. 
A s u bset of a p pr o xi matel y 1 6 s u bjects will u n der g o P K testi n g at select st u d y sites i n Part B.   
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 ns e nt will be assi g n e d a 
se q ue ntial s u bject i de ntificati o n n u m ber b y t he site.  O nce assi g n e d, t he s u bject i de ntificati o n 
n u m ber will n ot be re- assi g ne d a n d s h o ul d n ot be c 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.  S u bjects will be 
c o nsi dere d e nr olle d i nt o t he st u d y o n ce t he y are ra n d o mize d. 
5. 2. 2.  
Tre at me nt Assi g n me nt  
A fter a s u bject has met all prere q uisites f or ra n d o mizati o n o n Da y 1 ( Baseli ne/ Visit 2), st u d y 
sites will e x ec ute eac h r a n d o mizati o n via t he i nteracti ve we b ra n d o mizati o n s yste m (We b E Z ).  
St u d y site p ers o n nel, w h o are bli n de d t o treat me nt assi g n me nt, will r ecei ve a ra n d o mizati o n 
n otificati o n i n dicati n g t h e kit n u m ber  ( pac ka ge d i n vesti gati o nal pr o d u ct), 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 n e d, kit n u m bers ca n n ot be re-assi g ne d.  S u bjects 
will be c o nsi dere d e nr olle d i nt o t he st u d y o nce t he y are ra n d o mize d. 
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 W e b E Z ra n d o mizati o n n otificati o n t o 
t he pers o n res p o nsi ble f or pre parati o n of t he s yri n ge c o ntai ni n g i n vesti gati o nal pr o d uct ( O T O -
3 1 3 or place b o) .  T he u ni q ue kit n u m ber pr o vi de d b y W e b E Z will c orres p o n d t o a kit of 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
pac ka ge d i n vesti gati o nal pr o d uct la bele d wit h t he i de ntical kit n u m ber.  T he s yri n ge will be 
pre par e d fr o m t he c o nte nts of t he i n vesti gati o nal pr o d uct pac k a ge c orres p o n di n g t o t he We b E Z 
kit n u m ber acc or di n g t o t he i nstr ucti o ns i n t he st u d y P har m ac y Ma n u al .  T he s u bject 
i de ntificati o n n u m ber a n d kit n u m ber b ot h m ust be rec or de d i n t he s u bject’s rec or d. 
5. 2. 3.  
R a n d o miz ati o n Al g orit h m 
I n Part A, su bjects will be ra n d o mize d i n a 6: 2 rati o ( O T O- 3 1 3: place b o) of treat me nt gro u ps 
usi n g a p er m ute d bl oc k r a n d o mizati o n al g orit h m.  I n Part B, s u bjects will be ra n d o mize d i n a 1: 1 
rati o ( O T O- 3 1 3: place b o) of treat me nt gr o u ps usi n g a p er 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 vi a We b E Z  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.  I n v esti gati o nal pr o d uct kits will be la bele d wit h a u ni q ue kit n u m ber usi n g a 
se parat e a n d i n de p e n de nt ra n d o mizati o n al g orit h m.  N u m bere d kits will be dis pe nse d base d o n 
t he treat me nt assi g n me nt.   
5. 3.  
Bli n di n g  
T he st u d y will be d o u ble- bli n de d.  Eac h treat me nt 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 M a n ual .   
T he bli n d s h o ul d be br o ke n f or site pers o n nel 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 me dical  treatme nt.  I n all cases, t he In v esti gat or s h o ul d c o ns ult wit h t he 
me dical m o nit or pri or t o u n bli n di n g, if p ossi ble, a n d m us t c o ntact t he me dical m o nit or as s o o n as 
it is practical after u n bli n di n g has o cc urre d a n d treat me nt i nitiate d. 
If t he bli n d is br o ke n, t he s u bject will c o nti n ue t o be f oll o we d a n d e val uate d per- pr ot oc ol.  T h e 
date, ti me, a n d reas o n f or t 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 be re veale d t o st u d y s u bje cts, 
In v esti gat ors, cli nical staff, site ma na gers or t he S p o ns or u ntil all s u bjects ha ve c o m plete d t h e 
st u d y a n d t he d ata bas e 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.  
I n vesti g ati o n al Pr o d uct A d mi nistr ati o n  
O T O - 3 1 3 or place b o is pr o vi de d i n i n di vi d ual I n v esti gati o nal Pr o d uct kits.  All  kits m ust be 
st ore d at 2- 8° C u ntil use.    
S yri n ges c o nt ai ni n g O T O- 3 1 3 or place b o are pre pare d i n a clea n l ocati o n at r o o m te m perat ure.  
Refer t o t he P har m ac y M a n ual f or i nstr ucti o ns o n O T O- 3 1 3 a nd place b o  pre parati o n 
i nstr ucti o ns.   
O T O - 3 1 3 or place b o will be a d mi nistere d as a si n gle  ( 0. 2 m L v ol u me) i ntrat y m pa ni c i njecti o n t o 
a n aff ecte d (st u d y) ear.  O nl y a p h ysi cia n ma y  perf or m t he i ntrat y m pa nic i njecti o n.   




 
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•  I ntr at y m p a nic i njecti o n ot her t ha n t hat o utli ne d i n t he c urre nt st u d y. 
•  S yste mic c ortic oster oi ds  
•  Ot her i n vesti gati o nal dr u g(s) or de vice(s). 
•  Ot her N M D A rece pt or a nta g o nists (e. g. me m a n ti ne, de xtr o met h or p ha n). 
•  Me dicati o ns k n o w n as p ote ntiall y ti n nit us-i n d uci n g (e. g. a mi n o gl yc osi des, ot ot o xic 
c he m ot hera p e utic dr u gs , l o o p di uretics, q ui ni ne, hi g h d oses of as piri n or ot her n o n-
ster oi dal a nti-i nfla m mat or y dr u gs).  Usa ge of l o w d oses of as piri n or ot her n o n-
ster oi dal a nti-i nfla m mat or y dr u gs ma y be p er mitte d at t he I n vesti gat or’s dis creti o n. 
•  Me dicati o ns t hat are c o nsi dere d m o derate or str o n g i n d ucers of C Y P 2 B 6 (e. g. 
car ba m aze pi ne,  ef a vire nz, rifa m pi n, a n d rit o na vir).  
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 o c ol de viati o n. 
7. 2.  
S y m pt o m atic Relief Me dic ati o ns  a n d T her a pies  
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 ti n nit us d uri n g t he st u d y.  Sta ble d oses (ta ke n f or ≥ 1 m o nt h pri or t o Scree ni n g) of 
a nti de pressa nt a n d a nti- a n xiet y me dicati o ns  are all o we d d uri n g t he st u d y.  Sta ble  pri or use ( ≥ 1 
m o nt h pri or t o Scree ni n g) of o ver-t he-c o u nt er s u p ple me nts or me dicati o ns f or ti n nit us (e. g. 
Gi n g k o bil o ba, melat o ni n) ma y als o be use d.  N o ne w me dicati o ns or o v er-t he-c o u nter 
s u p ple me nts f or ti n nit us ma y b e i ntr o d uce d d uri n g t he st u d y.  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.   
Sta ble pri or use ( ≥ 1 m o nt h  pri or t o Scree ni n g) of heari n g ai ds, n oise ge n erat ors, a n d/ or s o u n d 
t hera p y de vices is all o we d a n d, if utilize d, these de vices s h o ul d be use d c o nsiste ntl y t hr o u g h o ut 
t he d urati o n of st u d y.  Si milarl y, a n y b e ha vi oral t hera p y f or ti n nit us s h o ul d als o be sta ble ( ≥ 1 
m o nt h pri or t o Scree ni n g) a n d c o nti n ue t hr o u g h o ut t he d urati o n of t he st u d y.  N o n e w heari n g 
ai ds, s o u n d/ n oise t hera p y de vices, or b e ha vi oral t h era p y f or ti n nit us ma y be i ntr o d uce d d uri n g 
t he st u d y.      
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  – P art A  
8. 1. 1.  
Scree ni n g Peri o d : U p t o 1 4 d a ys pri or t o B aseli ne – P art A  
T he f oll o wi n g assess me n ts, as liste d i n t he Time a n d E ve nts Sc he d ule f or P art A (Ta bl e 1 ), will 
be perf or me d d uri n g t he scree ni n g p eri o d : inf or m e d c o nse nt, re vie w a n d c o nfir m eli gi bilit y 
criteria, me dical hist or y, de m o gr a p hics, co n c o mita nt me dicati o ns , vital si g ns, hei g ht a n d wei g ht 
meas ure me nts , ser u m pre g na n c y test (f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y), cli nical 
la b orat or y tests, ty m p a n o metr y , au di o metr y, ot osc o p y, T FI ass ess me nt,  a n d C- S S R S assess me nt : 
Baseli ne v ersi o n .  T he m o difie d Ti n nit us Sa m ple Case Hist or y Q ues ti o n naire ( T S C H Q) will be 
c o m plete d at Scree ni n g as part of me dical hist or y t o ca pt ure ti n nit us -s pecifi c me dical hist or y.  
Eac h s u bject will als o vie w a s h ort e d ucati o nal vi de o o n cli nical res earc h partici pati o n e ntitle d 


 
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“ W hat It Mea ns t o Ta ke Part i n Cli n ical St u dies”.  Vie wi n g of t he vi de o will be c o m plete d  after 
i nf or me d c o nse nt b ut pri or t o a n y effi cac y assess me nts (e. g. T FI)  at t he s cree ni n g visit. 
8. 1. 2.  
C hec k -i n t o Rese a rc h U nit/ B aseli ne/I n vesti g ati o n al Pr o d uct A d mi nistr ati o n: 
D a y 1 – P a rt A  
O nce a s u bject has si g ne d c o nse nt, c o m plete d t he Scree ni n g ass ess me nts, a n d met all st u d y 
eli gi bilit y criteria, t he s u bject will c hec k i nt o t he Researc h U nit f or a n o v er ni g ht sta y.  Res ults 
fr o m t he c o nc o mita nt me dicati o ns re vie w, uri n e pre g n a nc y test (f or fe male s u bjects of 
c hil d beari n g p ote ntial) , a n d C-S S R S (“ Si nce Last Visit” versi o n) m ust be a vaila ble a n d re vie we d 
b y t he I n vesti gat or t o c o nfir m t he s u bject’s eli gi bilit y bef ore ra n d o mizati o n.  I n a d diti o n, t he 
f oll o wi n g ass ess me nts ar e t o be perf or me d o n all s u bjects pri or t o d osi n g t o esta blis h Baseli ne 
stat us:  me dical hist or y, vital si g ns, cli nical la b orat or y t ests, ot osc o p y, T FI, a n d pre - d os e P K 
sa m ple.   
If t he s u bject is n o l o n ger eli gi ble, t he s u bject will n ot be ra n d o mize d a n d s h o ul d be rec or de d as 
a scree n fail ur e .  Inf or mati o n relate d t o s pecific i n cl usi o n/e x cl usi o n criteria will be d oc u me nte d.  
O nce eli gi bilit y stat us is c o nfir me d  a n d t h e s u bject is ra n d o mize d, t he i n vesti gati o nal pr o d uct is 
a d mi nistere d  a n d t he r e m ai ni n g D a y 1 assess me nts (e. g. P K sa m pli n g at 0. 5, 1, 2, 4, 8, a n d 1 2 
h o urs [ ± 1 5 mi n utes at eac h ti me p oi nt] p ost- d ose, A E m o nit ori n g)  are c o m plete d .  
All assess me nts as liste d i n t he Ti me a n d  E ve nts Sc he d ule f or Part A (T a ble  1) are t o b e 
perf or me d at t his visit.  
8. 1. 3.  
Disc h ar ge f r o m Res e arc h U nit : D a y 2 – P art A   
Pri or t o disc har ge fr o m t he researc h u nit o n D a y 2, t he f oll o wi n g ass ess me nts are t o be 
perf or me d: c o nc o mita nt me dicati o ns, vital si g ns, A E c ollecti o n, a n d t he pl as ma P K sa m ple at 2 4 
h o urs.   
All assess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part A (T a ble  1) are t o b e 
perf or me d at t his visit.  
8. 1. 4.  
D a y 8 ( ± 2 d a ys): F oll o w U p a n d S afet y Re vie w – P art A  
T he pri mar y p ur p os e of Da y 8  visit  is t o ca pt ure s afet y a n d P K  d ata.  Safet y ass ess me nts i ncl u de 
c o nc o mita nt me dicati o ns, vital si g ns, cli nical la b orat or y tests, t y m p a n o metr y, a u di o metr y, 
ot osc o p y, C- S S R S, a n d A E c ollecti o n.  A fi nal P K sa m ple will be o btai ne d at t his visit (at a n y 
ti me d uri n g t he visit).  E x pl orat or y efficac y assess me nts i ncl u de t he T FI  a n d P GI C.   
All Da y 8  s afet y, efficac y, a n d P K assess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or 
Part A  (Ta ble  1) ar e t o be perf or me d. 
8. 1. 5.  
D a y 1 5 ( ± 2 d a ys): F oll o w U p – P art A  
T he  pri mar y p ur p os e of Da y 1 5 visit  is t o ca pt ure safet y data.  Safet y assess me nts i ncl u de 
c o nc o mita nt me dicati o ns, vital si g ns, t y m pa n o m etr y, a u di o metr y, ot osc o p y, C- S S R S, a n d A E 
m o nit ori n g.  E x pl orat or y e fficac y ass ess me nts i ncl u de t he T FI a n d P GI C.   
All Da y 1 5  s afet y a n d efficac y ass ess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part A 
(Ta ble  1) are t o b e perf or me d. 


 
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8. 1. 6.  
D a y 2 9 ( ± 2 d a ys): E n d of St u d y/ E arl y Ter mi n ati o n – P art A  
T he pri mar y p ur p os e of Da y 2 9 v isit is t o ca pt ure fi nal safet y dat a f or Part A.  Safet y 
assess me nts i ncl u de c o nc o mita nt me dicati o ns, wei g ht, vital si g ns, uri n e pre g na n c y test f or 
w o me n of c hil d beari n g p ote ntial, cli nical la b orat or y tests, t y m pa n o metr y, a u di o metr y, ot osc o p y, 
C- S S R S, a n d A E m o nit ori n g.  E x pl orat or y e fficac y ass ess me nts i ncl u de t he T FI a n d P GI C.   
All Da y 2 9  s afet y a n d efficac y ass ess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part A 
(Ta ble  1) are t o b e perf or me d. 
If a s u bject ter mi nates fr o m t he st u d y pri or t o Da y 2 9 ( E arl y- T er mi nati o n), e ver y atte m pt s h o ul d 
be ma de t o perf or m all assess me nts as liste d f or D a y 2 9.  
8. 2.  
St u d y Pr oce d ure s b y Visit – P art B  
8. 2. 1.  
Scree ni n g Peri o d: U p t o 1 4 d a ys pri or t o B aseli ne – P art B  
T he f oll o wi n g assess me nts, as liste d i n t he Ti me a n d E ve nts Sc he d ule f or P art B (Ta ble 2 ), will 
be perf or me d d uri n g t he scree ni n g p eri o d: i nf or m e d c o nse nt, re vie w a n d c o nfir m eli gi bilit y 
criteria, me dical hist or y, de m o gr a p hics, c o n c o mita nt me dicati o ns, vital si g ns, hei g ht a n d wei g ht 
meas ure me nts, ser u m pre g na n c y test (f or fe ma l e s u bjects of c hil d beari n g p ote ntial o nl y), cli nical 
la b orat or y tests, t y m p a n o metr y, a u di o metr y, ot osc o p y, T FI ass ess me nt, C-S S R S assess me nt : 
“Bas eli ne ” v ersi o n , a n d r e vie w of dail y N R S electr o nic diar y i nstr ucti o ns wit h t he s u bject.  T he 
m o difie d Ti n nit us Sa m ple Case Hist or y Q uesti o n naire ( T S C H Q) will als o be c o m plete d at 
Scree ni n g as p art of me di cal hist or y t o ca pt ure ti n nit us -s pecific me dical hist or y.  E ac h s u bject 
will als o  vie w a s h ort e d ucati o nal  vi de o o n cli nical researc h p artici pati o n e ntitle d “ W hat It 
Mea ns t o Ta ke Part i n  Cli nical St u d ies”.  Vie wi n g of t he vi de o will be c o m plete d after i nf or me d 
c o nse nt b ut pri or t o a n y efficac y assess me nts (e. g. T FI) at t he scree ni n g visit. 
8. 2. 2.  
Le a d -I n Peri o d: D a y - 1 4 t o D a y - 1 ( + 3 d a ys) – P art B  
T he s u bject will re c or d t heir ti n nit us l o u d ness a n d ti n nit us a n n o ya nce dail y, usi n g t he N R S f or 
eac h s y m pt o m, i n a n electr o nic diar y d uri n g t he 1 4- da y Lea d -I n assess me nt peri o d.   
8. 2. 3.  
B aseli ne/I n vesti g ati o n al Pr o d uct A d mi nistr ati o n: D a y 1 – P a rt B  
O nce a s u bject has si g ne d c o nse nt, c o m plete d t he Scree ni n g ass ess me nts, met all st u d y eli gi bilit y 
criteria, a n d c o m plete d t h e Lea d-I n peri o d, t he Da y 1 bas eli ne assess me nts a n d i n vesti gati o nal 
pr o d uct a d mi nistrati o n  ar e perf or me d .  Res ults fr o m t he c o nc o mita nt me dicati o ns re vie w, uri ne 
pre g na nc y t est (f or fe mal e s u bjects of c hil d beari n g p ote ntial), a n d C- S S R S (“ Si nce Last Visit” 
versi o n) m ust be a vaila bl e a n d re vi e we d b y t he I n vesti gat or t o c o nfir m t he s u bject’s eli gi bilit y 
bef ore ra n d o mizati o n.  I n a d diti o n, t he f oll o wi n g assess me nts are t o be p erf or me d o n all s u bjects 
pri or t o d osi n g t o esta blis h Baseli ne stat us:  me dical hist or y, vital si g ns, cli nical la b orat or y tests, 
t y m pa n o metr y, a u di o metr y, ot osc o p y, a n d T FI.  F or s u bjects u n der g oi n g P art B P K e v al uati o ns, 
a pre-d os e plas ma P K sa m ple will be o btai ne d o n Da y 1 at a n y ti me pri or t o i n vesti gati o nal 
pr o d uct a d mi nistrati o n.    
If t he s u bject is n o l o n ger eli gi ble, t he s u bject will n ot be ra n d o mize d a n d s h o ul d be rec or de d as 
a scree n fail ur e .  Inf or mati o n relate d t o s pecific i n cl usi o n/e x cl usi o n criteria will be d oc u me nte d.  
O nce eli gi bilit y stat us is c o nfir me d a n d t h e s u bject is ra n d o mize d, t he in vesti gati o nal pr o d uct is 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
a d mi nistere d a n d t he r e m ai ni n g D a y 1 assess me nts (e. g. P K sa m pli n g at 1 h o urs [ ± 1 5 mi n utes ] 
i n select s u bjects, A E m o nit ori n g) are c o m plet e d .  
All assess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part B (Ta ble 2 ) are t o b e 
perf or me d at t his visit.  
8. 2. 4.  
D a y 8 ( ± 2 d a ys): F oll o w U p a n d S afet y Re vie w – P art B  
T he pri mar y p ur p os e of Da y 8 visit is t o ca pt ure s afet y, P K, a n d preli mi nar y  efficac y dat a.  
Safet y assess me nts i ncl u de c o nc o mita nt me dicati o ns, vital si g ns, cli nical la b orat or y tests, 
t y m pa n o metr y, a u di o metr y, ot osc o p y, C- S S R S, a n d A E m o nit ori n g.  A fi nal P K sa m ple will be 
o btai ne d at t his visit (at a n y ti me d uri n g t he visit).  Efficac y assess me nt i ncl u de s t he P GI C.  
C o m plia nce f or c o m pleti n g t he d ail y N R S electr o nic diar y will be re vi e we d wit h t he s u bject.    
All Da y 8 s afet y, efficac y, a n d P K assess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or 
Part B (T a ble 2 ) are t o be perf or me d. 
8. 2. 5.  
D a y 1 5 ( ± 2 d a ys): F oll o w U p – P art B  
T he pri mar y p ur p os e of Da y 1 5 visit is t o ca pt ure safet y a n d preli mi nar y  efficac y data.  Safet y 
assess me nts i ncl u de c o nc o mita nt me dicati o ns, vital si g ns, t y m pa n o m etr y, a u di o metr y, ot osc o p y, 
C- S S R S, a n d A E m o nit ori n g.  Efficac y assess me nts i ncl u de t he T FI a n d P GI C.  C o m plia nce f or 
c o m pleti n g t he d ail y N R S electr o nic diar y will be re vie we d wit h t he s u bject.     
All Da y 1 5 s afet y a n d efficac y ass ess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part B 
(Ta ble 2 ) are t o b e perf or me d. 
8. 2. 6.  
D a y 2 9 ( ± 2 d a ys): F oll o w U p – P art B  
T he pri mar y p ur p os e of Da y 2 9 visit is t o ca pt ure safet y a n d preli mi nar y  efficac y data.  Safet y 
assess me nts i ncl u de c o nc o mita nt me dicati o ns, vital si g ns, t y m pa n o m etr y, a u di o metr y, ot osc o p y, 
C- S S R S, a n d A E m o nit ori n g.  Efficac y assess me nts i ncl u de t he T FI a n d P GI C.  C o m plia nce f or 
c o m pleti n g t he d ail y N R S electr o nic diar y will be re vie we d wit h t he s u bject.     
All Da y 1 5 s afet y a n d efficac y ass ess me nts as liste d i n t he Ti me a n d E ve nts Sc he d ule f or Part B 
(Ta ble 2 ) are t o b e perf or me d. 
8. 2. 7.  
D a y 5 7 ( + 3 d a ys ): E n d - of- St u d y/ E arl y Ter mi n ati o n – P ar t B 
T he pri mar y p ur p os e of Da y 5 7 visit  is t o ca pt ure fi nal safet y a n d preli mi nar y  efficac y data.  
Safet y assess me nts i ncl u de c o nc o mita nt me dicati o ns, wei g ht, vital si g ns, uri ne pre g n a nc y test f or 
w o me n of c hil d beari n g p ote ntial, cli nical la b orat or y tests,  t y m pa n o metr y, a u di o metr y, ot osc o p y, 
C- S S R S, a n d A E m o nit ori n g.  Efficac y assess me nts i ncl u de t he T FI a n d P GI C.   
All Da y 5 7 s afet y a n d e x pl orat or y efficac y assess me nts as liste d i n t he Ti me a n d E ve nts 
Sc he d ule f or Part B (T a ble 2 ) ar e t o be perf or me d. 
If a s u bject ter mi nates fr o m t he st u d y pri or t o Da y 5 7 ( E arl y- T er mi nati o n), e ver y atte m pt s h o ul d 
be ma d e t o perf or m all assess me nts as liste d f or D a y 5 7. 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
8. 2. 8.  
U nsc he d ule d Visit  
U nsc he d ule d V isits ma y occ ur i n t he e v e nt of safet y- relate d iss ues.  A p pr o priate safet y 
assess me nts  (e. g. ot osc o p y, vital si g ns, cli nical la b orat or y tests) ma y be c o n d ucte d at t he 
I n v estigat or’s discr eti o n  at U nsc he d ule d Visits. 
8. 3.  
Me dic al Hist or y  a n d De m o gr a p hic s 
T he  me dical hist or y will  be o btai ne d fr o m me di cal rec or ds a n d/ or via s u bject i nter vie w at t he 
Scree ni n g visit, a n d i ncl u des ge ner al me dical hist or y, me di cati o n hist or y, a n d re pr o d uc ti ve 
hist or y.  Ti n nit us- s pecifi c me dical hist or y i nf or m ati o n is als o o btai ne d b y ha vi n g p ote ntial 
s u bjects c o m plete t he m o difie d T S C H Q at Scree ni n g.  
De m o gra p hic i nf or mati o n will als o be o btai ne d at t he Scree n i n g visit a n d will i ncl u de: a ge; se x; 
race; h ei g ht, wit h o ut s h o es (c m); b o d y w ei g ht, wit h o ut s h oes ( k g); a n d hi g hest le vel of e d u cati o n 
c o m plete d.  
8. 4.  
Vi de o f or S u bjects o n Cli nic al Rese arc h P artici p ati o n  
S u bjects will vie w a n e d ucati o n al vi de o o n cli nical researc h p artici pati o n e ntitle d “ W hat It 
Mea n s t o Ta ke Part i n Cli nical St u dies”.  T his 7-mi n ute vi de o pr o vi des ge neral i nf or mati o n, i n 
la y ter ms, o n t he p ur p ose of bli n de d, c o ntr olle d cli nical researc h st u dies a n d t he r oles a n d 
res p o nsi bilities of a s u bject i n a cli nical res earc h st u d y.  Vie wi n g of t he vi de o will be c o m plete d 
after i nf or me d c o nse nt b ut pri or t o a n y effi cac y assess me nts (e. g. T FI)  at t he scree ni n g visit.  
8. 5.  
Effic ac y E v al u ati o ns  
Efficac y assess me nts i ncl u de:  
•  Ti n nit us F u ncti o nal I n d e x ( T FI) 
•  Dail y Ti n nit us A n n o ya n ce N R S  
•  Dail y Ti n nit us L o u d ness N R S  
•  Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C) 
S u bjects w h o use heari n g ai ds, n oise ge nerat ors, a n d/ or s o u n d t hera p y de vi ces s h o ul d c o nti n ue t o 
d o s o d uri n g t he st u d y a n d s h o ul d c o m plete t he ti n nit us assess me nts  a n d rati n gs (i.e. T FI, d ail y 
ti n nit us a n n o ya nce N R S, dail y ti n nit us l o u d ness N R S, a n d P GI C) bas e d o n t heir ti n nit us 
e x perie nce wit h t he de vi ces i n use.      
T he rec o m me n de d or d er i n w hic h st u d y q uesti o n n aire asse ss me nts are c o n d ucte d is: T FI, P GI C, 
a n d C-S S R S.  
8. 5. 1.  
Ti n nit us F u ncti o n al I n de x ( T FI)  
T he T FI  is a vali date d, 2 5-ite m q uesti o n naire t hat ca n be use d t o s cale o v erall se verit y of ti n nit us 
a n d t o assess treat me nt-r elate d c h a n ge i n ti n nit us (Mei k le et al., 2 0 1 2; He nr y et al., 2 0 1 5 ).  T he 
2 5 ite ms of t he T FI r e pr ese nt 8 s u bscales c o v eri n g m ulti ple d o mai ns of ti n nit us se verit y : 1) 
I ntr usi ve, 2) Se nse of C o ntr ol, 3) C o g niti ve, 4) Slee p, 5) A u dit or y, 6) Rela x ati o n, 7) Q ua lit y of 
Lif e, a n d 8) E m oti o nal.  S u b jects a ns wer eac h T FI q u esti o n b y rati n g t h eir e x perie nce o ver t he 
past wee k.   


 
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C o m pleti n g t he T FI pr o vi des a n i n de x sc ore fr o m 0 t o 1 0 0, wit h hi g her sc ores re prese nti n g a 
gr eater pr o ble m wit h ti n nit us.  A re d ucti o n i n t he T FI i n de x sc ore of 1 3 p oi nts or m ore is 
c o nsi dere d cli nicall y mea ni n gf ul i m pr o ve me nt i n ti n nit us (Mei kle et al., 2 0 1 2 ).    
I n Part A, su bjects will c o m plete t he T FI  at Scree ni n g, Da y 1 ( pre- d ose ), a n d Da ys 8, 1 5, a n d 2 9.   
I n Part B, s u bjects will c o m plete t he T FI at Scree ni n g, Da y 1 ( pre- d ose), a n d Da ys 1 5, 2 9, a n d 
5 7. 
8. 5. 2.  
D ail y Ti n nit us A n n o y a nce N R S  
I n Part B, su bjects will rec or d t heir dail y ti n nit us a n n o ya n ce usi n g a  ti n nit us N R S electr o nic 
diar y.  N u meric rati n g scales ha ve b ee n wi del y us e d t o ass ess ti n nit us se verit y a n d h a ve 
de m o nstrate d g o o d test-r etest relia bilit y a n d c o nc or da nce wit h ot her s u bjecti ve meas ures of 
ti n nit us (Mei kle et al. 2 0 0 8 ).  S u bjects rate t heir ti n nit us a n n o ya n ce o ver t h e past 2 4 h o urs.  
S u bjects res p o n d t o t he f oll o wi n g q uesti o n b y c hec ki n g t he b o x o n t he N R S scale c orres p o n di n g 
t o t heir de gree of ti n nit us a n n o ya nce o n a scale of 0 ( N ot a n n o yi n g) t o 1 0 ( E xtre mel y a n n o yi n g): 
 
S u bjects eli gi ble at scree ni n g i n Part B will be gi n usi n g t he ti n nit us N R S  diar y at t he start of t he 
L ea d-i n peri o d t o rec or d dail y ti n nit us a n n o ya nce a n d will  c o nti n ue t o rec or d t heir ti n nit us 
a n n o ya nce o nce p er da y t hr o u g h t h e 5 6- da y F oll o w U p peri o d.  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 ti n nit us N R S  diar y  will 
be m o nit ore d t hr o u g h o ut t he st u d y wit h re- trai ni n g as necess ar y. 
8. 5. 3.  
D ail y Ti n nit us L o u d ness N R S  
I n Part B, su bjects will rec or d t heir dail y ti n nit us l o u d ness usi n g a ti n nit us N R S electr o nic diar y.   
S u bjects rate t heir ti n nit us l o u d ness o ver t he past 2 4 h o urs.  S u bjects res p o n d t o t he f oll o wi n g 
q uesti o n b y c h ec ki n g t he b o x o n t he N R S scale c orres p o n di n g t o t he d e gree of  ti n nit us l o u d ness 
o n a scale of 0 ( N o ti n nit us ) t o 1 0 ( E xtre mel y l o u d ti n nit us): 
 
  
   


 
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S u bjects i n Part B will be gi n usi n g t he ti n nit us N R S diar y at t he st art of t he L ea d-i n peri o d t o 
rec or d d ail y ti n nit us l o u d ness a n d will c o nti n ue t o rec or d t h eir ti n nit us l o u d ness o nce per da y 
t hr o u g h t he 5 6- da y F oll o w U p peri o d.  S u bjects will be a ble t o rec or d misse d diar y e ntri es f or 1 
da y after a misse d e ntr y.  C o m plia nce wit h t he ti n nit us N R S diar y will be m o nit ore d t hr o u g h o ut 
t he st u d y wit h re-trai ni n g as necess ar y. 
8. 5. 4.  
P ati e 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 p atie nt-r e p orte d o utc o me t hat e v al uates t he c ha n ge i n o verall “ gl o bal” ti n nit us 
stat us as percei ve d b y t he s u bject (A da mc hi c et al. 2 0 1 2;  va n de He y ni n g et al. 2 0 1 4) .  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 ti n nit us? ”.  
T he be gi n ni n g of 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 i n vesti gati o nal pr o d u ct 
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 h e P GI C are:  
•  Ver y m uc h i m pr o ve d = 3 
•  M uc h i m pr o ve d = 2 
•  Mi ni mall y i m pr o v e d = 1 
•  U nc ha n ge d  = 0  
•  Mi ni mall y w orse = - 1 
•  M uc h w orse = - 2 
•  Ver y m uc h w orse = - 3 
I n Part A, su bjects will c o m plete t he  P GI C at Da ys 8, 1 5, a n d 2 9. 
I n Part B, s u bjects will c o m plete t he P GI C at Da ys 8, 1 5, 2 9, a n d 5 7. 
8. 6.  
Bl o o d S a m pli n g f or P l as m a P K E v al u ati o ns  
Bl o o d sa m ples f or plas m a gac ycli di ne ( i ncl u di n g ( +) a n d (-) e na nti o mers of gac ycli di ne a n d 
p ossi bl y its meta b olites) will be c ollecte d fr o m all s u bjects i n Part A a n d fr o m a s u bset of 
a p pr o xi matel y 1 6 s u bjects i n Part B .  Onl y select sites i n Part B will c o n d uct P K  sa m pli n g.  
C o n d ucti n g P K i n 1 6 s u bjects will e ns ure t hat a p pr o xi matel y 8 s u bjects will be e x p ose d t o O T O -
3 1 3, pr o vi di n g a s ufficie nt n u m ber f or t he a n al ysi s.   
I n Part A, o n Da y 1 ( Bas eli ne), a pr e-d ose s a m ple will be c ollecte d at a n y ti me  pri or t o t he 
i ntrat y m pa nic a d mi nistrati o n a n d p ost- d ose sa m ples will be c ollecte d at 0. 5, 1, 2, 4, 8, a n d 1 2 
h o urs ( ± 1 5 mi n utes at eac h ti me p oi nt ) after i ntrat y m pa nic a d mi nistrati o n.  O n Da y 2, a 2 4- h o ur 
P K sa m ple will be o btai ne d.  O n Da y 8, a fi na l P K sa m ple will be o btai ne d at a n y ti me d uri n g 
t he st u d y visit.   
I n Part B, o n D a y 1 ( Bas eli ne), a pr e-d ose s a m ple will be c ollecte d at a n y ti me  pri or t o t he 
i ntrat y m pa nic a d mi nistrati o n a n d a p ost- d ose sa m ple will be c ollecte d at 1 h o ur ( ± 1 5 mi n utes) 
after i ntrat y m pa ni c a d mi nistrati o n.  O n Da y 8, a t hir d a n d fi nal bl o o d sa m ple will be c ollecte d at 
a n y ti me d uri n g t he st u d y visit.  
C ollect i o n, st ora ge, a n d s hi p pi n g of plas ma P K sa m ples f or gac ycli di ne  will be perf or m e d as 
o utli ne d i n t he La b orat or y Ma n u al.  E ver y atte m pt s h o ul d be ma d e t o c ollect sa m ples at t he 
pr ot oc ol- s pecifi e d ti mes.   


 
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Plas ma sa m ples will be e val uate d f or gac ycli di ne i ncl u di n g ( +) a n d (-) e na nti o mers of 
gac ycli di ne a n d (p ossi bl y its meta b olites) usi n g vali date d a nal yti cal pr o ce d ures b y a 
bi oa nal ytical la b orat or y.   
8. 7.  
S afet y E v al u ati o ns  
Safet y assess me nts i ncl u de : 
•  Vital Si g ns a n d W ei g ht M eas ure me nts  
•  Cli nical La b or at or y Test s ( He mat ol o g y, Ser u m C he mistr y , a n d Uri nal ysis)  
•  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. 7. 1.  
Vit al Si g n s a n d Wei g ht Me as ure me nts  
I n Part A, vital si g ns 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 Scree ni n g , Da y 1 ( pre- d ose), Da y 2, D a y 8, Da y 1 5, a n d Da y 2 9. 
I n Part B, vital si g ns will be c ollecte d at Scree ni n g, D a y 1 ( pre- d ose), Da y 8, Da y 1 5, Da y 2 9, 
a n d Da y 5 7.   
Vital si g ns  will be meas ure d aft er s u bjects ha v e bee n seate d f or 5 mi n utes a n d w hile s u bjects are 
i n a sitti n g positi o n.   
W ei g ht will o nl y be meas ure d at Scree n i n g ( Part A a n d B) a n d at D a y 2 9 ( Part A) or D a y 5 7 
( Part B). 
8. 7. 2.  
Cli nic al L a b or at or y Tests 
All cli nical la b orat or y tests (e x ce pt f or uri ne pre g n a nc y) will be pr o cesse d b y a Ce ntral 
La b orat or y.  
Bl o o d a n d uri ne s a m ples f or he mat ol o g y, ser u m c he mistr y, uri nal ysis, a n d pre g na nc y t ests will 
be pre pare d usi n g sta n dar d pr oce d ures.   
F or Part A, c li nical la b or at or y t esti n g will be c o m plete d at Scree ni n g, Da y  1 ( pre- d os e), D a y 8, 
a n d Da y 2 9.  I n a d diti o n, fe male s u bjects of c hil d b eari n g p ote ntial will ha ve ser u m pre g na nc y 
test at Scree ni n g  a n d a uri ne pre g na n c y test at Da y  1 ( pre- d os e) a n d Da y 2 9.  T he uri ne 
pre g na nc y t ests will be perf or me d l o call y at t he site , s o res ults are a vaila bl e t hat da y. 
F or Part B, cli nical la b o r at or y t esti n g will be c o m plete d at Scree ni n g, Da y 1 ( pre- d os e), D a y 8, 
a n d Da y 5 7.  I n a d diti o n, fe male s u bjects of c hil d b eari n g p ote ntial will ha ve ser u m pre g na nc y 
test at Scree ni n g a n d a uri ne pre g na n c y test at Da y 1 ( pre- d os e) a n d Da y 5 7.  T he uri ne 
pr e g na nc y t ests will be perf or me d l o call y at t he site,  s o res ults are a vaila bl e t hat da y. 


 
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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 : h e m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt wit h 
differe ntial , 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, mea n c or p usc ular 
he m o gl o bi n c o n ce ntrati o n, a n d platelet c o u nt. 
Ser u m c he mistr y :  al b u mi n, al kali ne p h os p hatase, ala ni ne a mi n otra nsferas e, as partate 
a mi n otra nsfer ase, ga m m a gl uta m yl -tra ns pe pti das e, bicar b o n ate, bl o o d urea nitr o ge n, 
calci u m, c hl ori de,  creati ni ne, gl uc os e, lactat e 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, a n d t otal pr otei n. 
Uri nal ysis : a p p ear a nce, c ol or, p H, s pecific gra vit y, pr otei n, gl uc os e, ket o nes, nitrite, 
le u k oc yt e esterase, ur o bili n o ge n, a n d micr osc o pic se di me nt e x a mi nati o n.  
8. 7. 3.  
T y m p a n o met r 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, pr ess ure a n d v ol u me i n t he o uter ear  ca nal, a n d f u n cti o n of t he t y m pa nic me m bra ne, 
ossicles a n d e ustac hi a n t u be.   
I n Part A, ty m p a n o gra ms will be c o m plete d i n b ot h ears at Scree ni n g a n d  i n st u d y ear o nl y at 
Da ys  8, 1 5, a n d 2 9.   
I n Part B, t y m pa n o gr a ms will be c o m plete d i n b ot h ears at Scree ni n g a n d i n st u d y ear o nl y at  
Da y 1 ( pr e- d ose), Da y 8, Da y 1 5, Da y 2 9, a n d Da y 5 7. 
8. 7. 4.  
A u di o met r y  
A u di o metric assess me nts m ust be c o n d ucte d i n acc or da nce wit h A meri ca n -S peec h -La n g ua ge -
Heari n g Ass o ciati o n G ui deli nes ( A S H A, 2 0 0 5).  E q ui p me nt cali brati o n m ust be c urre nt a n d 
d oc u me n te d.  T he a u di o metric assess me nts m ust be c o n d ucte d b y a lice ns e d or certifie d 
a u di ol o gist or a q u alifie d assista nt wit h a p pr o priat e trai ni n g u n d er t he direct s u per visi o n of a 
lice nse d or certifie d a u di ol o gist. 
A u di o gr a ms ar e c o n d uct e d at 1 0 0 0, 2 0 0 0, 4 0 0 0, 6 0 0 0, a n d 8 0 0 0 Hz 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 u cti 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 assess e d.  S u bjects weari n g h eari n g ai ds s h o ul d be i nstr u cte d n ot t o wear t h eir 
heari n g ai ds d uri n g t he a u di o gra m. 
F or Part A, a u di o metr y will be use d t o assess heari n g f u n cti o n i n b ot h ears at Scree ni n g a n d i n 
st u d y ear o nl y at Da ys  8, 1 5, a n d 2 9.   
F or Part B, a u di o metr y will be use d t o assess heari n g f u n cti o n i n b ot h ears at Scree ni n g a n d i n 
st u d y ear o nl y at Da ys 1 ( pre- d os e), 8, 1 5, 2 9, a n d 5 7.   
8. 7. 5.  
Ot osc o p y 
Ot osc o pic e x a ms will be use d t o assess t he a u dit or y ca nal, t he a p peara nce of t he t y m pa ni c 
me m bra ne, a n d t h e heali n g of t he i ntr at y m p a nic i n jecti o n site.  Prese nce a n d size of t y m p a nic 
me m bra ne perf or ati o ns will be rec or d e d.  Perf orati o ns of t he t y m pa nic me m bra ne will be 
ca pt ure d as A Es if t he perf orati o n d oes n ot res ol ve b y t h e e n d of t he st u d y or i ncreases i n size .     


 
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F or Part A, o t osc o pi c e x a mi nati o ns will be perf or me d b y t he p h ysici a n i n b ot h ears at Scree ni n g 
a n d Da y 1 ( pre - d os e) a n d i n t he st u d y ear o nl y at Da ys 8, 1 5, a n d 2 9.  
F or Part B, ot osc o pic e x a mi nati o ns will be perf or me d b y t he p h ysici a n i n b ot h ears at Scree ni n g 
a n d Da y 1 ( pre- d os e) a n d i n t he st u d y ear o nl y at Da ys 8, 1 5, 2 9, a n d 5 7.  
8. 7. 6.  
C- S S R S Assess me nt  
T he C -S S R S is a scale t hat ca pt ures t h e occ urre n ce, se verit y, a n d fre q u e nc y of s uici d e -relate d 
t h o u g hts a n d be h a 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 deati o n a n d be ha vi or b e 
i ncl u de d i n cli nical st u dies i n v ol vi n g all dr u gs a n d bi ol o gical pr o d u cts f or ne ur ol o gi cal 
i n dicati o ns.  T his is tr ue w het her or n ot a partic ul ar 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 h e C -S S R S f ulfills t his 
re q uire me nt.  T h e scal e i ncl u des s u g geste d q uesti o ns t o s olicit t he t y p e of i nf or mati o n nee d e d t o 
deter mi ne if a s uici d e -r elate d t h o u g ht or b e ha vi or occ urre d.  T he C-S S R S m ust be a d mi nistere d 
b y a p pr o priatel y tr ai ne d a n d certifi e d pers o n n el.   
F or Part A, t he C -S S R S ass ess me nt will be a d mi nistere d at  Scree ni n g, Da y  1 (pre - d os e) a n d 
Da ys  8, 1 5, a n d 2 9.  T he “Bas eli ne ” v ersi o n of t he C- S S R S will be use d at Scree ni n g .  F or all 
ot her da ys, t he “ Si nce Last Visit ” versi o n will be use d.   
F or Part B, t he C- S S R S assess me nt will be a d mi nistere d at Scree ni n g, Da y 1 ( pre - d os e), a n d 
Da ys 8, 1 5, 2 9, a n d 5 7.  T he “ Baseli ne ” versi o n will be use d at Scree ni n g.  F or all ot her d a ys, t he 
“Si nce Last Visit ” versi o n will be use d.   
A n y s u bject w h o a ns w er e d “ Yes ” t o Q uesti o n 4 or 5 re gar di n g a cti ve s uici dal i deati o n at 
Scree ni n g or Bas eli ne ( D a y 1) visits  will be e x cl u de d  per e x cl usi o n criteri a # 8 .  I n a d diti o n, 
s u bjects dee me d b y t he I n vesti gat or t o b e at si g nifica nt ris k of s uici dal be h a vi or s h o ul d be 
e x cl u de d.   A n y s u bject wit h a p ositi ve sc ore o n t he “ Baseli ne ” versi o n of t he C- S S R S or re p ort 
of ne w s uici da l i deati o n or s uici dal be ha vi or o n t h e “ Si nce Last Visit ” versi o n m ust be e val uate d 
b y a cli nicia n/ me ntal healt h pr ofessi o nal s kille d i n t he e val uati o n of s uici dal i deati o n a n d 
be ha vi or ( e. g. ps yc hiatrist, lice nse d cli nical ps yc h ol o gist) w h o will deter mi ne if it is safe f or t h e 
s u bject t o partici pate/c o nti n ue i n t he st u d y. 
If a s u bject h as a n y p ost-Da y 1  C-S S R S sc ore of 1 - 3 f or I d eati o n (i.e., a “ yes” a ns wer t o 
Q uesti o ns 1, 2, or 3) or a “ yes” r es 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 or e is hi g her t h a n t he Da y 1  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.  Si milarl y, d uri n g t he scree ni n g p eri o d, if a s u bject has a p ost-Scree ni n g sc ore of 1 -3 f or 
I d eati o n (i.e., a “ yes ” a ns wer t o Q uesti o ns 1, 2, or 3) or a “ yes” res p o nse t o t he N o n-S uici dal 
Self -I nj uri o us Be ha vi or q uesti o n a n d t he sc ore is hi g her t h a n t he Scree ni n g C -S S R S sc ore, t he n 
t his assess me nt s h o ul d be rec or de d as a n A E.  T his i nf or mati o n is re p orte d as i n dicate d i n 
Secti o n  9  ( P ossi ble A E ter ms: S uici dal pla ns, S uici dal i deati o n, S uici dal te n de nc y, S uici dal 
be ha vi or, S uici dal i nte nti o n, S uici dal de pressi o n, Acti ve s uici dal i deati o n, Passi ve s uici dal 
i deati o n, Self-i nj uri o us be ha vi or wit h o ut s uici dal i nte nt). 
If a s u bject h as a n y p ost-Da y 1  C-S S R S  sc ore of 4 or 5 f or I d eati o n (i.e., a “ yes ” a ns w er t o 
q uesti o n 4 or 5) a n d/ or a n y q uesti o ns a ns w ere d yes f or S uici dal Be ha vi or ( wit h t he e x ce pti o n of 
a “ yes” res p o nse t o t he N o n -S uici dal Self -I nj uri o us Be ha vi or q uesti o n), a n d t his was n ot 
o bser ve d at D a y 1 testi 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 


 
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( S A E).  Si milarl y, d uri n g t he scree ni n g p eri o d, if a s u bject has a p ost- Scree ni n g C -S S R S sc ore of 
4 or 5 f or I d eati o n (i.e., a “ yes” a ns wer t o q u esti o n 4 or 5) a n d/ or a n y q uesti o ns a ns were d yes f or 
S uici dal Be ha vi or ( wit h t he e x ce pti o n of a “ yes” res p o nse t o t he N o n- S uici dal Self -I nj uri o us 
Be ha vi or q uesti o n), a n d t his was n ot o bser ve d at S cree ni n g testi 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 v e 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 T I N G 
Ti mel y, acc ur ate, 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 E s a n d seri o us a d v erse e ve nts ( S A Es), wit h t he e x ce pti o n of p ost-Scree ni n g A Es a n d S A Es 
relate d t o t he C-S S R S,  t hat are re p orte d or o bser v e d d uri n g or after d osi n g wit h t he 
i n vesti gati o nal pr o d u ct will be rec or d e 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.  
A n y p ost- Scree ni n g A Es a n d S A Es relate d t o t he C-S S R S  t hat occ ur pri or t o d osi n g will be 
ca pt ure d as A Es  (see Secti o n 8. 7. 6).  I nf or mati o n t o be c ollecte d i ncl u d es d escri pti o n  of e ve nt, 
date of o nset, I n v esti gat or- s pecifi e d assess me nt of t he se verit y a n d relati o ns hi p t o i n vesti gati o nal 
pr o d uct, relati o ns hi p t o t he i ntrat y m p a nic i njecti o n, date of res ol uti o n of t he e ve nt, seri o us ness, 
a n y re q uir e d treat me nt or e val uati o ns, a n d o utc o m e.  A d vers e e ve nts res ulti n g fr o m c o nc urre nt 
ill nesses, reacti o ns t o c o n c urre nt ill nesses, reacti o ns t o c o nc urre nt me di cati o ns, or pr o gressi o n of 
disease states m ust als o b e re p ort e d.   Perf orati o ns of t he t y m pa ni c me m bra ne will be ca pt ure d as 
A Es if t he perf orati o n d o es n ot res ol ve b y t he e n d of t he st u d y or i ncreases i n size . 
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 t h e i njecti o n, it s h o ul d be rec or de d as 
a n A E.  
 
9. 1.  
A d verse E ve nt Cl assific ati o n Defi niti o ns  
A d verse E ve nt:  
A n A E is a n y u nfa v ora bl e a n d u ni nte n de d dia g n osis, s y m pt o m, si g n, s y n dr o me or disease w hic h 
occ urs d uri n g t he st u d y, ha vi n g b ee n a bs e nt at bas eli ne, or, if pres e nt at bas eli ne, a p pears t o 
w orse n. 
T his i ncl u des a n y o cc urr e nce t hat is ne w i n o ns et or a g gra v ate d i n se verit y or fre q u e nc y fr o m t he 
baseli ne c o n diti o n, i ncl u di n g a b n or mal res ults of dia g n ostic pr o ce d ures a n d/ or la b orat or y test 
a b n or malities, w hic h ar e c o nsi dere d A Es if t he y: 
•  res ult i n disc o nti n uati o n fr o m t he st u d y 
•  re q uire tr eat me nt or a n y ot her t hera p e utic i nter ve nti o n 
•  re q uire f urt her dia g n ostic e val uati o n (e x cl u di n g a re petiti o n of t he sa me pr o ce d ure t o 
c o nfir m t he a b n or m alit y) 
•  are ass o ciate d wit h cli nical s i g ns or s y m pt o ms j u d ge d b y t h e In vesti gat or t o ha ve a 
si g nifica nt cli nical i m pact 
 


 
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Seri o us A d verse E ve nt ( S A E):  
A n S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat:  
•  res ults i n deat h, 
•  is life-t hreate ni n g ( N ote: t he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of d eat h at t he ti me of t he e ve nt rat her t ha n t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha v e ca use d d eat h if it were m ore se vere.),  
•  re q uires i n-p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y, or 
•  is a c o n ge nital a n o mal y/ birt h defect. 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o p ar dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d i n t he a b o ve defi niti o n.  T hese e ve nts 
s h o ul d be c o nsi dere d s eri o us. 
9. 1. 1.  
Assess me nt of Se verit y 
T he I n vesti gat or will ass ess t he i nte nsit y of t he A E a n d rate t h e A E as mil d, m o derate, or s e vere 
usi n g t he f oll o wi n g criteria:  
Gr a de 1 – Mil d:  T hese e ve nts are easil y t olerate d, re q uire mi ni mal or n o treat me nt, a n d d o 
n ot i nterfere wit h t he s u bject’s da il y acti vities. 
Gr a de 2 – M o der at e:  T hese e ve nts ca use s uffici e nt disc o mf ort t o i nterfere wit h dail y 
acti vit y a n d/ or re q uir e a si m ple d ose of me dicati o n, e. g., a nal gesics or a nti- e metics. 
Gr a de 3 – Se v ere:  T hes e e ve nts i nca p acitate a n d pre ve nt us ual acti vi t 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 – Lif e T hre ate ni n g:  T hese e ve nts are t h ose f or w hic h t h e s u bject was at ris k of 
deat h at t he ti me of t he e ve nt rat her t h a n a n e v e nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d 
deat h if it we r e m ore se v ere. 
Gr a de 5 – D e at h:  T h e e ve nt res ulte d i n t he deat h of t he s u bject. 
C ha n ges i n t he s e verit y of a n A E s h o ul d be d o c u me nte d t o all o w f or a n assess me nt of t he 
d urati o n of t he e v e nt at eac h le vel of i nte nsit y t o b e perf or me d.  
9. 1. 2.  
Assess me nt of C a us al it y 
T he I n vesti gat or will ass ess t he relati o ns hi p or ass ociati o n of t he i n vesti gati o nal pr o d uct 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 haract erize d usi n g t he f oll o wi n g classificati o n 
a n d criteri a:  
Defi nite:  A Es  t hat, after caref ul me dical e v al uati o n, are c o nsi d ere d d efi nitel y rel ate d t o t he 
i n vesti gati o nal pr o d u ct; 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. 


 
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Pr o b a ble:  A Es t hat, after car eful me dical e val uati o n, are c o nsi d ere d wit h a hi g h de gree of 
certai nt y t o be r elate d t o t he i n vesti gati o nal pr o d u ct.  T he f oll o wi n g c haracteristics will 
a p pl y: 
•  a reas o n a ble te m p or al rel ati o ns hi p e xists bet wee n t he e ve nt a n d e x p os ure t o t he 
i n vesti gati o nal pr o d u ct, a n d 
•  t he e ve nt is a k n o w n r eacti o n t o t he i n vesti gati o nal pr o d uct 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 o cc 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 i n vesti gati o nal pr o d uct b ut ca n n ot b e 
reas o na bl y e x plai ne d b y a n alter nati ve ca use. 
P ossi ble:  A Es t hat, after caref ul me dical e v al uati o n, d o n ot meet t he criteri a f or a d efi nite or 
pr o ba ble r elati o ns hi p t o t he i n vesti gati o nal pr o d uct, b ut f or w hic h a c o n n ecti 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 aft er e x p os ure t o t he i n vesti gati o nal pr o d uct, a n d 
•  t here is a r eas o na bl e te m p oral relati o ns hi p t o t he a p plicati o n, b ut t he e ve nt is n ot a 
k n o w n reacti o n t o t he i n vesti gati o nal pr o d u ct a n d c o ul d be e x plai ne d b y a c o m m o nl y 
occ urri n g alter nati ve ca use, or  
•  i n t he a bse nce of a r eas o na ble te m p oral relati o ns hi p, t he e ve nt ca n n ot b e e x plai ne d b y 
a n alter nati ve ca use.  
N ot rel at e d:  A Es  i n t his cate g or y will ha v e eit her of t he f oll o wi n g c haracteristics: 
•  t he e ve nt d oes n ot ha v e a reas o na bl e te m p oral relati o ns hi p t o i n vesti gati o nal pr o d uct 
a d mi nistrati o n a n d/ or ca n be e x plai ne d b y a c o m m o nl y occ urri n g alter nati v e ca use.  
9. 1. 3.  
F oll o w u p of A d vers e E ve nts  
T he I n vesti gat or will f oll o w a n o n- seri o us A E u ntil res ol uti o n, sta bilizati o n, or t he E n d of St u d y 
Visit.  T he I n v esti gat or will f oll o w a n S A E (re gar dless of relati o ns hi p t o i n vesti gati o nal pr o d u ct) 
u ntil t he e ve nt res ol ves, sta bilizes, or bec o mes n o n- seri o us.  All A Es i de ntifie d o n t he last 
sc he d ule d c o ntact m ust be rec or de d o n t he A E pa ge of t he e C R F a n d 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 W orl d wi de Cli nical Trials Dr u g 
Safet y  ( dr u gsafet y @ w orl d wi de.c o m) acc or di n g t o t he re p orti n g g ui deli nes i de ntifie d i n 
Secti o n  9. 2. 2 . 
9. 2.  
M o nit ori n g of A d verse E ve nts  
9. 2. 1.  
All A d verse E ve nts  
All A Es will be a nal yze d f or saf et y.  T h ose meeti n g t he d efi niti o n of S A E m ust be re p orte d usi n g 
t he S A E F or m.  S u bjects s h o ul d v ol u ntaril y re p ort a n y A Es or re p ort A Es i n res p o nse t o ge n eral, 
n o n- directe d q u esti o ni n g (e. g., " H o w has y o ur healt h bee n si nce t he last visit?").  F or 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 n ce wit h t he g ui deli nes t hat acc o m pa n y it.  
All A Es, re gar dl ess of seri o us ness, se verit y, or pres u me d relati o ns hi p t o i n vesti gati o nal pr o d u ct, 
m ust be rec or d e d usi n g me dical ter mi n ol o g y i n t he s o urce d o c u me nt a n d o n t he e C R F.  


 
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W he n e ver p ossi ble, dia g n oses s h o ul d be gi v e n w he n si g ns a n d s y m pt o ms are d 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 n eezi 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 p er r es pirat or y i nf ecti o n").  I n v esti 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 i n vesti gati o nal t hera p y.  All meas ures re q uire d f or A E 
ma na ge me nt m ust be r ec or de d i n t he s o urce d oc u me nt a n d re p ort e d acc or di n g t o S p o ns or 
i nstr ucti o ns. 
A n y n o n- seri o us A E t hat occ urs after a d mi nistrati o n  of i n vesti gati o nal pr o d uct 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 w e 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 v e nt, d ate of o nset, dat e of 
res ol uti o n, In v esti gat or assess me nt of se verit y a n d relati o ns hi p t o i n vesti gati o nal pr o d uct ( wit h 
rati o nale), seri o us ness ( wit h rati o nale), a n y re q uire d treat me nt or e v al uati o ns, a n d o utc o me.  
T he S p o ns or ass u mes res p o nsi bilit y f or a p pr o pri ate re p orti n g of A Es t o t h e re g ulat or y 
a ut h orities.  T he S p o ns or will als o re p ort t o t he I n vesti gat ors all S A Es t hat are u nliste d i n t he 
I n v esti gat or’s Br oc h ure a n d ass ociate d wit h t he us e of t he i n vesti gati o nal pr o d uct.  T he 
I n v esti 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) i n 
acc or d a nce wit h l ocal re g ulati o ns.  
9. 2. 2.  
Seri o us A d verse E ve nts  
All S A Es occ urri n g d uri n g cli nical st u dies m ust be re p ort e d wit hi n 2 4 h o urs t o W orl d wi de 
Cli nical Trials Dr u g Safet y . 
T he ca us e of deat h of a s u bject i n a cli nical st u d y, w het her t he e ve nt is e x pecte d or ass ociate d 
wit h t he i n vesti gati o nal pr o d uct, is a n S A E. 
T he i nitial re p ort of a n S A E ma y be ma de b y e mail t o: dr u gsafet y @ w orl d wi de.c o m .  T he 
I n v esti gat or m ust pr o vi de t he mi ni mal i nf or mati o n: i.e., pr ot oc ol n u m ber, s u bject's i nitials a n d 
date of birt h, s u bject n u m ber or me dicati o n c o de n u m ber, nat ure of t he S A E a n d I n vesti gat or's 
attri b uti o n of ca usalit y . 
All oral re p orts of a n S A E m ust be c o nfir me d wit hi n 2 4 h o urs b y a writte n, m ore det aile d re p ort 
a n d si g ne d b y t he I n vesti gat or.  F or t his p ur p os e, t he S p o ns or will pr o vi de t he I n vesti gat or wit h 
t he Seri o us A d verse E ve nt F or m f or Cli nical Trials. 
All S A Es t hat ha ve n ot res ol ve d b y t he e n d of t h e st u d y, or t hat ha v e n ot res ol ve d u p o n 
disc o nti n uati o n of t he s u bject's p artici pati o n i n t he st u d y, m ust be f oll o we d u ntil eit her: 
•  t he e ve nt res ol v es, 
•  t he e ve nt sta bilizes, or 
•  t he e ve nt bec o mes n o n-s eri o us 
T he I n vesti gat or s h o ul d r e p ort a n y f oll o w- u p i nf or mati o n as it bec o mes a vaila ble.  
9. 2. 3.  
Pre g n a ncies  
Pre g n a ncies o cc urri n g aft er t he first d ose of i n vesti gati o nal pr o d u ct a n d d uri n g partici pati o n of 
t he st u d y are c o nsi dere d i m me diatel y re p orta ble e v e nts.  W hile n ot c o nsi dere d a S A E u nless a 
seri o us criteri o n is met, pre g na nci es occ urri n g i n s u bjects e nr olle d o n t he st u d y m ust be re p orte d 
a n d f oll o we d t o o utc o me.  T he I n vesti gat or s h o ul d c o m plete t he pre g n a nc y re p ort e C R F wit hi n 




 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
At a n y p oi nt, t he I n v esti gat or ma y disc o nti n ue t he s u bject’s st u d y p artici pati o n at t he discreti o n 
of t he I n vesti gat or or at t he re q uest of t h e s u bject, a n d e ns ure t h e s u bj ect recei ves  a p pr o priate 
me dical care; t he I n v esti gat or m a 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 i n vesti gati o nal pr o d u ct 
a d mi nistrati o n, a n d f urt h er f oll o w- u p of t h e st u d y at a n y ti me.   
S h o ul d a re q uest f or earl y wit h dra wal fr o m t he st u d y wit h n o f urt h er f oll o w- u p be ma de, t he 
s u bject s h o ul d be e nc o ur a 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- S t u d y/E arl y -T er 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 w al 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 o c u m e nt. 
1 0. 2. 2.  
Re pl ace me nts  
I n or der t o meet t he tar get f or 5 0 e val ua bl e s u bjects f or Part B, 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 n o n-safet y rel ate d reas o ns will be re place d u p t o a ma xi m u m of 1 0 
a d diti o nal s u bjects. 
1 1.  
S T A TI S TI C A L M E T H O D S  
1 1. 1.  
S a m ple Size  
T he sa m ple size f or Part A ( 8 s u bjects) w as select e d base d o n cli nical j u d g me nt a n d is n ot base d 
o n statistical c o nsi derati o ns.  F or Part B, t he ass u me d tr ue sta n dar d d e viati o n ( S D) of t he c h a n ge 
fr o m Bas eli ne t o Da y 5 7 i n t he T FI o verall sc ore is 1 7 p oi nts.  Base d o n t h e use of a o n e-si de d 
t w o-sa m ple t test at t he α = 0. 0 5 le vel of si g nifica n ce, a sa m ple size of 5 0 s u bjects ( 2 5 s u bjects per 
ar m) will pr o vi d e 8 0 % p o wer t o detect a mea n differe n ce b et wee n gr o u ps of 1 2 p oi nts o n t he 
T FI.  
1 1. 2.  
A n al ysis Sets  
T he i nte nt- t o-treat a nal ysis set i ncl u des all s u bjects fr o m Part A a n d all s u bjects t hat are 
ra n d o mize d i n Part B.  All efficac y a nal yses will be carrie d o ut i n t he i nte nt -t o-treat a n al ysis set.   
S u bjects will be i ncl u de d i n t he gr o u p t o w hic h t h e y were ra n d o mize d. 
T he safet y a nal ysis set i ncl u des all s u bjects w h o recei ve st u d y treat me nt.  T he safet y a nal ysis set 
will be use d f or all s u m maries of safet y.   I n s afet y a nal ys es a n d s u m mari es, s u bjects will be 
i ncl u ded i n t he treat me nt gr o u p b ase d o n t he treat me nt t hat was recei ve d.  
1 1. 3.  
S u bject De m o gr a p hics, B aseli ne Dise ase St at us, a n d Dis p ositi o n   
Descri pti ve statistics f or s u bject de m o gra p hics, b aseli ne disease stat us, a n d s u bject dis p ositi o n 
will be pr o vi de d. 


 
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1 1. 4.  
St u d y E n d p oi nts  
1 1. 4. 1.  
S af et y  E n d p oi nt s – P art A  
T he safet y  e n d p oi nts f or Part A are: 
•  Assess me nt  of treat me nt -e mer ge nt a d v erse e ve nts ( T E A Es).  
•  Cli nicall y si g nifica nt a d v erse c h a n ge fr o m Baseli n e i n a u di o metr y assess me nts, 
t y m pa n o metr y, a n d ot osc o pic e x a mi nati o ns. 
•  Cli nicall y si g nifica nt a d v erse c h a n ge fr o m Baseli n e i n cli nical la b orat or y m eas ure m e nts 
( he mat ol o g y, s er u m c h e mistr y, a n d uri nal ysis) a n d vital si g ns meas ure me nts (s yst olic a n d 
diast olic bl o o d press ure, p ulse rate). 
•  Assess me nt of s uici dalit y via t he C- S S R S.  
1 1. 4. 2.  
Pl as m a P K E n d p oi nt – P art A  
T he P K  e n d p oi nt f or Part A is: 
•  Plas ma c o nce ntr ati o ns o f gac ycli di ne (i ncl u di n g ( +) a n d (-) e n a nti o mers of gac ycli di ne 
a n d p ossi bl y its meta b olites).  
1 1. 4. 3.  
E x pl or at or y Effic ac y E n d p oi nts  – P art A  
E x pl orat or y efficac y e n d p oi nts f or Part A are:   
•  C ha n ge i n T FI o v erall sc ore fr o m Baseli ne at Da y 8, 1 5, a n d 2 9. 
•  P GI C sc or es at D a y 8, 1 5, a n d 2 9. 
1 1. 4. 4.  
S af et y E n d p oi nts – P art B  
T he  safet y e n d p oi nt s f or Part B ar e: 
•  T y pe a n d i nci de n ce of tr eat me nt -e mer ge nt a d verse e ve nts ( T E A Es).  
•  Cli nicall y si g nifica nt a d v erse c h a n ge fr o m Baseli n e i n a u di o metr y assess me nts, 
t y m pa n o metr y, a n d ot osc o pic e x a mi nati o ns. 
•  Cli nicall y si g nifica nt a d v erse c h a n ge fr o m Baseli n e i n cli nical la b orat or y m eas ure m e nts 
( he mat ol o g y, s er u m c h e mistr y, a n d uri nal ysis) a n d vital si g ns meas ure me nts (s yst olic a n d 
diast olic bl o o d press ure, p ulse rate). 
•  Assess me nt of s uic i dalit y via t he C- S S R S.  
1 1. 4. 5.  
Pl as m a P K E n d p oi nt – P art B  
T he P K e n d p oi nt f or Part B is: 
•  Plas ma c o nce ntr ati o ns of gac ycli di ne (i ncl u di n g ( +) a n d (- ) e n a nti o mers of gac ycli di ne 
a n d p ossi bl y its meta b olites).  
1 1. 4. 6.  
Effic ac y E n d p oi nts  
T he pri mar y  efficac y e n d p oi nt f or P art B is: 


 
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•  C ha n ge i n T FI o v erall sc ore fr o m Baseli ne at Da y 5 7.  
1 1. 4. 7.  
E x pl or at or y Effic ac y E n d p oi nts 
T he e x pl orat or y effi cac y e n d p oi nts f or Part B are:  
•  C ha n ge fr o m Baseli ne i n t he 7- da y a v era ge N R S rati n gs of ti n nit us a n n o ya nce at Wee ks 
2, 4, a n d 8. 
•  C ha n ge fr o m Baseli ne i n t he 7- da y a v era ge N R S rati n gs of ti n nit us l o u d ness at Wee ks 2, 
4, a n d 8. 
•  C ha n ge fr o m Baseli ne i n T FI o verall sc ore fr o m Baseli ne at Da ys 1 5 a n d 2 9. 
•  T he occ urre n ce of at least a 1 3 - p oi nt re d ucti o n i n t he o verall T FI sc ore fr o m Baseli ne at 
Da ys 1 5, 2 9, a n d 5 7. 
•  C ha n ge i n T FI s u bs cale (I ntr usi ve ness, Se nse of C o ntr ol, C o g niti ve, Slee p, A u dit or y, 
Rela x ati o n, Q ualit y of Life, E m oti o nal) sc ores fr o m Baseli ne at Da ys 1 5, 2 9, a n d 5 7. 
•  P GI C sc or e s at D a ys 8, 1 5, 2 9, a n d 5 7. 
1 1. 4. 8.  
A n al ytic Met h o ds f or Effic ac y  
F or Part B, t he ke y pri mar y  e n d p oi nt (c ha n ge fr o m Baseli ne t o D a y 5 7 i n t he T FI o v erall sc ore) 
a n d all e x pl orat or y e n d p oi nts t hat are defi ne d i n t er ms of t he c h a n ge fr o m baseli ne will be 
a nal yze d usi n g a n al ysis of c o vari a nce ( A N C O V A) m o dels wit h treat me nt gr o u p as a fact or a n d 
t he baseli ne val ue of t he c orres p o n di n g e n d p oi nt as a c o vari ate.  All pr o p orti o n e n d p oi nts will be 
a nal yze d usi n g Pears o n’s c hi-s q uare t est, pr o vi de d t hat t he mi ni m u m e x pecte d cell c o u nt is at 
least 5.  Ot her wise, Fis her’s e x act test will be use d.  C orrelati o ns bet wee n e n d p oi nts will be 
assesse d usi n g t he Pears o n a n d S pear ma n c orrelati o n c oeffi cie nts.   All statistical a nal yses will be 
c o n d ucte d usi n g o ne- si de d tests at t he α = 0. 0 5 le v el of si g nifica n ce, wit h n o a dj ust me nts f or 
m ulti plicit y.  
1 1. 5.  
S afet y  E v al u ati o ns  
 Safet y e n d p oi nts t o be e x a 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 or at or y Tests  
•  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  
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 . 


 
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1 1. 5. 1.  
A d verse E ve nts  
T he c urr e nt versi o n of M e dical Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A), as i n dicate d i n 
t he Data Ma n a ge ment Pla n, will be use d t o c o de all A Es. 
T he pri mar y a n al ysis of A Es will c o nsi der o nl y treat me nt -e mer ge nt a d v ers e e ve nts ( T E 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 i n vesti gati o nal 
pr o d uct .  S u bject i nci de n ce of T E A Es a n d S A Es will be ta b ulate d b y Preferre d T er ms  ( P Ts) a n d 
S ys te m O r ga n C lass ( S O C).  Se verit y a n d rel ati o ns hi p t o i n vesti gati o nal pr o d uct will als o be 
prese nte d.  F or s u m mar y ta bles, a s u bject w h o e x perie nces t he sa me c o de d e ve nt m ore t ha n o n ce 
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 h e hi g h est se verit y le vel.  A Es will be prese nte d 
b y des ce n di n g or d er of fr e q ue nc y i n Me d D R A S O C  a n d P T . 
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 d eat 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 ort e d i n s u bject listi n gs.   
A d verse e ve nts f or t h e C-S S R S 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 
i n vesti gati o nal pr o d u ct will be re p orte d i n data listi n gs.  F urt her d etails will be pr o vi de d i n t he 
S A P.  
1 1. 5. 2.  
Vit al Si g ns a n d L a b or at or y P ar a meters 
T he a nal ysis of vital si g ns a n d la b orat or y p ara m eters will i ncl u de descri pti ve statistics f or t he 
c ha n ge fr o m Baseli ne t o t he e n d p oi nt visit, c ha n ge fr o m B aseli ne f or eac h visit ( vital si g ns o nl y).  
W here a p pr o pri ate, a n al yses  will als o i ncl u de s hifts fr o m B as eli ne t o t he e n d p oi nt visit.  F or 
la b orat or y val u es, t he n or mal ra n ges will be use d t o deter mi ne t he cl assificati o ns.  Val ues bel o w 
t he n or mal ra n ge will be classifie d as l o w, val u es a b o ve t he n or mal ra n ge will be classifie d as 
hi g h, a n d v al ues wit hi n t he n or mal ra n ge will be classifie d as n or mal. 
1 1. 5. 3.  
Ot osc o pic E x a mi n ati o ns 
O bser vati o ns rec or d e d d uri n g t he c o n d uct of ot os c o pic e x a ms will be descri pti ve i n nat ure.  T he 
n u m ber a n d perce nt of s u bjects prese nti n g wit h eac h Ot osc o pic classifi cati o n will be pr o vi de d b y 
treat me nt gr o u p a n d st u d y visit.  W here rel e va nt, t he n u m ber a n d pr o p orti o n of s u bjects wit h 
c ha n ges i n t heir o t osc o pi c classificati o n fr o m Baseli ne t o t he e n d p oi nt visit will als o be pr o vi de d 
f or eac h treat me nt gr o u p.   
1 1. 5. 4.  
A u di o met r y Assess me nts  
Descri pti ve s u m mar y statistics f or a u di o metric ass ess me nts of air a n d b o n e c o n d ucti o n 
t hres h ol ds at eac h fre q u e nc y will be pr o vi de d b y treat me nt gr o u p a n d st u d y visit.   
All a u di o metr y assess me nts will be ta b ulate d se paratel y f or t he treate d a n d u ntreate d ear.  
1 1. 5. 5.  
T y m p a n o met r 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 h a n ges will i ncl u de b ot h t he t y pe of t y m pa n o gra m ( A, B-s mall v ol u me a n d/ or 
n or mal, B-lar ge v ol u me, or C), as well as, w h et her t he t y m pa n o gra m was j u d ge d t o b e n or mal or 
a b n or mal. 


 
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1 1. 5. 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 priat e versi o n i.e. “Baseli ne ” or 
“Si nce Last Visit ”.   
T he “ Baseli ne ” versi o n of t he C- S S R S ca pt ures b ot h s uici dal i deati o n a n d s uici de be ha vi or 
(lifeti me).  T her e ar e 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.  T here are 4 s ui ci dal be ha vi or q u esti o ns, eac h ca pt ure d as yes/ n o f or t he s u bject’s 
lifeti me.  A n a d diti o nal q uesti o n as ks if s uici dal be ha vi or is pres e nt d uri n g t he visit.  All s uici dal 
i deati o n a n d be ha vi or al v aria 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. 
T he C - S S R S versi o n use d at visits s u bse q ue nt t o t he Bas eli ne Visit will be a m o difie d versi o n of 
t he “Baseli ne ” C-S S R S.  T his “ Si nce Last Visit” versi o n uses t he sa me i n di vi d ual varia bles f or 
s uici dal i deati o n a n d be h a vi or assesse d at Baseli ne t o ca pt ure c ha n ges, if a n y, fr o m pre vi o us 
assess me nts .  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 uici dal i deati o n or 
be ha vi or si nce t h e last visit.  All s uici dal i deati o n a n d be ha vi or v aria bles will be ta b ulate d o verall 
a n d b y tr eat me nt gr o u p f or eac h st u d y visit.  All C -S S R S data will be i ncl u de d i n data listi n gs.  
1 1. 6.  
H a n dli n g of Missi n g D at a, S u bject Wit h dr a w als, a n d Tre at me nt 
F ail ures  
T he S A P will i ncl u de detail s re gar di n g t he h a n dli n g of missi n g data as well as t he i nstr ucti o ns 
f or sc ori n g t he T FI, i ncl u di n g ha n dli n g of missi n g T FI q uesti o n naire ite ms.   E ver y reas o na ble 
eff ort will be ma d e t o e n c o ura ge c o m plia nce wit h st u d y meas ure me nt met h o ds a n d st u d y 
pr oce d ur es t o mi ni mize missi n g data.  
E ver y reas o na ble eff ort will be ma de t o f oll o w s u bjects w h o wit h dra w fr o m t he st u d y f or s afet y 
e val uati o n u ntil t he date t h e y w o ul d ha ve c o m plete d partici pati o n. 
1 1. 7.  
I nteri m A n al yses 
T here are n o f or mal i nteri m a nal yses pl a n ne d.  Bli n de d re vie ws 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 d e d t o i m pact t he st u d y 
c o n d uct u nless t here ar e safet y c o n cer ns.  As s u c h, it is e x pecte d t hat t he st u d y 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 n e x pecte d safet y iss ues. 
1 2.  
I N V E S TI G A TI O N A L P R O DU C T  I N F O R M A TI O N 
1 2. 1.  
P h ysic al Descri pti o n of I n vesti g ati o n al Pr o d uct  
T he i n vesti gati o nal pr o d uct a d mi nistere d t o s u bjects will be O T O - 3 1 3 a n d place b o.  O T O - 3 1 3 is 
s u p plie d as a 1 m L st erile s ol uti o n ( 1. 6 m g/ m L [ 0. 1 6 %] gac ycli di ne i n me di u m -c hai n 
tri gl yceri des) i n a vi al.  Place b o is pr o vi de d as 1 m L of sterile 1 0 0 % me di u m- c hai n tri gl yceri d e s 
s ol uti o n i n a vial.  T he vials  are pr o vi d e d as kits, a n d all kits m ust be st ore d at 2- 8° C u ntil use. 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
1 2. 2.  
Directi o ns f or Use  
O T O - 3 1 3 a n d place b o s yri n ges will  be pre pare d  i n a clea n, s ec ure l ocati o n at r o o m te m perat ure.  
Please ref er t o t he P har m ac y Ma n ual f or detaile d i n vesti gati o nal pr o d u ct pre parati o n i nstr ucti o ns. 
1 2. 3.  
P ac k a gi n g a n d L a beli n g  
1 2. 3. 1.  
P ac k a gi n g 
All i n vesti gati o nal pr o d u ct kits will be la bele d wit h i nf or mati o n t hat will meet t he a p plica bl e 
re g ulat or y r e q uire me nts.  
1 2. 3. 2.  
L a bels a n d L a beli n g I nstr ucti o ns  
A la bel will be affi x e d t o eac h kit b o x i n dicati n g kit n u m ber a n d st ora ge i nstr ucti o ns.  A la bel 
will be affi x e d t o t he O T O - 3 1 3 a n d place b o vials i n dicati n g c o nt e nts a n d st ora ge i nstr ucti o ns.   
1 2. 4.  
M a n a ge me nt of Cli nic al S u p plies  
T he cli nical s u p plies will be ma na ge d b y We b E Z ra n d o mizati o n s yst e m.  We b E Z  will create 
s hi p me nt re q uests t hat will be ge n erat e d base d o n i n ve nt or y t hres h ol ds t ha t are set f or eac h site.  
A s hi p me nt re q uest will be ge ner ate d b y We b E Z  a n d se nt t o t he cli nical s u p pl y ve n d or ( Al mac).  
U p o n s hi p me nt a n d recei pt of t he cli nical st u d y m aterial, t he site pers o n nel will ac k n o wle d ge t he 
s hi p me nt a n d i de ntif y a n y da m a ge d, missi n g, or u n usa ble kits s o t he y will n ot be dis pe nse d. 
1 2. 4. 1.  
St or a ge of Kits 
All kits will be st ore d at 2- 8° C, wit h all o wa ble te m perat ure e x c ursi o ns u p t o 2 5° C f or u p t o 7 2 
h o urs.  All te m perat ur e e x c ursi o ns of t he i n vesti gati o nal pr o d uct m ust be d oc u me nte d i n t he 
i n vesti gati o nal pr o d u ct acc o u nta bilit y l o g.   A n y e x c ursi o ns wit hi n t he all o wa ble te m perat ure 
ra n ge a n d c o n diti o ns s h o ul d be d oc u me nte d, b ut t he i n vesti gati o nal pr o d uct is still acce pta ble f or 
use a n d dis pe nsi n g t o s u bjects.  If an y e x c ursi o ns are o utsi de of t hese c o n diti o ns, t he 
i n vesti gati o nal pr o d u ct s h o ul d n ot be use d t o treat s u bjects.  If t his occ urs, t he i n di vi d ual 
pre pari n g t he i n v esti gati o nal pr o d uct s h o ul d i m me diatel y q u ara 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 We b E Z t o re m o ve it fr o m i n ve nt or y. 
1 2. 5.  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y  
It is t he r es p o nsi bilit y of t he In v esti gat or t o e ns ure t hat all i n vesti gati o nal pr o d uct recei ve 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 h e 
dr u g acc o u nt a bilit y f or m mai ntai ne d i n t he P har mac y Ma n ual.  T h e pers o n res p o nsi ble f or 
pre pari n g t he s yri n ge c o ntai n i ng t he i n vesti gati o nal pr o d uct will  be i nstr ucte d t o ret ur n all 
ori gi nal c o nt ai ners, w h et her e m pt y or c o nt ai ni n g i n vesti gati o nal pr o d u ct, w he n i nstr ucte d b y t he 
st u d y m o nit or t o ret ur n.  I n v esti gati o nal pr o d uct 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.  I n vesti gati o nal pr o d uct acc o u nt abilit y 
will be verifie d b y t he  st u d y m o nit or d uri n g t he st u d y.  I n v esti gati o nal pr o d uct will be st ore d i n a 
li mite d access ar ea or i n a l oc ke d r efri gerat or u n d er 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 i n v esti gati o nal pr o d uct t o a n y p ers o n ot her t ha n s u b-
I n v esti 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.  I n vesti gati o nal pr o d u ct 


 
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ma y n ot be rela b ele d or r eassi g n e d f or us e b y ot her s u bjects e x ce 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. 
T he I n vesti gat or will ret ai n a n d st ore all ori gi nal c o ntai ners ret ur n e d b y t he cli nical site staff 
u ntil t hese c o ntai ners are i n ve nt orie d b y t h e st u d y m o nit or.  U nless ot her wise i nstr ucte d b y t he 
S p o ns or, t he I n v esti gat or a grees at t he e n d of t h e st u d y t o ret ur n all ori gi n al c o ntai ners, w h et her 
e m pt y or c o n tai ni n g i n v esti gati o nal pr o d uct, 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 i n v esti gati o nal pr o d u ct 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 osal of ori gi n al c o ntai ners e m pt y or f ull of ret ur ne d or 
u n use d i n vesti gati o nal pr o d uct .  A p pr o priate d o c u me ntati o n will be mai ntaine d.  Per missi o n ma y 
be gra nte d f or l ocal dis p osal, 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 r es p o nsi ble f or e ns uri n g t hat t he cli nical st u d y is p erf or me d i n acc or d a nce 
wit h t he pr ot oc ol, t he Declarati o n of H elsi n ki, as well as wit h t he N ote f or G ui da nce o n G o o d 
Cli nical Practice (I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire m e nts.  T hese d oc u me nts set 
f ort h t hat t he i nf or me d c o nse nt of t he s u bjects is a n esse ntial prec o n diti o n f or partici pati o n i n t he 
cli nical st u d y.  
1 3. 2.  
I nstit uti o n al Re vie w B o ar d (I R B)  
T his st u d y will be u n dert a ke n o nl y after f ull a p pr o val of t he pr ot oc ol a n d a d de n da has bee n 
o btai ne d fr o m a d esi g n ate d I R B  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 m ust be i nf or m e 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 st u d y a n d its pr o gress will be s u b mitte d t o t he I R B b y t he 
In v esti gat or at i nter v als sti p ulate d i n t heir g ui deli n es.  
1 3. 3.  
I nf or me d C o nse nt 
Eac h s u bject m ust gi ve writte n c o nse nt a n d si g n ot her l ocall y re q uire d d oc u me nts after t he n at ure 
of t he st u d y h as bee n f ull y e x plai ne d.  T he c o nse nt f or m 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 c o m plete 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 o nse nt 
f or m t hat is used 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.  T he 
i nf or me d c o nse nt is i n acc or da nce wit h t he Declarati o n of Helsi n ki, c urre nt I nter nati o nal 
C o nfere nce f or Har m o nis ati o n (I C H) G o o d Cli nical Practice ( G C P) g ui d eli 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  a n d met h o ds of t he st u d y.  T h e 
I n v esti gat or m ust als o e x plai n p ote ntial disc o mf ort, be nefits , a n d ris ks of st u d y partici pati o n .  
S u bjects wi ll be i nf or me d t hat t he y are free n ot t o partici pate i n t he st u d y 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 h e y will be t ol d w hic h alter nati ve treat me nts are 
a vaila ble if t he y d ecli ne t o partici pate i n t he st u d y.  S u bjects will als o be t ol d t hat decli ni n g t o 


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
partici pate i n t he st u d y  will n ot prej u dice f ut ure treat me nt.  Fi nall y, t he y will be t ol d t hat t heir 
rec or ds ma y b e e x a mi ne d b y c o m p ete 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 strictly 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 
st u d y, 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 n at ure of t h e 
i nf or me d c o nse nt for m .  If a s u bject is u na bl e 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 m e d c o nse nt disc ussi o n.  T he si g nat ure of t he i m partial wit ness o n t he 
i nf or me d c o nse nt for m will certif y t he s u bj ect's c o nse nt.  T he s u bjec t s h o ul d recei v e a si g ne d a n d 
date d c o p y of t he i nf or m e 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 v esti 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 a p pr o v al, e x ce pt w here necessar y t o eli mi nate 
i m me diate hazar ds t o t he s u bjects or w he n t he c ha n ge(s) i n v ol ves o nl y l o gistical or 
a d mi nistrati ve as pects of t he st u d y ( e. g., c ha n ge i n m o nit or, c ha n ge of tel e p h o ne n u m ber).  
Res p o nsi bilities f or re p orti n g pr ot oc ol a me n d m e nts t o a n y Re g ulat or y A ut h orit y (if a p plica ble) 
a n d/ or I R B are f urt her d escri 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 ur e fr o m pr o ce d ures defi ne d i n t he pr ot oc ol, t he In v esti gat or or 
ot her p h ys i cia n i n atte n d a nce will c o ntact t he site ma na ger, M e dical M o nit or, or ot her 
a p pr o priate S p o ns or re pr ese ntati ve b y e mail or tel e p h o ne ( see S p o ns or C o ntact I nf or mati o n 
pa ge) .  If p ossi ble, t his c o ntact will be ma de bef ore i m ple me nti n g a n y d e part ure fr o m pr ot o c 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 t o disc uss t he sit uati o n 
a n d a gree o n a n a p pr o pri ate c o urs e of acti o n.  T he e C R F a n d s o urce d oc u m e nt will descri be a n y 
de viati o ns fr o m pr oce d ur es defi ne d i n t he pr ot o c ol a n d t he circ u msta n ces re q uiri n g s uc h 
de viati o ns. 
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 i n vesti gati o nal pr o d uct.  I n s o me cases, 
t here ma y be n e w d oc u m e 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 h e st u d y.   
Esse ntial d oc u me nts i ncl u de, b ut are n ot li 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 pr ot oc ol a p pr o val a n d ass o ciate 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 pres e 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 k a 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 v esti gat or 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 or t t he data c ollecte d fr o m eac h s u bject.  All st u d y 
d oc u me nts 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 (I C H E 6) a n d t he 


 
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a p plica ble r e g ulat or y r e q uire me nt(s)  will als o be c ollecte d fr o m eac h s u bject .  T he I n vesti gat or 
or i nstit utio n will ta ke meas ures t o pr e ve nt acci de ntal or pre mat ure destr ucti o n of t hese 
d oc u me nts.  Esse ntial d oc u me nts m ust be retai ne d u ntil at least t w o ( 2) years after t h e 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 after at least t w o ( 2) years h a ve el a 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 n e 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 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 I n vesti gat or retires, rel ocates, or f or ot her reas o ns wit h dra ws fr o m t he 
res p o nsi bilit y of kee pi n g t he st u d y r ec or ds, c ust o d y m ust be tra nsferre d t o a q ualifie d pers o n 
w h o will a cce 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 d dress , 
a n d q ualificati o ns of t he ne w c ust o dia n. 
1 4. 4.  
Electr o nic C ase Re p ort F or m (e C R F) 
e C R Fs will be c o m plete d b y site staff f or eac h s u bject.  Access f or d ata e ntr y will be pr o vi de d t o 
desi g nat e d site staff.  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 h e e C R Fs s h o ul d be c o m plete d b y I n v esti gat or site staff at t he ti me of t he s u bject's visit, wit h 
t he e x ce pti o n of res ults of tests perf or m e d o utsi de t he I n v esti gat or's offi ce, s o t hat t he e C R Fs 
al wa ys reflect t he lat est o bser vati o ns o n t he s u bjects partici pati n g i n t he st u d y.  
As t he site staff  e nters data, discre pa n cies will be a ut o maticall y ge nerate d wit hi n t he Electr o nic 
Data Ca pt ure ( E D C) s yst e m f or t he site staff t o res ol ve i m me diatel y.  I n a d diti o n, as a res ult of 
data re vie w b y t he S p o ns or or desi g nee, ma n ual q ueries will be rais e d electr o nicall y i n t he E D C 
s yste m.  Q ueries ma y als o be raise d as a res ult of s o urce dat a verifi cati o n b y t he cli nical m o nit or.  
All c orrecti o ns will be ma de wit hi n t he E D C s yst e m b y t he I n v esti gat or or ot her a ut h orize d st u d y 
site pers o n nel.  T he cli nical m o nit or a n d data ma n a ge me nt tea ms will e ns ure a p pr o pri ate 
res ol uti o n of q ueries.  T h e I n vesti gat or m ust a ut h orize c ha n ges t o t he safet y a n d effi cac y d ata  
rec or d e d i n t he E D C s yste m.  
1 4. 5.  
Ter mi n ati o n  
Cl os ure of a ce nter  or st u d y ter mi nati o n ca n be i nitiate d at a n y ti me eit her b y t he S p o ns or or b y 
t he In v esti gat or, pr o vi de d t hat reas o na bl e ca us e a n d s ufficie nt n otice are 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 k e n b y t h e Sp 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 st u d y 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 st u d y 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 o ce d ures, or 
G C P g ui deli nes 
•  Safet y c o ncer ns  
•  I n a de q uat e recr uitme 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 ni cal st u d y c o n d u cte d wi t h O T O- 3 1 3.   
T he me dical pers o n nel of t he S p o ns or a n d cli nical researc h or ga nizati o n ( C R O ) 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 verifi e d i n t he E D C  s yste m 
(Secti o n  1 4. 4 ).  All A Es c o de d t o t he S yste m Or ga n Class of ear a n d la b yri nt h dis or ders i n t he 
Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) will be re vie we d  f or si g nifi ca nt safet y 
tre n ds at least e v er y ot her m o nt h .  Reas o ns f or st u d y disc o nti n uati o n will be re vie w e d t o 
deter mi ne if a n y tr e n ds i n st u d y disc o nti n uati o n, s uc h as t he occ urre nce of s pecific S A Es or 
w orse ni n g of s y m pt o ms, are i de ntifie d.  
I n v esti gat ors ar e i nstr uct e 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 ).  Al l S A Es will be re vie we d b y t he Sp o ns or a n d C R O me dical pers o n n el 
wit hi n 1 - 2 da ys after recei pt w het her or n ot t he e v e nt was c o nsi dere d ass o ciate d wit h 
i n vesti gati o nal pr o d u ct.  T he S p o ns or ass u mes res p o nsi bilit y f or a p pr o pri ate re p orti n g t o t he 
re g ulator y a ut h orities.  T he I n vesti gat or ass u mes res p o nsi bilit y f or re p orti n g e v e nts t o t he I R B i n 
acc or d a nce wit h t he I R B  re q uire me nts, res pecti vel y.  All S A Es a n d n o n-s eri o us A Es will be  
re vie we d b y t h e me dical pers o n nel of t he C R O a n d S p o ns or d uri n g t he c o n d uct of t he st u d y. 
If, d uri n g o n g oi n g data r e vie w, t he S p o ns or deter mi nes t h at O T O- 3 1 3 pres e nts a si g nifi ca 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 r e g ulat or y a ut h orities, I n v esti gat ors a n d I R Bs as a p pr o priate. 
1 4. 6. 1.  
S af et y Re vie w C o m mitt ee  
T he decisi o n t o pr ocee d wit h i nitiati o n of d osi n g i n Part B will be ma de b y a Safet y Re vie w 
C o m mittee.  T he Safet y Re vie w C o m mittee will i ncl u de at a mi ni m u m t he Me dical M o nit or, t he 
I n v esti gat or at t he P hase 1 researc h u nit, a n d t he Cli nical Re prese ntati ve of t he S p o ns or.  Safet y 
data, i ncl u di n g a d vers e e ve nts, cli nical safet y la b orat or y meas ure me nts, a u di o metr y, ot osc o p y, 
t y m pa n o metr y, a n d C- S S R S data t hr o u g h D a y 8, will be e val uate d a n d t he decisi o n t o pr ocee d 
will be base d o n t he cli ni cal si g nifi ca nce of a n y a d verse e v e nts or s us pect e d i n vesti gati o nal 
pr o d uct-rel ate d fi n di n gs.  I nitiall y, all data will be re vie we d i n a bli n de d ma n ner wit h re gar d t o 
treat me nt assi g n me nt.  T he treat me nt assi g n me nt f or a n i n di vi dual s u bject ma y b e u n bli n de d, if 
dee me d necessar y t o e na ble me dical care or st u d y decisi o n -ma ki n g b y t he Safet y R e vie w 
C o m mittee.  
1 4. 7.  
M o nit ori n g  
T he S p o ns or or its re pr ese ntati ves will perf or m o n- site m o nit ori n g visits as fre q ue ntl y as 
necessar y base d o n site acti vit y t o re vie w pr ot oc ol c o m plia nce, c o m p are e C R Fs wit h i n di vi d ual 
s u bject’s me dical r ec or ds a n d cli nic c harts, a n d e ns ure t hat t he st u d y is b ei n g c o n d u cte d 
acc or di n g t o perti ne nt re g ulat or y re q uire m e nts.  T he dates of t he visits will be rec or de d b y t he 
m o nit or i n a st u d y ce nt er visit l o g t o be ke pt at t he site.  M o nit ori n g visit s will be ma de 
acc or di n g t o t he Cli nical M o nit ori n g Pla n.   At all visits, t he m o nit or will c o m pare t he dat a 
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 p erf 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.  


 
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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 ur es, a d here n ce t o pr ot oc ol pr oce d ures, a d e q uate re p orti n g a n d f oll o w- u p of A Es, 
a d mi nistrati o n of c o nc o mita nt me dicati o n, dr u g recei pt/ dis pe nsi n g/ret ur n rec or ds, a n d 
i n vesti gati o nal pr o d u ct 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 o c u me nts 
will be re vie we d wit h t he  I n v esti 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 o c u me nts will be disc usse d wit h t he I n vesti gat or.  T h e S p o ns or e x pects t hat, d uri n g 
m o nit ori n g visits, t he I n v esti gat or (a n d as a p pr o pri ate, t he st u d y c o or di nat or) will be a va ila ble, 
t he s o urce d o c 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 ur e t he acc urac y a n d relia bilit y of data i ncl u d e t he selecti o n of q ualifi e d 
I n v esti gat ors a n d a p pr o priate st u d y ce nters, re vie w of pr ot oc ol pr oce d ures wit h t he I n v esti gat or 
a n d ass ociate d p ers o n nel pri or t o st u d y i nitiati o n, a n d per i o dic m o nit ori n g visits b y t he Sp o ns o r 
or its re prese nt ati ves.  e C R Fs  will be re vie w e d f or acc urac y a n d c o m plete n ess 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 nt ati ves d uri n g a n d after o n- site m o nit ori n g visits, a n d a n y 
discre pa n cies will be res ol ve d wit h t he In v esti gat or or desi g nees, as a p pr o priate, a n d d oc u m e 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 h e S p o ns or's Q u alit y Ass ura nce de part me nt ma y visit t he site t o carr y o ut a n 
a u dit of t he st u d y i n c o m plia nce wit h re g ulat or y g ui deli nes a n d c o m pa n y p olic y.  S uc h a u dits 
will re q uire access t o all  st u d y rec or ds, i ncl u di n g s o urce d oc u m e nts, f or i ns pecti o n a n d 
c o m paris o n wit h t he e C R Fs. S u bject pri vac y m ust, h o we ver, b e res p ecte d.  S ufficie nt pri or 
n otice will be pr o vi de d t o all o w t he I n vesti gat or t o pre pare pr o perl y f or t h e a u dit. 
Si milar a u diti n g p r 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 In vesti gat or s h o ul d 
i m me diatel y n otif y t he Sp o ns or if t he y ha ve b ee n c o ntacte d b y a re g ulat or y a ge nc y c o ncer ni n g 
a n u pc o mi n g i ns pecti o n. 
1 4. 1 0.  
P u blic ati o n P olic y  
P u blicati o n of st u d y res ults  is a d dresse d i n t he cli nical trial a gree me nt.  


 
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Ot o n o m y, I n c. 3 1 3 -2 0 1 9 0 1 Pr ot oc ol V 3 . 0: 15  M A Y  2 0 1 9  
1 5.  
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