A Phase I/IIa, Randomized, Double-Blind, Placebo-Controlled, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Unilateral Intratympanic PIPE-505 in Subjects With Sensorineural Hearing Loss Associated With Speech-in-Noise Impairment
Phase: PHASE1
Conditions: Sensorineural Hearing Loss
Sponsor: Contineum Therapeutics

 
 
 
 
 
 
Pr ot o c ol:  
 
A P h a s e I/II a , R a n d o miz e d, D o u bl e-Bli n d, Pl a c e b o -C o ntr oll e d, S af et y, P h ar m a c o ki n eti c, 
a n d Pr eli mi n ar y E Bi c a cy St u d y of U nil at er al I ntr a ty m p a ni c PI P E -5 0 5 i n S u bj e ct s wit h 
S e n s ori n e ur al H e ari n g L o s s A s s o ci at e d wit h  S p e e c h -i n-N oi s e I m p air m e nt  
 
 
A m e n d m e nt 3 , V er si o n 4 . 0 (1 8 S e pt e m b er  2 0 2 0)  
 
I N D #: 1 4 4 4 1 8  
 

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3  of 7 3  
I N V E S TI G A T O R SI G N A T U R E O F A G R E E M E N T P A G E  
Pr ot oc ol Title:  
A P hase I/IIa, Ra n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, Safet y, 
P har mac o ki n eti c, a n d 
Preli mi nar y 
Effic ac y 
St u d y 
of 
U nilateral 
I ntraty m p a nic PI P E -5 0 5 i n S u bje cts wit h Se ns ori n e ural Heari n g L oss 
Ass ociate d wit h S pee c h -i n-N oise I m pair me nt  
Pr ot oc ol N u m ber:  P TI -5 0 5 -1 0 1  
Pr ot oc ol 
Ve rsi o n 
a n d D ate:  
Versi o n 4 . 0 (1 8  Se pte m ber  2 0 2 0 ) 
I ha ve rea d t his pr ot oc ol i n its e ntiret y. 
I u n dersta n d t h at t h e i nf or m ati o n i n t his pr ot oc ol is c o nfi de nti al a n d s h o ul d n ot be discl ose d, ot her 
t ha n t o t h ose directl y i n v ol v e d i n t he e x ec uti o n or t he scie ntific/ et hi cal re vie w of t he st u d y, wit h o ut 
writte n a ut h ori zati o n  fr o m t he S p o ns or . It is, h o we ver, per missi ble t o pr o vi d e i nf or mati o n 
c o ntai n e d herei n t o a s u bje ct i n or d er t o o bt ai n t h eir c o nse nt t o partici pat e.  
I a gree t o c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its re q uire me nts, s u bject 
t o et hic al a n d safet y c o nsi derati ons a n d g ui deli nes, a n d t o c o n d uct t h e st u d y i n acc or d a nce wit h 
I nter nati o nal C o nfere nc e o n Har m o ni sati o n  G ui deli nes o n G o o d Cli ni cal Practice a n d wit h t he 
a p plic a ble re g ul at or y r e q uire me nts.  I will i nf or m all w h o assist me i n t he c o n d uct of t his st u d y of 
their res p o nsi biliti es a n d o bli gati o ns. F urt her m or e, I u n dersta n d t hat t he S p o ns or a n d t he 
I nstit uti o n al Re vie w B oar d/ Et hics C o m mitt ee (I R B/IE C) m ust a p pr o ve t h e pr ot o c ol a n d a n y 
c ha n ges t o t h e pr ot o c ol i n writi n g bef or e i m ple m e ntati o n, u nless a d e viati o n i s re q uire d t o 
eli mi nat e a n i m me diat e safet y hazar d t o a s u bj ect. I n s uc h cases, I will n otif y t he S p o ns or a n d t h e 
I R B/IE C as s o o n as p ossi ble.  
I u n dersta n d t hat fail ure t o c o m pl y wit h t h e re q uire me nts of t he pr ot oc ol m a y l ea d t o m y 
partici pati o n as a n I n ve sti gat or f or t his st u d y t o be t er mi nat e d. 
 
Pri nci p al I n vesti g at or N a me:  
 
I nstit uti o n: 
 
 
Si g n at ure:  
 
 
 
D ate:  
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4  of 7 3  
E M E R G E N C Y C O N T A C T I N F O R M A TI O N  
I n t he e ve nt of a Seri o us A d verse E ve nt ( S A E), t he I n vesti gat or m ust fa x or e -mail t he Seri o us 
A d verse E ve nt F or m  wit hi n 1  b usi ness da y  t o t h e f oll o wi n g:  
T a ble 1 : S A E a n d  Pre g n a nc y Re p orti n g C o nt acts  
 
 
 
 
F or pr ot oc ol or safet y  relat e d iss ues ot her t ha n S A E re p orti n g  d uri n g n or m al b usi ness h o urs  (8 
a m –  5 p m E T ), c o ntact t h e Me di cal M o nit or : 
 
 
 
  
 
F or pr ot oc ol  - or safet y -relate d iss ues o utsi de of n or m al b usi ness h o urs  ( 5 p m –  8 a m E T ), t he 
I n vesti gat or m ust c o nt act t he f oll o wi n g: 
  
  
 
 
 
 
 
 
 
 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5  of 7 3  
T A B L E O F C O N T E N T S  
S P O N S O R P R O T O C O L A P P R O V A L P A G E  ........................................................................... 2  
I N V E S TI G A T O R SI G N A T U R E O F A G R E E M E N T P A G E .................................................... 3  
E M E R G E N C Y C O N T A C T I N F O R M A TI O N  ........................................................................... 4  
T A B L E O F C O N T E N T S  ............................................................................................................ 5  
LI S T O F T A B L E S  .................................................................................................................... 1 0  
LI S T O F FI G U R E S  .................................................................................................................. 1 0  
A B B R E VI A TI O N S  .................................................................................................................. 1 1  
S T U D Y S Y N O P SI S  ................................................................................................................. 1 4  
S C H E D U L E O F E V E N T S  ....................................................................................................... 1 8  
1.  
I N T R O D U C TI O N ........................................................................................................ 2 0  
1. 1  
Bac k gr o u n d  ................................................................................................................... 2 0  
1. 2  
T he C o n diti o n Bac k gr o u n d a n d C urre nt Treat me nt  ..................................................... 2 1  
1. 3  
Pr o d uct Bac k gr o u n d  ..................................................................................................... 2 2  
1. 3. 1  Precli ni cal I nf or mati o n  .......................................................................................... 2 3  
1. 4  
Rati o nale f or t h e St u d y  ................................................................................................. 2 5  
2.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ................................................................ 2 6  
2. 1  
St u d y O bjecti v es  ........................................................................................................... 2 6  
2. 1. 1  Pri mar y O bjecti ves  ................................................................................................. 2 6  
2. 1. 2  Sec o n dar y O bjecti ves  ............................................................................................. 2 6  
2. 1. 3  E x pl orat or y O bj ecti ves  .......................................................................................... 2 6  
2. 2  
E n d p oi nts  ...................................................................................................................... 2 6  
2. 2. 1  Pri mar y E n d p oi nt  ................................................................................................... 2 6  
2. 2. 2  Sec o n dar y E n d p oi nts .............................................................................................. 2 6  
2. 2. 3  E x pl orat or y E n d p oi nts  ........................................................................................... 2 6  
3.  
S T U D Y D E SI G N A N D D E S C RI P TI O N  ..................................................................... 2 7  
3. 1  
St u d y Desi g n  ................................................................................................................. 2 7  
3. 2  
Se nti nel D osi n g Pla n ..................................................................................................... 2 8  
3. 3  
Data M o nit ori n g C o m mitte e  ......................................................................................... 2 8  
3. 4  
St u d y S us pe nsi o n R ules  ................................................................................................ 2 8  
3. 5  
N u m ber a n d T y pe of S u bj ects  ...................................................................................... 2 9  
3. 6  
Sites a n d Re gi o ns  .......................................................................................................... 2 9  
4.  
S T U D Y P O P U L A TI O N  ............................................................................................... 3 0  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6  of 7 3  
4. 1  
I ncl usi o n Crit eria .......................................................................................................... 3 0  
4. 2  
E xcl usi o n Criteri a  ......................................................................................................... 3 0  
4. 3  
Re pr o d ucti v e P ote ntial a n d Pre g na nc y A v oi da n ce ....................................................... 3 2  
4. 4  
Restricti o ns  ................................................................................................................... 3 3  
4. 5  
Wit h dra wal of S u bjects ................................................................................................. 3 3  
4. 5. 1  Reas o ns f or S u bject Disc o nti n uati o n  ..................................................................... 3 3  
4. 6  
Earl y T er mi n ati o n of St u d y/ Cl os ure of Sit e  ................................................................. 3 4  
5.  
P RI O R A N D C O N C O MI T A N T T R E A T M E N T  ......................................................... 3 5  
5. 1  
Pri or Treat me nt  ............................................................................................................. 3 5  
5. 2  
C o nc o mit a nt Tr eat me nt  ................................................................................................ 3 5  
6.  
I N V E S TI G A TI O N A L P R O D U C T .............................................................................. 3 6  
6. 1  
Descri pti o n of I n vesti gati o nal Pr o d uct  ......................................................................... 3 6  
6. 2  
Ra n d o miz ati o n C o d e Ge nerati o n a n d St ora g e  .............................................................. 3 6  
6. 3  
A d mi nistrati o n of I n vesti g ati o n al Pr o d uct(s)  ............................................................... 3 7  
6. 3. 1  I n de x Ear Sel ecti o n a n d D osi n g Pr oce d ure............................................................ 3 7  
6. 3. 2  Bli n di n g t h e Tre at m e nt Assi g n me nt  ...................................................................... 3 8  
6. 3. 3  All ocati o n of S u bjects t o Tre at me nt  ...................................................................... 3 9  
6. 3. 4  U n bli n di n g t he Treat me nt Assi g n me nt  .................................................................. 3 9  
6. 4  
La beli n g, Pac ka gi n g, St ora ge, a n d Ha n dli n g ................................................................ 4 0  
6. 4. 1  La beli n g  ................................................................................................................. 4 0  
6. 4. 2  Pac ka gi n g  ............................................................................................................... 4 0  
6. 4. 3  St ora ge  ................................................................................................................... 4 0  
6. 4. 4  Ha n dli n g  ................................................................................................................. 4 1  
6. 5  
I n vesti gati o nal Pr o d uct Q ualit y C o m pl ai nts ................................................................. 4 1  
6. 6  
Dr u g A cc o u nta bilit y  ..................................................................................................... 4 1  
7.  
S T U D Y P L A N .............................................................................................................. 4 3  
7. 1  
St u d y Sc he d ule  ............................................................................................................. 4 3  
7. 1. 1  Scree ni n g Peri o d  .................................................................................................... 4 3  
7. 1. 1. 1  
S u bject I D N u m ber Assi g n me nt & Tra c ki n g  .............................................. 4 3  
7. 1. 1. 2  
Scree n Fail ur es  ............................................................................................ 4 3  
7. 1. 2  Ra n d o miz ati o n a n d D ose A d mi nistrati o n Visit ( Da y 0)  ........................................ 4 4  
7. 1. 2. 1  
I nteracti ve V oi ce/ W e b Res p o nse S yste m f or S u bje ct Trac ki n g/ Data 
C ollecti o n ..................................................................................................... 4 4  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 7  of 7 3  
7. 1. 3  F oll o w -u p Peri o d ( D a ys 1 -9 0)  ............................................................................... 4 4  
7. 1. 4  Earl y T er mi n ati o n  .................................................................................................. 4 4  
7. 1. 5  A d diti o nal C are of S u bje cts After t he St u d y  ......................................................... 4 4  
7. 2  
St u d y E val uati o ns a n d Pr oce d ur es ................................................................................ 4 5  
7. 2. 1  I nf or me d C o nse nt ................................................................................................... 4 5  
7. 2. 2  De m o gra p hics, Me di cal Hist or y, a n d Me dicati o n Hist or y  .................................... 4 5  
7. 2. 3  P h ysical E xa mi nati o n  ............................................................................................. 4 5  
7. 2. 4  Ot ol o gical E xa mi nati o n  ......................................................................................... 4 5  
7. 2. 5  Vital Si g ns  .............................................................................................................. 4 6  
7. 2. 6  E C G Pr oce d ur e  ...................................................................................................... 4 6  
7. 2. 7  Pre g na nc y Testi n g  .................................................................................................. 4 6  
7. 2. 8  M o ntreal C o g niti ve Assess me nt ( M o C A) .............................................................. 4 6  
7. 2. 9  La b orat or y a n d A u dit or y E val uati o ns  .................................................................... 4 7  
7. 2. 9. 1  
Cli nic al Safet y La b or at or y Assess me nts  ..................................................... 4 7  
7. 2. 9. 2  
Bl o o d Sa m pli n g f or P K A nal ysis  ................................................................ 4 8  
7. 2. 1 0  T y m pa n o m etr y  ....................................................................................................... 4 8  
7. 2. 1 1  Mi d dle Ear M uscl e Refl e x ( M E M R)  ..................................................................... 4 8  
7. 2. 1 2  S peec h Rec o g niti o n T hres h ol d ( S R T)  ................................................................... 4 9  
7. 2. 1 3  W or d Rec o g niti o n Sc ore ( W R S) ............................................................................ 4 9  
7. 2. 1 4  Ti n nit us Re acti o n Q uesti o n naire ( T R Q)  ................................................................ 4 9  
7. 2. 1 5  S peec h, S pati al, a n d Q ualities of Heari n g Scale ( S S Q)  ......................................... 4 9  
7. 2. 1 6  Q uic k SI N -E P  ......................................................................................................... 4 9  
7. 2. 1 7  W or ds -i n-N oise ( WI N)  .......................................................................................... 5 0  
7. 2. 1 8  S o u n d Fiel d S pe ec h T est: Q uic k SI N -S F  ................................................................ 5 0  
7. 2. 1 9  P ure T o ne A u di o metr y  ........................................................................................... 5 0  
7. 2. 2 0  Dist orti o n Pr o d uct Ot oa c o ustic E missi o n ( D P O A E)  ............................................. 5 1  
7. 2. 2 1  A u dit or y Brai nste m Res p o nse ( A B R) .................................................................... 5 1  
7. 2. 2 2  Electr oc oc hle o gra p h y ( E C o c h G)  ........................................................................... 5 2  
8.  
A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S A S S E S S M E N T  .......................... 5 3  
8. 1  
Defi niti o n of A d verse E ve nts, Peri o d of O bser vati o n, Rec or di n g of A d verse E ve nts  . 5 3  
8. 1. 1  Se verit y Cate g ori zati o n  .......................................................................................... 5 3  
8. 1. 2  Relati o ns hi p Cat e g oriz ati o n  ................................................................................... 5 4  
8. 1. 3  O utc o me Cate g ori zati o n  ........................................................................................ 5 5  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 8  of 7 3  
8. 1. 4  S y m pt o ms of t he Disease U n der St u d y .................................................................. 5 5  
8. 1. 5  Cli nic al L a b orat or y E val uati o ns  ............................................................................ 5 5  
8. 1. 6  Pre g na nc y  ............................................................................................................... 5 5  
8. 1. 7  Me dicati o n Err or  .................................................................................................... 5 6  
8. 2  
Seri o us A d verse E ve nt Pr oce d ures  ............................................................................... 5 6  
8. 2. 1  Refere nc e Safet y I nf or m ati o n  ................................................................................ 5 6  
8. 2. 2  Re p orti n g Pr oce d ur es  ............................................................................................. 5 6  
8. 2. 3  Seri o us A d verse E ve nt Defi niti o n .......................................................................... 5 7  
8. 2. 4  Seri o us A d verse E ve nt C ollecti o n Ti mefra me ....................................................... 5 7  
8. 2. 5  Seri o us A d verse E ve nt O nset a n d R es ol uti o n Dates  ............................................. 5 7  
8. 2. 6  Fat al O utc o me  ........................................................................................................ 5 8  
8. 2. 7  Re g ulat or y A ge n c y, I nstit uti o nal Re vi e w B oar d, I n de pe n de nt Et hi cs 
C o m mittee, a n d Site R e p orti n g  .............................................................................. 5 8  
9.  
D A T A M A N A G E M E N T A N D S T A TI S TI C A L M E T H O D S  ..................................... 5 9  
9. 1  
Data C oll ecti o n  ............................................................................................................. 5 9  
9. 2  
Cli nic al Dat a Ma na ge me nt  ........................................................................................... 5 9  
9. 3  
Statisti cal A nal ysis Pr ocess  .......................................................................................... 5 9  
9. 4  
Selecti o n of S u bjects t o be I ncl u de d i n t he A nal yses  ................................................... 5 9  
9. 5  
S u bject Dis p ositi o n  ....................................................................................................... 6 0  
9. 6  
De m o gra p hic a n d Baseli ne C hara cteristics  .................................................................. 6 0  
9. 7  
Pri or a n d C o nc o mita nt Me dicati o n  ............................................................................... 6 0  
9. 8  
Safet y A nal yses  ............................................................................................................ 6 0  
9. 9  
Preli mi n ar y Effi cac y A nal yses  ..................................................................................... 6 1  
9. 1 0  
I nteri m A nal ysis............................................................................................................ 6 2  
9. 1 1  
P har mac o ki n eti c A nal yses  ............................................................................................ 6 2  
9. 1 2  
Sa m ple Siz e Cal c ulati o n a n d P o wer C o nsi derati o ns  .................................................... 6 3  
1 0.  
S P O N S O R’ S A N D I N V E S TI G A T O R’ S R E S P O N SI BI LI TI E S  ................................. 6 4  
1 0. 1  
S p o ns or’s Res p o nsi bilities  ............................................................................................ 6 4  
1 0. 1. 1  G o o d Cli nical Practice C o m pli a nce  ....................................................................... 6 4  
1 0. 1. 2  P u blic P osti n g of St u d y I nf or mati o n  ...................................................................... 6 4  
1 0. 1. 3  St u d y S us pe nsi o n, Ter mi nati o n, a n d C o m pleti o n  .................................................. 6 4  
1 0. 2  
I n vesti gat or’s Res p o nsi bilities ...................................................................................... 6 4  
1 0. 2. 1  G o o d Cli nical Practice C o m pli a nce  ....................................................................... 6 4  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 9  of 7 3  
1 0. 2. 2  Pr ot oc ol A d here nc e a n d I n vesti g at or A gree me nt  .................................................. 6 5  
1 0. 2. 3  D oc u me ntati o n a n d R ete nti o n of Rec or ds  ............................................................. 6 5  
1 0. 2. 3. 1  Case Re p ort F or ms  ...................................................................................... 6 5  
1 0. 2. 3. 2  Rec or di n g, Acc ess, a n d Rete nti o n of S o urce Dat a a n d St u d y D oc u me nts .. 6 5  
1 0. 2. 3. 3  A u dit/I ns pecti o n  .......................................................................................... 6 6  
1 0. 2. 3. 4  Fi na n cial Discl os ure  .................................................................................... 6 6  
1 0. 3  
Et hic al C o nsi der ati o ns  .................................................................................................. 6 7  
1 0. 3. 1  I nf or me d C o nse nt ................................................................................................... 6 7  
1 0. 3. 2  I nstit uti o n al Re vie w B oar d .................................................................................... 6 7  
1 0. 4  
Pri vac y a n d C o nfi d e nti alit y  .......................................................................................... 6 7  
1 0. 5  
C o m plia n ce wit h La w, A u dit, a n d De bar me nt  ............................................................. 6 8  
1 0. 6  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ........................................................................ 6 9  
1 0. 7  
P u blicati o n P olic y  ......................................................................................................... 6 9  
1 1.  
R E F E R E N C E S  ............................................................................................................. 7 0  
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 0  of 7 3  
List of Ta bles  
Ta ble 1: S A E a n d Pre g na nc y R e p orti n g C o ntacts  ...................................................................... 4  
Ta ble 2: Sc he d ul e of E ve nts  ..................................................................................................... 1 8  
Ta ble 3: Cli nical La b orat or y Tests  ........................................................................................... 4 7  
Ta ble 4: A d verse E ve nt Se verit y  .............................................................................................. 5 4  
Ta ble 5: A d verse E ve nt Ca usalit y Assess me nt  ......................................................................... 5 4  
Ta ble 6: Plas ma P K Para m eters f or A nal ysis  ........................................................................... 6 2  
Ta ble 7: 
 
 
 ................................. 6 3  
 
List of Fi g ures  
Fi g ure 1: 5 0 5 -1 0 1 St u d y Sc he m ati c  .......................................................................................... 2 7  
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 1  of 7 3  
A B B R E VI A TI O N S  
A B R  
A u dit or y brai nste m res p o nse  
A E  
A d verse e ve nt  
A N F  
A u dit or y ner ve fi b er  
A P  
A cti o n p ote ntial  
A U C  
A rea u n der t he c ur v e 
B MI  
B o d y mass i n de x  
B P  
Bl o o d press ure  
C F R  
C o de of Fe d eral R e g ulati o ns  
C L/ F  
A p pare nt cl eara nc e  
C ma x  
M a xi m u m pl as ma c o n ce ntrati o n  
C R A  
Cli nic al Rese arc h Ass ociate  
C R F  
Case Re p ort F or m  
C R O  
C o ntract R esearc h Or ga ni zati o n  
C S  
C oc hlear s y na pt o pat h y  
da Pa  
D e ka Pascals  
d B  
D eci bel  
D C C  
Delete d i n c ol or ectal ca n cer  
D M C  
Data M o nit ori n g C o m mitte e  
D P O A E  
Di st orti o n pr o d uct ot oac o ustic e missi o n 
E C G  
E lectr ocar di o gra m 
E C oc h G  
Electr oc oc hle o gra p h y  
E M A  
E ur o pea n Me di ci nes A ge nc y  
F A S  
F ull anal ysis set  
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
F O C P  
F e m ales of c hil d -be ari n g p ote ntial  
F S H  
F ollicl e -sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b or at or y Practice  
H C G  
H u ma n c h ori o ni c g o na d otr o pi n  
H E D  
H u ma n e q ui vale nt d ose  
H H L  
H i d de n-heari n g -l oss 
HI P A A  
Healt h I ns ura nc e P orta bilit y a n d Ac c o u nta bilit y Act  
H z  
H ertz  
I B 
I n vesti gat or’s Br oc h ur e 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 2  of 7 3  
I C F 
I nf or me d C o nse nt F or m  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Te c h nic al Re q uire m e nts f or 
P har mace utic als f or H u ma n Use  
I E C 
I n de pe n de nt Et hi cs C o m mitte e 
I E E E 
I nstit ute of Ele ctri cal a n d Ele ctr o ni cs E n gi ne ers 
I H C 
In ner hair c ells  
I P 
I n vesti gati o nal pr o d u ct 
I R B 
I nstit uti o n al Re vie w B oar d 
I U D 
Intra uteri ne de vice  
I x R S 
M C L  
I nteracti ve V oi ce/ W e b Res p o nse S yste m 
M ost C o mf orta ble Le vel  
Me d D R A  
Me dical Di cti o n ar y f or Re g ulat or y Acti viti es  
M E M R  
Mi d dle Ear M uscl e Refl e x  
M H R A  
Me dici nes a n d He alt h care Pr o d ucts Re g ulat or y A ge n c y ( U K)  
m L  
M illiliter 
M m h o  
Milli m h os  
M M R M  
M i xe d m o del wit h re pe ate d meas ure m e nts 
M o C A  
M o ntreal C o g niti ve Assess me nt  
M R S D  
Ma xi m u m Re c o m m e n de d Safe D ose  
n H L  
N or mal iz e d heari n g le vel  
N H P  
N o n h u ma n pri mates  
N O A E L  
N o O bser ve d A d verse Effect Le v el  
O H C  
O uter hair c ells  
PI P E -5 0 5  
I n vesti gati o nal Pr o d uct 
P K  
P har mac o ki n eti c  
P P S  
Per -p r ot oc ol set  
Q uic k SI N  
Q uic k Se nte nc es -i n-N oise  
R B C  
R e d bl o o d cell  
R O A  
R o ute of a d mi nistrati o n  
S A E  
S eri o us a d verse e ve nt  
S A P  
Statisti cal A nal ysis Pla n  
S G N  
S piral ga n gli o n ne ur o ns  
S N H L  
S e ns ori ne ural he ari n g l oss  
S N R  
Si g nal -t o-n oise r ati o  
S O C  
S yste m or ga n cl ass  
S O E  
Sc he d ule of e v e nts  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 3  of 7 3  
S O P  
Sta n dar d o perati n g pr oce d ur e  
S P  
S u m mati n g p ote ntial  
S R  
S p o nta ne o us rate  
S R T  
S peec h Rec o g niti o n T hres h ol d  
S S Q  
S peec h, S pati al a n d Q ualities  
t½  
A p pare nt ter mi nal -p hase dis p ositi o n half -life 
T E A E  
T reat me nt-e mer ge nt a d verse  
tma x  
T i me t o ma xi m u m plas ma c o nce ntr ati o n 
T M  
T y m pa ni c me m bra ne  
T T S  
T e m p orar y t hres h ol d s hifts  
W B C  
W hite bl o o d cell  
WI N  
W or ds i n N oise  
W H O  
W orl d Healt h Or ga nizati o n  
W R S  
W or d Rec o g niti o n Sc ore  
V z/ F 
A p pare nt v ol u m e of distri b uti o n  
z 
Ter mi n al eli mi nati o n rate c o nsta nt  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 4  of 7 3  
S T U D Y S Y N O P SI S  
Pr ot oc ol n u m ber: 5 0 5 -1 0 1  
D r u g: PI P E -5 0 5  
Title of t he st u d y:  
A P has e I/IIa, R a n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, Safet y, P har mac o ki netic, a n d Preli mi nar y Efficac y 
St u d y of U nilateral I ntrat y m pa nic PI P E -5 0 5 i n S u bjects wit h Se ns ori ne ural Heari n g L oss Ass ociate d wit h S peec h -
i n-N ois e I m pair me nt  
N u m ber of s u bjects (t ot al a n d f or e ac h tre at m e nt ar m):  
A p pr o xi matel y 2 4  s u bjects will be e nr olle d ( 1 8 A cti ve: 6 P lace b o)  
I n vesti g at ors/ Sites: A p pr o xi matel y 7  sites i n t he U S 
Cli nic al p h as e:  P has e I/IIa  
O bjecti ves:  
Pri m ar y: T o ass ess  t he safet y a n d t olera bilit y pr ofile of PI P E-5 0 5 w he n a d mi nistere d as a si n gle u nilateral 
i ntrat y m pa nic i njecti o n 
Sec o n d ar y: T o assess t he si n gle d os e plas ma P K pr ofile of PI P E-5 0 5 f oll o wi n g  a si n gle u nilateral i ntrat y m pa nic 
i njecti o n 
E x pl or at or y:   
•  
T o e x pl ore t he effect of a si n gle u nilateral i ntrat y m pa nic i njecti o n of PI P E -5 0 5 o n a u dit or y s kills re q uiri n g 
si g nal-t o-n ois e pr ocessi n g a n d e nc o di n g . 
•  
T o e x pl ore t he effect of a si n gle u nilateral i ntrat y m pa nic i njecti o n of PI P E -5 0 5 o n heari n g  t hres h ol ds a n d 
o uter hair cell f u ncti o n . 
•  
T o e x pl ore t he effect of  a si n gle u nilateral i ntrat y m p a nic i njecti o n of PI P E -5 0 5 o n a u dit or y 
electr o p h ysi ol o gical meas ures . 
I n vesti g ati o n al pr o d uct, d os e , a n d m o de of a d mi nistr ati o n : 
Se parate v ials of PI P E -5 0 5  i n cr ystalli ne p o w der f or m  a n d a Dil ue nt c o nsisti n g of a sterile t her m ore versi ble gel 
(P ol o xa mer 4 0 7 ) will be pr o vi de d t o t he sites f or l ocal f or m ulati o n of t he S us pe nsi o n acc or di n g t o  a  d os e 
c o nce ntrati o n  of 0. 7 5 % . T he Dil ue nt al o ne will s er ve as  t he P lace bo.  
PI P E -5 0 5 or P lace b o will be a d mi nistere d i n a v ol u me o f 2 0 0 micr oliters via a u nilateral i ntrat y m pa nic i njecti o n 
tar geti n g t he r o u n d wi n d o w nic he. T he r o u n d wi n d o w me m bra ne will per mit s ustai ne d releas e diff usi o n i nt o t he 
c oc hlea wit h ne gli gi ble s yste mic e x p os ure. At t he dis creti o n of t he i n vesti gat or, l ocal a nest hesia ma y  be 
a d mi nistere d t o picall y t o t he t y m pa nic me m bra ne ( T M) p ri or t o st u d y dr u g a d mi nistrati o n. 
Met h o d ol o g y:  
T he P has e I/IIa i n vesti gati o n will be c o n d ucte d as a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, si n gle d os e 
st u d y wit h a p pr o xi matel y 2 4  s u bjects ( 18  A cti ve: 6  P lace b o). S u bjects w h o pr o vi de writte n i nf or me d c o ns e nt a n d 
meet eli gi bilit y criteria will be ra n d o mize d t o recei ve a si n gle i ntrat y m pa nic d os e of PI P E -5 0 5 S us pe nsi o n or 
P lace b o ( P ol o xa mer 4 0 7). A s e nti nel d osi n g strate g y will be e m pl o ye d s uc h t hat t he first 2 s u bjects ( 1: 1, PI P E-
5 0 5: Place b o) will be d os e d a n d c o m plete t he Da y 1 ass ess me nt  pri or t o d osi n g t he re mai n i n g s u bjects. T he PI P E -
5 0 5 or P lace b o i njecti o n will be a d mi nistere d i nt o t he ear wit h t he w ors e a u di o metr y res ults (i.e., t he I n de x Ear, 
a d diti o nal criteria a p pl y, refer t o Secti o n 6. 3. 1 ).  
T he pri mar y, s ec o n dar y a n d e x pl orat or y e n d p oi nts will be meas ure d o ver t he c o urs e of 3 m o nt hs f oll o wi n g d os e 
a d mi nistrati o n. 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 5  of 7 3  
T he safet y assess me nts i ncl u de vital si g ns, e lectr ocar di o gra ms (E C G ), cli nical la b orat or y test res ults (r o uti ne 
he mat ol o g y, c he mistr y, a n d uri nal ysis), p h ysical a n d ot os c o pic e xa mi nati o ns, A Es/ S A Es, a u di o metr y,  a n d 
t y m pa n o metr y. 
T he preli mi nar y eff icac y ass ess me nts i ncl u de a u di o metr y, dist orti o n pr o d uct ot oac o ustic e missi o n, a u dit or y 
brai nste m res p o nses, electr oc oc hle o gra p h y  ( E C oc h G), mi d dl e ear m uscle refle x, S peec h S patial Q ualities of 
Heari n g Scale, W or d R ec o g niti o n Sc ore  ( W R S), S peec h R ec o g niti on T hres h ol d  ( S R T), Q uic k Se nte nces-i n-N ois e 
( Q uic k SI N), a n d W or ds i n N ois e ( WI N). 
Eli gi bilit y Criteri a:  
S u bjects m ust m eet e ac h of t he f oll o wi n g i ncl usi o n criteri a t o be eli gi ble f or r a n d o miz ati o n: 
1.  A bilit y t o pers o nall y pr o vi de writte n, si g ne d, a n d date d i nf or me d c o ns e nt t o partici pate i n t he st u d y.  
2.  S u bject’s pri mar y la n g ua ge is E n glis h.  
3.  M ale or fe male bet wee n 1 8 a n d 7 5  years  of a ge,  i ncl usi ve, at ra n d o mizati o n. 
4.  Dia g n osis of bilateral se ns ori ne ural heari n g l oss ( S N H L) wit h air c o n d ucti o n t hres h ol d ele vati o n b y p ure t o ne 
a u di o metr y t hat is n o greater t ha n  5 5 d B at 2 5 0, 5 0 0, a n d 1 0 0 0 Hz, n o greater t ha n  6 5  d B  at 2 0 0 0 Hz, a n d  n o 
greater t ha n 8 5  d B  at 4 0 0 0 a n d 8 0 0 0 Hz  at Scree ni n g i n eit her ear.  
5.  T hres h ol d o n t he Q uic k SI N -E P > 4  d B S N R L oss at Scree ni n g i n at least o ne ear.  
6.  N or mal t y m pa n o gra m i n t he ear i nte n de d f or i njecti o n (i.e., t he I n de x Ear), as  g ui de d  b y a ra n ge of -1 4 0 t o + 4 0 
de ka Pas cals [ da Pa] a n d 0. 3 -2. 9 milli m h os [ m m h o]) at Scree ni n g , a n d as deter min e d b y t he I n vesti gat or.  
7.  M ale or fe male s u bjects wit h re pr o d ucti ve p ote ntial a gree t o c o m pl y wit h a p pr o ve d d o u ble barrier 
c o ntrace pti ve met h o d (e. g., c o n d o m pl us i ntra uteri ne de vice [I U D], c o n d o m pl us h or m o nal c o ntrace pti o n, or 
d o u ble barrier met h o d, i.e., c o n d o ms a n d dia p hra g ms wit h s per mici dal gel or f oa m) d uri n g a n d f or 3 m o nt hs 
after st u d y dr u g a d mi nistrati o n.  
S u bjects are c o nsi dere d of n o n -re pr o d ucti ve p ote ntial if: 
a. P ost -me n o pa us al fe male wit h ≥1 2 c o ns ec uti ve m o nt hs of s p o nta ne o us a me n orr hea a n d a ge ≥5 1 
years wit h  f ollicle-sti m ulati n g h or m o ne (F S H ) > 3 0 mI U/ m L at Scree ni n g  
b.  S ur gicall y sterile fe male a n d at least 6 wee ks p ost -sterilizati o n (i.e., bilateral o o p h orect o m y or 
h ysterect o m y)  
c. Sterilize d 
male at least 1 -year p ost vas ect o m y a n d c o nfir me d t hat t he y ha ve o btai ne d 
d oc u me ntati o n of t he a bs e nce of s per m i n t he ejac ulate  
8.  T he s u bject is i n ge neral g o o d me dical healt h wit h n o cli nicall y si g nifica nt or rele va nt a b n or malities, i ncl u di n g 
me dical hist or y, p h ysical e xa m, vital si g ns, E C G, a n d la b orat or y e val uati o ns ( he mat ol o g y, c he mistr y, a n d 
uri nal ysis) as ass ess e d b y t he I n vesti gat or.  
9.  A n u n dersta n di n g, a bilit y, a n d willi n g ness t o f ull y c o m pl y wit h st u d y pr oce d ures a n d restricti o ns.  
S u bjects are e xcl u de d f r o m t he st u d y if a n y of t he f oll o wi n g e xcl usi o n criteri a  are m et:  
1.  M o ntreal C o g niti ve Ass ess me nt ( M o C A) sc ore less t ha n 2 6 at Scree ni n g.  
2.  Hist or y of c hr o nic otitis e xter na or me dia, ot her c hr o nic mi d dle ear dis or ders, or peril y m p h fist ula.  
3.  Pres e nce of a ge netic, s y n dr o mal or de vel o p me ntal a u dit or y dis or der.  
4.  Pres e nce of a n a ut oi m m u ne or s eri o us ne ur ol o gical dis or der t hat c o ul d c o ntri b ute t o a u dit or y l oss, as 
deter mi ne d b y t he I n vesti gat or.  
5.  Hist or y of her pes z oster otic us, or ot her i nfecti o us eti ol o g y of he ari n g l oss as deter mi ne d b y t he I n vesti gat or.  
6.  Hist or y of bar otra u ma as deter mi ne d b y t he I n vesti gat or.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 6  of 7 3  
7.  E vi de nce of c urre nt c o n d ucti ve heari n g l oss, mi xe d heari n g l oss or ot os cler osis as deter mi ne d b y t he 
I n vesti gat or i ncl u di n g si g nifica nt air-b o ne ga ps (i. e., > 1 0 d B  o n a u di o metric testi n g , wit h t he e xce pti o n of 4 0 0 0 
Hz ). 
8.  Hist or y of a u dit or y l oss relate d t o e x p os ure t o k n o w n ot ot o xic dr u gs, s uc h as hi g h -d ose a mi n o gl yc osi de 
a nti bi otics (e. g., stre pt o m yci n, ge nta mici n, t o bra m yci n, a mi kaci n, ne o m yci n, or mi n oc ycli ne) , as deter mi ne d 
b y t he I n vesti gat or .  
9.  A n y pri or e x p os ure t o plati n u m -bas e d me dicati o ns.  
1 0.  Ot ol o gical dis or ders t hat w o ul d precl u de s afe t y m pa nic i njecti o n (e. g., hist or y or pres e nce of c h olesteat o ma, 
T M perf orati o n, otitis me dia, or mi d dle ear a n at o mic a n o mal y) as deter mi ne d b y t he I n vesti gat or. 
1 1.  Pres e nce of a c oc hlear i m pla nt . 
1 2.  Hist or y of M e niere’s dis eas e or e n d ol y m p hatic h y dr o ps.  
1 3.  Hist or y of b ot hers o me ti n nit us, as deter mi ne d b y t he I n vesti gat or.  
1 4.  Past ot ol o gic s ur gical pr oce d ures t hat w o ul d precl u de s afe i ntrat y m pa nic i njecti o n as deter mi ne d b y t he 
I n vesti gat or. 
1 5.  I ntrat y m pa nic i njecti o n wit hi n 6 m o nt hs of ra n d o mizati o n. 
1 6.  Us e of a n i n vesti gati o nal pr o d uct or i nter ve nti o n ot her t ha n a n o n -i nter ve nti o nal re gistr y st u d y (i ncl u di n g 
vacci ne st u dies) wit hi n t he greater of 3 0 da ys or 5 half -li ves (if k n o w n) pri or t o Scree ni n g or e x pecte d d uri n g 
t he st u d y. 
1 7.  As y m metrical a u di o metric t hres h ol d res ults > 1 5 d B bet wee n ears at a n y octa ve fre q ue nc y bet wee n 2 5 0 a n d 
8 0 0 0 Hz at Scree ni n g  A N D t he patter n of as y m metr y is  i nc o nsiste nt wit h S N H L per I n vesti gat or j u d g me nt . 
1 8.  Hist or y of mali g na nc y  u n der c urre nt acti ve treat me nt or c o nsi dere d at s u bsta ntial ris k f or pr o gressi o n or 
rec urre nce d uri n g t he st u d y i nter val, as deter mi ne d b y t he I n vesti gat or .  N ote, ce ntral ner v o us s yste m 
ne o plas m s or hea d a n d nec k ca ncer  are e xcl u de d fr o m eli gi bilit y re gar dless of treat me nt stat us. 
1 9.  T he s u bject has a Q T c F b y E C G > 4 5 0 millis ec o n ds f or males or > 4 7 0 millis ec o n ds f or fe males . 
2 0.  T he s u bject has a hist or y of d ysr h yt h mia (s uc h as at rial fi brillati o n or ve ntric ular tac h ycar dia) t hat is c o nsi dere d 
u nsta ble b y t he I n vesti gat or.  
2 1.  T he s u bject has e x perie nce d a si g nifica nt s yste mic ill ness, as j u d ge d b y t he I n vesti gat or, wit hi n 3 0 da ys pri or 
t o Scree ni n g. 
2 2.  T he s u bject has a c urre nt or rele va nt hist or y of p h ysical or ps yc hiatric ill ness, or a n y me dical dis or der t hat ma y 
re q uire treat me nt or ma ke t he s u bject u nli kel y t o f ull y c o m plete t he st u d y, or a n y c o n diti o n t hat pres e nts u n d ue 
ris k fr o m t he i n vesti gati o nal pr o d uct or pr oce d ure, as deter mi ne d b y t he I n vesti gat or.  
2 3.  K n o w n or s us pecte d i nt olera nce or h y pers e nsiti vit y t o t he i n vesti gati o nal pr o d uct or cl os el y -relate d 
c o m p o u n ds. 
2 4.  T he s u bject is pre g na nt or breastfee di n g or pla ns t o bec o me pre g na nt d uri n g t he st u d y.  
2 5.  Hist or y of alc o h ol or ot her s u bst a nce a b us e wit hi n 6 m o nt hs of Scree ni n g as deter mi ne d b y t he I n vesti gat or.  
2 6.  S u bject is He patitis B p ositi ve (s u bjects w h o are s urface a nti b o d y p ositi ve sec o n dar y t o i m m u nizati o n are 
eli gi ble). 
2 7.  Hist or y of He patitis C.  
2 8.  S u bject is H u ma n I m m u n o deficie nc y Vir us ( HI V) s er o p ositi ve. 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 7  of 7 3  
D ur ati o n of s u bject i n v ol ve m e nt i n t he st u d y:  
•  
Scree ni n g peri o d: u p t o 8 wee ks 
•  
T reat me nt peri o d: si n gle i ntrat y m pa nic i njecti o n o n Da y 0  
•  
F oll o w -u p  peri o d : 1 2 wee ks 
•  
T otal d urati o n of s u bject partici pati o n: u p t o 2 0  wee ks  
St atistic al C o nsi der ati o ns:  
St u d y E n d p oi nts  
•  
T he pri mar y e n d p oi nt is t he n u m ber a n d s e verit y of a d vers e e ve nts ( A Es) u p t o 3 m o nt hs f oll o wi n g a si n gle 
u nilateral i ntrat y m pa nic i njecti o n of PI P E-5 0 5.  
•  
T he s ec o n dar y e n d p oi nt of t he st u d y is t he si n gle d os e plas ma P K para meters of PI P E-5 0 5, i ncl u di n g A U C t, 
A U C 2 4, A U C C ma x , tma x , t½, C L/ F, V z/ F, z. 
•  
E x pl orat or y E n d p oi nts will ass ess efficac y as f oll o ws:  
•  
M ea n c ha n ge fr o m bas eli ne t o 3 m o nt hs i n W R S  (perf or me d i n q uiet ), Q uic k SI N ( m o na ural a n d 
bi na ural), S peec h S p atial Q ualities ( S S Q),  S R T , a n d WI N tests 
•  
M ea n c ha n ge fr o m bas eli ne t o 3 m o nt hs i n p ure t o ne a u di o metr y a n d dist orti o n pr o d uct ot oac o ustic 
e missi o n ( D P O A E)  
•  
M ea n c ha n ge fr o m bas eli ne t o 3 m o nt hs i n Mi d dle Ear M us cle R efle x ( M E M R), A u dit or y Brai nste m 
R es p o nse ( A B R) , a n d E C oc h G 
Statistical A nal ys es & Sa m ple Size j ustificati o n  
T he sa m ple size of t his st u d y is n ot bas e d o n statistical c o nsi derati o ns. A sa m ple size of 2 4 s u bjects  ( 18: 6  PI P E -
5 0 5: Place b o) is c o nsi dere d s ufficie nt t o c haracterize t he i nitial s afet y, t olera bilit y, si n gle d os e p har mac o ki netic 
(P K ) pr ofiles, a n d e x pl orat or y preli mi nar y efficac y e n d p oi nts as 
meas ure d b y cli nical be ha vi oral a n d 
electr o p h ysi ol o gical res p o nses.  
Safet y a n d preli mi nar y efficac y  res ults fr o m t his st u d y will be ass ess e d usi n g s u m mar y statistics (e. g., n, mea n, 
me dia n, mi ni m u m, ma xi m u m, f or c o nti n u o us e n d p oi nts; n a n d % f or bi nar y a n d cate g orical e n d p oi nts).  A Es  will 
be pres e nte d i n listi n gs b y s yste m or ga n class (S O C ) a n d s u m mariz e d b y treat me nt, relate d ness, a n d s e verit y. 
R es ults of vital si g ns, E C G, a n d la b orat or y res ults will be liste d a n d c ha n ge fr o m bas eli ne val ues will be 
s u m marize d usi n g s hift ta bles.  
P K para meters will be s u m marize d usi n g des cri pti ve statistics ( n, arit h me tic mea ns, ge o metric mea ns, sta n dar d 
de viati o n, % c oefficie nt of variati o n, me dia n, mi ni m u m, a n d ma xi m u m). Fi g ures will be create d t o dis pla y mea n 
a n d i n di vi d ual s u bject PI P E -5 0 5 c o nce ntrati o n ti me c ur ves i n plas ma o n b ot h a li near a n d l o garit h mic s cale.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 8  of 7 3  
S C H E D U L E O F E V E N T S  
T a ble 2 : Sc he d ule of E ve nts 
Pr oce d ure  
Visit  
Scree ni n g  
1  
2  
3  
4  
5  
6  
7  
D a y  
-5 6 t o -1  
0  
1  
7  
1 4  
3 0  
6 0  
9 0 a  
Wi n d o w  
- 
- 
- 
+/ - 2  
+/ -2  
+/ -3  
+/ -7  
+/ - 7  
I nf or me d C o ns e nt  
X  
 
 
 
 
 
 
 
I ncl usi o n/E xcl usi o n C riteria 
X  
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
M e dical a n d M e dicati o n H ist or y 
X  
X  
 
 
 
 
 
 
P h ysical E xa mi nati o n  
X  
 
 
 
 
 
 
X  
Ot ol o gical E xa mi nati o n b 
X  
X  
X  
X  
X  
X  
X  
X  
Wei g ht  
X  
 
 
 
 
 
 
X  
Vital S i g nsc 
X  
X d  
X  
X  
X  
X  
 
X  
E C G e  
X  
X f 
X  
X  
 
 
 
X  
F S H g  
X  
 
 
 
 
 
 
 
Pre g na nc y T est h  
X h  
X h 
 
 
 
 
 
X h 
He p B, He p C, HI V  
X  
 
 
 
 
 
 
 
Uri nal ysis  
X  
 
 
 
 
 
 
 
C oa g ulati o n Pa nel  
X  
 
 
 
 
 
 
 
He mat ol o g y  
X  
X i 
X  
X  
X  
X  
X  
X  
Ser u m C he mistr y  
X  
X i 
X  
X  
X  
X  
X  
X  
P K B l o o d C ollecti o n  
 
X j 
X  
X  
X  
X  
X  
X  
C o nc o mita nt M e dicati o ns 
X  
X  
X  
X  
X  
X  
X  
X  
A Es  
X  
X  
X  
X  
X  
X  
X  
X  
St u d y D r u g ( PI P E-5 0 5) or P lace b o A d mi n  
 
X k 
 
 
 
 
 
 
T R Q  
X  
 
 
 
 
 
 
X  
M o C A  
X  
 
 
 
 
 
 
 
A u di o metr y ( wit h ultra -hi g h fre q ue nc y l) 
X  
 
 
 
 
X  
X  
X  
D P O A E  
X  
 
 
 
 
X  
 
X  
A B R/ E C oc h G  
X  
 
 
 
 
X  
 
X  
T y m pa n o metr y  
X  
 
 
 
 
X  
 
X  
M E M R  
X  
 
 
 
 
X  
 
X  
S S Q  
X  
 
 
 
 
 
 
X  
W R S  
X  
 
 
 
 
X  
X  
X  
S R T  
X  
 
 
 
 
X  
X  
X  
Q uic k SI N -E P  ( m o na ural via earp h o nes)  
X  
 
 
 
 
X  
X  
X  
WI N  ( m o na ural via earp h o nes)  
X  
 
 
 
 
 
 
X  
Q uic k SI N ( bi na ural via s o u n d fiel d) m  
X  
 
 
 
 
X  
 
X  
F o ot n otes:  
a S u bjects w h o recei ve st u d y dr u g a n d wit h dra w or are wit h dra w n fr o m t he st u d y earl y will be re q ueste d t o c o m plete earl y 
ter mi nati o n pr oce d ures o utli ne d u n der Da y 9 0. 
b Ot ol o gical e xa mi nati o n will assess t he f oll o wi n g u n der direct ma g nificati o n : e xter nal ear, e xter nal a u dit or y ca nal, T M a n d T M 
m o bilit y . T he ot ol o gical e xa mi nati o ns will be c o n d ucte d b y t he u n bli n de d ot ol o gist  w h o perf or ms t he i ntrat y m pa nic i njecti o n 
a n d a ls o c o n d ucts all p ost-i njecti o n ot ol o gical e xa mi nati o ns t hr o u g h at least Da y 3 0 a n d prefera bl y t hr o u g h o ut t he st u d y. 
c Vital si g ns (i.e., bl o o d press ure, p ulse rate, res pirat or y rate, a n d te m perat ure) will be rec or de d after s u bject is at rest i n a seate d o r 
s u pi ne p ositi o n f or at least 5 mi n utes . 
d O n Da y 0, vital si g ns will be c o n d ucte d pre -d ose, 3 0 ( ± 5) mi n utes p ost -d ose, a n d 4 h o urs ( ± 1 5 mi n utes) p ost -d ose.   
e E C G will be rec or de d after s u bject is at rest i n a s u pi ne p ositi o n f or at least 5 mi n utes .  
f O n  Da y 0, E C G will o nl y be c o n d ucte d at 4 h o urs  ( ± 1 5 mi n utes) p ost -d ose.  
g F S H le vel will be o btai ne d o n p ost -me n o pa usal w o me n o nl y ( defi ne d as c o nti n u o us a me n orr hea of at least 1 2 m o nt hs a n d n ot 
s ur gicall y sterile). 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 1 9  of 7 3  
h O nl y f e male s u bjects of c hil d beari n g p ote ntial will re q uire a ne gati ve ser u m pre g na nc y test at S cree ni n g a n d ne gati ve uri ne 
pre g na nc y test pri or t o ra n d o mizati o n at Da y 0 . Fe male s u bjects of c hil d beari n g p ote ntial will als o re q uire a u ri ne pre g na nc y test 
at C o m pleti o n or Earl y Ter mi nati o n.  
i O n Da y 0,  he mat ol o g y a n d c he mistr y la b  sa m ples will be c ollecte d pri or t o d osi n g b ut d o n ot ha ve t o be a nal yze d pri or t o d ose .  
J O n Da y 0, P K sa m ples will be c ollecte d pre -d ose a n d 4 h o urs ( ± 1 5 mi n utes) p ost -d ose.  
k T he  i ntrat y m pa nic i njecti o n will be perf or me d b y a n u n bli n de d ot ol o gist w h o will als o c o n d uct all p ost -i njecti o n ot ol o gical 
e xa mi nati o ns t hr o u g h at least Da y 3 0  a n d prefera bl y t hr o u g h o ut t he st u d y . 
l Ultra -hi g h fre q ue nc y a u di o gra m testi n g [ 1 0, 0 0 0 -1 6, 0 0 0 Hz] will be perf or me d if a vaila ble base d o n site a u di o meter s pecificati o ns. 
m  S o u n d fiel d bi na ural testi n g usi n g a si n gle 0 0 azi m ut h l o u ds pea ker. 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 0  of 7 3  
1.  
I N T R O D U C TI O N 
1. 1  
B ac k gr o u n d  
Rece nt st u di es i n a ni m al m o dels  ha ve de m o nstrate d t hat ac o ustic da m a ge rel ate d t o n oise a n d/ or 
a gi n g ca n res ult i n de ge n erati o n of t he s y na ptic c o ntacts bet wee n t he s pir al ga n gli o n ne ur o ns 
( S G N) a n d t he i n ner hair cells (I H C) of t he c oc hlea (K uja wa  a n d Li ber ma n , 2 0 15 ). T he s y na ptic 
de ge nerati o n is n o w r ec o g ni ze d t o prec e de I H C a n d/ or o uter h air cells ( O H C ) l oss a n d has be e n 
de m o nstrat e d i n a ni m al m o dels e x p ose d t o o nl y mi n or a u dit or y i ns ults, als o referre d t o as 
te m p orar y t hres h ol d s hifts ( T T S). Rese arc h i n a ni m al m o dels has als o i n dic ate d t hat n ot o nl y is 
t he s y na pse b et wee n t he S G N a n d I H C, als o ref erre d t o as t he c oc hl ear s y na pse, pri m aril y 
res p o nsi ble f or e nc o di n g c o m ple x a u dit or y si g nals, b ut it ma y be s pecific all y v ul n era bl e t o 
de ge nerati o n i n d e pe n d e nt of i n ner a n d o uter h air cells. Res ults fr o m rece nt a ni mal st u dies str o n gl y 
s u g gest t hat de ge nerati o n of h u ma n S G N s y na ptic f u ncti o n (i.e., c oc hlear s y na pt o p at h y  [C S ]) ma y 
si g nifica ntl y c o ntri b ut e t o t he i m pair me nt i n s pe ec h p erce pti o n i n t he setti n g of bac k gr o u n d n oise, 
w hile se nsiti vit y t o s o u n d pr ocessi n g i n q uiet setti n gs is n ot disr u pte d (Pla c k  et al., 2 0 1 6). It has 
bee n s u g geste d t hat t h e dis pr o p orti o nat e i n n er vati o n of ea c h I H C b y m ulti ple S G Ns facilitat es 
selective differ e ntiati o n of wea k si g nals of i m p ort a nce t o t he list e ner fr o m t he ba c k gr o u n d of 
c o m peti n g sti m uli (K uja wa  a n d Li ber ma n , 2 0 1 9). T he i na bilit y t o hear a n d u n dersta n d s peec h i n 
c hall e n gi n g n oise bac k gr o u n ds i n e v er y da y se tti n gs is c o m m o nl y re p orte d b y patie nts wit h 
se ns ori ne ural heari n g l oss ( S N H L), a n d t o date t here is n o effecti ve treat me nt f or rest ori n g t his 
s pecific a u dit or y f u n cti o n (K o bel  et al., 2 0 1 7). 
E mer gi n g d ata fr o m a ni mal st u dies f oc use d o n t he c oc hle ar s y na pse s u p p ort t he h y p ot hesis t hat 
deaffere ntati o n of I H Cs is a c o m m o n pat h ol o g y acr oss t he s pectr u m of h u ma n S N H L eti ol o gies, 
re gar dless of t he de gre e of o vert heari n g l oss as me as ure d b y a u di o m etr y (Li ber m a n  a n d K uja wa, 
2 0 1 7 ). A ni mal i n vesti g ati o ns ha v e re ve ale d t hat n ois e e x p os ure ca usi n g T T S, pre vi o usl y t h o u g ht 
t o be i n n oc u o us, c a n pr o d uce a l oss of as ma n y as 5 0 % of t he s y na pses a n d c oc hl ear ner v e 
ter mi n als i n ner v ati n g t he I H C, res ulti n g i n pr o n o u nce d C S (K uja w a a n d Li b er ma n , 2 0 0 9 ; 
B hara d waj  et al., 2 0 1 5; Li n  et al., 2 0 1 1 ; L o bari nas  et al., 2 0 1 6; Hic k o x  et al., 2 0 1 7). E vi de n ce of 
n oise -i n d uce d C S has  als o bee n o bser ve d i n t he g ui n ea pi g (Li n  et al., 2 0 1 1; F ur m a n et al., 2 0 1 3), 
c hi nc hilla (Hi c k ma n et al., 2 0 1 8 ), a n d rat (Si n ge r et al., 2 0 1 3), as well as n or mal a gi n g (Ser ge ye n k o  
et al., 2 0 1 3; Altsc h uler  et al., 2 0 1 5; M ö hrl e  et al., 2 0 1 6) a n d a d mi nistrati o n of ot ot o xi ns (B o urie n  
et al., 2 0 1 4; Li  et al., 2 0 1 6). 
C ollecti ve a ni mal data has f urt her i n dicate d t h at t he T y pe I s y na pse, i n parti c ular t h e l o w 
s p o nta ne o us rate ( S R) ne ur o ns, ma y be a partic ularl y v ul nera ble li n k i n t he a u dit or y ner ve circ uit 
a n d relat e d heari n g f u ncti o n (Hi c k o x  et al., 2 0 1 7 ). N or mal res p o nse pr o perties of l o w S R ne ur o ns, 
i n q uiet a n d i n n oise, ha ve le d t o s pec ul ati o n re gar di n g f u ncti o n al c o nse q ue nc es of t heir tar g ete d 
l oss i n h u m a ns a n d t he c o ntri b uti o n t o t he cl assic i m pair me nt of s peec h-i n-n oise diffic ult y se e n i n 
S N H L (K uja wa  a n d Li ber ma n , 2 0 1 5 ; Plac k  et al., 2 0 1 4). T he a u dit or y pr o perties a n d f u ncti o n of 
t he l o w S R ne ur o ns ma y b e partic ularl y rele va nt t o d ecli n es i n perf or ma n ce wit h a ge t hat i n cl u de 
decrease d s pe ec h u n derst a n di n g i n n oise a n d re d uce d a bilit y t o utilize s patial sti m ul us ti mi n g a n d 
a m plit u de m o d ul ati o n c ues (Sc h mi e dt  et al., 1 9 9 6). C S als o ma y be a ke y elicit or of ti n nit us a n d 
h y perac usis, t w o of t he m ost  tr o u bli n g se ns or y s y m pt o ms ass ociat e d wit h S N H L. 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d
D o w nl oa de d b y Ga vi n C hase o n 1 6 Fe b 2 0 2 2

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 1  of 7 3  
Fi nall y, t he e mer gi n g el ectr o p h ysi ol o gic al a n d hist ol o gical a ni mal data ha ve  als o parallele d rec e nt 
h u ma n st u dies w here b ot h ele ctr o p h ysi ol o gical me as ures a n d p ost -m orte m a nal yses ar e c o nsiste nt 
wit h h u ma n C S, i ncl u di n g te m p or al a n d s patial a u dit or y pr ocessi n g (Me h raei et al., 2 0 1 6 ; 
B hara d waj  et al., 2 0 1 4 ; W u  et al., 2 0 1 8). Ele ctr o p h ysi ol o gi cal testi n g has c o nsiste ntl y 
de m o nstrat e d re d u cti o n i n Wa ve I of t he a u dit or y br ai nste m res p o nse ( A B R) i n a ni mal m o d els of 
b ot h n oise -i n d uce d a n d a ge-r elate d c oc hlear det eri orati o n. Wa v e I ori gi nates wit h t he s y na ptic 
c o m p o ne nt of t h e a u dit or y ner v e circ uit a n d t he A B R ulti mat el y assesses t he a u dit or y circ uit 
e xte n di n g t o t h e brai n ste m a n d te m p or al c orte x. Si milar re d ucti o ns i n Wa v e I a m plit u des has b ee n 
s h o w n i n select p o p ulati o ns wit h k n o w n hist ories of a u dit or y i ns ults (Bra m hall  et al., 2 0 1 7 ). P ost-
m orte m st u dies ha ve e x a mi n e d h u ma n t e m p oral b o n e s peci me ns i n p ati e nt s ra n gi n g fr o m 5 5-8 9 
years of a ge wit h de m o nstrate d l oss of s y na ptic c o n necti o ns wit h t he I H C ra n gi n g fr o m 1 5 
s y na pses per I H C i n y o u n ger patie nts t o 2. 5 s y na pses per I H C i n ol der p ati e nts - wit h o ut maj or 
l oss of I H C or O H Cs i n t he sa me te m p oral b o nes (W u  et al., 2 0 1 8). M ore i m p orta ntl y, t h ese p ost-
m orte m st u dies h a ve als o de m o nstrat e d s ur vi val of vi a ble S G N, i n di cati n g t h at t he pri mar y se ns or y 
ne ur o n re mai ns i nta ct a n d is p ote nti all y r es p o nsi ve t o s y na ptic rest or ati o n.   
S y na ptic de g e nerati o n is n o w pr o p ose d as a maj or c o ntri b ut or t o t h e cl assic s pee c h -i n-n oise 
i m pair me nt ass ociate d wit h S N H L (K uja w a  a n d Li ber ma n , 2 0 1 5; Plac k  et al., 2 0 1 4; B hara d w aj et 
al., 2 0 1 5; L e Prell  a n d Br u n gart , 2 0 1 6; Le Prell, 2 0 1 9 ). Base d o n e x peri me nt al w or k i n n oise -
i n d uce d a n d a gei n g r o de nt m o d els of heari n g l oss, the lea di n g f u ncti o n al o ut c o me of s y na pti c 
de ge nerati o n i n h u ma ns is h y p ot hesi ze d t o pr o d u ce diffic ult y wit h liste ni n g i n n ois y bac k gr o u n ds 
(Bra m ha ll et al., 2 0 1 9 ). C S ma y be o ne of t he e arliest ma nifest ati o ns of f ut ure S N H L w herei n b ot h 
hair cell l oss a n d s y na ptic de ge nerati o n c o -e xist, t h e l atter of w hic h ma y sele cti v el y i m p act s peec h 
perce pti o n i n c o m ple x list e ni n g c o n d iti o ns. Res ults i n a ni mal stu dies ha ve f urt h er i n di cate d t hat 
t he s y na ptic c o n n ecti o n bet wee n t h e a u dit or y ner ve fi bers ( A N F ) a n d I H Cs are t he m ost v ul nera ble 
ele m e nt wit hi n t he c oc hl ea , a n d d e ge ner ate b ef ore t he l oss of hair cells. H o we ver, t he l o n g-ter m 
s ur vi val of t h e S G N a n d t he ce ntr al a x o n i n h u m a ns u n derlies t he eff ecti ve ness of c o c hle ar 
i m pla nts (K uja wa  a n d Li ber ma n , 2 0 1 9). T he a ge-r elate d s y na ptic de ge n erati o n de m o nstrate d i n 
p ost -m orte m te m p oral b o ne st u dies par all el t he fi n di n gs i n a g e -rel ate d C S i n m ulti ple a ni mal 
m o dels. T h e pre dict a bilit y of t he a ni mal m o dels is f urt her s u p p orte d b y t h e a g e -rel ate d c ha n g es i n 
A B R 
Wa ve I m or p h ol o g y se e n i n b ot h r o d e nt a n d h u ma n s u bj ects (Le Prell, 2 0 1 9 ). Fi n all y, 
correlati o n wit h perf or m a nce o n s peec h -i n-n oise ass ess me nts (e. g., t he Q uic k Se nte n ces i n N oise  
[Q uic k S I N], t he 
W or ds-i n-N oise test  [WI N ]) a n d A B R 
Wa ve I a m plit u de ha v e als o  bee n 
rec o g niz e d i n h u m a ns, f urt her i n dicati n g t h e r ole of t he c oc hlear s y na pse i n c o m ple x s pee c h 
perce pti o n  a n d s peec h -i n-n oise i m pair me nt  (Le Prell, 2 0 1 9 ). T h us, re pair of t he c oc hlear s y na pse 
ma y lea d t o i m pr o ve d s peec h -i n-n oise pr ocessi n g a n d a d dress o ne of t he mai n disa bilities 
ass ociate d wit h S N H L.  
1. 2  
T he C o n diti o n B ac k gr o u n d a n d C urre nt Tre at me nt  
S N H L is t he maj or ca use of he ari n g i m pair me nt i n a d ults, c o m prisi n g b ot h n oise -i n d uce d a n d a ge-
relat e d a u dit or y dis or ders. It is esti mate d t hat a b o ut t w o -t hir ds of pe o pl e o ver t he a ge of 7 0 ha ve a 
de gree of a ge -relate d heari n g l oss w hic h ca n l ea d t o s ocial is olati o n a n d d ecrease d q ualit y of life 
(Heeri n ga  a n d K ö p pl, 2 0 1 9 ). T he w orl d wi de pre val e nce of disa bli n g heari n g l oss is t h o u g ht t o 
e xcee d 5 % a cc or di n g t o t he 
W orl d Healt h Or ga nizati o n  ( W H O), a n d t he m aj orit y of cases 
( p ossi bl y u p t o 9 0 %) are classifie d as se ns ori ne ural (N y ber g  et al., 2 0 1 9 ). T he u n derl yi ng c oc hl ear 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d
D o w nl oa de d b y Ga vi n C hase o n 1 6 Fe b 2 0 2 2

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 2  of 7 3  
hist o pat h ol o g y has hist oric all y be e n c haracteri ze d as l oss of t he pri mar y se ns or y cells (i n ner a n d 
o uter hair cells), b ut as n ot e d a b o v e t he c oc hlear s y na pse ma y be e v e n m or e v ul n era bl e t o n oise  
e x p os ure a n d a gi n g. T h e s y na pti c c o n n ecti o n bet we e n t he a u dit or y n er ve a n d t he I H C ma y pla y a 
pri mar y r ol e i n t he n or mal pr o cessi n g of c o m ple x a u dit or y sti m uli, a n d f u ncti o nal a u dit or y defi cits 
sec o n dar y t o de ge nerati o n of t he s y na pse ma y be c o m para bl e t o t he i m pair me nt relate d t o O H C 
l oss.  
Cli nic al ma ni f estati o ns of S N H L are t y pic all y c har a cteri ze d b y ele vati o n i n he ari n g t hres h ol ds as 
meas ure d b y t he p ure t o ne a u di o metr y, b ut a u di o metr y al o ne d oes n ot assess t he f ull s pectr u m of 
heari n g per ce pti o n diffic ulties re p orte d b y patie nts. 
W hil e a m plifi cati o n m a y a u g m e nt s o u n d 
detecti o n w he n heari n g l oss is se vere , s uc h as pr o vi de d b y heari n g ai ds, pr ocessi n g m ore 
c hall e n gi n g a u dit or y tas ks s uc h as u n dersta n di n g s peec h i n t he setti n g of bac k gr o u n d n oise are n ot 
a d dresse d b y a m plifi cati o n al o n e. I n t h at re g ar d, a le a di n g c o m plai nt a m o n g patie nts wit h S N H L 
is diffic ult y heari n g  c o n versati o ns i n n ois y e n vir o n me nts , si nce a u di o m etri c t hres h ol ds d o n ot 
assess t he f ull e xt e nt of heari n g d ysf u ncti o n i n v ol vi n g s peec h p erce pti o n -i n-n oise is n ot m eas ure d 
b y a u di o metr y, t hi s a u dit or y disa bilit y has als o bee n referre d t o as hi d de n -heari n g -l oss ( H H L). 
I n s u m mar y, de ge nerati o n of t he c oc hle ar s y na pse bet wee n t he a u dit or y ner ve a n d I H C, i.e., C S , 
ma y re d uc e si g nal -t o-n oise pr ocessi n g i n c halle n gi n g liste ni n g e n vir o n m e nts. T her e is n o c urre nt 
dr u g treat me nt f or s peec h -i n-n oise i m pair me nt, a n d  e xisti n g tec h n ol o gies d o n ot a m eli or ate  t his 
s pecific d o mai n of h eari n g f u ncti o n. H o we ver, treat m e nt desi g n e d t o rest ore s y na pti c f u ncti o n ma y 
lea d t o i m pr o ve d te m p or al, s patial, a n d si g nal-to -n oise pr ocessi n g, a n d c o nse q ue ntl y a d dress o ne 
of t he maj or a u dit or y disa bilities i n S N H L.  
1. 3  
Pr o d uct B ac k gr o u n d  
PI P E -5 0 5 is a n o vel, i ntrat y m pa ni c all y bi oa vaila ble i n hi bit or of ga m ma -secr etase, a me m br a ne 
b o u n d e nz y me r e g ulati n g ke y p at h wa ys i n v ol v e d i n i n ner ear de v el o p m e nt, i n cl u di n g se ns or y hair 
cell d e vel o p me nt via N ot c h si g nali n g a n d s pir al ga n gli o n o ut gr o wt h vi a netri n -del ete d i n c ol orectal 
ca ncer ( D C C) si g nali n g (re vi e we d i n Haa pasal o  a n d K o vacs , 20 1 1 ). T he c urre nt p h ar mac ol o gic al 
data s u p p ort a k e y r ole f or N ot c h si g nali n g acti vit y i n O H C differe ntiati o n i n t he c o c hle a ( Z he n g 
et al., 2 0 0 0 ; Zi ne et al., 2 0 0 1 ; Y a m a m ot o et al., 2 0 0 6 ; De yts et al., 2 0 1 6 ; Br u ge a d et al., 2 0 1 4 ) a n d 
netri n -D C C si g nali n g acti vit y i n n e urit e g ui d a nce a n d o ut gr o wt h  at t h e S G N (B ai  et al., 2 0 1 1; Ki m  
et al., 2 0 1 6). 
PI P E -5 0 5 re g ulates b ot h N otc h acti vit y as well as D C C acti vit y b y bi n di n g t o t he g a m m a -secret ase 
pr otease c o m ple x. PI P E -5 0 5 i n hi bits tra ns me m bra ne clea v a ge a n d s u bse q ue nt release of t h e N otc h 
i ntrac ell ular d o mai n. As a res ult, ge nes acti vate d b y t he N otc h i ntrac ell ular d o mai n, e. g., Hes 1, 
He y 1, He y 2, a n d Hes 5 are d o w nre g ul ate d. O ne c o nse q ue nce of Hes 5 d o w nre g ulati o n is t he d e -
re pressi o n of t he tra nscri pti o n fact or At o h 1, w hic h sti m ul ates e ar hair cell differ e nti ati o n (Li n V  
et al., 2 0 1 1). I n a d diti o n, i n hi biti o n of ga m ma-secret ase b y PI P E-5 0 5 pre ve nts cle a va ge of D C C 
o n S G N, res ulti n g i n persist e nt e x pressi o n of t he r ece pt or a n d c o nse q ue nt i ncr eases i n a x o nal 
le n gt h to war d I H C s w here s y na ptic c o n ne cti o ns ref or m.  
Base d o n  t he bi ol o gi cal pr o perti es as a g a m ma -se cr etase i n hi bit or, PI P E -5 0 5 is  c urre ntl y  u n der 
de vel o p m e nt f or t he treat me nt of S N H L ass ociate d wit h s peec h-i n-n oise i m pair m e nt ( p ote ntiall y 
sec o n dar y t o C S ). N o ncli nic al  i n vitr o st u dies a n d i n viv o e x peri me nts  wit h  rele va nt a ni m al m o d els 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 3  of 7 3  
(s u m mariz e d i n Se cti o n 1. 3. 1  bel o w ) ha v e de m o nstrate d t he t w o disti nct mec h a nis ms-of -acti o n as 
o utli ne d a b o ve.  
T he I n vesti gat or ’s Br oc h ure (I B) s u m mari zes t he m ost c urre nt i nf or mati o n re g ar di n g t he safet y 
a n d effic ac y of  PI P E -5 0 5.  
1. 3. 1  
Precli nic al Inf or m ati o n  
PI P E -5 0 5 has bee n  e val u ate d  i n a series of n o ncli nic al  i n vitr o a n d i n viv o st u dies i n a ni mal m o dels 
wit h rele va nt  a u dit or y i ns ults. As state d a b o v e, t he precli nical st u dies  ha ve d e m o nstrat e d t w o 
disti nct me c ha nis ms  of acti o n t h at m a y rest or e h eari n g f u ncti o n i n S N H L. S pecificall y , 1) 
re ge nerati o n of s y na pses bet wee n T y pe I S G N a n d I H C via t he n etri n-D C C pat h wa y , a n d 2) o uter 
hair cell re g e nerati o n via t he N otc h pat h wa y. T h e o ut c o me of select st u di es are s u m mariz e d bel o w . 
Wit hi n t he a u dit or y se ns or y n er ve p at h wa y a n d c o c hlea, t he g a m m a -secretase c o m pl e x clea v es 
a n d s u bse q ue ntl y i nacti vates, me m br a ne s u bstrates w hic h are i n v ol ve d i n ne urite o ut gr o wt h a n d 
pat hfi n di n g. D C C is a k n o w n s u bstrate of ga m m a -secretase a n d t he n etri n-D C C  c o m ple x has bee n 
i m pli cat e d i n a x o nal g ui d a nce (L ee  a n d War c h ol , 2 0 0 8; Ki m  et al., 2 0 1 6). Wit hi n t he c oc hlea, 
D C C is e x presse d b y S G N a n d netri n is e x presse d b y I H Cs (S hrest ha  et al., 2 0 1 8). I n hi biti o n of 
ga m ma -se cretase pre v e nts t h e clea v a ge of D C C, res ulti n g i n p ersiste nt e x pressi o n of sele ct 
rece pt ors a n d c o nse q ue nt i n crease d a x o nal le n gt h. 
•  I n vitr o st u dies usi n g 
m o use disass ociate d c oc hlea c ult ure de m o nstrate d t hat 
i n hi biti o n of ga m ma-se cret ase d ose de p e n de ntl y i n d u ces ne urit e o ut gr o wt h of T y pe I 
S G Ns. F u ncti o n bl oc ki n g a nti b o di es a gai nst t he a x o n g ui da nce pat h wa y (i.e., D C C 
a n d netri n) i n hi bit PI P E -5 0 5 i n d uce d ne urite o ut gr o wt h, i n dicati n g t hat ne urit e 
sti m ulati o n is ge nerat e d b y PI P E-5 0 5 via t he netri n -D C C pat h wa y a n d ai ds s y na pse 
re ge nerati o n. 
•  I n viv o st u dies wit h T T S  i n a m o use  m o del ha ve pr o d uce d s y na pti c de g e nerati o n 
w hic h is re verse d b y treat m e nt wit h PI P E -5 0 5 as de m o nstrat e d b y rest orati o n of 
s y na ptic hist ol o g y a n d i m pr o ve m e nt i n Wa ve I of t h e A B R.  
•  I n viv o st u dies wit h  a g ui nea pi g ot ot o xicit y m o del h a ve als o s h o w n s y na pse re c o ver y 
b y hist ol o g y t hat persists u p t o 3 m o nt hs p ost -i nje cti o n.  
 
Ga m ma -secr etase i n hi biti o n als o le a ds t o i n hi biti o n of N otc h si g nali n g, res ulti n g i n t he de -
re pressi o n of t h e At o h 1 e n ha nc er ele m e nt a n d s u bse q ue nt i n d u cti o n of At o h 1 ( a ke y re g ul at or of 
o uter hair cell differe ntiati o n)  i n s u p p orti n g pr o ge nit or cells. 
•  Ex viv o  st u di es wit h r o de nt c oc hlear e x pla nts ha ve s h o w n i ncrease d O H C s i n b ot h 
naï ve m o d els , as well as a m o del of ot ot o xi cit y se c o n dar y t o ge nt a mi ci n e x p os ure . 
•  I n viv o st u di es i n a m uri ne m o del of n oise-i n d u ce d he ari n g l oss de m o nstr ate d 
i m pr o ve d A B R t hres h ol ds acr oss 3 fre q ue n cies ( 1 6, 2 4, a n d 3 2 k Hz) a n d mic e wit h 
1 0 d B i m pr o ve me nt or m ore s h o we d a str o n g tre n d of a n a vera ge of 2 0 % or m ore 
O H Cs after a si n gle i ntrat y m pa nic i nje cti o n of PI P E-5 0 5 .  
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 4  of 7 3  
P ote ntial l ocal a n d s yste mic t o xicit y of PI P E -5 0 5  (a d mi nister e d b ot h orall y a n d b y i ntr at y m p a nic 
i njecti o n) has be e n test e d i n G o o d La b or at or y Practice ( G L P )-c o m pli a nt re p eat -d ose st u di es i n 
rats, g ui nea pi gs, a n d m o n ke ys. PI P E -5 0 5 was well -t olerat e d acr oss all of t he a ni mal st u dies, a n d 
n o s yste mic or l ocal safet y e ve nts wer e o bser ve d . I n s u m mar y, t h e N o O bser ve d A d verse Effe ct 
Le vel ( N O A E L) was i de ntifie d  at t h e l ocal i ntr at y m p a nic d ose le ve l of 5. 0 % i n n o ncli nical st u dies 
perf or me d wit h g ui nea pi gs.  
T his st u d y 
will be t h e first -i n-h u m a n i n vesti gati o n of 
PI P E -5 0 5, a n d t her ef ore t he 
p har mac o ki netics  ( P K) a n d met a b olis m ha v e n ot yet bee n m eas ure d i n h u ma n s u bj ects. B ase d o n 
n o ncli ni cal st u dies i n se v eral differe nt a ni mal s pecies, si n gl e u nil ater al i ntrat y m pa ni c 
a d mi nistr ati o n s h o ul d res ult i n me as ura ble dr u g pres e nce wit hi n t he c oc hlea p eril y m p h f or at least 
o ne m o nt h after i nj ecti o n. S yste mic e x p os ure ma y pri maril y res ult via t he E usta c hia n t u b e a n d 
s u bse q ue nt a bs or pti o n t hr o u g h t he gastr oi ntesti nal r o ute. N o ncli ni cal st u di es ha ve s h o w n t hat t he 
a m o u nt of s yste mic e x p os ure f oll o wi n g a n i ntr at y m pa nic a d mi nistrati o n is ver y li mite d a n d 
restrict e d t o wit hi n 7 da ys of dr u g a d mi nistrati o n (ref er t o the I B f or a s u m mar y of t he n o ncli nical 
P K st u dies ). H u ma n P K will be assesse d base d o n t he c oll ecti o n pla n as o utli ne d i n t he Sc he d ule 
of E ve nts  ( S O E) f or all s u bj ects d ose d wit h PI P E -5 0 5 . 
As n ote d a b o ve, n o h u m a n dat a wit h PI P E -5 0 5 has b ee n c ollecte d, b ut  n o n cli nical st u dies i n dicate 
t hat rest orati o n of t he c oc hlear s y na pse a n d ge ner ati o n of ne w O H Cs c o ul d i m pr o ve a u dit or y 
f u ncti o n i n s u bje cts wit h S N H L wit h s pe ec h-i n-n oise i m pair me nt (sec o n d ar y t o s us pecte d C S ). 
T he p h ysi ol o g y a n d f u ncti o n of t he h u ma n c oc hl ear s y na pse i n di cat es t hat t he t hera pe utic effe ct 
of PI P E -5 0 5, a n d t here b y preli mi nar y effi cac y (ref er t o e x pl or at or y o bj ecti v es a n d e n d p oi nts ), 
c o ul d i n cl u de i m pr o ve d si g nal -t o-n oise pr o cessi n g. T his tre at m e nt effect will be d ete cte d b y 
i m pr o ve d perf or ma nce fr o m baseli ne o n t h e Q uic k SI N a n d/ or t he WI N, s pecific s pee c h-i n-n oise 
meas ures t hat test t h e a bilit y of t he s u bject t o hear s peec h or w or ds i n t he setti n g of c o m peti n g 
bac k gr o u n d n oise. Ot her heari n g meas ures t hat c o ul d refle ct e vi de nc e of preli mi n ar y effi cac y 
i ncl u de t h e W or d Rec o g niti o n Sc ore ( W R S ), S peec h Rec o g niti o n T hres h ol d ( S R T ), a n d S peec h 
S pecial 
Q ualities ( S S Q ). I m pr o ve d c o c hle ar s y na ptic f u n cti o n 
ma y als o be d ete cte d b y 
electr o p h ysi ol o gi cal c ha n ges i n t h e A B R , el ectr o c oc hle o gra p h y ( E C oc h G) , a n d/ or t he Mi d dle Ear 
M uscle Refle x ( M E M R) . Fi nall y, t he treat me nt effect, p ote nti all y r elate d 
m or e t o O H C 
re ge nerati o n, c o ul d als o be refle cte d i n c h a n ges fr o m baseli n e i n p ur e t o ne a u di o m etr y a n d 
dist orti o n pr o d uct ot oa c o ustic e missi o n ( D P O A E).  
Gi ve n t he l oc al, a n d u nilat eral , a d mi nistrati o n  of PI P E -5 0 5 directl y i nt o t he t y m pa nic ca vit y as a 
si n gle d ose, a fa v ora ble s yste mic safet y pr ofil e is a ntici pate d. E x p ecte d a d verse e v e nts  ( A Es) are 
li kel y t o be rel ate d t o t he effe cts of i ntrat y m pa nic i nje cti o n a n d ha v e bee n o bser ve d i n ot her st u di es 
i n v ol vi n g t h e sa me r o ute-of -a d mi nistr ati o n (Me y er, 2 0 1 3 ; Staec k er  et al., 2 0 1 7 ). T h e m ore 
c o m m o n ot ol o gic/a u di ol o gic res p o nses ass ociate d wit h t y m p a nic i nje cti o n ma y i ncl u de tr a nsie nt 
verti g o, e ar pai n, di zzi n ess, na usea, ear f ull ness or tra nsie nt re d ucti o n i n h eari n g. T he e x pe cte d 
A Es relate d t o t his st u d y a n d PI P E -5 0 5 ar e f ull y s u m mariz e d i n t h e I B. 
T he  d ose of PI P E -5 0 5  i n t his st u d y is base d o n t he N O A E L esta blis he d i n n o n cli nical  st u dies (as 
s u m mariz e d a b o ve) a n d t he rele v a nt H u ma n E q ui v al e nt D ose ( H E D) c o n versi o n  deri ve d fr o m  t he 
all o m etri c differe n ce i n  p eril y m p h v ol u me fr o m t he g ui nea pi g  t o t he h u m a n. A te n-f ol d safet y 
fact or ( H E D/ 1 0) is t he n a p plie d t o t h e H E D t o calc ul ate t he Ma xi m u m Re c o m m e n de d  S afe D ose 
( M R S D). Base d o n t he n o ncli nic al  st u di es (s u m mari ze d i n t he I B), the M R S D  cal c ulate d f o r t his 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 5  of 7 3  
st u d y is a 0. 7 5 % PI P E -5 0 5 S us pe nsi o n  i n 2 0 0 mi cr olit ers (i.e., 1. 5 m g of acti ve i n gr e die nt). 
A d diti o nal d etails re gar di n g t he n o ncli nic al p har mac ol o g y a n d t o xicit y st u di es are s u m m arize d i n 
t he c urre nt versi o n of t he I B.  
1. 4  
R ati o n ale f or t he St u d y  
N o ncli nic al  effic ac y st u dies  ha v e d e m o nstrate d t he p ote nti al f or i ntrat y m p a nic a d mi nistr ati o n of 
PI P E -5 0 5 t o rest ore c oc hlear s y na pti c f u ncti o n a n d t o re ge nerate O H Cs i n a ni mal m o dels wit h 
i n d uce d c oc hl ear d ysf u ncti o n. S pe cifi call y, t h e c o c hlear s y na pse is a ke y ele me nt i n si g nal-t o-
n oise pr ocessi n g k n o w n t o be di mi nis he d i n b ot h n oise -i n d uce d a n d a ge-relat e d S N H L 
p o p ulati o ns. Diffic ult y wit h s peec h -i n-n oise is o ne of t he m ost c o m m o n c o m pl ai nts of patie nts 
wit h heari n g l oss, a n d t h ere ar e n o c urr e nt a p pr o v e d tr eat m e nts f or t his defici t i n a u dit or y f u ncti o n. 
Re ge nerati o n of c o c hle ar s y na pti c f u ncti o n m a y i m pr o ve si g nal -t o-n oise a u dit or y pr ocessi n g a n d 
t here b y s pe ec h-i n-n oise c o m pre he nsi o n, a d dressi n g o ne of t he maj or perc e pt ual disa bilities 
ass ociate d wit h S N H L.  
T he pri mar y o bj ecti ve of  t his first-i n-h u m a n st u d y is t o assess t he safet y a n d t ol era bilit y of PI P E -
5 0 5 w he n a d mi nist ere d as si n gle u nilateral i ntr at y m pa nic i njecti o n. Preli mi nar y effic ac y will be 
e x pl ore d b y c h a n ges fr o m baseli ne i n a u dit or y perf or ma nce as assesse d b y s peec h -i n-n oise tests 
a n d ele ctr o p h ysi ol o gical meas ures li n ke d t o c oc hle ar s y na ptic f u ncti o n. C ollecti vel y t hese data, i n 
a d diti o n t o s yste mic P K e x p os ure, will i nf or m t he desi g n of f ut ure cli nical st u di es wit h PI P E -5 0 5 
i n s u bjects wit h S N H L ass ociate d wit h  s pe ec h-in -n oise heari n g i m pair me nt.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d
D o w nl oa de d b y Ga vi n C hase o n 1 6 Fe b 2 0 2 2

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 6  of 7 3  
2.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1  
St u d y O bjecti ves  
2. 1. 1  
Pri m ar y  O bjecti v es  
T o assess t he safet y a n d t olera bilit y pr ofile of PI P E -5 0 5 w he n a d mi nistere d as a si n gl e u nilat eral 
i ntrat y m pa ni c i nj ecti o n. 
2. 1. 2  
Sec o n d ar y  O bjecti ves  
T o assess t he si n gle d ose plas ma P K pr ofile of PI P E-5 0 5 f oll o wi n g  a si n gle u nilateral  
i ntrat y m pa ni c i nj ecti o n. 
2. 1. 3  
E x pl or at or y  O bjecti ves  
•  T o e x pl ore t he effe ct of a si n gle u nilat eral i ntrat y m pa nic i njecti o n of PI P E -5 0 5 o n 
a u dit or y s kills re q uiri n g si g n al -t o-n oise pr ocessi n g  a n d e nc o di n g . 
•  T o e x pl ore t he effe ct of  a si n gle u nilat eral i ntrat y m pa nic i njecti o n of PI P E -5 0 5 o n 
heari n g t hr es h ol ds a n d o uter hair cell f u ncti o n . 
•  T o e x pl ore t he effe ct of a si n gle u nilat eral i ntrat y m pa nic i njecti o n of PI P E -5 0 5 o n 
a u dit or y electr o p h ysi ol o gi cal meas ures . 
2. 2  
E n d p oi nts  
2. 2. 1  
Pri m ar y  E n d p oi nt  
T he p ri m ar y en d p oi nt of t he st u d y is t he n u m ber a n d se verit y of A Es u p t o 3 m o nt hs f oll o wi n g a 
si n gle u nil ater al i ntrat y m pa nic i nje cti o n of PI P E -5 0 5.  
2. 2. 2  
Sec o n d a r y E n d p oi nts  
Si n gle d ose  plas m a P K  para m eters of PI P E -5 0 5, i n cl u di n g  A U C t, A U C2 4, A U C C ma x , tma x , t½, 
C L/ F, V z/ F, z). 
2. 2. 3  
E x pl or at or y  E n d p oi nts  
•  M ea n c ha n ge fr o m baseli ne t o 3 m o nt hs i n W R S  (perf or me d i n q uiet), Q uic k SI N, S S Q, 
S R T, a n d WI N tests  
•  M ea n c ha n ge fr o m baseli n e t o 3 m o nt hs i n p ure t o n e a u di o metr y a n d D P O A E  
•  M ea n c ha n ge fr o m baseli n e t o 3 m o nt hs i n M E M R, A B R a n d E C oc h G  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 7  of 7 3  
3.  
S T U D Y D E SI G N A N D D E S C RI P TI O N  
3. 1  
St u d y D esi g n 
T his is a  P hase I/II a ra n d o miz e d, d o u bl e-bli n d, pla c e b o -c o ntr olle d, si n gle d ose  st u d y i n s u bjects 
wit h S N H L ass ociate d wi t h s peec h-i n-n oise i m pair m e nt . Fi g ure  1  pr o vi des a sc he matic o ver vi e w  
of t he st u d y  desi g n.  
Fi g ure 1 : 5 0 5-1 0 1 St u d y Sc he m atic  
 
A p pr o xi matel y  2 4  a d ults will be e nr olle d i nt o  a si n gle d ose c o h ort c o m prise d of 1 8 A cti ve a n d 6 
P lace b o s u bj ects acc or di n g t o a 3: 1 ra n d o mizati o n. All st u d y pr o ce d ures will b e p erf or me d i n a n 
o ut pati e nt setti n g. S u bjects w h o pr o vi de writte n i nf or me d c o nse nt a n d m eet eli gi bilit y criteria will 
be ra n d o mi ze d t o r ecei v e a si n gl e i ntr at y m p a nic d ose of PI P E -5 0 5 or P lace b o ( 18 :6  PI P E -
5 0 5: P lace b o). T he P lac eb o i njecti o n will c o nt ai n t he t her m ore v ersi ble gel al o n e ( P ol o xa mer 4 0 7).  
F oll o wi n g c o nfir m ati o n of eli gi bilit y  a n d c o m pleti o n of baseli ne assess me nts , s u bjects will be 
ra n d o ml y assi g ne d t o recei ve eit her PI P E-5 0 5 or P lace b o. T he PI P E -5 0 5 or P lace b o i njecti o n will 
be a d mi nister e d i nt o t he ear wit h t he w orse a u di o metr y res ults (i.e., t he I n de x Ear , a d diti o nal 
criteria a p pl y, refer t o Secti o n 6. 3. 1 ) as a si n gle 2 0 0 micr oliter i njecti o n. T he i nj ecti o n, tar geti n g 
deli ver y n ear t he r o u n d wi n d o w nic h e, will b e perf or me d b y an ot ol o gist  or ne ur o -ot ol o gist  u n der  
ot o sc o pic vis ualizati o n of t he t y m pa nic me m bra ne ( T M), a n d will be c o n d ucte d as a n o ut-patie nt 
pr oce d ure. S u bje cts will re m ai n i n t he cli nic u ntil c o m pleti o n of t h e  assess me nts at  3 0 mi n utes 
p ost -i njecti o n, aft er w hic h t he s u bj ects ma y  lea ve t he cli nic b ut m ust ret ur n t o u n der g o t he 4-h o ur  
p ost -i njecti on  assess me nts  as per t he S O E . T h ereafter, s u bjects will  ret ur n f or visits a n d pr o ce d ures  
acc or di n g t o t he S O E  descri be d i n T a ble 2 .  
T he pri mar y, sec o n dar y a n d e x pl orat or y preli mi n ar y efficac y e n d p oi nts will be meas ure d f or u p 
t o 3 m o nt hs f oll o wi n g d ose a d mi nistrati o n.  
L ocal a d mi nistrati o n of PI P E -5 0 5 i nt o t he t y m pa nic ca vit y p er mits acc ess t o t he c oc hl ea vi a 
diff usi o n t hr o u g h t he r o u n d a n d o val wi n d o w, pr o vi di n g a r o ute of d eli v er y t h at c o n ce ntr ates t he 
acti v e pr o d uct t o t he c oc hlea a n d peril y m p h, t he t ar get or ga n a n d tiss ue of i nterest (c o nsiste nt wit h 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 8  of 7 3  
t he r o ute of a d mi nistrati o n [R O A ] i n vesti gat e d i n n o ncli ni cal st u dies i n v ol vi n g se ver al s pecies, 
i ncl u di n g n o n h u m a n pri mates [ N H P s]). T he l ocal a d mi nistr ati o n als o 
mi ni mizes s yste mic 
e x p os ure, a n d t he f or m ulati o n i n a t her m ose nsiti v e gel facilitates l o n ger e x p os ure wit hi n t he 
t y m pa ni c ca vit y, pr o xi mit y t o t he r o u n d a n d o v al wi n d o w, a n d ulti matel y l o n ger ti mes t o all o w 
o pti mal diff usi o n i nt o t he c oc hl ea.  
3. 2  
Se nti nel D osi n g Pl a n  
A se nti nel d osi n g strat e g y will b e e m pl o y e d s uc h t hat t he first 2 s u bje cts ( 1: 1, PI P E -5 0 5 :P lac e b o) 
will be d ose d a n d assesse d f or at least 2 4 h o urs pri or t o ra n d o mizi n g s u bse q ue nt s u bje cts ( 17 :5 , 
PI P E -5 0 5: P lace b o). D osi n g  of t he s u bse q ue nt n o n -se nti nel s u bjects ma y  pr ocee d aft er re vie w a n d 
a p pr o val of t he Da y 1 safet y a n d t oler a bilit y of t he 2  se nti nel s u b je cts b y t he res pe cti v e 
In vesti gat or (s) at eac h sit e (as a p plic a ble) a n d Me dic al M o nit or. If t he In vesti gat or (s) a n d M e dic al 
M o nit or d o n ot a p pr o ve d osi n g of n o n -se nti nel s u bjects, t he n t he D M C  will re vie w t he a vaila bl e 
data a n d pr o vi de f urt her r ec o m me n dati o ns wit h res p ect t o d osi n g of n o n -se nti nel s u bjects. 
3. 3  
D at a M o nit ori n g C o m mittee  
T he D M C will be c o m p ose d of at l east o ne n e ur o -ot ol o gist  a n d o n e a u di ol o gist, i n a d diti o n t o t he 
Me dical M o nit or, a bi ost atistici a n, a n d S p o ns or  re prese ntati v es. T he D M C will be res p o nsi ble f or 
t he f oll o wi n g: 
•  O n g oi n g re vie w of safet y a n d t oler a bilit y of t h e st u d y  
•  R e vie w a n d a n al ysis of all S A E re p orts 
•  R ec o m m e n dati o n t o re -i nitiate d osi n g if st u d y s us pe nsi o n criteria were o bser ve d 
•  R ec o m m e n dati o n t o t er mi n ate t h e st u d y at a n y p oi nt f or safet y p ur p oses  
F urt her d etails re g ar di n g t h e D M C, i ncl u di n g m e m bers hi p, ca n b e f o u n d i n t he D M C c harter, 
w hic h will be a vaila ble pri or t o t h e a d mi nistrati o n of i n vest i gati o nal pr o d uct (I P). T here is n o 
pla n ne d i nteri m a nal ysis or a da pti v e desi g n ele m e nt i n t his st u d y.  
3. 4  
St u d y S us pe nsi o n R ules  
If a n y of t he f oll o wi n g oc c ur, f urt her d osi n g will b e wit h hel d u ntil t he e ve nts are e val uate d b y t h e 
D M C.  
•  A n y 2 or m ore s u bjects  e x perie n ce t he sa m e or relate d se vere A E, seri o us a d verse e ve nt 
( S A E), or ot her me di call y si g nific a nt e v e nt 
•  A n y 2 or m ore s u bjects e x perie nce a 2 0  d B i ncre ase (i.e., w orse ni n g) i n a u di o metric 
t hres h ol ds at a n y o ne test fre q ue n c y ( 8 0 0 0 Hz a n d bel o w) or 1 0 d B i ncrease at a n y t w o 
a djac e nt t est fre q ue n cies at 3 0 da ys p ost -i njecti o n or be y o n d ( 8 0 00  Hz a n d b el o w)  i n t h e 
In de x E ar.  
•  At t he rec o m me n d ati o n of t he D M C base d o n o n g oi n g re vie w of c u m ulati ve safet y d ata  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 2 9  of 7 3  
Base d o n t his assess me nt, t he D M C will rec o m m e n d t o t he S p o ns or if  t he st u d y s h o ul d be 
ter mi n ate d or c o nti n u e d, a n d/ or w het her i m pl e me ntati o n of a d diti o nal safet y m o nit ori n g is 
warra nte d. If r elate d ness t o st u d y dr u g ca n n ot be r ef ute d, t he n t he e ve nts will  b e c o nfir me d as d ose 
li miti n g t o xicit y a n d d osi n g will n ot res u m e. 
3. 5  
N u m ber a n d T y pe of S u bjects  
T he st u d y is e x pecte d t o e nr oll a p pr o xi m atel y  2 4  s u bjects wit h S N H L ass ociat e d wit h s pee c h-i n-
n oise i m pair me nt . S pecificall y, t he st u d y s u bje cts will de m o nstrate e vi d e nce of el e vate d heari n g 
t hres h ol ds b y a u di o metr y a n d ha ve diffi c ult y he ari n g i n t he setti n g of bac k gr o u n d n oise as 
meas ure d b y t he Q uic k SI N test of s peec h -i n-n oise. It is esti mat e d t h at b et wee n 6 0  a n d 8 0  s u bjects 
will be scre e ne d t o c o m plete e nr oll m e nt.  
W hile t he pl ace b o eff ect h as hist oric all y b ee n c o nsi dere d s mall i n S N H L, i ncl u di n g a bli n de d 
c o ntr ol gr o u p will deli neate safet y a n d t oler a bilit y iss ues relate d t o t he R O A a n d t her m ose nsiti ve 
gel, as well as t h e p ot e nti al tr eat me nt effect siz e. Gi ve n  t he m o dest t o mi ni mal pl ace b o effect i n 
t his pati e nt p o p ul ati o n, a 3: 1 ra n d o mizati o n was c o nsi dere d j ustifie d. 
3. 6  
Sites a n d Re gi o ns  
T he st u d y will be c o n d u cte d i n N ort h A merica a n d is e x pecte d t o e nr oll s u bjects acr oss 
a p pr o xi matel y  7  i n vesti gati o nal c e nters  i n t h e U S . A d diti o nal sit es ma y be recr uite d t o e ns ure 
ti mel y e nr oll me nt of t he a p pr o priat e s u bjects. 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 0  of 7 3  
4.  
S T U D Y P O P U L A TI O N  
4. 1  
I ncl usi o n Criteri a 
S u bjects m ust m eet eac h of t he f oll o wi n g i ncl usi o n criteri a t o be eli gi ble f or ra n d o miz ati o n: 
1.  A bilit y t o pers o nall y pr o vi d e writte n, si g ne d, a n d dat e d i nf or me d c o nse nt t o parti ci pate i n t he 
st u d y. 
2.  S u bject’s pri m ar y la n g u a ge is E n glis h.  
3.  Male or fe m ale bet wee n 1 8 a n d 7 5  y ears  of a ge, i ncl usi ve, at ra n d o miz ati o n.  
4.  Dia g n osis of bilateral S N H L wit h air c o n d u cti o n t hr es h ol d el e vati o n b y p ure t o ne a u di o m etr y 
t hat is n o greater t h a n  5 5 d B at 2 5 0, 5 0 0, a n d 1 0 0 0 H z, n o greater t h a n  6 5  d B  at 2 0 0 0 Hz, a n d 
n o greater t ha n  8 5  d B  at 4 0 0 0 a n d 8 0 0 0 Hz at Scr ee ni n g i n eit her e ar.  
5.  T h res h ol d o n t he Q ui c k SI N-E P  >  4  d B S N R L oss at Scree ni n g i n at l east o ne e ar.  
6.  N or mal t y m p a n o gra m i n t he e ar i nte nd e d f or i nj ecti o n (i.e., t he I n d e x Ear),  as g ui d e d b y  a 
ra n ge of -1 4 0 t o + 4 0 de ka Pascals [ da Pa] a n d 0. 3 -2. 9 milli m h os [m m h o ]) at Scre e ni n g, a n d as 
deter mi ne d b y t h e I n vesti gat or . 
7.  Male or fe mal e s u bjects wit h re pr o d ucti ve p ot e nti al a gree t o c o m pl y wit h a p pr o v e d d o u ble 
barrier c o ntr ace pti ve m et h o d (e. g., c o n d o m pl us i ntra uteri ne de vi ce [I U D], c o n d o m pl us 
h or m o nal c o ntra ce pti o n, or d o u ble barrier met h o d, i.e., c o n d o ms a n d dia p hra g ms wit h 
s per mici d al gel or f oa m) d uri n g a n d f or 3 m o nt hs aft er st u d y dr u g a d mi nistrati o n.  
S u bjects are c o nsi dere d of n o n -re pr o d u cti v e p ote ntial if:  
a. P ost -me n o pa usal fe m ale wit h ≥1 2 c o nsec uti ve m o nt hs of s p o nta ne o us a me n orr hea 
a n d a ge ≥5 1 years wit h  f olli cle-sti m ul ati n g h or m o ne (F S H ) > 3 0 mI U/ m L at 
Scree ni n g  
b.  S ur gicall y sterile fe male a n d at least 6 wee ks p ost -sterili zati o n (i.e., bil ateral 
o o p h orect o m y or h yst erect o m y)  
c. Sterili ze d m ale at l east 1 -ye ar p ost vasect o m y a n d c o nfir me d t hat t he y ha v e 
o btai ne d d o c u me ntati o n of t he a bse n ce of s per m i n t he eja c ulate  
8.  T he s u bje ct is i n ge ner al g o o d me dical he alt h wit h n o cli ni call y si g nifica nt or rel e v a nt 
a b n or maliti es, i ncl u di n g m e dic al hist or y, p h ysical e x a m, vital si g ns, electr o car di o gra m ( E C G), 
a n d la b orat or y e v al uati o ns ( he mat ol o g y, c he mistr y, a n d uri nal ysis) as assesse d b y t he 
I n vesti gat or. 
9.  A n u n dersta n di n g, a bilit y, a n d willi n g n ess t o f ull y c o m pl y wit h st u d y pr oce d ures a n d 
restricti o ns. 
4. 2  
E xcl usi o n Criteri a  
S u bjects are e xcl u d e d fr o m t he st u d y if a n y of t h e f oll o wi n g e xcl usi o n crit eria ar e met:  
1.  M o ntreal C o g niti ve Assess me nt ( M o C A) sc ore less t ha n 2 6 at Scre e ni n g.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 1  of 7 3  
2.  Hist or y of c hr o nic otitis e xter n a or me dia, ot her c hr o nic mi d dl e ear dis or ders, or peril y m p h 
fist ula. 
3.  Prese nce of a ge netic, s y n dr o m al or de v el o p m e ntal a u dit or y dis or der.  
4.  Prese nce of a n a ut oi m m u ne or seri o us ne ur ol o gic al dis or der t hat c o ul d c o ntri b ut e t o a u dit or y 
l oss, as deter mi n ed b y t he I n v esti gat or.  
5.  Hist or y of her pes z oster otic us, or ot h er i nf ecti o us eti ol o g y of heari n g l oss as det er mi n e d b y 
t he I n vesti g at or. 
6.  Hist or y of bar otra u m a as deter mi ne d b y t he I n vesti g at or.  
7.  E vi de nc e of c urre nt c o n d ucti ve heari n g l oss, mi xe d h eari n g l oss  or ot oscler osis as deter mi ne d 
b y t he I n vesti gat or, i ncl u di n g si g nifica nt air -b o ne g a ps (i.e., > 1 0 d B o n a u di o metric testi n g , 
wit h t he e x ce pti o n of 4 0 0 0 Hz ). 
8.  Hist or y of a u dit or y l oss relate d t o e x p os ure t o k n o w n ot ot o xic dr u gs, s uc h as hi g h -d ose 
a mi n o gl y c osi de a nti bi otics (e. g., str e pt o m y ci n, ge nta mici n, t o bra m y ci n, a mi ka ci n, ne o m yci n, 
or mi n oc ycli ne) , as deter mi ne d b y t h e I n vesti g at or.  
9.  A n y pri or e x p os ure t o p lati n u m-b ase d me di cati o ns.  
1 0.  Ot ol o gical dis or ders t hat w o ul d precl u d e saf e t y m pa nic i njecti o n (e. g., hist or y or prese nc e of 
c h oleste at o m a, T M perf or ati o n, otitis m e dia, or mi d dle e ar a nat o mi c a n o mal y) as det er mi n e d 
b y t he I n vesti g at or . 
1 1.  Prese nce of a c oc hlear  i m pl a nt. 
1 2.  Hist or y of M e niere’s disease  or e n d ol y m p hatic h y dr o ps . 
1 3.  Hist or y  of b ot hers o me ti n nit us, as deter mi ne d b y t he I n vesti gat or . 
1 4.  Past ot ol o gic s ur gical pr oce d ur es t hat w o ul d precl u de saf e i ntr at y m p a nic i nje cti o n as 
deter mi ne d b y t h e I n vesti gat or.  
1 5.  I ntraty m p a nic i nje cti o n wit hi n 6 m o nt hs of ra n d o miz ati o n.  
1 6.  Use of a n i n vesti gati o nal pr o d u ct or i nt er ve nti o n ot her t ha n a n o n -i nt er ve nti o nal re gistr y st u d y 
(i ncl u di n g vac ci ne st u di es) wit hi n t he great er of 3 0 da ys or 5 half-li ves (if k n o w n) pri or t o 
Scree ni n g or e x p ecte d d uri n g t he st u d y.  
1 7.  As y m metric al a u di o metric t hres h ol d res ults > 1 5 d B bet wee n ears at a n y oct a ve fre q ue nc y 
bet wee n 2 5 0 a n d 8 0 0 0 Hz at Scre e ni n g  A N D t he p atter n of as y m metr y is  i nc o nsist e nt wit h 
S N H L  per I n vesti gat or j u d g me nt . 
1 8.  Hist or y of mali g na nc y  u n der c urre nt acti v e treat m e nt or c o nsi dere d at s u bsta nti al ris k f or 
pr o gressi o n or rec urre nce d uri n g t h e st u d y i nter v al, as deter mi n e d b y t he I n vesti g at or . N ote, 
ce ntral ner v o us s y ste m n e o plasms  or h ea d a n d ne c k ca nc er are e xcl u de d fr o m eli gi bi lit y 
re gar dless of treat me nt stat us. 
1 9.  T he s u bject has a Q Tc F b y E C G >  4 5 0 millisec o n ds f or males or > 4 7 0 millisec o n ds f or 
fe mal es.   
2 0.  T he s u bje ct h as a hist or y of d ysr h yt h mia (s uc h as atrial fi brillati o n or ve ntric ul ar t ac h yc ar dia, 
etc.) t h at is c o nsi d ere d u nsta bl e b y t he I n v esti gat or.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 2  of 7 3  
2 1.  T he s u bject has e x perie nce d a si g nifica nt s yste mic ill ness, as j u d ge d b y t he I n vesti gat or, wit hi n 
3 0 da ys pri or t o Scree ni n g.  
2 2.  T he s u bject has a c urre nt or rele v a nt hist or y of p h ysi cal or ps yc hiatric ill n ess, or a n y me dic al 
dis o r der t hat ma y re q uire tr eat me nt or ma ke t he s u bject u nli kel y t o f ull y c o m plet e t he st u d y, 
or a n y c o n diti o n t hat prese nts u n d ue ris k fr o m t he i n vesti gati o nal pr o d uct or pr o ce d ure, as 
deter mi ne d b y t h e I n vesti gat or.  
2 3.  K n o w n or s us pecte d i nt ol era nce or h y perse n siti vit y t o t he i n vesti gati o nal pr o d uct or cl osel y-
relat e d c o m p o u n ds. 
2 4.  T he s u bject is pre g na nt or breastfe e di n g or pl a ns t o b ec o me pr e g na nt d uri n g t he st u d y.  
2 5.  Hist or y of alc o h ol or ot her s u bsta nce a b use wit hi n 6 m o nt hs of Scree ni n g as deter mi ne d b y t he 
I n vesti gat or. 
2 6.  S u bject is He patitis B p ositi v e ( S u bje cts w h o ar e s urface a nti b o d y p ositi v e sec o n d ar y t o 
i m m u ni zati o n are eli gi ble). 
2 7.  H ist or y of H e patitis C. 
2 8.  S u bject is H u ma n I m m u n o defici e nc y Vir us ( HI V) ser o p ositi ve . 
4. 3  
Re pr o d ucti ve P ote nti al  a n d Pre g n a nc y A v oi d a nce  
Se x uall y acti ve fe males of c hil d beari n g p ot e nti al ( F O C P ) m ust a gre e t o use a n a cce pta bl e f or m of 
c o ntrac e pti o n. F O C P  will  be a d vise d t o use a cce pta bl e c o ntra ce pti ves fr o m t he ti m e of si g ni n g t h e 
I nf or me d C o nse nt F or m (I C F) a n d f or at l east 3 m o nt hs  f oll o wi n g t he a d mi nistrati o n of t he  I P. If 
h or m o nal c o ntra ce pti ves ar e use d t he y s h o ul d be a d mi nister e d a cc or di n g t o t he pac k a ge i nsert , i n 
a d diti o n t o use of a n a p pr o v e d b arrier met h o d . F O C P  w h o are n ot c urr e ntl y se x uall y acti ve m ust 
a gree t o use a cce pta bl e c o ntrace pti o n, as defi n e d bel o w , if t he y bec o m e se x uall y acti ve d uri n g t he 
st u d y peri o d . 
Male s u bjects wit h re pr o d ucti ve p ote ntial a gree t o c o m pl y wit h a p pr o ve d d o u ble barri er 
c o ntrac e pti v e met h o d  fr o m ti me of si g ni n g t he I C F a n d f or 3 m o nt hs aft er I P a d mi nistrati o n . I n 
a d diti o n, t he y m ust b e a d vise d t o n ot d o nate s per m d uri n g t his peri o d.  
A n acce pta bl e met h o d of c o ntra ce pti o n is defi ne d as o ne t hat has n o hi g her t ha n a 1 % fail ure rate. 
I n t his st ud y, t he o nl y acc e pta ble met h o ds of c o ntra c e pti o n ar e:  
C o n d o ms use d wit h t he f oll o wi n g ac ce pt a ble c o ntrac e pti ves:  
•  I U Ds 
•  H or m o nal c o ntr ace pti ves ( oral, d e p ot, patc h, i njecta ble, or va gi n al ri n g)  
Ot her acc e pta bl e d o u ble b arrier c o ntra ce ptive  met h o ds are:  
•  D o u b le barrier met h o ds (e.g ., c o n d o ms a n d dia p hr a g ms wit h s per mici dal g el or f oa m) 
•  Male c o n d o m P L U S s per mi ci de  
•  Ca p ( pl us s per mici dal crea m or jell y) P L U S male c o n d o m a n d s per mi ci de  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 3  of 7 3  
•  Dia p hra g m ( pl us s per mici d al cre a m or j ell y) P L U S male c o n d o m a n d s per mici de  
•  C o p per T P L U S c o n d o m or s per mi ci de . 
4. 4  
Restri cti o ns  
S u bjects s h o ul d c o m pl y wit h t h e f oll o wi n g r estricti o n s after i ntr at y m p a nic i njecti o n.  
•  Pre ve nt water e x p os ure  (e. g., s h o wer s pra y) or s u b mersi o n  (e. g., s wi m mi n g, bat hi n g ) of 
t he i njecte d e ar, u ntil cle are d b y f oll o w -u p ot ol o g y e xa mi nati o n t o c o nfir m cl os ure of t he 
T M  o pe ni n g.  S u bj ects will be i nstr uct e d o n h o w t o c o m pl etel y c o v er t h e In de x E ar t o 
e na ble s h o weri n g u ntil clear e d.  
•  A bstai n fr o m hea v y p h ysi cal e xerti o n f or 2 4 h o urs f oll o wi n g i nj ecti o n.  
•  N o  i nserti o n of c ott o n-ti p p e d a p plicat ors i nt o t he e xter nal ear ca nal of  eit h er e ar u ntil 
clear e d b y f oll o w -u p ot ol o g y e xa mi nati o n t o c o nfir m cl os ure of t he T M  o pe ni n g.  
•  N o use of a n  occl u di n g ear m ol d heari n g ai d i n t h e I n de x Ear f or 3 da ys f oll o wi n g i nject i on . 
4. 5  
Wit h dr a w al of S u bjects  
A s u bject ma y wit h dra w fr o m t he st u d y at a n y ti me f or a n y re as o n wit h o ut prej u dice t o t heir f ut ure 
me dic al care ; h o we ver, pri or t o ra n d o mizati o n, it s h o ul d be ma de cl ear t o p ote ntial s u bje cts t h at 
earl y wit h dra wal fr o m t h e st u d y i ncl u di n g l oss t o f oll o w u p ma y p ose s o me ris k t o t h e s u bje ct a n d 
ca n be da m a gi n g t o t h e sci e ntific r esearc h. O nce a s u bject has be e n ra n d o miz e d, t h e In vesti gat or 
will ma k e e ver y r eas o na ble eff ort t o k ee p t h e s u bject i n t he st u d y.  
T he I n vesti gat or or S p o ns or  ma y wit h dra w t he s u bj e ct at a n y ti me d uri n g t h e st u d y i n t h e i nterest 
of s u bject saf et y. I n s uc h cases, th e wit h dra wal of a s u bject b y  t he I n vesti gat or s h o ul d be disc usse d 
w he ne ver p ossi ble wit h t he Me di cal M o nit or . 
After st u d y dr u g a d mi nistr ati o n, s u bjects s h o ul d c o nti n ue t o be f oll o we d t hr o u g h c o m pleti o n of 
t he st u d y u nless a s u bje ct wit h dr a ws c o nse nt or is l ost t o f oll o w u p. 
R e gar dles s of t he reas o n(s) f or earl y ter mi nati o n of a s u bject, fi nal e val uati o ns are t o be p erf or me d 
as c o m pletel y as p ossi ble.  C o m me nts (s p o nta ne o us or elicite d) or c o m plai nts ma de b y t he s u bject , 
t he reas o n f or ter mi nati o n, date of wit h dr a wal , a n d t he t otal a m o u nt of I P a d mi nist ere d  m ust b e 
d oc u me nt e d . 
S u bjects w h o disc o nti n ue pri or t o t h e Da y 3 0 assess me nt f or a re as o n ot her t ha n a n A E ma y be  
re plac e d a n d ra n d o miz e d t o t he sa me tre at m e nt assi g n me nt . S u bjects w h o disc o nti n ue after Da y 
3 0 will n ot be r e pla ce d. 
4. 5. 1  
Re as o ns  f or S u bject Disc o nti n u ati o n  
Reas o ns f or s u bject disc o nti n uati o n i n cl u de, b ut are n ot li mite d t o:  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 4  of 7 3  
•  A d verse e ve nt: A s u bje ct m a y be disc o nti n ue d fr o m st u d y d ue t o A E  o nl y fr o m t he ti m e of 
ra n d o miz ati o n ( offi cial st u d y e ntr y) u ntil t h e ti m e of I P a d mi nistrati o n. If a s u bject 
e x perie n ces a n A E  aft er t h e si n gle d ose I P a d mi nistr ati o n, t he s u bj ect s h o ul d c o nti n ue t o 
be f oll o we d i n t he st u d y a n d w o ul d o nl y disc o nti n u e pre mat ur el y if t h e s u bject wit h dr a ws 
c o nse nt or is l ost t o f oll o w u p. 
•  Pr ot oc ol  vi ol ati o n or s u bj ect n o n -c o m plia nce. 
•  S u bject w it h dra wal of c o nse nt : A s u bj ect s h o ul d be c o nsi dere d t o ha ve wit h dra w n c o nse nt 
w he n t he s u bje ct n o l o n ger wis hes t o partici pat e i n a n y as pect of t h e st u d y, a n d d oes n ot 
w a nt a n y f urt her assess me nts, visits, or c o ntact. A s u bject’s ref usal t o partici p ate i n s pecific 
as pects of t h e st u d y, s uc h as a r ef usal t o c o nti n ue t o pr o vi de bl o o d sa m pl es, will N O T 
c o nstit ut e wit h dr a wal of c o nse nt. I n vesti gat ors s h o ul d ma k e e v er y eff ort t o fa cilitate t he 
s u bject’s c o nti n ue d partici pati o n i n re m ai ni n g as pects of t he st u d y.   
•  L ost t o f oll o w -u p : A s u bject will n ot be c o nsi dere d l ost t o f oll o w-u p u ntil t he e n d of t he 
1 2 -wee k f oll o w u p peri o d a n d after all eff orts t o c o ntact t he s u bject ha ve be e n e x ha ust e d. 
At least 3  d o c u me nte d att e m pts m ust be ma d e t o c o ntact a n y s u bj ect l ost t o f oll o w -u p at 
a n y ti m e p oi nt  pri or t o t he last sc he d ule d c o ntact ( office visit or tele p h o ne c o ntact) . O ne of 
t hese d oc u me nte d atte m pts m ust i n cl u de a writte n c o m m u nic atio n se nt t o t he s u bj ect’s last 
k n o w n a d dress via c o urier or mail ( wit h a n ac k n o wle d ge m e nt of recei pt re q uest ) as ki n g 
t hat t h e y ret ur n t o t he site f or fi nal safet y e val u ati o ns. 
4. 6  
E arl y Ter mi n ati o n of St u d y/ Cl os ure of Site  
T he st u d y m a y be ter mi nat e d earl y if n e w t o xi c ol o gi cal fi n di n gs or res ults affecti n g t h e safet y of 
t he s u bje cts be c o me a vaila bl e. T h e S p o ns or reser ves t he ri g ht t o t er mi n ate t he st u d y at a n y ti me 
f or a n y reas o n. 
T he S p o ns or ma y ter mi n ate a st u d y sit e at a n y ti me f or a n y reas o n, i ncl u di n g i n a de q uate s u bject 
recr uit me nt, G o o d Cli nic al Practi ce (G C P ) n o n -c o m plia n ce, p o or q ualit y dat a, e vi de n ce of 
atte m pte d or pr o v e n fra u d, or f or a n y re as o n at t h e S p o ns or’s discreti o n.  
I n t he e ve nt t he S p o ns or ter mi nates a par tic ular st u d y site pri or t o t he e n d of t he trial, t he sit e staff 
is res p o nsi ble f or n otif yi n g t he I nstit uti o nal R e vie w B oar d (I R B). 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 5  of 7 3  
5.  
P RI O R A N D C O N C O MI T A N T T R E A T M E N T  
5. 1  
Pri or Tre at me nt  
Pri or treat me nt i ncl u des all tre at m e nt (i n cl u di n g her b al tre at m e nts, vita mi ns, n o n-p h ar ma c ol o gi cal 
treat me nt s uc h as ps yc h ot hera p y as a p pr o pri ate) re cei ve d wit hi n 3 0 da ys of si g ni n g t he I C F. Pri or 
treat me nt i nf or mati o n m ust b e rec or de d o n t he a p pr o priate case re p ort f or m ( C R F ) p a ge.  
5. 2  
C o nc o mit a nt  Tre at me nt  
C o nc o mi t a nt tre at m e nt ta k e n fr o m t he date of si g ni n g t he I C F t hr o u g h t he 9 0-d a y f oll o w -u p visit 
will be  liste d o n t h e a p pr o pri ate C R F pa g e. 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 6  of 7 3  
6.  
I N V E S TI G A TI O N A L P R O D U C T 
Refer t o t he P TI -5 0 5 -1 0 1 P har mac y Ma n u al f or f urt h er details re g ar di n g ha n dli n g of t he I Ps i n t his 
st u d y. 
6. 1  
Descri pti o n  of  I n vesti g ati o n al Pr o d uct  
 
  
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
 
 
. 
A d diti o nal i nf or mati o n is pr o vi d e d i n t h e I B a n d t he P har mac y Ma n ual.  
6. 2  
R a n d o mi z ati o n C o de G e ner ati o n a n d St or a ge  
T he ra n d o mizati o n sc he d ule will be ge n erat e d b y t he S p o ns or  or desi g nee a n d l oa de d t o t he 
I nteracti ve V oi ce/ W e b Res p o nse S yste m (I x R S) p ri or t o the start of t he st u d y.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 7  of 7 3  
6. 3  
A d mi nistr ati o n of I n vesti g ati o n al Pr o d uct(s)  
6. 3. 1  
I n de x E ar Selecti o n a n d D osi n g  Pr oce d ure  
T he I P or P lace b o will be a d mi nistere d b y a n i ntrat y m pa nic i nje cti o n as a n o ut-patie nt pr o ce d ure  
b y a q ualifi e d ot ol o gist or ne ur o -ot ol o gist. T he  e ar select e d f or d osi n g (i.e., t he  In de x E ar) will b e 
i de ntifie d base d o n t he a u di o metr y a n d Q uic k SI N res ults at Scre e ni n g as f oll o ws :  
•  T he ear wit h t he w orse a u di o metr y, as det er mi n e d b y t he PI, will be i de ntifie d as t he I n de x 
E ar. 
•  If b ot h ears are e q u al b y a u di o metr y, t he e ar wit h t h e hi g hest S N R o n t he Q uic k SI N will 
be defi ne d as t he In de x E ar. 
•  If t he a u di o m etr y a n d Q uic k SI N are e q u al i n e ac h e ar, t he PI a n d s u bject will deter mi n e 
t he In de x E ar. 
Ot osc o p y of t he I n de x Ear ca nal a n d T M  will be perf or me d pri or t o a d mi nistrati o n  a n d excessi ve 
ear wa x or de bris will be  ma n uall y cle are d. At t he discreti o n of t he ot ol o gist or ne ur o -ot ol o gist  
perf or mi n g t he i ntr a-t y m p a nic i nj ecti o n, a t o pical a nest heti c (e. g., E M L A crea m  [e ute cti c 
li d ocai ne/pril oc ai ne mi xt ure ] or  x yl ocai ne [4 % li d o cai ne s ol uti o n or 1 0 % p u m p s pra y ]) ma y  be 
a p plie d  t o t he e xter n al t y m pa nic me m br a ne. Gi v e n t h e tra nsi e nt disc o mf ort ass ociate d wit h t o pical 
a nest hesia a n d t he e xtre mel y s mall ga u g e of t he nee dle use d f or i njecti o n,  t he In vesti gat or ma y 
als o elect t o perf or m t he i ntra-t y m pa ni c i nje cti o n wit h o ut use of a t o pical a n est hetic , aft er 
disc ussi o n  wit h t he s u bj ect . If a p pli e d, an y  re mai ni n g a nest hetic i n t he e xt er nal ca nal will b e 
s ucti o ne d off pri or t o t he i nj ecti o n i n or der t o a v oi d s pilla g e i nt o t he t y m pa ni c ca vit y a n d p ossi ble 
verti g o or di zzi n ess. A n y l ocal a nest h eti c, if utili ze d, s h o ul d be rec or de d in t he s u bje ct’s s o urce 
rec or d a n d t h e C o nc o mita nt Me dicati o ns case r e p ort f or m.  
T he i nje cti o n will  be perf or me d u n der ot o micr osc o p y  f oll o wi n g sta n dar d tra nst y m pa nic 
pr oce d ural tec h ni q ue, a n d wit h t he s u bj ect recli n i n g at a n a n gle of u p t o 3 0 ° o n t he e xa mi nati o n 
ta ble or c hair. T h e s u bject’s hea d will be tilte d 4 5° t o war ds t he u naffecte d ear d uri n g t he i njecti o n 
a n d f or 1 0  mi n utes f oll o wi n g t he a d mi nistrati o n . T his will all o w t he r o u n d wi n d o w nic he a n d 
me m bra n e  t o be at t h e l o west p oi nt of t he t y m pa nic c a vit y, facilitati n g t he I P t o c oll ect i n t he r o u n d 
wi n d o w nic he a n d ha ve direct c o nt act wit h t he r o u n d wi n d o w  me m bra ne. T he i njecti o n will be 
perf or me d usi n g a 1 m L l uer-l oc k syri n ge  w it h a 3. 5 -i nc h 2 5 -2 7 -ga u ge  ne e dle  ( g a u ge base d o n 
In vesti gat or prefer e nce) . T h e p osteri or i nferi or q ua dra nt of t he T M  will be p u nct ure d wit h t he 
i njecti o n ne e dl e of c h oic e, a n d t h e 2 0 0 mi cr oliters of eit her t he PI P E -5 0 5  S us pe nsi o n  or Dil ue nt  
al o ne ( P lac e b o) will be deli vere d t o t h e t y m pa nic ca vit y o ver 5 -1 0 sec o n ds. T he In vesti gat or will 
mai nt ai n vis uali zati o n of t he ne e dle be vel past t he T M o pe ni n g t o a v oi d c o ntact wit h t he r o u n d 
wi n d o w a n d ot her critic al mi d dle e ar str uct ur es.  
S u bjects will re mai n i n t his p ositi o n f or a p pr o xi m atel y 1 0 mi n utes  in or der t o a v oi d earl y l oss of 
me dic ati o n i nt o t he nas o p har y n x t hr o u g h t h e E ust ac hia n t u b e . I n a d diti o n, su bje cts  will be as ke d 
t o refrai n fr o m e x cessi ve s wall o wi n g, ya w ni n g, or s peec h f or 3 0 mi n ut es  f oll o wi n g t he i nje cti o n. 
After 3 0 mi n utes, t h e s u bject will ha v e n o restricti o n o n activit y , wit h t h e e xc e pti o n of restricti o ns 
o utli ne d i n Secti o n  4. 4 . 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 8  of 7 3  
6. 3. 2  
Bli n di n g t he T re at me nt A ssi g n me nt 
St u d y dr u g s u p plies will be pr o vi de d t o sites as f ol l o ws: 
O pe n -la bel vials of D il ue nt f or PI P E-5 0 5 S us pe nsi o n  (als o a d mi nistere d al o n e as P lace b o) will be 
pr o vi de d i n b ul k f or mat t o b e st ore d at 2 -8 C. A n o p e n -la bel D il u e nt vial will be utilize d f or ea c h 
d ose a d mi nistr ati o n, w het her mi xe d wit h t he A cti v e In gre die nt or gi ve n al o ne as P lac e b o. 
I de ntic al a p peari n g st u d y dr u g kits will be s u p plie d t o sites a n d st ore d at c o ntr oll e d r o o m 
te m per at ure. Ea c h kit will c o nt ai n eit her an o pe n -la b el vial of PI P E -5 0 5 A cti ve In gre die nt, or s ha m 
c o nte nts t o mi mic t he wei g ht of a vial of A cti ve In gr e die nt. Kits will be la bele d wit h a u ni q ue kit 
n u m ber t o be assi g ne d t o s u bje cts as t he y are ra n d o mi ze d vi a t h e I x R S s yste m f or d osi n g. Alt h o u g h 
t he trai ne d p har macist  or n urse (i.e., d ose pre parer) pre pari n g t he st u d y dr u g d ose f or 
a d mi nistr ati o n is u n bli n d e d, t he i de ntic al a p pe ari n g bli n de d kits are utili ze d t o pre ve nt u n bli n di n g 
of bli n de d st u d y staff w h o m a y ha ve ge n eral acc ess t o t he st u d y dr u g st ora ge areas . 
A n u n bli n de d d ose pre par er  will:  
•  Be res p o nsi ble f or pr e pari n g t he st u d y d ose  of PI P E -5 0 5 or Place b o acc or di n g t o t he 
ra n d o miz ati o n assi g n me nt ( kit n u m b er) o btai n e d t hr o u g h t he I x R S  
•  Deli ver t he pr el oa d e d s yri n ge t o t h e u n bli n d e d ot ol o gist  or ne ur o -ot ol o gist  r es p o nsi ble f or 
a d mi nist eri n g t he d ose t o t he s u bject. T he prel oa de d s yri n ge will be c o vere d  t o pre ve nt 
c o nte nt vis uali zati o n b y a n y ot h er pers o n ( ot her t ha n t he res p o nsi ble pers o n  perf or mi n g t h e 
i njecti o n) Be i de ntifi e d o n t he site d ele g ati o n of res p o nsi bilit y l o g as t he u n bli n de d d ose 
pre parer  
•  Be restricte d fr o m p artici pati n g i n a n y s u bj ect assess me nt  
•  Be restrict e d fr o m discl osi n g tr eat me nt assi g n m e nts t o a n y st u d y staff, wit h t he  e xc e pti o n 
o utli ne d i n Secti o n 6. 3. 4   
T he P lace b o f or m ulati o n will c o nsist of t he t h er m ose nsiti ve gel (P ol o xa mer 4 0 7)  alo ne.  D ue t o 
f or m ulati o n ste ps, as well as t he cle ar c ol or of t he g el al o ne  i n c o m paris o n t o t he o pacit y of t he 
PI P E -5 0 5 S us pe nsi o n, t he ot ol o gist perf or mi n g t he intrat y m p a nic i njecti o n ca n n ot be m as ke d fr o m 
s u bject’s assi g n me nt.  
A n  u n bli n de d ot ol o gist /n e ur o -ot ol o gist  is res p o nsi ble f or st u d y dr u g a d mi nistrati o n. T h e u n bli n de d 
ot ol o gist or ne ur o -ot ol o gist is per mitt e d t o perf or m a n d/ or i nter pret safet y assess me nts i ncl u di n g 
vital si g ns, electr ocar di o gr a ms ( E C G), cli nic al la b orat or y t est res ults (r o uti ne h e mat ol o g y, 
c hemistr y a n d uri nal ysis), p h ysic al a n d ot ol o gic al e xa mi nati o ns a n d A Es/ S A Es as descri be d i n 
Secti o n 8 , A d verse a n d Seri o us A d verse E ve nts Assess me nt. T he u n bli n de d o t ol o gist/ne ur o -
ot ol o gist is pr o hi bit e d fr o m c o n d ucti n g a u di o metr y, dist orti o n pr o d u ct o pt o ac o usti c e missi o n, 
a u dit or y br ai nste m res p o nses, electr oc oc hle o gra p h y ( E C oc h G), mi d dle ear m uscle refl e x, S pee c h 
S patial Q ualities of Heari n g Sc ale, 
W or d Rec o g niti o n Sc ore ( W R S), S peec h Re c o g niti o n 
T hres h ol d ( S R T), Q uic k Se nt e nces -i n-N oise ( Q uic k SI N), a n d W or ds -i n-N oise ( WI N).  
T he s u bject , all assess ors res p o nsi ble f or e val u ati n g t he s u bjects or i nter pr eti n g d ata o btai n e d 
t hr o u g h t hese assess me nts, a n d ot h er t ea m me m b ers will re mai n bli n de d  t o s u bje ct assi g n me nt f or 
t he e ntir e st u d y d urati o n (i.e., t hr o u g h data base l o c k) wit h t he e xce pti o ns of t he d ose pre parer a n d 
ot ol o gist/ n e ur o -ot ol o gist w h o a d mi nisters st u d y dr u g . T he s u bject will be pre ve nte d fr o m 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 3 9  of 7 3  
vis ualizi n g t he f or m ulati o n d uri n g t h e pr oce d ure. All ot her In vesti g at ors a n d assess ors will be 
bli n de d.  
6. 3. 3  
All oc ati o n of S u bjects t o Tre at me nt  
T he a ct ual tr eat me nt a d mi nister e d t o i n di vi d ual s u bjects is det er mi n e d b y t he r a n d o mi zati o n 
sc he d ule. R a n d o mi zati o n will occ ur se que ntiall y  vi a t he I x R S , i n t he or der b y w hic h eli gi bl e 
s u bjects ar e ra n d o mize d i n t he I x R S o n Da y 0  ( Da y 0 is t he da y of ra n d o mizati o n a n d tr eat me nt). 
All s u bjects m ust h a ve c o m plete d eli gi bilit y verifi cati o n pri or t o tr eat me nt all o cati o n.  
T he S u bject I D n u m ber  assi g ne d at Scr ee ni n g will b e retai ne d t hr o u g h o ut t he st u d y a n d use d b y 
t he cli nic al sit e t o i d e ntif y t he s u bject f or all as pects of t he st u d y. 
O verall, s u bje cts will be ra n d o miz e d i n a 3: 1 rati o ( PI P E -5 0 5: P lace b o) b ut i n di vi d uall y will b e 
base d o n t he f oll o wi n g criteria:  
•  Se nti nel s u bj ects (i. e., first 2 s u bj ects t o be d ose d) will be ra n d o miz e d i n a 1: 1 rati o ( PI P E -
5 0 5: P lace b o) 
•  Re mai ni n g s u bjects will be r a n d o mi ze d i n a 1 7 :5  rati o ( PI P E-5 0 5: P lace b o) 
6. 3. 4  
U n bli n di n g t he T re at me nt A ssi g n me nt 
T he i n v esti gati o nal dr u g bli n d s hall n ot be br o ke n u nless i nf or mati o n c o ncer ni n g t h e 
i n vesti gati o nal dr u g is necessar y f or t he me dic al tre at me nt of t he s u bject. All st u d y assess me nts 
a n d ca usalit y assess me nt s h o ul d be perf or me d, if p ossi ble, pri or t o u n bli n di n g. I n t he e ve nt of a 
me dic al e mer ge n c y, if p ossi bl e, t h e 
M e dic al M o nit or s h o ul d be c o nta cte d b ef ore t h e 
i n vesti gati o nal dr u g bli n d is br o ke n t o disc uss t he n e e d f or u n bli n di n g. 
I n t he rare e ve nt t hat a n e mer g e nc y u n bli n di n g is re q uire d, t he i n vesti gati o nal dr u g treat me nt 
assi g n me nt c a n be o bt ai ne d t hr o u g h t he I x R S. 
T he S p o ns or  m ust be n otifie d as s o o n as p ossi ble if t he i n vesti gati o nal dr u g bli n d is i nt e nti o n all y 
or acci de ntall y br o ke n. T h e dat e, ti m e, a n d re as o n t he bli n d is br o ke n m ust be re c or de d i n t h e 
s o urce d oc u me nts a n d t he sa me i nf or m ati o n ( e xce pt t he ti me) m ust b e rec or de d o n t he electr o nic 
case re p ort f or m (e C R F). 
U ni nte nti o n al u n bli n di n g of treat me nt assi g n m e nt m ust be re p ort e d t o t he S p o ns or  as s o o n as 
p ossi ble, a n d wit hi n 2 4 h o urs of oc c urre nc e.  S u bje cts w h o are u ni nt e nti o n all y u n bli n d e d (i. e., 
s u bject or bli n d e d assess or bec o mes a ware of t heir treat me nt assi g n m e nt f or reas o ns ot her t h a n 
me dic al e m er ge ncies) will c o nti n ue i n t he st u d y . A n a d diti o nal s u bje ct ma y be a d d e d at t he 
discreti o n of t he S p o ns or, i n c o ns ult wit h t he D M C. A bli n de d site staff me m ber w h o bec o mes 
u n bli n de d f or a gi v e n s u bject will be pr o hi bit e d fr o m s u bse q ue nt a u di ol o gi cal assess me nts of t hat 
s u bject a n d will ne e d t o be re plac e d . 
N o c ha n ge s h o ul d be m a de t o a n y  saf et y assess me nt of t he s u bject aft er u n bli n di n g.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 0  of 7 3  
F oll o wi n g assess me nt of t h e A E dat a a n d pre -d efi ne d crit eria f or st u d y t er mi nati o n, d osi n g  m a y  
be i nt err u pte d/st o p pe d a n d t h e bli n d br o ke n f or f urt her a nal ysis. Base d o n re vi e w of u n bli n de d 
data, t he S p o ns or  i n c o ns ultati o n wit h t he D M C a n d I n vesti gat ors will deci d e if a n d h o w it is 
a p pr o priat e f or t he st u d y t o pr ocee d.  
6. 4  
L a beli n g , P ac k a gi n g, St or a ge, a n d H a n dli n g  
6. 4. 1  
L a beli n g  
L a bels pertai ni n g t o t he i n vesti gati o nal s u p pl y vi als m ust meet all a p plic a ble re q uire me nts of t he 
F D A, A n ne x 1 3 of c G M P ( Ma n ufact ur e of I n v esti gati o nal Me dici nal Pr o d ucts, J ul y 2 0 0 0) a n d/ or 
ot her l oc al re g ulati o ns, as a p plic a ble.  
6. 4. 2  
P ac k a gi n g  
 
 
 
6. 4. 3  
St or a ge  
A ll I P kits a n d D il ue nt vials will be st or e d as per t h e la bel e d i nstr ucti o ns.  
T he I n vesti gat or has o ver all ac c o u nta bilit y  f or e ns uri n g t hat I P is st or e d i n a sec ure, li mit e d-acc ess 
l ocati o n. D ose pre par ati o n  s h o ul d be del e gat e d t o t h e trai ne d u n bli n de d p h ar ma cist or n urse a n d  
m ust be d oc u m e nte d . I Ps are f or m ul ate d a n d tra ns p orte d t o t he i n di vi d ual res p o nsi ble f or 
a d mi nistr ati o n  i n a bli n de d m a n ner.  
IP  m ust be st ore d i n acc or da n ce wit h l a bel e d st or a ge c o n diti o ns. T e m per at ure m o nit ori n g is 
re q uire d at t he st ora g e l ocati o ns t o e ns ure t hat t he I P is mai ntai ne d wit hi n a n esta blis he d 
te m per at ure r a n ge. T he I n v esti gat or is res p o nsi bl e f or e ns uri n g t hat t h e t e m per at ure is m o nit ore d 
t hr o u g h o ut t he d ur ati o n of t he st u d y a n d t hat rec or ds are mai ntai n e d; t h e te m perat ure s h o ul d b e 
m o nit ore d c o nti n u o usl y b y usi n g eit her  a n i n-h o use s yste m, a mec h a nic al r ec or di n g de vi ce, s uc h 
as a cali brate d c hart r ec or der, or b y ma n ual mea ns, s uc h t hat b ot h mi ni m u m a n d m a xi m u m 
t her m o m etri c val ues o ver a s pe cifi c ti m e peri o d c a n be rec or de d a n d retrie v e d as re q uire d. S uc h a 
de vice ( e. g., certifie d 
Mi n/ Ma x T her m o meter) w o ul d re q uir e 
ma n ual resetti n g u p o n e ac h 
rec or di n g. T he S p o ns or  m ust be n otifi e d u p o n disc o ver y of a n y e xc ursi o n fr o m t he est a blis he d 
ra n ge. T e m per at ure e xc ursi o ns will r e q uire site i n v esti gati o n as t o c a use a n d re m e diati o n. T he 
S p o ns or  will det er mi ne t he ulti mate i m pact of e xc ursi o n s o n t he I P a n d will pr o vi de s u p p orti ve 
d oc u me nt ati o n as ne cessar y.  U n der n o circ u msta nc es s h o ul d pr o d uct be dis pe nse d t o s u bj ects u ntil 
t he i m p act is deter mi ne d a n d pr o d u ct is de e me d a p pr o priate f or use b y S p o ns or . 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 1  of 7 3  
6. 4. 4  
H a n dli n g  
Detail e d d ose pre parat i o n i nstr ucti o ns ar e pr o vi d e d i n t he P har ma c y Ma n ual. I n di vi d ual d oses i n 
t he s yri n ge pre pare d f or a d mi nistrati o n t o a s u bject s h o ul d be c o vere d b y a c o oli n g bl a n ket or pa d 
fr o m t he ti me of f or m ulati o n u ntil a d mi nistr ati o n, pr otect e d fr o m li g ht, a n d m ust b e a d mi nist ere d 
wit hi n 3 h o urs  of f or m ulati o n . 
T o mai ntai n t h e bli n d, d oses pre par e d f or a d mi nistr ati o n will  b e deli vere d i n a bli n de d ma n ner 
fr o m t he d ose pre parer  t o t h e i n vesti g at or w h o will a d mi nister t h e d ose. Neit her t h e st u d y s u bject, 
n or a n y ot her b li n de d staff s h o ul d be per mitt e d t o vis ualize t h e c o nte nt. O nce pre pare d, t h e d ose 
will  be mas ke d (e. g., seale d b o x  or ot her t y pe of sec ure c o ver ) d uri n g tra ns p ort a n d u ntil 
a d mi nistr ati o n t o pre ve nt u n bli n di n g of a n y bli n de d staff me m bers . 
6. 5  
I n vesti g ati o n al Pr o d uct Q u alit y C o m pl ai nts  
I n vesti gat ors ar e re q uire d t o re p ort I P q ualit y c o m plai nts t o t he S p o ns or  wit hi n 1  b usi ness da y . 
T his i ncl u des a n y i nsta n ces w herei n t he q ualit y or perf or ma n ce of  t he I P d o es n ot meet 
e x pect ati o ns ( e .g ., i na d e q uat e or f a ult y cl os ure, pr o d uct c o nta mi nati o n) or t hat t he pr o d u ct di d n ot 
meet t he s pecificati o ns defi ne d i n t he a p pli cati o n f or t he pr o d uct (e .g ., wr o n g pr o d uct s uc h t h at t he 
la bel a n d c o nt e nts are differe nt pr o d ucts). Re p orti n g i nstr ucti o ns are i ncl u de d i n t he P har m ac y 
Ma n ual.  
6. 6  
Dr u g Acc o u nt a bilit y  
I n vesti gat ors will b e pr o vi de d wit h s ufficie nt a m o u nts of t he bli n de d I P kits t o c arr y o ut t his 
pr ot oc ol f or t he a gree d n u m ber of s u bjects. T he recei vi n g st u d y staff will ac k n o wle d ge recei pt of 
all st u d y dr u g kit s hi p me nts  via t he I x R S s yste m . Acc urate rec or ds of all I P dis pe nse d, use d, 
ret ur ne d, a n d/ or destr o ye d m ust be mai ntai ne d as det aile d f urt her i n t his secti o n.   
T he I n vesti gat or has o verall res p o nsi bilit y f or e ns uri n g t hat a n a p pr o pri ate dele gate, i.e., u n bli n de d 
trai ne d p har m acist  or n urse , pr e pares a n d dis pe ns es  I P f or t he a p pr o priate s u bjects per t he st u d y 
pr ot oc ol a n d P har ma c y Ma n ual . T his del e gati o n m ust be d o c u me nte d  i n t h e a p pli ca bl e st u d y 
dele gati o n of a ut h orit y f or m . 
T he In vesti gat or  is als o res p o nsi ble f or e ns uri n g t hat t he I P is a d mi nistere d o nl y t o s u bjects 
i ncl u de d i n t his st u d y b y a q ualifie d desi g nee  (i. e., t h e u n bli n de d ot ol o gist, as d oc u me nte d b y t h e 
I n vesti gat or i n t h e a p pli ca bl e st u d y dele gati o n of a ut h orit y f or m) f oll o wi n g t he pr oc e d ures set o ut 
i n t he st u d y pr ot oc ol a n d P har m ac y Ma n ual . Eac h s u bject will be gi ve n o nl y t h e I P carr yi n g his/ her 
treat me nt assi g n me nt. All dis pe nsi n g will be d oc u me nte d  i n t h e I P acc o u nta bilit y re c or ds.  
After t he te ar -off la b el h as bee n re m o v e d fr o m t he assi g ne d st u d y dr u g kit a n d affi x e d t o t h e Dr u g 
Acc o u nta bilit y L o g , t h e u n bli n de d d ose pr e parer a n d/ or a d mi nisteri n g ot ol o gist/ ne ur o-ot ol o gist 
s h o ul d pr o perl y dis p ose use d kits, vi als, n ee dles, a n d s yri n ges i m me diatel y u p o n use per l oc al, 
state, a n d n ati o n al re g ulati o ns. 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 2  of 7 3  
N o I P st oc k or ret ur ne d i n ve nt or y fr o m t h e S p o ns or  ma y be re m o ve d fr o m t he site w her e ori gi nall y 
s hi p pe d wit h o ut pri or k n o wle d ge a n d c o nse nt b y t he S p o ns or . If s uc h tra nsfer is a ut h ori ze d  b y t h e 
S p o ns or , all a p pli ca bl e l oc al, state, a n d nati o nal la ws m ust be a d her e d t o f or t h e tra nsfer.  
T he S p o ns or  or its re pr ese ntati ves m ust be per mitt e d acc ess t o re vie w t he s u p plies st ora g e a n d 
distri b uti o n pr o ce d ures a n d r ec or ds pr o vi de d t hat t he o verall bli n d of t h e st u d y is n ot c o m pr o mise d.  
At t he e n d of t he st u d y, or as i nstr ucte d b y t he S p o ns or , all u n use d st oc k a n d re mai ni n g u n use d I P 
pac ka gi n g  ma y  be se nt t o t he S p o ns or or desi g ne e. IP  bei n g ret ur ne d t o t h e S p o ns or  or desi g nee  
m ust be verifi e d b y t he S p o ns or  or desi g nee  pri or t o ret ur n s hi p me nt. T a m p er e vi de nt feat ure s 
m ust n ot be br o ke n. S hi p m e nt ret ur ns m ust  be d o c u me nt e d o n t he a p pr o priat e acc o u nta bilit y 
rec or ds. S hi p me nt of all r et ur ne d I P m ust c o m pl y wit h l ocal, st ate, a n d nati o nal la ws.  
Wit h t he writt e n a gree m e nt of t he S p o ns or , u n use d st oc k  a n d e m pt y /use d I P pac ka gi n g  ma y be 
destr o ye d at t he site or a l oc al facilit y  acc or di n g t o t h e site’s sta n dar d o perati n g pr oce d ur es ( S O P) . 
In t his case , destr ucti o n rec or ds m ust be r etai ne d wit h c o pies  pr o vi de d t o t h e S p o ns or . Destr ucti o n 
of I P m ust be i n ac c or da nce wit h l oc al, state, a n d n ati o nal l a ws.  
Base d o n e ntries i n t he sit e dr u g acc o u nta bilit y f or ms, it m ust be p ossi ble t o rec o n cil e I Ps deli vere d 
wit h t h ose use d a n d ret ur ne d. All I Ps m ust be acc o u nte d f or a n d all discre pa n cies i n vesti gate d a n d 
d oc u me nt e d.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 3  of 7 3  
7.  
S T U D Y P L A N  
7. 1  
St u d y Sc he d ul e   
All pr oce d ures will be c o n d ucte d ac c or di n g t o t h e S O E  pr o vi de d i n Ta ble 2 . F or a n y gi ve n  
pr oce d ure, s u bjects are t o be assesse d b y t he sa m e In vesti gat or or sit e pers o n nel, w he ne ver 
p ossi ble , t hr o u g h o ut t h e d urati o n of t he st u d y. 
7. 1. 1  
Scree ni n g P e ri o d  
Scree ni n g assess me nts ma y b e gi n after t he s u bj ect has pr o vi de d writte n i nf or m e d c o nse nt as 
d oc u me nt e d b y a si g ne d I C F. S cre e ni n g pr oc e d ures ma y be c o n d u cte d o v er m ulti pl e da ys b ut m ust 
occ ur wit hi n 5 6  d a ys of ra n d o mi zati o n.  
7. 1. 1. 1  S u bject I D N u m ber Assi g n me nt & Tr acki n g  
U p o n si g ni n g of a n I C F, ea c h scree ne d s u bj ect will be re gistere d f or Scr ee ni n g i n t he I x R S a n d 
assi g ne d  a u ni q u e S u bject I D  n u m ber t o be ret ai ne d t hr o u g h o ut t h e d urati o n of t he st u d y. T he 
s u bject I D n u m ber will c o nsist of 6 di gits ( X X X-Y Y Y; w here X X X  =  3 -di git site n u m ber a n d 
Y Y Y  =  3 -di git se q ue ntial n u m ber  wit hi n e ac h sit e ).  
7. 1. 1. 2  Scree n F ail ures  
A scree n fail ure is a s u bj ect w h o has gi ve n i nf or m e d c o nse nt a n d faile d t o meet t h e i n cl usi o n a n d/ or 
meet s at least 1 of t h e e xcl usi o n criteria a n d has n ot b ee n ra n d o mi ze d or a d mi nist ere d I P as defi ne d 
b y t he pr ot oc ol.  
Scree ni n g assess me nts ma y be re peate d b y I n v esti gat or discreti o n if t he I n vesti gat or belie ves t h e 
i niti al assess me nt m a y n ot be c orr ect or a n a n o mal y. Scree n fail e d su bjects ma y be rescre e ne d f or 
t he st u d y o ne ti m e if t h e I n vesti g at or belie v es t hat circ u mst a nces ha v e c ha n g e d s uc h t hat t h e 
s u bject w o ul d bec o me eli gi bl e an d t he 
Me di cal 
M o nit or a grees. R e-scree n e d s u bjects are 
re gistere d i n I x R S as ne w scree ns a n d recei ve a ne w S u bject I D n u m ber. S u bject I D n u m bers 
assi g ne d t o s u bjects w h o fail S cre e ni n g are n ot re use d.  
I n vesti gat ors m ust ac c o u nt f or all s u bj ects w h o si g n the I C F. Reas o ns f or scre e n fail ure m ust be 
d oc u me nt e d i n t h e s u bject rec or d a n d e C R F f or all scree n faile d s u bjects.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 4  of 7 3  
T he pri m ar y reas o n f or s cree n f ail ur e is rec or d e d usi n g t he f oll o wi n g cat e g ories:  
•  Di d n ot meet i ncl usi o n criteri a or di d me et e x cl usi o n cr iteria 
•  Si g nifica nt pr ot oc ol de vi ati o n  
•  L ost t o f oll o w -u p  
•  V ol u ntar y wit h dra wal  
•  St u d y ter mi n ati o n  
•  Ot her  
7. 1. 2  
R a n d o miz ati o n a n d D ose A d mi nistr ati o n Visit ( D a y 0)  
S u bjects w h o q ualif y f or t he st u d y will ret ur n t o t he st u d y cli ni c f or a d diti o nal baseli ne a n d pr e -
d ose  pr oce d ures a n d c o nfir mati o n of c o nti n ue d eli gi bilit y  as per t he S O E.  F oll o wi n g 
ra n d o miz ati o n a n d a d mi nistrati o n of t he st u d y d ose, s u bjects will re m ai n i n t he cli nic u ntil 
c o m pleti o n of  t h e assess me nts at 3 0 mi n utes p ost-i nj ecti o n, after w hic h t he s u bje ct s ma y lea v e t he 
cli ni c b ut m ust ret ur n t o u n der g o t he 4-h o ur  p ost -i nj ecti on assess me nts as per t h e S O E.  S u bjects 
ma y be ke pt i n t h e cli nic l o n g er aft er eit her p ost -i nje cti o n assess me nt b ase d o n t he I n vesti gat or’s 
me dic al discr eti o n (e. g., t o ma n a ge a n y A Es ).  
7. 1. 2. 1  I nter acti ve V oice/ W e b Res p o nse Syst e m f or S u bject Tr acki n g/ D at a C oll ecti o n 
A n I x R S will be use d t o assi g n ra n d o miz e d tre at m e nt assi g n me nts. I nstr ucti o ns f or use of t he I x R S 
will pr o vi de d i n a se par ate m a n ual.  
7. 1. 3  
F oll o w -u p P eri o d  ( D a ys 1-9 0)  
S u bjects will r et ur n t o t he st u d y cli ni c i n a cc or da nce wit h t h e S O E ( Ta bl e 2 ) f or f oll o w-u p 
pr oce d ures o ver t he c o urse of 3 m o nt hs, starti n g 1 da y after t h e st u d y dr u g a d mi nistrati o n.  
7. 1. 4  
E arl y Ter mi n ati o n  
S u bjects w h o disc o nti n ue earl y will be e nc o ura g e d t o ret ur n t o t he site t o c o m pl ete e arl y 
ter mi n ati o n assess me nts f or safet y p ur p oses. Earl y ter mi nati o n pr oce d ures s h o ul d f oll o w t he Da y 
9 0 sc he d ule acc or di n g t o t he S O E ( Ta ble 2 ). T he re as o n f or disc o nti n uati o n m ust be d oc u m e nte d 
i n t he s o urce d o c u me nt a n d e C R F.  
F or all s u bj ects rec ei vi n g st u d y m e dic ati o n, t h e In vesti gat or m ust c o m plete t he E n d of St u d y e C R F 
pa ge.  
7. 1. 5  
A d d iti o n al Care of S u bjects A fter t he S t u d y 
N o after care is pla n ne d f or t his st u d y.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 5  of 7 3  
7. 2  
St u d y E v al u ati o ns a n d Pr oce d ures  
N ote, de taile d descri pti o ns of t h e m et h o ds use d  f or t h e a u diol o gical assess me nts ( Secti o n 7. 2. 1 0  –  
Secti o n  7. 2. 2 2  bel o w ) are i n cl u de d se par atel y i n t h e St u d y Assess me nt Ma n ual. 
7. 2. 1  
I nf or me d C o nse nt 
T he re q uire m e nts of t he I C F are descri b e d i n Secti o n 1 0. 3. 1 . T he I C F m ust be o btai ne d pri or t o 
t he s u bject e nt eri n g i nt o t he st u d y, a n d bef ore a n y pr ot oc ol-relate d pr oce d ures are perf or m e d, 
i ncl u di n g r e q uesti n g t hat a s u bject fast f or la b or at or y e val uati o ns. 
7. 2. 2  
De m o gr a p hics, Me dic al Hist or y, a n d Me dic ati o n Hist or y  
De m o gra p hic i nf or mati o n t o be o btai ne d will i ncl u d e date of birt h, se x, His pa nic et h nicit y, rac e as 
descri be d b y t h e s u bject, a n d s m o ki n g stat us of t he s u bject at Scre e ni n g.  
Me dical hist or y t o b e o bt ai ne d will i ncl u de d eter mi ni n g w het her t he s u bject h as a n y si g nific a nt 
c o n diti o ns or diseases t h at st o p p e d at or pri or t o si g ni n g t he I C F. T he me di cal hist or y s h o ul d als o 
i ncl u de a det ail e d a u di ol o gical i nt er vie w. 
Me dicati o n hist or y i nf or m ati o n t o be o btai ne d i n cl u des a n y m e dic ati o n rel e va nt t o eli gi bilit y 
criteria st o p pe d at or wit hi n 3 0 da ys pri or t o si g ni n g of I C F.  
7. 2. 3  
P h ysic al E x a mi n ati o n  
C o m plet e p h ysic al e x a mi n ati o ns  p er e ac h i nstit uti o n ’s g ui deli n es, will b e perf or me d acc or di n g t o 
t he S O E (Ta ble 2 ). B o d y wei g ht will b e meas ure d at Scree ni n g a n d Visit 7 ( E n d of St u d y),  a n d 
hei g ht will o nl y be m eas ure d at Scree ni n g. A b n or m aliti es i de ntifie d at t he Scr ee ni n g Visit will be 
d oc u me nt e d i n t h e s u bject’s s o urce d oc u me n ts a n d o n t he me dical hist or y C R F.  
A n y a b n or mal c ha n ge fr o m t he baseli n e  p h ysical e xa mi nati o n assess me nt m ust be assesse d as n ot 
cli ni call y si g nifi ca nt or cli ni call y si g nifi ca nt b y t he In vesti gat or a n d rec or d e d i n t he s o urc e 
d oc u me nt a n d e C R F. A n y cli nica ll y si g nifica nt c ha n ge or ne w dia g n osis as a res ult of a cli ni call y 
si g nifica nt c ha n ge, as det er mi n e d b y t he In vesti g at or, will be rec or d e d as a n A E i n s o urce 
d oc u me nt ati o n as  descri be d i n Se cti o n  8 .  
7. 2. 4  
Ot ol o gic al E x a mi n ati o n  
T he ot ol o gic e xa mi nati o n  will i ncl u d e dir ect e xa mi n ati o n of t he e xter nal ear, ear ca nal a n d T M  b y 
ot osc o pe, as well as  sta n d ar d t esti n g of t y m p a nic m o bilit y. T he ot ol o gical e x a mi n ati o ns will be 
c o n d ucte d b y t h e u n bli n de d ot ol o gist or n e ur o -ot ol o gist w h o perf or ms t he i ntr at y m p a nic i nj ecti o n 
a n d als o c o n d u cts all p ost -i nj ecti o n ot ol o gic al e x a mi nati o ns t hr o u g h at l east Da y 3 0, a n d 
prefera bl y t hr o u g h o ut t h e st u d y.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 6  of 7 3  
7. 2. 5  
Vit al Si g n s 
Vital si g ns ( p ulse rat e, res pirati o n rat e, b o d y te m perat ure, a n d bl o o d press ure [B P ]) will be 
rec or de d after t he s u bj ect h as bee n seate d or s u pi ne f or at le ast 5  mi n utes.  
O n Da y 0 ( D osi n g Da y), vital si g ns ar e c o n d u cte d at 3 ti m e p oi nts: pre -d ose, 3 0 ( 5) mi n utes p ost -
d ose, a n d 4 h o urs ( 1 5 mi n ut es) p ost -d ose.  
B P  s h o ul d be deter mi n e d b y cuff ( usi n g t he sa me m et h o d, t he sa me ar m, a n d i n t he sa m e p ositi o n 
t hr o u g h o ut t he st u d y). A n y cli nicall y si g nific a nt de viati o ns fr o m baseli n e vital si g ns w hic h are 
dee me d cli nicall y si g nifica nt i n t he o pi ni o n of t h e I n vesti gat or are rec or d e d as a n A E. 
Vita l si g ns s h o ul d be m eas ure d at t he sa me ti me of t he da y a cr oss visits if p ossi ble. W h e n vit al 
si g ns are sc he d ule d at t h e sa me visit  as bl o o d dra ws, t he vit al si g ns s h o ul d be re c or de d first . 
7. 2. 6  
E C G Pr oce d ure  
Sta n dar d 1 2 -le a d E C Gs will be re c or de d at ti me p oi nts s pecifie d i n t he S O E (Ta ble 2 ). T h e E C G 
at Scree ni n g ma y be r e peate d at t he I n vesti gat or’s dis creti o n t o c o nfir m t he Q Tc F res ult.  T he  Da y 
0 E C G will o nl y b e c o n d u cte d at 4 h o urs  ( ± 1 5 mi n ut es) p ost -d ose . S u bjects s h o ul d be i n a s u pi ne 
p ositi o n f oll o wi n g a n a p pr o xi mat e 5 -mi n ute rest p eri o d f or E C G r ec or di n gs.  W he n a n E C G is 
sc he d ule d at t he sa me ti me as bl o o d dra ws or vit al si g ns, t he E C G  s h o ul d pre ce de t he vitals a n d 
bl o o d dra w.  A d diti o nal u nsc he d ul e d E C Gs m a y be re c or de d w here cli nic all y nec essar y f or s u bje ct 
safet y. 
All stati o n ar y 1 2 -lea d E C G mac hi nes will be ca pa ble of me as uri n g Q Tc . S h o ul d te c h nic al 
diffic ulties oc c ur d uri n g re c or di n g  of t h e E C G, a re as o na ble atte m pt s h o ul d be m a de t o r e peat t he 
E C G s h ortl y after t he faile d att e m pt. O ne c o p y of t he 1 2 -lea d E C G wit h t he p h ysicia n’s si g nat ur e 
a n d date of assess me nt will b e file d wit h t he s o urc e d oc u me nts.  
7. 2. 7  
Pre g n a nc y Testi n g   
F S H le vels will be o bt ai ne d o n p ost-me n o pa usal w o me n o nl y t o v erif y c hil d be ari n g p ote ntial.  
A ser u m beta h u ma n c h ori o nic g o n a d otr o pi n ( H C G ) pre g na nc y t est is perf or m e d o n all  fe mal es of 
c hil d-be ari n g p ote ntial  (F O C P ) d uri n g t h e Scree ni n g Peri o d. A  uri ne pre g na nc y t est will b e 
perf or me d  at s u bse q ue nt ti me p oi nts. I f pre g na nc y is s us pecte d pri or t o d osi n g , t h e s u bje ct will b e 
wit h dra w n  fr o m t h e st u d y. If pr e g na nc y is s us pecte d after d osi n g, t he s u bj ect s h o ul d re m ai n i n t he 
st u d y f or f oll o w-u p safet y pr oce d ur es  t hro u g h st u d y c o m pleti o n.  
7. 2. 8  
M o ntre al C o g niti ve Assess me nt ( M o C A)  
T he M o C A  is a brief 3 0-q uesti o n test t hat assesses s u bjects f or de me ntia. T h e test e v al uates 
orie ntati o n, s h ort -ter m m e m or y, e xec uti ve f u ncti o n, vis u os patial a bilit y, l a n g ua ge s kill, atte nti o n, 
a n d a bstracti o n. Sc ores o n t he M o C A ra n ge fr o m zer o t o 3 0, wit h a sc or e of 2 6 or hi g her ge nerall y 
c o nsi dere d n or m al. T h e test t a kes 1 0 -1 2 mi n utes t o a d mi nister.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 7  of 7 3  
7. 2. 9  
L a b or at or y a n d A u dit or y E v al u ati o ns  
7. 2. 9. 1  Cli nic al S afety L a b or at ory Assess me nts  
A ce ntral la b, sele cte d a n d c o ntr act e d b y t he S p o ns or, will be res p o nsi bl e f or a nal ysis of  la b orat or y 
tests o utli n e d i n Ta ble 3 . T he ce ntr al l a b will pr o vi de a la b ma n ual wit h sa m pl e pr ocessi n g 
i nstr ucti o ns, sa m pli n g kits a n d s hi p pi n g materials t o eac h site. T he n a me a n d a d dress of e ac h 
cli ni cal la b orat or y use d i n t his st u d y will be mai nt ai n e d i n t he I n v esti gat or’s files at eac h site.  
All cli ni cal la b orat or y assa ys will be perf or me d a cc or di n g t o t he la b or at or y’s n or mal pr oce d ures. 
Refere nc e ra n ge s s u p plie d b y t he la b orat or y will be use d t o assess t he cli nical l a b orat or y dat a f or 
cli ni cal si g nifi ca nce a n d o ut -of -ra n ge pat h ol o gic al c h a n ges. T he I n vesti g at or s h o ul d assess o ut-of -
ra n ge cli nical la b or at or y val ues f or cli nical si g nifi ca nce, i n dicati n g if t he val ue(s) is/are n ot 
cli ni call y si g nific a nt  or cli ni call y si g n ific a nt. A b n or mal cli nic all y si g nifica nt l a b orat or y val ues, 
w hic h are u n e x pect e d or n ot e x plai ne d b y t he s u bj ect’s cli nic al c o n diti o n ma y b e, at t he discreti o n 
of t he I n vesti g at or or S p o ns o r, re peat e d u ntil c o nfir me d, e x pl ai ne d, or r es ol ve d.  
Cli nic al l a b orat or y tests are liste d i n Ta bl e 3 . 
T a ble 3 : Cli nic al L a b or at o r y Tests 
He m at ol o g y  
Ser u m C he mistr y  
Uri n al ysis 1  
C o a g ul ati o n 1  
Ot her tests1  
He mat ocrit  
He m o gl o bi n  
Platelets  
R e d bl o o d cell 
(R B C ) c o u nt 
W hite bl o o d cell 
(W B C ) w/ 
differe ntial ( % 
a n d a bs ol ute) 
ala ni ne a mi n otra nsferas e  
al b u mi n 
al kali ne p h os p hatas e 
a m ylas e 
as partate 
a mi n otra nsferas e 
bicar b o nate  
bl o o d urea nitr o ge n  
calci u m 
c hl ori de  
creati ne ki nas e 
creati ni ne  
ga m ma -gl uta m yl 
tra nsferas e 
gl uc os e  
i n or ga nic p h os p h or us 
lactate de h y dr o ge nase 
li pas e 
p otassi u m  
s o di u m 
t otal bilir u bi n 
t otal pr otei n 
uric aci d  
 
 
Bilir u bi n  
Bl o o d  
Gl uc os e  
Ket o nes  
le u k oc yte esteras e 
micr os c o p y 5  
nitrite  
p H  
pr otei n  
s pecific gra vit y 
ur o bili n o ge n  
acti vate d partial 
t hr o m b o plasti n 
ti me 
i nter nati o nal 
n or malize d rati o  
partial 
t hr o m b o plasti n 
ti me 
Ser u m Pre g na nc y 2  
Uri ne pre g na nc y 3  
F S H 4  
He patitis B  
He patitis C  
HI V  
1perf or me d o nl y at Scree ni n g  
2perf or me d o nl y i n F O C B P at Scree ni n g  
3perf or me d o nl y i n F O C B P o n Da y 0 pri or t o R a n d o mizati o n  a n d at eit her Earl y T er mi nati o n or C o m pleti o n  
4perf or me d o nl y i n p ost -me n o pa us al w o me n   
5perf or me d o nl y as nee de d base d o n p ositi ve di pstic k test res ults  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 8  of 7 3  
7. 2. 9. 2  Bl o o d S a m pli n g f or P K A n alysis  
Bl o o d sa m ples f or a nal ysis of PI P E -5 0 5  plas ma c o nce ntrati o ns will be c oll ect e d at eac h of t he 
desi g nate d ti me p oi nts . N ote t h at o n Da y 0, P K sa m ples will be c ollecte d pre -d ose a n d 4 h o urs ( ± 1 5 
mi n utes) p ost -d ose. I nstr ucti o ns f or sa mple c ollecti o n, pr ocessi n g , st ora ge, a n d s hi p me nt are 
pr o vi de d i n a se parate l a b ma n ual.  All plas ma P K sa m ples will be a nal yze d b y a ce ntral 
bi oa nal ytic al l a b .  
7. 2. 1 0  
T y m p a n o m etr y 
T y m pa n o m etr y assesses t he  relati o ns hi p bet wee n t he air press ure i n t he ear ca n al a n d t he 
m o ve me nt of t h e T M . T h e t est me as ures  t he c o m pli a nce of t he T M t o c h a n ges i n air press ure, as 
well as refl e x c o ntra cti o n of t he mi d dle ear m uscles (Secti o n 7. 2. 1 1 ).  
Ot osc o pic e xa mi nati o n 
will d oc u m e nt t h at t h e T M is clear a n d 
wit h o ut p erf orati o n. 
A 
t y m pa n o m eter pr o be is i nserte d i nt o t he ear w hic h  c h a n ges press ure wit hi n t h e ca n al a n d ge n erat es 
a t o ne of 2 2 6 Hz. T he ge n erat e d t o ne is tra ns mitte d t hr o u g h t he mi d dle ear a n d t he reflecte d s o u n d 
is e x presse d as c o m plia nc e. T he dat a meas ure d b y t y m pa n o metr y are pl otte d as a t y m pa n o gr a m 
t hat c hara cterizes t he ear c a nal v ol u me (c m 3), ma x pr ess ure ( da Pa), a n d pea k c o m plia nc e ( m L). A  
T y pe A  t y m pa n o gra m is c o nsi dere d reflecti ve of n or mal press ure i n t he mi d dl e ear a n d n or m al 
m o bilit y of t he T M a n d ossicles.  Pr o of of c ali br ati o n of t he t y m pa n o met er will be d o c u me nte d f or 
eac h sit e.  
7. 2. 1 1  
Mi d dle E ar M uscl e Refle x ( M E M R)  
T he M E M R  (als o ref erre d t o as t he st a pe di us or a c o ustic refle x ) m eas ures t he f u ncti o n a n d i nte grit y 
of t he mi d dl e a n d i n ner e ar,  as well as  t he se ve nt h a n d ei g ht h cra nial n er ve s ( pr o xi mal t o t he 
i n ner vati o n of sta pe di us) . T he M E M R  is use d t o m o nit or t h e sta pe dial r efle x t hat o cc urs i n 
res p o nse t o hi g h -i nt e nsit y s o u n d, a n d e m pl o ys t he s a me t ec h ni q u e as use d wit h t y m pa n o m etr y. 
W he n prese nte d wit h a hi g h -i nt e nsit y s o u n d sti m ul us, t he sta pe di us a n d te ns or t y m pa ni m uscles 
of t he  ossicles c o ntract. T he sta pe di us stiffe ns t he ossic ular c hai n b y p ulli n g t h e sta pes of t h e 
mi d dle e ar a wa y fr o m t h e o val wi n d o w of t he c oc hle a a n d t he t e ns or t y m pa ni m uscle stiff e ns t he 
ossic ular c hai n b y l o a di n g t h e T M w he n i t p ulls t he mall e us i n t o war d t he mi d dle ear. T he refle x 
decreases t h e tra ns missi o n of vi brati o n al e n er g y t o t h e c oc hl ea .  
T he M E M R meas ures t he  s o u n d press ure le vel fr o m w hic h a s o u n d sti m ul us of a gi ve n fre q ue nc y 
tri g gers t h e a c o ustic refle x (i.e., w he n t he sta p e di us m uscle c o ntra cts, t h e ossic ular c hai n stiffe ns, 
ca usi n g a s mall c ha n g e i n c o m pli a nce i n t h e 
mi d dle ear s yste m t hat is detect e d b y t he 
t y m pa n o m eter). D y na mic c ha n ges w hic h r es ult fr o m c o ntracti o n of sta p e di us i n res p o nse t o sti m uli 
of 1 0 0 0, 2 0 0 0, a n d 4 0 0 0  Hz, at i nt e nsiti es of 7 0 – 1 1 5  d B s o u n d press ure le vel, are m eas ure d a n d 
t he t hres h ol ds f or acti vati o n d oc u m e nte d. B ot h i psilater al a n d c o ntral ateral sti m ulati o n will be 
m pl o ye d.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 4 9  of 7 3  
7. 2. 1 2  
S peec h Rec o g niti o n T hres h ol d ( S R T)  
T he S R T is t h e s oftest i nte nsit y s p o n dee w or d ( test e d i n q uiet c o n diti o ns ) t hat t he s u bje ct ca n 
re peat at le ast 5 0 % of t h e ti m e. S p o n dees are defi ne d as bis ylla bi c w or ds t hat e q uall y e m p hasiz e 
b ot h s ylla bl es. T he bis ylla bi c w or ds are prese nt e d t o eac h e ar se paratel y t hr o u g h i nsert ear p h o nes  
i n t he s o u n d b o ot h. Base d o n t he p ure t o ne t hres h ol ds, t he i niti al i nte nsit y is set at a n a u di ble l e vel. 
T he s u bject is as ke d t o re peat t he prese nte d w or d. If t he res p o nse is c orrect, t he sti m ul us i nte nsit y 
if decrease d b y 1 0 d B; a n i nc orre ct res p o nse will lea d t o a n i ncrease i n t he sti m ul us i nt e nsit y b y 
5 d B. Sta n dar d brac keti n g pr oce d ur es are c o nti n u e d u ntil t h e sti m ul ati o n le vel f or s pee c h 
rec o g niti o n is 5 0 % c orr ect, t here b y i de ntif yi n g t h e S R T f or t hat s u bject. Effe cti v e mas ki n g s h o ul d 
be pr o vi de d (a n d re c or de d) as per t h e a u di ol o gist c o n d ucti n g t h e test . T h e S R T res ult f or eac h e ar 
s h o ul d be c o nsiste nt wit h t he p ur e t o ne a vera ge.  
7. 2. 1 3  
W or d Rec o g niti o n Sc ore ( W R S)  
T he 
W R S i n q uiet assesses t he  a bilit y t o re peat p h o ne mic all y bal a nce d si n gl e s ylla ble w or d s 
u n k n o w n t o t he s u bject. T he w or ds ar e prese nte d at 3 5 -4 0 d B S L or at M ost C o mf ort a ble Le v el 
( M C L), as deter mi ne d b y t he e xa mi ner, vi a i nsert e ar p h o nes or hea d p h o n es i n t h e s o u n d b o ot h . 
T he rec or de d list of N U -6 w or ds  ( N ort h wester n U ni versit y A u dit or y Test N o. 6) are prese nte d t o 
eac h e ar se par atel y, a n d t he s u bje ct is as ke d t o re peat t h e w or ds. T he n u m ber of c orrect a n d 
i nc orrect res p o nses are d oc u m e nte d as a perc e nta g e f or eac h e ar.  
7. 2. 1 4  
Ti n nit us Re acti o n Q uesti o n n aire ( T R Q)  
T he T R Q is a self -re p orte d scale desi g n e d t o assess t he ps yc hol o gical distr ess ass ociate d wit h 
ti n nit us. T he sc ale rec or ds ti n nit us-relate d effects o n lifest yle  a n d g e neral well -bei n g . S pecificall y, 
the 2 6 -ite m sc ale c o vers ge n eral distress, i nterfere n ce wit h w or k a n d l eis ure a cti viti es, si g ns of 
se vere distress, a nd a v oi da nc e of a cti viti es. T he s u bje ct rat es eac h ite m o n a 5 -p oi nt sc ale acc or di n g 
t o t he de gr ee of a p plica bilit y.  
7. 2. 1 5  
S peec h , S p ati al , a n d Q u alities of He ari n g Sc ale ( S S Q) 
T he S S Q was de vel o pe d t o assess liste ners’ s u bjecti ve se nse of list e ni n g a bilit y a n d list e ni n g 
e x perie n ce i n e v er y da y c o m pl e x sit u ati o ns t hat ofte n i n v ol ve  s pati al h eari n g. T he 4 9-it e m self-
assess me nt of heari n g meas ures t he a bilit y/ disa bilit y i n a variet y of c o m pl e x liste ni n g sit uati o ns 
t y pical of t h ose e nc o u nt ere d i n e ver y d a y lif e. T he s u bject will c o m pl ete t h e res p o nse t o eac h 
q uesti o n a n d t h e a ns wers will be sc ore d b y t he In vesti gat or.  
7. 2. 1 6  
Q uic k SI N -E P  
T he Q uic k SI N T M  ( Et y m otic Resear c h) is a s pe ec h-i n-n oise test t h at q uic kl y a n d easil y m eas ures 
t he a bilit y t o he ar i n n oise. T h e Q ui c k SI N i ncl u d es a t ot al of 1 8 u ni q u e 6 -se nte nc e lists c o m p ose d 
of I nstit ute of Electric al a n d Electr o nics  E n gi n e ers (I E E E) s e nt e n c es, w hi c h w er e d esi g n e d t o  
pr o vi de li mite d c o nte xt u al c ues t o ai d i n u n derst a n di n g.  T he se nte nc es are s p o ke n b y a fe mal e 
tal ker a n d are prese nt e d at a c o nsta nt le vel i n a bac k gr o u n d of 4-tal ker ba b ble ( o ne male a n d t hree 
fe mal es). T he ba c k gr o u n d n oise is c o nsi der e d m ost re prese ntati ve of t he n oise e n c o u ntere d i n 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 0  of 7 3  
t y pical s ocial sit uati o ns. T he ba b bl e le v el i n e ac h list decr eases i n i nte nsit y i n 5 d B ste ps fr o m + 2 5 
t o 0 d B i n or der t o var y t he si g nal-t o-n oise rati o ( S N R)  (Killi o n  et al. , 2 0 0 4 ). T he t est pr o vi des a n 
assess me nt of t he s u bject’s a bilit y t o u n dersta n d s pee c h i n n oise as a S N R rat her  t ha n as a perce nt 
c orrect sc ore . F or t he p ur p oses of t his st u d y, t he Q uic k SI N perf or me d wit h i nsert ear p h o nes will 
be referre d as Q uic k SI N -E P.  
T he s u bject is as ke d t o re p eat t he se nte n ces prese nte d b y i nsert ear p h o nes  i n t he s o u n d b o ot h, a n d 
eac h se nt e nce has 5 ke y w or ds. Eac h c orrectl y re p eate d w or d is a war de d o ne p oi nt f or a p ossi ble 
sc ore of 3 0 p oi nts per list. T he sc ore is deter mi ne d b y t he use of t he f or m ula 2 5. 5  - T otal W or ds 
C orrect = S N R l oss. T he S N R l oss sc ore , calc ul ate d f or eac h e ar se paratel y, r e prese nts t h e S N R a 
liste ner wit h heari n g l oss re q uires a b o v e t he S N R a n or mal he ari n g liste ner r e q uires t o ac hi e ve 
5 0 % c orrect se nte n ce i d e ntificati o n (Killi o n , 1 9 9 7 ). T he test will b e c o n d uct e d acc or di n g t o t he 
m o st c urre nt ma n ual a n d versi o n.  
T he Q uic k SI N will  als o a d mi nister e d b y  s o u n d fiel d (see Secti o n 7. 2. 1 8  bel o w) t o assess bi na ural 
s peec h-i n-n oise p erf or ma nc e.  
7. 2. 1 7  
W or ds -i n-N oise ( WI N ) 
T he W or ds -i n-N oise test e val u ate s t he a bilit y of a liste ner t o u n dersta n d w or ds i n t he setti n g of 
m ulti -tal k er ba b ble bac k gr o u n d. T h e le vel of t he m ulti -tal k er bac k gr o u n d is fi xe d a n d t he sti m ul us 
w or ds are prese nte d at se ve n si g nal -t o-n oise rati os fr o m 2 4 t o 0 d B i n 4 d B de cre m e nts. T he  w or d 
lists are base d  o n  t he N ort h west er n U ni versit y A u dit or y Test N o. 6 (Till ma n a n d Car hart, 1 9 6 6 ) 
a n d s p o ke n b y a f e mal e s pea k er. T h e m o n os ylla bic w or ds are pre -re c or de d wit h a n ois y 
bac k gr o u n d. T h e t est is a d mi nister e d usi n g i nsert ear p h o nes i n t he s o u n d b o ot h a n d is c o n d uct e d 
i n eac h e ar se parat el y. T h e test assesses t he si g nal-t o-n oise rati o f or ea c h ear at w hic h rec o g niti o n 
perf or ma nc e is 5 0 % acc or di n g t o t h e S pear m a n -Kar ber e q uati o n (Wils o n  et al., 2 0 0 7). 
7. 2. 1 8  
S o u n d Fiel d S peec h Test : Q uic k SI N-S F  
S o u n d -fiel d (fre e-fiel d) S pee c h testi n g si g nals are prese nte d via a si n gle fr o nt s pe a ker at a 0 ° 
azi m ut h t o t h e s u bject’s face w h o is p ositi o ne d i n t he ce nter of t he r o o m.  T he Q uic k SI N test c o nte nt 
will be use d t o assess s peec h detecti o n i n t h e setti n g of bac k gr o u n d m ulti -tal k er ba b ble, all o wi n g 
bi na ural meas ure me nt of s peec h -i n-n oise p erf or ma n ce  i n t he s o u n d fiel d. F or t he p ur p oses of t his 
st u d y, t he Q uic k SI N perf or me d i n t he s o u n d fiel d will be ref erre d as Q uic k SI N -S F.  
7. 2. 1 9  
P ure T o ne A u di o metr y  
T he p ure t o ne a u di o gra m m eas ures  t h e s u bje ct’s he ari n g a bilit y b y fre q u e nc y ( pitc h) a n d i nte nsit y 
( v ol u me) b y b ot h air a n d b o ne c o n d ucti o n . T he a u di o gra m det er mi n es t he de gre e, t y pe, a n d 
c o nfi g urati o n of heari n g l oss. T he test assess es  air a n d b o ne c o n d ucti o n t hres h ol ds f or eac h ear 
o ver fre q ue n cies fr o m 2 5 0 Hz t o 8 0 0 0 Hz  ( n ote, b o ne c o n d ucti o n is n ot me as ure d at 2 5 0 or 
8 0 0 0 Hz) . E xte n de d h i g h fre q u e nc y heari n g fr o m 1 0 0 0 0 Hz t o 1 6 0 0 0 Hz will als o be assesse d , if 
a vail a ble base d o n site a u di o meter s pecificati o ns.  T o re d uce a m bie nt n oise, p ure -t o n e a u di o m etr y  
will be perf or me d i n a s o u n d b o ot h c o n n ecte d t o a n e xter nal a u di o meter wit h  i nsert ear p h o nes u p 
t o 8 0 0 0 Hz a n d circ u ma ural hea d p h o n es  f or fre q ue ncies a b o ve 8 0 0 0 Hz. T he insert e ar p h o nes are 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 1  of 7 3  
s mall tra ns d uc ers w hic h fit i nt o t he ear ca n al a n d f urt her re d uce a m bie nt n oise a n d cr oss o ver of 
a u dit or y sti m uli t o t he n o n -test e ar. 
T he a u di o metr y , usi n g p ulse d t o ne sti m ul us, will be perf or me d ac c or di n g t o st a n dar ds as o utli n e d 
b y t he  m o difi e d H u g hs o n 
Westla k e pr oce d ure as  per A N SI sta n dar ds (A N SI S 3. 2 1 -1 9 7 8 [R -
1 9 8 2 ]). P ure t o ne air a n d b o n e c o n d u cti o n t hr es h ol d a u di o metr y ma y be meas ure d wit h a n d 
wit h o ut mas ki n g. Eff ecti ve mas ki n g le vels s h o ul d be rec or de d. A n a u di o meter i nstr u me nt/ de vic e 
t y pical t o a u di ol o g y cli nics, i nclu di n g hi g h fre q ue nc y ca pa bilities  w he n a vail a ble , will be use d t o 
prese nt p ulse d p ur e t o nes a n d det er mi n e t hres h ol ds. F or t hr es h ol ds of fre q ue ncies bet wee n 0. 2 5 
a n d 8 k Hz ( 0. 2 5, 0. 5, 1, 2, 3, 4, 6, a n d 8 k Hz) i nsert e ar p h o nes ( E R -3 A) will be pla ce d i nt o t he ear 
ca nal. T o deter mi ne ultra -hi g h fre q u e nc y t hres h ol ds at 1 0, 1 1. 2, 1 2. 5, 1 4, 1 5, a n d 1 6 k Hz, 
circ u m a ural e ar p h o nes will b e use d , if a vaila ble base d o n site a u di o met er s pecificati o ns. A 
m o difie d H u g hs o n -Westla ke pr oce d ur e will be use d t o deter mi n e t hr es h ol ds at eac h fre q ue n c y 
usi n g a d o w n 1 0 d B, u p 5 d B st e p siz e f or i nte nsit y a n d w here t hres h ol d is t h e l o west  p ulse d t o ne  
i nte nsit y t hat t he s u bje ct res p o n ds at 5 0 % a cc ura c y i n at le ast 2/ 3 trials.  
D oc u me ntati o n c o nfir mi n g t he a n n ual sta n dar diz e d c ali brati o n of t he a u di o m eter, ear p h o n es, a n d 
s pea kers will be r e q uire d. 
7. 2. 2 0  
Dist orti o n Pr o d uct Ot o ac o ustic E missi o n ( D P O A E)  
T he D P O A Es are a n o bjecti ve i n dicat or of n or mall y f u ncti o ni n g c o c hlea r o ut er hair cells . D P O A E 
are ge nerate d b y  t he O H Cs  as t he y e x pa n d a n d c o ntr act i n res p o nse t o  t w o si m ulta n e o us t o nes of 
differe nt fre q ue n c y.  T he test d oes n ot re q uire a res p o nse fr o m t he s u bject, a n d a s o u n d b o ot h is n ot 
re q uire d. 
S u bjects will be  fitte d wit h a s oft fle xi bl e pr o be, c o nsisti n g of a se nsiti ve micr o p h o ne a n d 
tra ns d ucers, w hic h will cr eat e a seal w he n i nserte d i nt o t he e ar c a nal.  D P O A Es will be t este d i n at 
least 4 fre q ue ncies wit h a si n gle sti m ul us le vel a n d v ar yi n g fre q ue nc y. T o be c o nsi d ere d a prese nt 
D P O A E, t he n oise fl o or will be assesse d t o deter mi n e if  it is l o w e n o u g h t o e val uat e t he res p o nses 
a n d t he diff ere nce b et wee n t he res p o nse a n d t he n ois e fl o or at eac h fre q u e nc y will e xc ee d 5 d B.  
D oc u me ntati o n c o nfir mi n g  t he a n n ual sta n dar dize d d e vice cali brati o n will be r e q uire d. 
7. 2. 2 1  
A u dit or y Br ai n ste m Res p o nse ( A B R)  
A B R a u di o metr y is a ne ur ol o gic test of a u dit or y br ai nste m f u n cti o n i n r es p o nse t o brief a u dit or y 
(e. g., clic k or t o n e -b urst ) sti m uli. A u dit or y e v o ke d p ote ntials are e xtr act e d fr o m u n derl yi n g 
brai n ste m el ectrical acti vit y a n d rec or d e d b y ele ctr o d es  plac e d o n t he sc al p or i n t he ear -c a nal  wit h 
t he s u bject i n t h e s o u n d b o ot h or a q ui et r o o m .  
T he n or mal res p o nse t o t he 2 -4 k Hz clic k sti m ul us prese nte d at hi g h i nt e nsiti es ( e. g., 7 0 -9 0 d B 
n or mal i ze d heari n g  l e vel [ n H L]) c o nsists of a series of ne utrall y -ge n erat e d  wa ve f or ms wit hi n 1 0 
millisec o n ds of t he a u dit or y sti m ul us  b y ti p -tr o de. W a ves I-III are g e nerate d b y t he a u dit or y bra nc h 
of t he ei g ht h cr a nial ner ve, a n d 
W a ve I V -V is ge nerate d b y t h e u p per brai nste m. T he A B R 
wa vef or ms will b e  assesse d b y a m plit u de ( mi cr o v olta ge), lat e nc y ( millisec o n ds), i nter pea k 
late n c y, a n d i ntera ural late nc y.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 2  of 7 3  
T he A B R  W a ve I res p o nse is a far-fiel d re pr ese ntati o n of t he c o m p o u n d a u dit or y ner v e acti o n 
p ote nti al  ( A P) i n t he distal p orti o n of t h e 8t h cra ni al ner ve  a n d is h y p ot hesiz e d t o arise fr o m t he 
de n drites of t h e a u dit or y ner ve . It has bee n s u g gest e d t hat A B R W a v e I a m plit u d e, as well as t he 
s u m mati n g p ot e nti al ( S P)-t o-A P  rati o a n d s peec h rec o g niti o n i n n oise, offers a n effecti ve 
n o n be ha vi oral me as ure of C S  (B ar bee  et al., 2 0 1 8). T ra ns d ucer c ali br ati o n will be d oc u me nt e d at 
eac h sit e. 
7. 2. 2 2  
Electr o c oc hle o g r a p h y ( E C oc h G)  
E C oc h G is si milar t o A B R i n t h at el ectrical p ot e ntials are me as ure d i n res p o nse t o s o u n d 
sti m ulati o n b ut is rec or de d usi n g a n o n-i n vasi ve e xtr a-t y m pa nic ele ctr o de pla ce d i n t h e e ar c a nal 
(i.e., ti p-tr o de). T he t hree p ote ntials ge nerate d b y E C oc h G i ncl u d e t he c oc hlear mi cr o p h o nic, t he 
S P a n d A P. T he S P: A P rati o is c o nsi dere d p ossi bl y r elat e d t o t h e stat us of t h e c oc hl ear s y na pse.   
T he E C o c h G will be c o n d ucte d as a c o m p o n e nt of t he A B R. T he i psil ater al ele ctr o de will be pair e d 
wit h t he c o ntralat eral, or refer e nce, electr o d e i n t he n o n -test ear. T he f ore h ea d or nasi o n will be 
use d as t he gr o u n d electr o de. I m pe d ance s h o ul d be l ess t ha n 5 0 0 0 o h ms, b ut ma y be hi g her f or t he 
i psilat eral electr o de. T he tra ns d ucer si g nal will c o nsist of a clic k at 9 0 d B n H L, a n d t he test will 
be  re peate d u ntil a relia ble wa vef or m is o bser ve d. Tra ns d ucer cali br ati o n will be d oc u me nte d
 
eac h sit e.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 3  of 7 3  
8.  
A D V E R S E A N D S E RI O U S A D V E R S E E V E N T S A S S E S S M E N T  
8. 1  
Defi niti o n of A d verse E ve nts, Peri o d of O bser v ati o n, Rec or di n g of 
A d verse E ve nts  
A n A dverse Eve nt ( A E) is a n y u nt o war d m e dic al o cc urre nce i n a cli nical i n vesti g ati o n s u bject 
a d mi nist ere d a p har m ace utical pr o d uct a n d t h at d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h t his tr eat me nt . A n A E ca n t heref ore be a n y u nfa v ora ble  a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal l a b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociat e d wit h t he use of a 
me dici nal ( i n vesti gati o nal) pr o d u ct, w het her or n ot rel ate d t o t he me dici nal  (i n vesti gati o nal) 
pr o d uct  (I C H G ui d a nce E 2 A, 1 9 9 5).  
All A Es s h o ul d be ca pt ur e d  o n t he A E C R F.  
All A Es are c ollecte d fr o m t he ti me t he i nf or me d c o nse nt is si g ne d  u ntil t h e fi nal visit is c o m pl ete d 
at a p pr o xi mat el y 9 0 d a ys p ost -i nje cti o n. All A Es are t o be re c or de d o n t h e a p pr o pri ate A E pa ges 
i n t he C R F a n d i n s o urce d oc u m e nts. W h ere p ossi bl e, a di a g n osis, rat h er t h a n a list of s y m pt o ms, 
s h o ul d be rec or de d. If a dia g n osis has n ot bee n ma de, t he n e ac h s y m pt o m s h o ul d be list e d 
i n di vi d uall y. I n a d diti o n t o u nt o war d A Es , u ne x pect e d be nefits o utsi de t he I P i n dicati o n s h o ul d 
als o be ca pt ure d o n t h e A E C R F.  
All A Es m ust b e f oll o we d t o cl os ure (t he s u bj ect’s he alt h h as ret ur n e d t o his/ her baseli ne st at us or 
all varia bl es ha ve ret ur n e d t o n or m al), a n o ut c o me is reac he d, sta bili zati o n (t he I n v esti gat or d oes 
n ot e x pect a n y f urt h er i m pr o ve me nt or w orse ni n g of t he e ve nt), or t he e ve nt is ot her wise e x plai n e d 
re gar dless of w het her t he s u bject is still parti ci pati n g i n t he st u d y. W he n a p pr o priate, me dical tests 
a n d e xa mi nati o ns are perf or m e d s o t hat r es ol uti o n of e ve nt(s) ca n b e d oc u me nte d.  
8. 1. 1  
Se verit y C ate g oriz ati o n  
T he se verit y of A Es m ust be rec or de d d uri n g t he c o urse of t he e ve nt i ncl u di n g t he start a n d st o p 
dates f or eac h c ha n g e i n se verit y. A n e ve nt t hat c h a n ges i n se verit y s h o ul d be ca pt ur e d as a ne w 
e ve nt. W orse ni n g of pre -tr eat m e nt e ve nts, after i nitiati o n of I P, m ust be rec or de d as ne w A Es (f or 
e xa m pl e, if a s u bject e x perie nc es mil d i nter mitte nt d ys pe psia pri or t o d osi n g of I P, b ut t he 
d ys pe psia bec o m es se vere a n d m ore fre q ue nt aft er first d ose of I P has bee n a d mi nister e d , a n e w 
A E of se vere d ys pe psia [ wit h t he a p pr o priate date of o nset]  is rec or d e d o n t he a p pr o priate C R F). 
T he me dical assess me nt of se verit y is det er mi n e d b y usi n g t he defi niti o ns pr o vi d e d i n T a ble 4 : 
 
 
 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 4  of 7 3  
T a ble 4 : A d verse E ve nt Se verit y 
Se verit y  
Descri pti o n  
Mil d  
A t y pe of A E t hat is us uall y tr a nsie nt a n d ma y re q uir e o nl y mi ni mal tre at m e nt 
or t hera pe utic i nter ve nti o n. T h e e ve nt d oes n ot ge n er all y i nterfer e wit h us ual 
acti viti es of dail y li vi n g.   
M o derate  
A t y pe of A E t hat is us uall y alle viate d wit h s pecific t hera pe utic i nter ve nti o n. 
T he e ve nt  i nt erferes wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort b ut 
p oses n o si g nifica nt or p er ma n e nt ris k of har m t o t he researc h s u bject.  
Se vere  
A t y pe of A E t hat i nterr u pts us ual acti vities of dail y li vi n g, or si g nifi ca ntl y 
affects cli ni cal stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter v e nti o n.  
8. 1. 2  
Rel ati o ns hi p C ate g oriz ati o n  
T he I n vesti gat or, w het her bli n de d or u n bli n d e d (i.e., t he ot ol o gist or ne ur o-ot ol o gist perf or mi n g 
t he i ntrat y m pa ni c i nj ecti o n), m us t e val uat e t h e p ote ntial r elati o ns hi p t o “St u d y Dr u g ”  f or e ac h A E, 
w here i n “St u d y Dr u g ” will i ncl u de b ot h  Pl ace b o a n d PI P E -5 0 5 S us pe nsi o n . T heref ore, t h e 
I n vesti gat or s h o ul d attri b ute ca usati o n t o t h e St u d y Dr u g if t he A E  is m ost c o nsiste nt wit h an  effe ct 
sec o n dar y t o i njecti o n of a s u bsta nc e, eit her Pla ce b o or PI P E -5 0 5 S us pe nsi o n , i nt o t he t y m p a nic 
s pace. If t here is n o vali d re as o n f or s u g gesti n g a relati o ns hi p, t he n t he A E s h o ul d be classifie d as 
‘ n ot relate d’. Ot her wise, if t here is a n y vali d reas o n, e ve n if u n deter mi ne d or u nteste d, f or 
s us pecti n g a p ossi ble ca use-a n d-effect relati o ns hi p b et wee n t he ‘St u d y Dr u g’  a n d t he occ urre n ce 
of t he A E, t h e n t he A E s h o ul d be c o nsi d ere d ‘relat e d’.  T he c a usalit y assess me nt i n rel ati o n t o 
St u d y Dr u g ( wit h o ut rec or di n g a n y u n bli n di n g i nf or mati o n) m ust be d oc u me nt e d i n t he s o urce 
d oc u me nt  a n d gra d e d acc or di n g t o Ta ble 5  bel o w.  T he A E patter ns s pecifi c t o  treat me nt 
assi g n me nt (s u bj ects w h o rec ei ve d acti ve PI P E-5 0 5 S us pe nsi o n vers us Plac e b o) will ulti m atel y be 
deter mi ne d u p o n fi n al a nal ys is of t he u n m as ke d dat a base at st u d y c o n cl usi o n.  
T a ble 5 : A d verse E ve nt C a us alit y Assess me nt 
Ter m  
Rel ati o ns hi p  
Defi niti o n  
Relat e d  
Yes  
T he te m p oral relati o ns hi p bet wee n t h e e ve nt a n d t he 
a d mi nistr ati o n 
of t he 
i n vesti g ati o nal 
pr o d uct is 
c o m pelli n g a n d/ or f oll o ws a k n o w n or s us pect e d 
res p o nse patter n t o t h at pr o d u ct, a n d t he e ve nt ca n n ot be 
e x plai n e d b y t he s u bj ect’s me di cal c o n diti o n, ot her 
t hera pi es, or acci d e nt. 
N ot Relat e d  
N o  
T he e ve nt ca n b e rea dil y e x plai n e d b y ot her f act ors s u c h 
as t he 
s u bject’s 
u n derl yi n g 
m e dic al 
c o n diti o n, 
c o nc o mita nt t her a p y , or acci de nt a n d n o pla usi ble 
te m p oral or bi ol o gi c rel ati o ns hi p e xists bet wee n t he 
i n vesti gati o nal pr o d uct a n d t he e v e nt.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 5  of 7 3  
8. 1. 3  
O utc o me C ate g ori z ati o n  
T he o ut c o me  of A Es m ust be rec or d e d d uri n g t h e c o urse of t he st u d y o n t he C R F . O utc o mes ar e 
as f oll o ws: 
•  Fat al  
•  N ot Rec o vere d/ N ot Res ol ve d  
•  Rec o vere d/ Res ol ve d  
•  Rec o vere d/ Res ol ve d w it h Se q uela e  
•  Rec o veri n g/ Res ol vi n g  
•  U n k n o w n  
8. 1. 4  
S y m pt o ms of t he D ise ase U n der S t u d y 
S u bjects wit h S N H L ass ociate d wit h s pe ec h-i n-n oise i m pair me nt  ma y e x peri e nce t he o nset of 
ti n nit us, h y perac usis, a n d r e d uce d heari n g ca pa bilit y c o nsiste nt wit h t he s pectr u m h eari n g l oss 
s y m pt o matic pr o gressi o n.  
S y m pt o ms of t he disease u n d er st u d y s h o ul d n ot be classe d as A Es as l o n g as t he y are wit hi n t he 
n or mal da y -t o-da y fl u ct uati o n or e x pect e d pr o gressi o n of t he disease. H o we ver, si g nifica nt 
w orse ni n g of t he s y m pt o ms s h o ul d be r ec or de d as a n A E.  
8. 1. 5  
Cli nic al L a b or at or y E v al u ati o ns  
A c ha n ge i n t he v a l ue of a cli ni cal la b or at or y i n vesti gati o n ca n re prese nt a n A E if t he c ha n ge is 
cli ni call y rel e va nt or if, d uri n g tr eat me nt wit h t he  I P, a s hift of a para met er is o bser ve d fr o m a 
n or mal val u e t o a n a b n or m al val u e, or a f urt her w orse ni n g of a n alrea d y a b n or mal val ue . W he n 
e val uati n g s uc h c ha n g es, t he e xt e nt of de viati o n fr o m t he refere n ce ra n ge, t he d urati o n u ntil ret ur n 
t o t he refere nc e ra n ge, eit h er w hile  c o nti n ui n g treat me nt or after t he e n d of treat me nt wit h t he  I P, 
a n d t he ra n ge of variati o n of t he res p ecti v e para met er wit hi n its refere nc e ra n ge, m ust be ta ke n 
i nt o c o nsi der ati o n. 
If, at t h e e n d of t he treat me nt p hase, t here are a b n or mal cli nical  la b or at or y val ues w hic h wer e n ot 
prese nt at b aseli ne, f urt h er cli ni cal or la b orat or y i n vesti gati o ns s h o ul d b e perf or me d u ntil t h e 
val ues ret ur n t o wit hi n  t h e refere nc e ra n ge, t he val u e sta bili zes, or u ntil a pla usi ble e x pla n ati o n 
(e.g ., c o nc o mita nt disease) is f o u n d f or t h e a b n or m al cli ni cal la b orat or y val ues. 
T he I n vesti gat or s h o ul d deci de, b ase d o n t he a b o ve cri teri a a n d t he cli nic al c o n diti o n of a s u bject, 
w het her a c ha n ge i n a cli ni cal la b orat or y par a meter is cli ni call y si g nifica nt a n d t heref or e re prese nts 
a n A E.  
8. 1. 6  
Pre g n a nc y  
All pre g na ncies are t o be re p ort e d fr o m t he ti m e i nf or me d c o nse nt is si g ne d u ntil t he fi nal visit is 
c o m plete d at a p pr o xi matel y 9 0 da ys p ost -i nj ecti o n. A n y re p ort of pre g n a nc y f or a n y fe m ale s u bject 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 6  of 7 3  
or t he part n er of a m ale s u bject  m ust be r e p orte d wit hi n 1  b usi ness da y t o  t he S p o ns or  (Ta bl e 1 ) 
usi n g t h e Pre g na nc y Re p ort F or m. Si nc e t his is a si n gle d ose st u d y, n o f urt her d osi n g will be 
a d mi nist ere d t o t he s u bj ect a n d t he s u bject will c o nti n ue t o b e f oll o we d a cc or di n g t o t he S O E , 
u nl ess, at t he discreti o n of t he I n vesti gat or, s pe cifi c t ests are c o ntr ai n di cate d f or t he pre g n a nc y.  
If t he fe male s u bject a n d/ or fe male part n er of a male s u bject a grees t o t he pri mar y car e p h ysicia n 
bei n g i nf or me d, t he In vesti g at or s h o ul d n otif y t h e pri mar y care p h ysicia n t hat t he s u bje ct/fe mal e 
part ner of t he s u bje ct was parti ci pati n g i n a cli nical st u d y at t he ti me s he bec a me pr e g na nt a n d 
pr o vi de det ails of tr eat me nt t h e s u bject rec ei ve d . 
E ver y eff ort s h o ul d be m a de t o g at her i nf or mati o n re gar di n g t he pr e g n a nc y o utc o m e a n d c o n diti o n 
of t he i nfa nt.  It is t he res p o nsi bilit y of t he I n vesti gat or t o o btai n t his i nf or mati o n wit hi n 3 0 cale n d ar 
da y s after t h e i nitial n otificati o n a n d a p pr o xi matel y 3 0 cale n d ar da ys p ost -part u m.  
Pre g na nc y c o m plicati o ns s uc h as s p o ntane o us a b orti o n/ miscarria ge or c o n g e nit al a b n or m alit y are 
c o nsi dere d S A Es a n d m ust be re p orte d usi n g t he S A E F or m.  N ote , an electi ve a b or ti o n is n ot 
c o nsi dere d a n S A E.  
8. 1. 7  
Me dic ati o n Er r or  
M e dicati o n err or  (as defi ne d b el o w ) m ust be r e p orte d t o t he S p o ns or  acc or di n g t o t he S A E 
re p orti n g pr oce d ure w het h er or n ot t he y res ult i n a n A E/ S A E as descri be d pre vi o usl y i n t his 
secti o n. N ot e: T he 1  b usi ness d a y re p orti n g r e q uire me nt f or S A Es d oes n ot a p pl y t o re p orts of 
me dic ati o n err or s u nless t hese res ult i n a n S A E .  
•  Me dic ati o n  Err or –  A n err or  ma de i n prescri bi n g, dis pe nsi n g, a d mi nistrati o n, a n d/ or use 
of a n I P. 
8. 2  
Seri o us A d verse E ve nt Pr oce d ures  
8. 2. 1  
Refere nce S afet y I nf or m ati o n  
T he refer e nce f or safet y i nf or m ati o n f or t his st u d y is t he I B w hic h t h e S p o ns or  has pr o vi de d u n der 
se parate c o ver t o all I n vesti gat ors. 
8. 2. 2  
Re p orti n g Pr oce d ures  
All i nitial a n d f oll o w -u p S A E  r e p orts 
m ust be re p ort e d b y t he In v esti gat or t o t he 
P har mac o vi gila n ce  c o nt act wit hi n 1  b usi ness da y of t he first a ware n ess of t he e ve nt.  N ot e: T h e 1  
b usi ness da y re p orti n g r e q uire me nt f or S A Es d oes n ot a p pl y t o re p orts of me di cati o n err ors ( see 
Secti o n 8. 1. 7 ) u nl ess t he y res ult i n a n S A E .  
T he In vesti gat or m ust c o m pl ete, si g n , a n d dat e t he S A E  F or m a n d verif y t he acc ur ac y of t he 
i nf or mati o n rec or de d o n t he f or m wit h t he c orres p o n di n g s o urce d oc u me nts ( N ote: S o urce 
d oc u me nts are n ot t o be se nt u nl ess re q ueste d) a n d fa x or e-mail t he f or m t o t h e P har mac o vi gil a nce 
De part me nt  (Ta ble 1 ).  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 7  of 7 3  
8. 2. 3  
Seri o us A d verse E ve nt Defi niti o n  
A Seri o us A dverse Eve nt  ( S A E) is a n y u nt o war d m e dical occ urr e nce ( w het her c o nsi dere d t o be 
relat e d t o I P or n ot) t h at at a n y d ose:  
•  Res ults i n deat h  
•  Is life-thre ate ni n g  
N O T E:  T he ter m ‘life -t hreate ni n g’ i n t h e defi niti o n of ‘seri o us’ refers t o a n e ve nt i n w hic h 
t he s u bject was at ris k of deat h at t he ti me of t he e v e nt; it d oes n ot r efer t o a n e v e nt w hic h 
h y p ot heti call y mi g ht ha ve ca use d deat h if it was m or e se v ere.  
•  Re q uires i n patie nt h os pitaliz ati o n  or pr ol o n g ati o n of e xisti n g h os pit ali zati o n  
•  Res ults i n persiste nt or si g nifi ca nt disa bilit y/i nca p acit y  
•  Is a c o n ge nit al a b n or malit y/ birt h defe ct 
•  Is a n im p orta nt m e dical eve nt ; N ote: I m p orta nt m e dic al ev e nts t h at ma y n ot r es ult i n de at h, 
be lif e -t hreate ni n g, or re q uire h os pit ali zati o n  m a y be c o nsi dere d a n S A E w he n, base d u p o n 
a p pr o priat e me dical j u d g me nt, t he y ma y j e o par diz e t he s u bject a n d ma y r e q uire me di cal 
or s ur gical i nter v e nti o n t o pr e ve nt o n e  of t he o ut c o m e s liste d i n t his defi niti o n. E xa m ples 
of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nt e nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o m e; bl o o d d yscrasi as or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitali zati o n ; or t h e de vel o p me nt of dr u g d e pe n de nc y or dr u g a b use.  
H os pitaliz ati o ns , w hic h ar e t he res ult of electi ve or pre vio usl y sc he d ule d s ur ger y f or pre -e xisti n g 
c o n diti o ns, w hic h ha ve n ot w orse ne d after i niti ati o n of treat m e nt, s h o ul d n ot be classifie d as S A Es . 
F or e x a m pl e,  a n a d missi o n f or a pre vi o usl y sc he d ule d ve ntral her nia r e pair w o ul d n ot be cl assifie d 
as a n S A E.   
H o we ver, c o m pli cati o n(s) res ulti n g fr o m a h os pit ali z ati o n  f or a n ele cti v e or pre vi o usl y sc h e d ule d 
s ur ger y t hat m eets seri o us criteri a m ust be r e p orte d as S A E(s). 
8. 2. 4  
S eri o us A d verse E ve nt  C ollecti o n Ti m efr a me  
All S A Es are c ollecte d fr o m t he ti me t h e s u bje ct si g ns i nf or me d c o nse nt u ntil t h e fi nal st u d y visit 
at a p pr o xi m atel y 9 0 da ys p ost -i njecti o n. All S A Es occ urri n g d uri n g t his peri o d  m ust be re p ort e d 
t o t he P har ma c o vi gila nc e c o nt act ( T a ble 1 ) wit hi n 1  b usi ness da y of t he first a ware ness of t he 
e ve nt.  
8. 2. 5  
S eri o us A d verse E ve nt  O nset a n d Re s ol uti o n D ates 
T he o nset date of t he S A E is defi ne d as t he date t he e ve nt meets seri o us criteria. The res ol uti o n 
date is t he date t h e e ve nt n o l o n ger me ets seri o us criteri a, t he date t h e s y m pt o ms res ol ve, or t he 
e ve nt is c o nsi dere d c hr o nic . I n t he c ase of h os pitaliz ati o ns , t he h os pit al a d missi o n a n d disc har ge 
dates are c o nsi dere d t h e o nset a n d r es ol uti o n d ates, r es pecti v el y.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 8  of 7 3  
I n a d diti o n, a n y si g ns or s y m pt o ms e x peri e nce d b y t he s u bject pri or t o st u d y e ntr y or l ea di n g u p 
t o t he o nset dat e of t he S A E or f oll o wi n g t h e res ol uti o n dat e of t he S A E, m ust be r ec or de d as a n 
A E , if a p pr o priate. 
8. 2. 6  
F at al O utc o me  
A n y S A E t hat res ults i n t he s u bje ct’s deat h (i .e., t h e S A E was n ote d as t he pri mar y ca use of deat h) 
m ust ha ve fat al c hec k e d as a n o ut c o me wit h t he date of de at h re c or de d as t he res ol uti o n date. F or 
all ot h er e ve nts o n g oi n g at ti me of de at h t h at di d n ot c o ntri b ut e t o t he s u bj ect’s de at h, t he o utc o m e 
s h o ul d be c o nsi dere d n ot res ol ve d, wit h o ut a res ol uti o n date re c or de d.  
F or a n y S A E t hat r es ults i n t he s u bject’s deat h or a n y o n g oi n g e v e nts at t he ti m e of d eat h, t he 
acti o n t a ke n wit h t he I P s h o ul d be rec or de d as “ d ose n ot c ha n ge d” or “ n ot a p plica bl e” (if t h e 
s u bject ne v er recei ve d I P). 
8. 2. 7  
Re g ul at or y A ge nc y, I nstit uti o n al Re vie w B o ar d, I n de pe n de nt Et hics C o m mittee , 
a n d  Site Re p orti n g  
T he S p o ns or  is res p o nsi ble f or n otif yi n g t h e rel e v a nt re g ulat or y a ut h oriti es a n d t he C o ntr act 
Researc h Or ga nizati o n ( C R O ) is res p o nsi ble f or n otif yi n g st u d y sites a n d t h e c e ntral I R B of 
relat e d, u ne x pecte d S A E s.  
I n a d diti o n, S p o ns or  is resp o nsi bl e f or n otif yi n g a cti ve  sites of all relate d, u ne x pe cte d S A Es  
occ urri n g d uri n g all i nter ve nti o nal st u dies a cr oss t he PI P E -5 0 5  pr o gra m .  
T he In vesti gat or is res p o nsi ble f or n otif yi n g his/ her  l ocal I R B or t he r ele v a nt l ocal re g ul at or y 
a ut h orit y of all S A Es t hat occ ur at his or her sit e as r e q uire d.  
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 5 9  of 7 3  
9.  
D A T A M A N A G E M E N T A N D S T A TI S TI C A L M E T H O D S  
9. 1  
D at a C oll ecti o n  
A n e C R F f or ea c h s u bject will be pr o vi de d. All a p pr o priate s u bject data gat here d d uri n g t he st u d y 
will be r ec or de d i n E n glis h o n t hese  f or ms. W he ne v er p ossi ble, all i nf or mati o n re q uest e d o n t h e 
e C R F s h o ul d be c o m pl ete d. If i nf or mati o n is n ot a vaila bl e, it s h o ul d b e d oc u m e nte d as s uc h.   
9. 2  
Cli nic al D at a M a n a ge me nt  
Q ualit y c o ntr ol a n d data v ali d ati o n pr oc e d ures are a p plie d t o e ns ure t h e vali d it y a n d ac c urac y of 
t he cli nic al data base. 
Data ar e t o be re vie we d a n d c h ec ke d f or o missi o ns, err ors, a n d v al ues re q uiri n g f urt her 
clarificati o n usi n g c o m p uteriz e d a n d/ or m a n ual pr o ce d ures. Data q ueri es re q uiri n g clarificati o n 
are t o be c o m m u ni cat e d t o t he  site f or res ol uti o n. O nl y a ut h orize d pers o n nel will ma ke c orre cti o ns 
t o t he cli ni cal d ata base, a n d all c orre cti o ns ar e d oc u me nte d i n a n a u dita ble ma n n er. 
T he c o m pl ete d C R Fs or c o m pl ete d pri nt o ut a n d/ or el ectr o ni c c o p y of t he e C R Fs f or t his st u d y are 
t he pr o pert y of Pi peli n e a n d s h o ul d n ot be ma de a v aila ble t o t hir d parties, e xc e pt f or a ut h ori ze d 
re prese ntati ves of a p pr o priat e healt h/re g ul at or y a ut h oriti es, wit h o ut writte n per missi o n fr o m 
Pi peli ne . 
9. 3  
St atisti c al A n al ysis Pr ocess  
Details re g ar di n g t h e statistic al m et h o ds a n d d efi niti o ns will be pr o vi d e d i n t h e Statistic al A nal ysis 
Pla n ( S A P). T he S A P will ser ve as a c o m pl eme nt t o t he pr ot oc ol a n d s u perse des it i n case of 
differe nc es.  T he S A P will b e fi n ali ze d pri or t o u n bli n di n g t o  preser ve t he i nt e grit y of t h e statistical 
a nal ysis a n d st u d y c o n cl usi o ns.  
All statistic al a nal yses will b e perf or me d after t he data base is l o c ke d a n d u n bli n de d. St atistical 
a nal yses will be p erf or me d usi n g Versi o n 9. 4 or hi g h er of S A S  ( S A S I nstit ute, Car y, N C 2 7 5 1 3). 
S u m mar y ta bles a n d listi n gs of data will be pr o vi d e d. S u m mar y statistics will be pr ese nte d b y d ose 
gr o u p a n d f or all s u bjects c o m bi ne d as a p pr o priate. F or c o nti n u o us varia bles, data will be 
s u m mariz e d wit h t he n u m ber of s u bj ects ( N), mea n, sta n dar d de viati o n, m e dia n, mi ni m u m, a n d 
ma xi m u m b y tre at m e nt gr o u p. F or cate g ori cal varia bles, data will be ta b ul ate d wit h t he n u m ber 
a n d pr o p orti o n of s u bje cts f or eac h cat e g or y b y tre at me nt gr o u p.  
9. 4  
Sel ecti o n of S u bjects t o be I ncl u de d i n t he A n al yses  
E nr o lle d Set –  S u bj ects w h o ha ve si g ne d i nf or me d c o nse nt a n d ha v e be g u n s o m e st u d y pr oce d ur es 
(e.g ., dis pe nse d I P c urre nt dr u g has be e n wit h dra w n) . 
R a n d o mize d Set  –  E nr olle d s u bje cts f or w h o m a ra n d o mizati o n n u m b er has bee n assi g ne d . 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 0  of 7 3  
S afet y A n al ysis Set  –  E nr o ll e d/ Ra n d o mize d s u bje cts w h o ha ve u n der g o ne d os i n g of  I P. Safet y 
data f or t h ese s u bjects will be s u m mariz e d b y tre at m e nt act uall y recei ve d.  
F ull A n al ysis Set  –  S u bjects i n t h e Safet y A nal ysis Set w h o ha ve at least 1 p ost -b aseli n e val u e 
effica c y assess me nt . Effica c y data will be s u m m ariz e d b y assi g ne d treat me nt re gar dl ess of act ual 
treat me nt ta ke n. 
Per -P r ot oc ol Set –  S u bje cts i n t h e F ull A nal ysis Set w h o d o n ot ha ve pre -defi ne d pr ot o c ol 
de viati o ns  a n d w h o c o m pl ete d t he fi nal sc he d ul e d assess me nt.  
P h ar m ac o ki netic Set –  S u bj ects i n t he Saf et y A nal ysis Set wit h n o m aj or d e viati o ns relat e d t o I P 
i nta ke, f or w h o m t he pri mar y P K  data is c o nsi d ere d s ufficie nt a n d i nt er preta ble.  
9. 5  
S u bject Dis p ositi o n  
Dis p ositi o n of s u bjects i n ea c h a nal ysis set will be s u m mariz e d b y t reat me nt gr o u p usi n g 
descri pti v e statistics. I n a d diti o n, f or s u bjects w h o pre mat ur el y disc o nti n ue fr o m t h e st u d y, t he 
reas o ns f or disc o nti n uati o n will be s u m m arize d b y tr eat m e nt gr o u p.  
9. 6  
De m o gr a p hic a n d B aseli ne C h ar act eristi cs  
Descri pti ve s u m m aries of de m o gra p hic a n d baseli ne c haracteristics will be prese nt e d b y treat me nt 
gr o u p a n d o verall f or t he Safet y A nal ysis Set a n d F ull A nal ysis Set  ( F A S).  
De m o gra p hics a n d baseli ne c h aracteristi cs will b e e xa mi n e d t o assess t he c o m par a bilit y of t he 
treat me nt gr o u ps at baseli ne. C o nti n u o us varia bl es s uc h as s u bject a ge, wei g ht, hei g ht, a n d b o d y 
mass i n de x ( B MI) will be s u m mari ze d usi n g n u m ber of o bser vati o ns, mea n, sta n dar d d e viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m val u es. Cate g ori c al varia bl es s uc h as s u bject se x a n d r ace will 
be s u m mari ze d usi n g n u m b er of o bs er vati o ns a n d p erce nta g es f or eac h c ate g or y.  
Me dical hist or y a n d hist or y of S N H L will be s u m marize d b y treat me nt gr o u p usi n g t he n u m ber of 
o bser vati o ns a n d per ce nta g es of s u bjects re p orti n g e ac h cate g or y.  
9. 7  
Pri or a n d C o nc o mit a nt Me di c ati o n  
Pri or a n d c o nc o mit a nt me di cati o ns will b e c o de d usi n g t he m ost c urre nt versi o n of t he W H O dr u g 
dicti o n ar y , as of t h e start of t he st u d y. Pri or a n d c o nc o mita nt me di cati o ns will b e list e d a n d 
s u m mariz e d b y t her a pe uti c are a preferr e d dr u g na me a n d treat me nt gr o u p.  
9. 8  
S afet y A n al yses  
A Es  will be c o de d usi n g t he m ost c urre nt versi o n of  Me dical Dicti o nar y f or Re g ulat or y Acti vities 
(Me d D R A ) as of t he start of t h e st u d y. T he n u m ber of e v e nts, i n ci de n ce, a n d per ce nt a ge of 
treat me nt-e mer ge nt a d v erse e v e nts ( T E A E) will b e calc ulat e d o verall, b y s yste m or ga n class 
( S O C), a n d b y preferre d t er m. E v e nts wit h missi n g o nset dat es will be i ncl u de d as tr eat me nt -
e mer ge nt. Treat me nt e mer g e nt e ve nts are c o nsi dere d t h ose e ve nts wit h o nset dat es o n or after 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 1  of 7 3  
stu d y dr u g e x p os ure or e ve nts wit h dates of o nset or w orse ni n g after st u d y dr u g e x p os ure. If a 
s u bject e x p erie n ces m or e t ha n o ne oc c urre nc e of t h e sa me A E, t he o cc urre n ce w it h t he gr eat est 
se verit y a n d t he cl osest ass ociati o n wit h t he st u d y dr u g will be s u m m arize d. T E A Es  will be f urt her 
s u m mariz e d b y se verit y a n d rel ati o ns hi p t o I P. A Es  relate d t o I P, A Es l ea di n g t o wit h dr a wal, 
S A Es, a n d deat hs will be s u m mari ze d/liste d.  
Cli nic al l a b orat or y tests, vital si g ns, a n d E C G fi n di n gs will be s u m m ariz e d b y tre at m e nt gr o u p a n d 
visit. C ha n ge fr o m b aseli n e val u es will be s u m m ari ze d usi n g s hift ta bles. P ote ntiall y cli nicall y 
i m p orta nt fi n di n gs will als o be s u m mari ze d or liste d. 
9. 9  
Preli mi n ar y Effi c ac y A n al yses  
As descri be d i n Secti o n 2. 2. 3 , effica c y e n d p oi nts i ncl u de me a n c ha n g e fr o m baseli ne t o M o nt h 3 
p ost -baseli ne i n:  
•  W R S ( perf or me d i n q uiet)  
•  Q uic k SI N -E P a n d Q uic k SI N -S F  
•  S S Q  
•  S R T  
•  WI N  
•  P ure t o ne a u di o metr y 
•  D P O A E  
•  M E M R  
•  A B R  
•  E C oc h G.  
Effica c y para m eters will be s u m marize d a n d a nal yze d se paratel y f or t he In de x E ar a n d N o n -In de x 
E ar usi n g t he F A S as t he pri mar y p o p ulati o n f or effic a c y a nal yses. I n a d diti o n, differ e nces b et wee n 
treat me nt gr o u ps will be cal c ulate d as st u d y dr u g mi n us P lace b o. C ha n ge fr o m b aseli n e will be 
calc ulat e d as t he val ue at a f oll o w -u p st u d y visit mi n us t he b aseli ne val ue, w her e baseli ne val u e is 
defi ne d as t he last n o n -missi n g meas ure me nt re c or de d pri or t o i nitiati o n of st u d y d r u g. S u m maries 
of mea n c ha n ge fr o m baseli n e f or eac h effica c y data will be prese nte d b y treat me nt gr o u p a n d b y 
st u d y visit, as a p pr o pri ate, wit h ass ociate d 9 5 % c o nfi de nce i nter vals.  
E x pl orat or y i nfere ntial a nal yses will b e c o n d ucte d t o c o m p are effica c y o u tc o mes i n s u bj ects 
assi g ne d t o st u d y dr u g vers us t h ose assi g ne d t o P lac e b o. I n a d diti o n, c o m paris o ns of eac h d ose of 
test dr u g t o P lace b o will be c o n d uct e d. T he n ull h y p ot hesis t o be teste d is t hat t h ere is n o differe nc e 
f or t he effica c y varia bl e bet wee n test dr u g a n d P la ce b o wit h t h e alter nati ve of a n o n-zer o differe n ce 
bet wee n t he m. U nless ot her wise s pecifie d, effica c y para met ers will be a nal y ze d usi n g a mi xe d 
m o del wit h re p eat e d me as ure me nts ( M M R M) t o ac c o u nt f or t he l o n git u di n al nat ure of t he data. 
T hes e a n al yses will i ncl u de t h e fi x e d c ate g orical eff ect of tre at m e nt ( PI P E -5 0 5 or P la ce b o) a n d 
fi xe d c o nti n u o us effect of t he b aseli n e val ue of t h e effica c y varia bl e. Visit will be tre ate d as t he 
re peat e d me as ure, a n d tr eat me nt-b y -visit a n d treat me nt -b y -basel i n e val u e i nt eracti o n t er ms will b e 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 2  of 7 3  
i ncl u de d. Si g nifi ca nce tests will b e base d o n le ast-s q uares me a ns usi n g a t w o-si de d α = 0. 0 5. T h e 
pri mar y tr eat me nt c o m paris o n will be t h e c o ntr ast bet wee n tre at m e nts at t he M o nt h 3 visit.  
S u p ple me nt ar y a nal yses of effic ac y d ata a vaila ble i n t he  Per -Pr ot oc ol Set  (P P S ) will be c o n d u cte d 
usi n g t he met h o d descri b e d a b o ve.  
9. 1 0  
I nteri m A n al ys is 
N o i nteri m a nal ysis is pl a n ne d i n t his st u d y.  
9. 1 1  
P h ar m ac o ki netic A n al yses  
P K para met ers of PI P E -5 0 5 will be deri v e d usi n g n o n -c o m part me nt al a nal ysis met h o ds fr o m t h e 
c o nce ntr ati o n -ti m e dat a f or all e val ua bl e s u bje cts. Act ual sa m pli n g ti mes, rat her t ha n sc he d ule d 
sa m pli n g ti mes, will be use d i n all c o m p utati o ns i n v ol vi n g sa m pli n g  ti mes. Ta ble 6  descri b es t he 
P K para meters t h at will be det er mi n e d fr o m c o n ce ntr ati o ns of PI P E -5 0 5 i n plas m a.  
T a ble 6 : Pl as m a P K P ar a met ers f or An al ysis  
P ar a mete r  
Defi niti o n  
A U C ∞  
Area u n der t he plas ma  c o n ce ntr ati o n -ti m e c ur ve fr o m ti m e 0 t o i nfi nit y, 
calc ulat e d as A U C ∞= A U C t+ C last/ λz, w here Clast is t h e last q ua ntifia ble 
c o nce ntr ati o n.  
A U C 2 4 
Area u n der t he plas ma c o n ce ntr ati o n -ti m e c ur ve fr o m ti m e 0 t o 2 4 h o urs, 
calc ulat e d usi n g t he li near tra pe z oi dal r ule.  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntr ati o n.  
C L/ F  
A p pare nt cl eara nc e aft er e xtr a vasc ul ar a d mi nistrati o n, calc ulat e d as 
D ose/ A U C ∞ after a si n gle d ose.  
λ z 
Ter mi n al eli mi nati o n rate c o nsta nt, cal c ulate d as t h e ne gati v e of t he sl o p e of 
t he l o g-li near r e gressi o n of t he nat ural l o garit h m c o n ce ntrati o n-ti me c ur ve 
d uri n g t he t er mi n al p hase.  
t1/ 2z 
Ter mi n al eli mi nati o n half -life, c alc ulat e d as l n( 2)/ λz. 
tma x  
Ti me t o rea c h Cma x . 
V z/ F 
A p pare nt v ol u m e of distri b uti o n d uri n g t he t er mi nal p hase after e xtra vasc ular 
a d mi nistr ati o n, cal c ulate d as ( C L/ F)/ λ z. 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 3  of 7 3  
9. 1 2  
S a m ple Si ze C al c ul ati o n a n d P o wer C o nsi der ati o ns  
T he pla n n e d sa m ple siz e of 2 4  s u bj ects ( 18  A cti v e a n d 6 P l ace b o) is n ot base d o n statistic al 
c o nsi derati o ns b ut is e x pecte d t o be s ufficie nt t o c ate g ori ze i nitial safet y, t olera bilit y, a n d P K  
c haracteristics of PI P E -5 0 5.  
 
 
 
 
 
 
 
 
 
T a ble 7 : 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 4  of 7 3  
1 0.  
S P O N S O R’ S A N D I N V E S TI G A T O R’ S R E S P O N SI BI LI TI E S  
T his st u d y is c o n d ucte d i n acc or d a nce wit h c urr e nt a p plic a ble U S re g ulati o ns, I nter nati o nal 
C o nfere nce  o n Har m o nisati o n G ui deli nes (I C H) G C P G ui deli n es,  a n d l ocal et hi cal a n d l e gal 
re q uire m e nts.  
1 0. 1  
S p o ns or ’s Res p o nsi biliti es 
1 0. 1. 1  
G o o d Cli nic al P r acti ce C o m pli a nce  
T he st u d y S p o ns or  a n d desi g nees will u n d erta k e t heir assi g ne d r oles f or t his st u d y i n c o m pli a nce 
wit h  all a p pli ca bl e i n d ustr y re g ulati o ns a n d I C H G o o d G C P G ui d eli n e E 6 (R 2)  (2 0 1 8 ). 
Visits t o sit es are c o n d ucte d b y re prese ntati ves of t h e st u d y S p o ns or  or desi g n ee  t o i ns pe ct st u d y 
data, s u bje cts’ me dical re c or ds , a n d C R Fs i n ac c or da nce wit h c urre nt G C P a n d t he res pe cti v e l oc al 
a n d i nter/ n ati o n al g o ver n m e nt re g ul ati o ns a n d g ui deli nes . Rec or ds a n d data m a y a d diti o nall y be 
re vie we d b y a u dit ors or b y re g ulat or y a ut h oriti es. 
T he S p o ns or  e ns ures t hat L oc al R e g ulat or y A ut h orit y re q uire m e nts ar e m et bef or e t h e start of t he 
st u d y. T he S p o ns or  ( or a n o mi nate d desi g n ee) is res p o nsi ble f or t he pre par ati o n, s u b missi o n, a n d 
c o nfir mati o n of rec ei pt of a n y Re g ulat or y A ut h orit y a p pr o vals re q uire d pri or t o release of I P f or 
s hi p me nt t o t he sit e. 
1 0. 1. 2  
P u blic P osti n g of St u d y I nf or m ati o n  
T he S p o ns or  is res p o nsi ble f or p osti n g a p pr o priat e st u d y i nf or mati o n o n a p plica ble we bsit es. 
I nf or mati o n i ncl u de d i n cli nic al st u d y re gistries ma y i ncl u de parti ci pati n g In vesti g at ors’ na mes 
a n d c o nta ct i nf or mati o n.   
1 0. 1. 3  
St u d y S us pe nsi o n, T er mi n ati o n, a n d C o m pleti o n  
T he S p o ns or  m a y s us pe n d or ter mi nate t he st u d y or p art of t he st u d y at a n y ti me f or a n y re as o n . If 
t he st u d y is s us pe n de d or t er mi n ate d, t he S p o ns or  will e ns ure t hat a p plica ble r e g ulat or y a ge n cies 
a n d I R Bs are n otifi e d as a p pr o priat e. A d diti o nall y, t h e disc o nti n uati o n of a re gist ere d cli ni cal st u d y 
w hic h has bee n p oste d t o a desi g nate d p u blic we bsit e will be u p d ate d acc or di n gl y . 
1 0. 2  
I n vesti g at or’s Res p o nsi biliti es  
1 0. 2. 1  
G o o d Cli nic al P r acti ce C o m pli a nce  
T he I n vesti gat or m ust u n dert a ke t o perf or m t he st u d y i n acc or da n ce wit h I C H G C P G ui d eli n e 
E 6 (R 2)  (2 0 1 8 ), a n d a p plica ble re g ul at or y re q uire m e nts a n d g ui deli nes . 
It is t he I n v esti gat or’s res p o nsi bilit y t o e ns ure t h at a de q u ate ti me a n d a p pr o priate l y trai n e d 
res o urces are a vail a ble at t he site pri or t o c o m mit me nt t o partici pate i n t his st u d y. T he I n vesti gat or 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 5  of 7 3  
s h o ul d als o be a ble t o esti mate or de m o nstrate a p ote nti al f or recr uiti n g t he re q uire d n u m ber of 
s uita ble s u bj ects wit hi n t he a gree d re cr uit me nt p eri o d. 
T he I n vesti gat or will mai ntai n a list of a p pr o priatel y q ualifie d p ers o ns t o w h o m t he I n vesti g at or 
has 
dele g ate d si g nifi ca nt 
st u d y-rel ate d tas ks. C urric ul u m vit a e  f or I n v esti ga t ors a n d 
s u b-i n vesti gat ors ar e pr o vi de d t o t he st u d y S p o ns or  ( or desi g nee) bef ore st arti n g t he st u d y. 
1 0. 2. 2  
Pr ot oc ol A d here nc e a n d I n vesti g at or A gree me nt  
T he I n vesti gat or a n d a n y c o -i n vesti g at ors m ust a d h er e t o t he pr ot oc ol as d etaile d i n t his d oc u me nt. 
T he I n ve sti gat or is res p o nsi ble f or e nr olli n g o nl y t h ose s u bjects w h o ha ve met pr ot oc ol eli gi bilit y 
criteria. I n vesti gat ors are r e q uire d t o si g n a n I n vesti gat or A gree me nt t o c o nfir m acc e pta nc e a n d 
willi n g ness t o c o m pl y wit h t he st u d y pr ot o c ol.  
If t he I n vesti gat or s us pe n ds or ter mi nates t he st u d y at t heir site, t he I n v esti gat or will pr o m ptl y 
i nf or m t h e S p o ns or  a n d t he I R B a n d pr o vi d e t he m wit h a d etaile d writt e n e x pla nati o n.  T he 
I n vesti gat or will als o r et ur n all I P, c o nt ai ners, a n d ot h er st u d y m aterials t o t h e S p o ns or . U p o n st u d y 
c o m pleti o n, t h e I n vesti gat or will pr o vi de t he S p o ns or , I R B, a n d re g ulat or y a g e nc y wit h fi n al 
re p orts a n d s u m maries as re q uire d b y (i nter) n ati o n al re g ulati o ns. 
C o m m u nic ati o n wit h l oc al I R Bs , t o e ns ure acc urat e a n d ti mel y inf or mati o n is pr o vi d e d at all 
p hases d uri n g t he st u d y , ma y be d o ne b y t he S p o ns or  or desi g nee , I n vesti gat or, or f or m ulti-site 
st u dies, t he C o or di nati n g I n vesti gat or acc or di n g t o n ati o nal pr o visi o ns a n d will b e d oc u me nte d i n 
t he I n vesti g at or A gree me nt. 
1 0. 2. 3  
D oc u me nt ati o n a n d Rete nti o n of R ec or ds 
1 0. 2. 3. 1  C ase Re p ort F or ms  
Access t o t he e C R F s will be pr o vi de d b y t he S p o ns or or desi g nee a n d s h o ul d be ha n dle d i n 
acc or da n ce wit h i nstr ucti o ns fr o m t he C R O . 
T he I n vesti gat or is res p o nsi ble f or mai nt ai ni n g a d e q u ate a n d ac c urat e me di cal re c or ds fr o m w hic h 
acc urate i nf or mati o n is rec or de d o n t o eC R Fs, w hic h ha ve bee n desi g ne d t o rec or d all o bser vati o ns 
a n d ot her data perti ne nt t o t he cli nical i n vesti gati o n.  
All d ata se nt t o t h e S p o ns or  m ust be e n d orse d b y t h e I n vesti gat or.  
T he Cli ni cal R esearc h Ass ociat e ( C R A )/St u d y M o nit or will  verif y t he c o nte nts a g ai nst t he s o urce 
rec or ds. If t he data ar e u ncl ear or c o ntra dict or y, q ueries are se nt f or c orrecti o ns or verificati o n of 
data.  
1 0. 2. 3. 2  Rec or di n g, A ccess , a n d R ete nti o n of S o urce D at a a n d S t u dy D oc u me nts  
Ori gi nal s o urce d oc u me nts t o be re vie we d d uri n g t his st u d y ma y i ncl u de, b ut are n ot li mite d t o, 
q uesti o n nair es, la b orat or y re p orts, E C G tra ci n gs, x -ra ys, ra di ol o gist re p orts, or re p orts, 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 6  of 7 3  
p h ot o gra p hs, cli ni c n otes or p har m ac y rec or ds a n d a n y ot her si milar re p orts or rec or ds of a n y 
pr oce d ure perf or me d i n a cc or da nc e wit h t he pr ot oc ol. S o urce d oc u me nts ma y als o i n cl u de  C R Fs 
or electr o nic d e vices w he n i nf or mati o n is rec or d e d directl y o nt o s uc h f or ms or de vices.  
W he ne ver p ossi ble, t he ori gi nal re c or di n g of a n o bser vati o n s h o ul d be retai ne d as t h e s o urce 
d oc u me nt; h o we ver, a p h ot o c o p y is acc e pta ble pr o vi de d t hat it is a clear, le gi ble, a n d e x act 
d u plicati o n of t h e ori gi n al d oc u me nt.  
All ke y dat a m ust be r ec or de d i n t he s u bje ct’s me dic al rec or ds.  
T he I n vesti gat or m ust per mit a ut h orize d  re pr ese ntati ves of t he S p o ns or , t he res pecti ve nati o nal, 
l ocal, or f orei g n re g ulat or y a ut h orities, t h e I R B, a n d a u dit ors t o i ns pect fa ciliti es a n d t o ha v e direct 
access t o ori gi nal s o urce r ec or ds rel e va nt t o t his st u d y, re gar dless of me dia. 
T he C R A/ St u d y M o nit or (a n d a u dit ors, I R B or re g ul at or y i ns pect ors) ma y c he c k t he eC R F e ntri es 
a gai nst t h e s o urce d o c u me nts . T he c o nse nt f or m i ncl u des a stat e me n t b y w hic h t he s u bje ct a gr ees 
t o t he m o nit or/ a u dit or fr o m t h e S p o ns or  or its re prese ntati ves, nati o n al or l ocal re g ulat or y 
a ut h orities , or t he I R B h a vi n g a ccess t o s o urce d at a (e .g ., s u bject’s me di cal file, a p p oi nt m e nt 
b o o ks, ori gi nal l a b orat or y r e p orts, e tc.).  
T hese rec or ds m ust be ma de a vail a ble wit hi n re as o na ble ti m es f or i ns pecti o n a n d d u plicati o n, if 
re q uire d, b y a pr o p erl y a ut h oriz e d  re prese ntati ve of a n y re g ulat or y a ge nc y ( e .g ., t he U S F o o d a n d 
Dr u g A d mi nistrati o n [ F D A], E ur o p ea n Me dici nes A ge nc y [ E M A], U K Me dici n es a n d Healt hc are 
P r o d ucts Re g ulat or y A ge n c y [ M H R A]) or a n a u dit or ).  
Esse ntial d oc u m e nts m ust be mai ntai ne d acc or di n g t o I C H G C P r e q uire m e nts a n d m a y n ot be 
destr o ye d w it h o ut writte n p er missi o n fr o m t he S p o ns or .  
1 0. 2. 3. 3  A u dit/I ns pe cti o n  
T o e ns ure c o m plia nce wit h rele v a nt re g ul ati o ns, dat a ge nerat e d b y t his st u d y m ust be a vaila bl e f or 
i ns pecti o n u p o n re q u est b y re prese ntati ves of, f or e xa m ple, t h e U S F D A (as well as ot her U S 
nat i o nal a n d l oc al re g ul at or y a ut h oriti es), t he E M A, t he M H R A, ot her re g ulat or y a ut h oriti es, t he 
S p o ns or  or its re prese ntati ves, a n d t h e I R B/I E C f or e ac h  site. 
1 0. 2. 3. 4  Fi n a nci al D iscl os ure 
T he I n vesti gat or is re q uire d t o discl ose a n y fi na n cial arra n ge me nt d uri n g t he st u d y a n d f or 1 year 
after, w her e b y t h e val ue of t he c o m p e nsati o n f or c o n d ucti n g t he st u d y c o ul d be i nfl u e nce d b y t h e 
o utc o me of t he st u d y. T he f oll o wi n g i nf or mati o n is c olle cte d: a n y si g nifica nt pa y me nts fr o m t he 
S p o ns or  or s u bsi diaries s uc h as a gra nt t o  f u n d o n g oi n g researc h, c o m pe nsati o n i n t he f or m of 
e q ui p me nt, retai ner f or o n g oi n g c o ns ultati o n or h o n oraria; a n y pr o priet ar y i nt erest i n  I P; a n y 
si g nifica nt e q uit y i nt erest i n t he S p o ns or  or s u bsi diaries as defi ne d i n 2 1 C F R 5 4 2( b)  (2 0 1 8 ). 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 7  of 7 3  
1 0. 3  
Et hic al C o nsi der ati o ns  
1 0. 3. 1  
I nf or me d C o nse nt  
It is t he res p o nsi bilit y of t he I n vesti g at or t o o bt ai n writte n inf or m e d co nse nt fr o m all st u d y s u bjects 
pri or t o a n y st u d y relate d pr oce d ures i ncl u di n g S cree ni n g assess me nts . All c o nse nt d oc u me ntati o n 
m ust be i n acc or da nc e wit h a p plic a ble re g ul ati o ns a n d G C P.  Eac h s u bject or t he s u bject’s le gall y -
I C F a ut h orize d  r e prese nt ati v e as a p plica ble is re q u este d t o si g n t h e S u bject I nf or me d C o nse nt 
F or m or a certifi e d tr a nslati o n, if a p plic a ble aft er t h e s u bject has r ecei ve d a n d re a d ( or bee n rea d) 
t he writte n s u bject i nf or mati o n a n d rec ei ve d a n e x pl a nati o n of w hat t h e st u d y i n v ol ves, i ncl u di n g 
b ut n ot li mite d t o: t he o bje cti v es, p ote nti al be nef its a n d ris k, i nc o n ve nie nc es, a n d t he s u bject’s 
ri g hts a n d res p o nsi bilities. A c o p y of t he i nf or me d c o nse nt  d oc u me nt ati o n ( i.e., a c o m plet e set of 
s u bject i nf or mati o n s heets a n d f ull y e xec ute d si g n at ure pa ges ) m ust be gi ve n t o t h e s u bje ct or t he 
s u bject’s le g all y-a ut h ori ze d  re pr ese ntati ve as a p pli ca ble . If a p plica ble, it is pr o vi de d i n a certifie d 
tra nslati o n of t he l ocal la n g ua g e. Si g ne d c o nse nt f or ms m ust re mai n i n e ac h s u bject’s st u d y file 
a n d m ust be a v ail a ble f or verific ati o n at a n y ti m e.  
T he  I n vesti gat or pr o vi des t he S p o ns or  wit h a c o p y of t he c o nse nt f or m w hic h was re vi e we d b y t he 
I R B a n d w hic h re cei v e d t heir fa v ora ble o pi ni o n/ a p pr o val. A c o p y of t he I R B writte n f a v ora ble 
o pi ni o n/a p pr o v al of t hese d oc u me nts m ust be pr o vi de d t o t he S p o ns or , pri or t o t he start of t h e 
st u d y. A d diti o nall y, if t h e I R B r e q uires m o difi cati o n of t he sa m pl e S u bje ct I nf or mati o n a n d 
co nse nt d oc u me nt pr o vi de d b y t he S p o ns or , t h e d oc u me ntati o n s u p p orti n g t his r e q uire me nt m ust 
be pr o vi de d t o t he S p o ns or . 
1 0. 3. 2  
I nstit uti o n al Re vie w B o ar d  
It is t he res p o nsi bilit y of t he I n v esti gat or t o s u b mit t his pr ot oc ol, t h e i nf or m e d c o nse nt d oc u me nt 
(a p pr o ve d b y t he S p o ns or  or t heir desi g nee) , rele v a nt s u p p orti n g i nf or m ati o n a n d all t y p es of 
s u bject re cr uit me nt i nf or m ati o n t o his/ h er  l oc al I R B f or re vie w, a n d all m ust b e a p pr o ve d pri or t o 
site i nitiati o n. 
Pri or t o i m ple m e nti n g c h a n ges i n t he st u d y, t he S p o ns or  a n d t he I R B m ust a p pr o ve a n y re visi o ns 
of a n y re vise d i nf or m e d c o nse nt d oc u me nts a n d a me n d me nts t o t he pr ot oc ol u nless t her e is a 
s u bject safet y iss ue. 
IP  s u p plies will n ot be release d u ntil t h e S p o ns or  ( or t heir del e gat e) has recei v e d writte n I R B/I E C 
a p pr o val of a n d c o pies of re vise d d o c u me nts.  
T he I n vesti g at or is res p o nsi ble f or kee pi n g his/ her l o cal  I R B/I E C a p pr aise d of t he pr o gr ess of the 
st u d y a n d of a n y c ha n g es ma de t o t he pr ot o c ol, at l east o nce a y ear . T h e I n vesti gat or m ust als o 
kee p t he l ocal I R B i nf or me d of a n y seri o us a n d si g nifica nt A Es . 
1 0. 4  
Pri v ac y a n d C o nfi de nti alit y  
All U S -base d sites a n d la b orat ories or e ntiti es pr o vi di n g s u p p ort f or t his st u d y, m ust, w here 
a p plic a ble, c o m pl y wit h t he He alt h I ns ura n ce P orta bilit y a n d Ac c o u nta bilit y Act of 1 9 9 6 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 8  of 7 3  
( HI P A A). A site t hat is n ot a C o vere d E ntit y as d efi ne d b y HI P A A, m ust pr o vi de d oc u m e ntati o n 
of t his fact t o  t he C R O.  
T he c o nfi de ntialit y of re c or ds t hat ma y be a ble t o i d e ntif y s u bjects will be pr ote cte d i n acc or d a nce 
wit h a p pli ca bl e la ws, re g ulati o ns , a n d g ui d eli n es.  
After s u bjects ha ve c o nse nt e d t o ta k e part i n t he st u d y, t he S p o ns or  a n d/ or desi g nee re vie ws t heir 
me dic al r ec or ds a n d data c olle cte d d uri n g t he st u d y.  T hese rec or ds a n d data ma y, i n a d diti o n, be 
re vie we d b y ot hers i ncl u di n g t h e f oll o wi n g: i n de pe n de nt a u dit ors w h o vali date t he d ata o n be half 
of t he S p o ns or ; t hir d p arti es wit h w h o m t he S p o ns or  ma y d e vel o p, re gist er, or mar ket PI P E -5 0 5 ; 
nati o nal or l oc al re g ulat or y a ut h orities; a n d t he I R B(s) w hic h ga ve a p pr o val f or t he st u d y t o 
pr ocee d.  T he S p o ns or  a n d/ or its re prese nt ati v es accessi n g t he re c or ds a n d data will ta k e all 
reas o na ble pr eca uti o ns i n acc or d a nce wit h a p plic a ble la ws, re g ulati o ns, a n d g ui deli nes t o mai ntai n 
t he c o nfi d e nti alit y of s u bjects' i de ntities. 
S u bjects are assi g ne d a u ni q ue i de ntif yi n g n u m ber. H o we ver, t heir i nitials a n d dat e of birt h  m a y 
als o be c oll ect e d a n d use d t o assist t he S p o ns or  t o verif y the ac c urac y of t he dat a, f or e xa m ple, t o 
c o nfir m t h at l a b orat or y res ults ha ve be e n assi g ne d t o t he c orre ct s u bject.  
T he res ults of st u dies –  c o ntai ni n g s u bjects’ u ni q ue i de ntif yi n g n u m b er, rele v a nt m e dic al rec or ds, 
a n d p ossi bl y i nitials a n d dat es of birt h  –  will be re c or de d. T he y m a y be tr a nsferre d t o, a n d use d i n, 
ot her c o u ntries w hic h ma y n ot aff or d t he sa me le vel of pr otecti o n t h at a p pli es wit hi n t he c o u ntri es 
w here t his st u d y is c o n d ucte d.  T he p ur p ose of a n y s uc h tra nsfer w o ul d i ncl u de: T o s u p p ort 
re g ulat or y s u b missi o ns, t o c o n d uct ne w dat a a nal yses t o p u blis h or prese nt t he st u d y r es ults, or t o 
a ns wer q uesti o ns as ke d b y re g ulat or y or healt h a ut h orities.  
1 0. 5  
C o m pli a nce wit h L a w, A u dit, a n d De b ar me nt  
B y si g ni n g t his pr ot oc ol, t he I n vesti gat or a grees t o c o n d u ct t he st u d y i n a n effi cie nt a n d dili g e nt 
ma n ner a n d i n c o nf or ma n ce wit h t his pr ot oc ol; g e nerall y ac ce pte d sta n dar ds of G C P; a n d all 
a p plic a ble l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he cli nical st u d y.  
T he I n vesti g at or als o a grees t o  all o w m o nit ori n g, a u dits, I R B/ I E C re vie w a n d re g ulat or y a ge nc y 
i ns pecti o n of trial-r elate d d oc u me nts a n d pr oce d ur es a n d pr o vi d e f or direct a ccess t o all st u d y-
relat e d s o urce dat a a n d d oc u me nts. 
T he I n vesti g at or s hall pre par e a n d m ai nt ai n c o m plete a n d ac c u rat e st u d y d oc u m e ntati o n i n 
c o m pli a nce wit h G C P sta n dar ds a n d a p plica ble l oc al la ws, r ules a n d re g ulati o ns; a n d, f or ea c h 
s u bject partici pati n g i n t he st u d y, pr o vi d e all data, a n d u p o n c o m pleti o n or ter mi nati o n of t he 
cli ni cal st u d y s u b mit a n y ot her re p ort s t o t h e S p o ns or as re q uir e d b y t his pr ot o c ol or as ot h er wise 
re q uire d p urs ua nt t o a n y a gre e me nt wit h t h e S p o ns or. 
St u d y d oc u me nt ati o n will be pr o m ptl y a n d f ull y discl ose d t o t he S p o ns or b y t he I n v esti gat or u p o n 
re q uest a n d als o s hall b e ma de a vaila ble at t he I n v esti gat or’s site u p o n re q u est f or i ns pecti o n, 
c o p yi n g, re vi e w a n d a u dit at reas o na ble ti mes b y re prese ntati ves of t he S p o ns or or a n y re g ulat or y 
a ge nci es. T he I n vesti gat or a grees t o pr o m ptl y ta k e a n y reas o na ble st e ps t hat are r e q ueste d b y t he 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 6 9  of 7 3  
S p o ns or  as a res ult of a n a u dit t o c orre ct d eficie ncies i n t he st u d y d oc u me nt ati o n a n d case r e p ort 
f or ms. 
I nter nati o nal C o nfere n ce o n Har m o nizati o n’s G C P g ui deli n es rec o m me n d t h at t he I n vesti g at or 
i nf or m t h e s u bje ct’s pri mar y p h ysicia n a b o ut t h e s u bject’s p arti cipati o n i n t h e st u d y if t he s u bj ect 
has a pri mar y p h ysi cia n a n d if t he s u bj ect a grees t o t he pri mar y p h ysi cia n b ei n g i nf or m e d.  
T he I n vesti g at or will pr o m ptl y i nf or m t h e S p o ns or of a n y re g ul at or y a g e nc y i ns pe cti o n c o n d uct e d 
f or t his st u d y a n d pr o vi de t he fi nal res ults (i.e., fi nal o bser vati o ns a n d res p o nses).  
Pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical st u di es b y a n y c o urt or re g ulat or y a g e nc y 
will n ot be all o we d t o c o n d uct or w or k o n t his st u d y. T he I n vesti gat or will i m me diat el y discl ose 
i n writin g t o t h e S p o ns or if a n y pers o n w h o is i n v ol ve d i n c o n d ucti n g t he st u d y is de barre d or if 
a n y pr ocee di n g f or de bar m e nt is pe n di n g or, t o t he best of t he I n vesti gat or’s k n o wle d ge, 
t hreat e ne d. 
I n t he e ve nt t he S p o ns or pre mat urel y t er mi n ates a partic ul ar st u d y site, t h e S p o ns or will pr o m ptl y 
n otif y t he I R B/ I E C. 
1 0. 6  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce  
B y si g ni n g t his pr ot oc ol, t he S p o ns or a grees t o e ns ure t hat st u dies are c o n d uct e d a n d data are 
ge nerat e d, d oc u me nte d, a n d re p ort e d i n c o m plia nc e wit h  t he pr ot oc ol, a cce pte d sta n dar ds of G C P 
u n der q ualit y ass ura nce s yste ms wit h writte n st a n d ar d o perati n g pr oce d ur es, a n d all a p plic a ble 
l ocal la ws, r ules a n d re g ulati o ns relati n g t o t h e c o n d uct of t he cli nical st u d y. 
1 0. 7  
P u bli c ati o n P oli c y  
All ma n uscri pts, a bs tracts, or ot her m o des of prese ntati o n arisi n g fr o m t he res ults of t he st u d y m ust 
be re vie we d a n d a p pr o ve d i n writi n g b y t he S p o ns or , i n a d va nce of s u b missi o n. T he re vi e w is 
ai me d at pr otecti n g t he S p o ns or ’s pr o priet ar y i nf or mati o n e xisti n g eit her at t h e date of t he 
c o m me n ce m e nt of t he st u d y or ge nerate d d uri n g t he st u d y.  
 
 
 
 
 
 
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 7 0  of 7 3  
1 1.  
R E F E R E N C E S  
Altsc h uler R A, D ol a n D F, Halse y K, Ka nic ki A, D e n g N, et al. ( 2 0 1 5) A ge -relat e d c h a n ges i n 
a u dit or y ner ve –  i n ner hair cell c o n necti o ns, hair cell n u m bers, a u dit or y brai n ste m res p o nse a n d 
ga p dete cti o n i n U M -H E T 4 mice. Ne ur osci 2 9 2: 2 2 -3 3.  
Bai G, C hi vata kar n O, B o na n o mi D, Letti eri K, Fra nce L, et al. ( 2 0 1 1) Prese nili n -de p e n de nt 
rece pt or pr o cessi n g is re q uire d f or a x o n g ui da n ce. C ell 1 4 4( 1): 1 0 6-1 1 8.  
Bar bee C M, Ja mes J A, Par k J H, S mit h E M, J o h ns o n C E, et al. ( 2 0 1 8) Effe cti v e ness of a u dit or y 
meas ures f or d ete cti n g hi d de n heari n g l oss a n d/ or c oc hle ar s y na pt o p at h y: a s yste matic r e vie w. 
Se mi n Hear 3 9( 2): 1 7 2 -2 0 9.  
B hara d waj H M, Ver h ulst S, S ha hee n L, Li ber ma n M C, S hi n n -C u n ni n g ha m B G ( 2 0 1 4) C oc hlear 
ne ur o pat h y a n d t he c o di n g of s u pra -t hres h ol d s o u n d. Fr o nt S yst Ne ur osci 8( 2 6): 1-1 8.  
B hara d waj H M, Mas u d S, Me hraei G, Ver h ulst S, S hi n n -C u n ni n g ha m B G ( 2 0 1 5) I n di vi d ual 
differe nc es re veal c orrel ates of hi d d e n heari n g de ficits. J Ne ur osci 3 5( 5): 2 1 6 1-2 1 7 2.  
B o urie n J, Ta n g Y, Batr el C, H uet A, L e n oir M, et al. ( 2 0 1 4) C o ntri b uti o n of a u dit or y n er ve fi b ers 
t o c o m p o u n d a cti o n p ote ntial of t he a u dit or y ner ve. J Ne ur o p h ysi ol 1 1 2: 1 0 2 5-1 0 3 9.  
Bra m hall N F, Beac h E, E p p B, Le Prel l C G, L o pe z-P o ve da E A, et al. ( 2 0 1 9) T he searc h f or n oise -
i n d uce d c o c hle ar s y na pt o pat h y i n h u ma ns: Missi o n i m p ossi ble? Hear Res 3 7 7: 8 8-1 0 3.  
Bra m hall N F, K o nra d -Marti n D, Mc Milla n G P, Gri est S E ( 2 0 1 7) A u dit or y br ai nste m res ps o nse 
alter e d i n h u ma ns wit h n o ise e x p os ure des pite n or mal o uter hair cell f u ncti o n. Ear He ar 3 8( 1): e 1-
e 1 2.  
Br u gea u d A, T o n g M, L u o L, E d ge A S B ( 2 0 1 4) I n hi biti o n of re p ulsi ve g ui d a nce m ol ec ul e, R G Ma, 
i ncreases affer e nt s y na pse f or m ati o n wit h a u dit or y h air cells. De v Ne ur o bi ol 7 4( 4): 45 7 -4 6 6.  
De yts C, Cl utter M, Herrera S, J o va n o vic N, G o d di A, et al. ( 2 0 1 6) L oss of prese nili n f u ncti o n is 
ass ociate d wit h a sel ecti v e gai n of A P P f u ncti o n. e Life 5: 1 -2 4.  
E M A ( 1 9 9 5) I C H T o pic E 2 A Cli nical Safet y Data Ma na ge me nt: Defi niti o ns a n d Sta n d ar ds f or 
E x pe dit e d Re p orti n g . 
F ur ma n A C, K uja wa S G, Li b er ma n M C ( 2 0 1 3) N oise -i n d uce d c oc hlear ne ur o p at h y is sele cti v e 
f or fi bers wit h l o w s p o nta ne o us rates. J Ne ur o p h ysi ol 1 1 0: 5 7 7-5 8 6.  
Haa pasal o A a n d K o vacs D M ( 2 0 1 1) T he ma n y s u bstrates of prese nili n/ -secret ase. J Alz hei mers 
Dis 2 5( 1): 3 -2 8.  
Heeri n ga A N a n d K ö p pl C ( 2 0 1 9) T he a gi n g c oc hlea: t o war ds u nra veli n g t he f u ncti o nal 
c o ntri b uti o ns of strial d ysf u ncti o n a n d s y na pt o pat h y. Hear Res 3 7 6: 1 1 1 -1 2 4.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 7 1  of 7 3  
Hic k ma n T T, S malt C, B o br o w J, Q uatieri T, Li ber ma n M C ( 2 0 1 8) Blast -i n d u ce d c oc hle ar 
s y na pt o pat h y i n c hi nc hill as. Sci Re p orts 8: 1 0 7 4 0.  
Hic k o x A E, Larse n E, Hei nz M G, S hi n o b u L, W hitt o n J P ( 2 0 1 7) Tra nslati o nal iss ues i n c oc hl ear 
s y na pt o pat h y. Hear R es 3 4 9: 1 6 4-1 7 1.  
Killi o n M C ( 1 9 9 7) Heari n g ai ds: past, prese nt, f ut ure: m o vi n g t o war d n or mal c o n versati o ns i n 
n oise. Br J A u di ol 3 1: 3, 1 4 1 -1 4 8.  
Killi o n M C, Ni q uette P A, G u d m u n dse n GI, R e vis LJ, Ba nerje e S ( 2 0 0 4) De vel o p me nt of a q uic k 
s peec h-i n-n oise test f or m eas uri n g si g n al -t o-n oise rati o n l oss i n n or m al -he ari n g  a n d he ari n g -
i m pair e d list e ners. J Ac o ust S oc A m 1 1 6( 4 Pt 1): 2 3 9 5-4 0 5.  
Ki m YJ, Wa n g S, T y m a ns k yj S, Ma L, Ta o H W, et al. ( 2 0 1 6) Dcc me di ates f u n cti o n al asse m bl y 
of peri p heral a u dit or y circ uits. Sci Re p 6: 2 3 7 9 9.  
K o bel M, Le Prell C G, Li u J, Ha w ks J W, Ba o J ( 2 0 1 7) N oise-i n d uce d c oc hl ear s y na pt o pat h y: past 
fi n di n gs a n d f ut ure st u dies. Hear Res 3 4 9: 1 4 8-1 5 4.  
K uja wa S G a n d Li ber ma n M C ( 2 0 0 9) A d di n g i ns ult t o i nj ur y: c oc hl ear ner ve d e ge ner ati o n after 
“te m p or ar y” n oise -i n d uce d he ari n g l oss. J Ne ur osci 2 9( 4 5): 1 4 0 77 -1 4 0 8 5.  
K uja wa S G a n d Li ber m a n M C ( 2 0 1 5) S y na pt o pat h y i n t h e n oise -e x p ose d a n d a gi n g c oc hlea: 
pri mar y ne ur al de ge n erati o n i n a c q uire d se ns ori n e ur al heari n g l oss. Hear Res 3 3 0( 0 0): 1 9 1 -1 9 9.  
K uja wa S G a n d Li ber m a n M C ( 2 0 1 9) Tra nslati n g a ni mal m o dels t o h u m a n t hera p e uti cs i n n oise -
i n d uce d a n d a ge-rel ate d h eari n g l oss. Hear Res 3 7 7: 4 4-5 2.  
Le Prell C G ( 2 0 1 9) Effects of n oise e x p os ure o n a u dit or y brai nste m res p o nse a n d s peec h -i n-n oise 
tas ks: a re vi e w of t he literat ure. I nt J A u di ol 5 8(s u p 1): S 3-S 3 2.  
Le Prell C G a n d Br u n gart D S ( 2 0 1 6) S peec h -i n-n oise tests a n d s u pra -t hr es h ol d a u dit or y e v o ke d 
p ote nti als as metrics f or n oise da ma g e a n d cli ni cal tri al o ut c o me m eas ures. Ot ol Ne ur ot ol 
3 7( 8):e 2 9 5 -3 0 2.  
Lee K H a n d Warc h ol M E ( 2 0 0 8) Pr o m oti o n of ne urite o ut gr o w n a n d a x o n  g ui da n ce i n s piral 
ga n gli o n c ells b y netri n -1. Arc h Ot olar y n g ol Hea d N ec k S ur g 1 3 4( 2): 1 4 6 -1 5 1.  
Li S, Ha n g L, Ma Y ( 2 0 1 6) F G F 2 2 pr otects heari n g f u ncti o n fr o m ge nt a m yci n ot ot o xicit y b y 
mai nt ai ni n g ri b b o n s y na pse n u m ber. Hear R es 3 3 2: 3 9 -4 5.  
Li ber m a n M C a n d K uja wa S G ( 2 0 1 7) C oc hlear s y na pt o pat h y i n ac q uire d se ns ori ne ural he ari n g 
l oss: manifest ati o ns a n d mec h a nis ms. Hear Res 3 4 9: 1 3 8 -1 4 7.  
Li n H W, F ur ma n A C, K uja wa S G, Li b er ma n M C ( 2 0 1 1) Pri mar y ne ural de ge n erati o n i n t he g ui n ea 
pi g c oc hlea after r e versi bl e n oise -i n d uce d t hres h ol d s hift. J Ass oc Res Ot olar y n g ol 1 2( 5): 6 0 5-6 1 6.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 7 2  of 7 3  
Li n V, G ol u b J S, N g u ye n T B,  H u me C R, Oest erle E C, et al. ( 2 0 1 1) I n hi biti o n of n ot c h acti vit y 
pr o m otes n o n -mit oti c re g e nerati o n of hair c ells i n t he a d ult m o use utricl es. J Ne ur osci 3 1( 4 3): 
1 5 3 2 9 -1 5 3 3 9.  
L o bari nas E, Sal vi R, Di n g D ( 2 0 1 6) Selecti ve i n ner hair cell d ysf u ncti o n i n c hi nc hill as i m pairs 
heari n g -i n-n oise i n t h e a bse nce of o uter hair cell l oss. J Ass oc Res Ot olar y n g ol 1 7: 8 9 -1 0 1.  
Me hraei G, Hic k o x A E, B hara d waj H M, G ol d ber g H, Ver h ulst S, et al. ( 2 0 1 6) A u dit or y brai nste m 
res p o nse late n c y i n n oise as a mar ker of c oc hl ear s y na pt o pat h y. J Ne ur osci 3 6( 1 3): 3 7 5 5 -3 7 6 4.  
Me yer T ( 2 0 1 3) I ntrat y m pa ni c tre at m e nt f or ti n nit us: a re vie w. N oise Healt h 1 5: 8 3 -9 0.  
M ö hrle D, Ni K, Vara ki na K, Bi n g D, Lee S C, et al. ( 2 0 1 6) L oss of a u dit or y se nsiti vit y fr o m i n ner 
hair cell s y na pt o p at h y c a n be  c e ntall y c o m pe nsate d i n t he y o u n g b ut n ot ol d br ai n. Ne ur o bi ol 
A gi n g 4 4: 1 7 3 -1 8 4.  
N y ber g S, A b b ott NJ, S hi X, Ste y ger P S, Da b d o u b A ( 2 0 1 9) Deli ver y of t hera p e utics t o t h e i n ner 
ear: t h e c halle n ge of t he bl o o d -la b yri nt h barri er. Sci Tra nsl Me d 1 1( 4 8 2): e aao 0 9 3 5.  
Plac k CJ, Bar ker D, Pre n ger gast G ( 2 0 1 4) Perce pt ual c o nse q ue nc es of “ hi d de n” he ari n g l oss. 
Tre n ds i n Heari n g 1 8: 1 -1 1.  
Plac k CJ, Lé ger A, Pre n der gast G, Kl u k K, G uest H, et al. ( 2 0 1 6) T o war d a dia g n ostic t est f or 
hi d de n heari n g l oss. Tre n ds i n Hear i n g 2 0: 1-9.  
Sc h mie dt R A, Mills J H, B oettc h er F A ( 1 9 9 6) A ge -relate d l oss of acti vit y of a u dit or y-ner ve fi bers. 
J Ne ur o p h ysi ol 7 6( 4): 2 7 9 9-2 8 0 3.  
Ser ge ye n k o Y, Lall K, Li ber ma n M C, K uja wa S G ( 2 0 1 3) A ge -relat e d c o c hle ar s y na pt o pat h y: a n 
earl y -o nset c o ntri b ut er t o a u dit or y f u ncti o nal decli ne. J Ne ur osci 3 3( 3 4): 1 3 6 8 6 -1 3 6 9 4.  
S hrest ha B R, C hia C, W u L, K uja wa S G, Li ber ma n M C, et al. ( 2 0 1 8) Se ns or y ne ur o n di versit y i n 
t he i n ner ear is s ha pe d b y a cti vit y. Cell 1 7 4: 1 2 2 9-1 2 4 6.  
Si n ger W, Z ucc otti A, J ua ma n n M, Lee S C, Pa nf or d -Wals h R, et al. ( 2 0 1 3) N oise -i n d uc e d i n ner 
hair cell ri b b o n l oss dist ur bs ce ntral arc 
m o bilizati o n: a n o vel 
m ole c ular p ara di g m f or 
u n dersta n di n g ti n nit us. M ol Ne ur o bi ol 4 7: 2 6 1 -2 7 9.  
Staec ker H, M orel o c k M, Kra mer T, C hr b ol k a P, A h n J H, et al. ( 2 0 1 7) Saf et y of r e peat e d -d ose 
i ntrat y m pa ni c i nj ecti o ns wit h A M-1 0 1 i n ac ute i n ner ear ti n nit us. Ot ol Ne ur ot ol 1 5 7( 3): 4 7 8 -4 8 7.  
Till ma n T W a n d Car h art  R ( 1 9 6 6 ) A n E x pa n de d Test f or S peec h Discri mi nati o n Utilizi n g C N C 
M o n os ylla bic W or ds. N ort h wester n U ni v er sit y A u dit or y Test N o. 6. 
Wils o n R H a n d Mc Ar dle R ( 2 0 0 7) I ntra - a n d i nter -sessi o n test, retest relia bilit y of t he w or ds-i n-
n oise ( WI N) test. J A m Aca d A u di ol 1 8: 8 1 3 -8 2 5.  
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d

Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
Pr ot oc ol P TI -5 0 5 -1 0 1, A me n d me nt 3  
Versi o n 4. 0   
Pa ge 7 3  of 7 3  
Wils o n R H, Mc Ar dle R A, S mit h S L ( 2 0 0 7) A n e val u ati o n of t h e B K B -SI N, HI N T, Q uic k SI N, a n d 
WI N materials o n liste n ers wit h n or mal he ari n g a n d liste ners wit h heari n g l oss. 
J S peec h L a n g 
Hear Res 5 0( 4): 8 4 4 -8 5 6.  
W u P Z, Li ber ma n L D, Be n nett K, de Gr utt ola V, O’ Malle y J T, et al. ( 2 0 1 8) Pri mar y ne ural 
de ge nerati o n i n t he h u m a n c o c hlea: e vi de nce f o r hi d d e n heari n g l oss i n t he a gi n g e ar. Ne ur oscie n ce 
4 0 7: 8 -2 0.  
Ya ma m ot o N, T a ni ga ki K, Ts uji M, Ya be D, It o J, et al. ( 2 0 0 6) I n hi biti o n of N ot c h/ R B P -J 
si g nali n g i n d u ces hair cell f or mati o n i n ne o n ate m o use c oc hle as. J M ol Me d 8 4: 3 7 -4 5.  
Z he n g J L, S h o u J, G uille m ot F, Ka ge ya ma R, Ga o W ( 2 0 0 0) Hes 1 is a ne gati ve re g ul at or or i n ner 
ear hair cell differe ntiati o n. De vel o p me nt 1 2 7: 4 5 5 1 -4 5 6 0.  
Zi ne A, A u bert A, Qi u J, T heria n os S, G uille m ot F, et al. ( 2 0 0 1) Hes 1 a n d Hes 5 acti vities are 
re q uire d f or t he n or mal de vel o p m e nt of t he h air c ells i n t he m a m m ali a n i n ner e ar. J Ne ur osci 
2 1( 1 3): 4 7 1 2 -4 7 2 0.  
 
Pr ot oc ol _ A me n d me nt 3 _ 4. 0 _ 1 8 Se p 2 0 2 0 | V V- T M F- 1 5 6 6 6 4 0 | 1. 0
A p pr o ve d