Clinical trial NCT04462198
Conditions: Sensorineural Hearing Loss
Keywords: Hearing Loss Cochlear synaptopathy Deafness Speech-in-noise hearing difficulty
Sponsor: Contineum Therapeutics
Start date: 2020-10-15; Completion date: 2021-06-17
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind study of PIPE-505, or placebo, in subjects with hearing loss associated with speech-in-noise impairment.

Detailed description:
This is a randomized-controlled, double-blind study of PIPE-505 or placebo given as an injection one time in subjects with sensorineural hearing loss associated with speech-in-noise difficulty. Visits to the clinic will occur at baseline, dosing, and days 1, 7, 14, 30, 60 and 90 after treatment. Safety will be assessed by periodic measurement of vital signs, ear examination, electrocardiogram (ECG), blood laboratory analyses and occurrence of adverse events (AE). Efficacy will be assessed by periodic audiometry and other audiological tests.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: PIPE-505 intervention 2: Placebo
Intervention descriptions: intervention 1: Intratympanic injection intervention 2: Intratympanic injection

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
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  
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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
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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
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Pi peli ne T hera pe utics, I nc.  
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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
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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
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Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
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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  
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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
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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
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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  
 
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Pi peli ne T hera pe utics, I nc.  
C O N FI D E N TI A L  
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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 
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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  
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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  
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C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
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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. 
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C O N FI D E N TI A L  
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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.  
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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. 
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C O N FI D E N TI A L  
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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
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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
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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
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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  
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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 
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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  
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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. 
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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.  
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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.  
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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  
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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:  
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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). 
 
 
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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. 
 
 
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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.  
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A p


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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 . 
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C O N FI D E N TI A L  
1 8 S e pte m ber 2 0 2 0  
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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 
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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.  
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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 . 
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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. 
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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.  
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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.  
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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 
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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 
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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.  
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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.  
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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 : 
 
 
 
 
 
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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.  
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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 
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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 ).  
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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.  
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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.  
 
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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 . 
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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 
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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 
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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. 
 
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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 : 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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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 
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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, 
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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 ). 
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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 
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( 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 
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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

SAP_001.pdf: 
Statistical Analysis Plan: 
Sponsor Name: Pipeline Therapeutics, Inc. 
Protocol Number: PTI-505-101 
Protocol Title: A Phase I/IIa, Randomized, Double-Blind, Placebo-Controlled, Safety, 
Pharmacokinetic, and Preliminary EIicacy Study of Unilateral Intratympanic PIPE-505 in 
Subjects with Sensorineural Hearing Loss Associated with Speech-in-Noise Impairment 
Protocol Version and Date: Amendment 3 V4.0 (18-Sep-2020) 
IND #: 144418 


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 4 of 50
Table of Contents 
Revision History......................................................................................................................... 2
Approvals ................................................................................................................................. 3
1.
Glossary of Abbreviations ................................................................................................. 8
2.
Purpose .......................................................................................................................... 10
2.1.
Responsibilities ................................................................................................... 10
2.2.
Timings of Analyses ............................................................................................ 10
3.
Study Objectives ............................................................................................................. 11
3.1.
Primary Objective ................................................................................................ 11
3.2.
Secondary Objective ........................................................................................... 11
3.3.
Exploratory Objectives.................................. ..
................................................. 11
3.4.
Brief Description ...........................................
.... ............................................... 11
3.5.
Subject Selection ................................... ...... .................................................... 12
3.5.1.
Inclusion Criteria ..................
........................................................................... 12
3.5.2.
Exclusion Criteria ........... ...
............................................................................ 13
3.6.
Determination of Sample Size ...
.... .................................................................. 14
3.7.
Treatment Assignment and Blinding .................................................................... 15
3.8.
Administration of Study Medication...................................................................... 16
3.9.
Study Procedures and Flowchart ......................................................................... 17
4.
Endpoints ...............
............
..................................................................................... 19
4.1.
Primary Endpoint ................................................................................................. 19
4.2.
Secondary Endpoint ............................................................................................ 19
4.3.
Exploratory Endpoints ......................................................................................... 19
5.
Analysis Sets .................................................................................................................. 20
5.1.
Enrolled Set ......................................................................................................... 20
5.2.
Randomized Set .................................................................................................. 20
5.3.
Safety Analysis Set ............................................................................................. 20
5.4.
Full Analysis Set .................................................................................................. 20
5.5.
Per-Protocol Set .................................................................................................. 20
5.6.
Pharmacokinetic Set ........................................................................................... 20
6.
General Aspects for Statistical Analysis .......................................................................... 21
6.1.
General Methods ................................................................................................. 21
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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pp
Study Medication.
ures and Flowchart
App
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Endpoint .............
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Endpoint .............
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A
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 5 of 50
6.2.
Key Definitions .................................................................................................... 21
6.2.1.
Baseline .............................................................................................................. 21
6.2.2.
Study Day ........................................................................................................... 21
6.2.3.
End of Study ....................................................................................................... 21
6.3.
Missing Data ....................................................................................................... 22
6.3.1.
Birth Dates .......................................................................................................... 22
6.3.2.
Medication/Procedure Dates .............................................................................. 22
6.3.3.
Adverse Events .................................................................................................. 22
6.4.
Visit Windows ...................................................................................................... 23
6.5.
Pooling of Centers ............................................................................................... 23
6.6.
Subgroups .................................................... ..
................................................. 23
7.
Demographic, Other Baseline Characteristics and Medication ........................................ 24
7.1.
Subject Disposition and Discontinuation ........ .................................................... 24
7.2.
Inclusion/Exclusion Criteria ............ .................................................................... 24
7.3.
Protocol Deviation .................... ....
................................................................... 24
7.4.
Demographic and Other Baseline Characteristics ............................................... 24
7.5.
Medical History and Audiological/Otological History ............................................ 24
7.6.
Other Baseline Characteristics ............................................................................ 25
7.7.
Prior and Concomitant Medication/Procedures .................................................... 25
7.7.1.
Prior Medication ................................................................................................ 25
7.7.2.
Concomitant Medication ..................................................................................... 25
7.7.3.
Concomitant Procedure ...................................................................................... 25
8.
Efficacy Analysis ............................................................................................................. 26
8.1.
Exploratory Efficacy Endpoints ............................................................................ 26
8.1.1.
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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....... ...................
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....... ...................
....... ....
.............
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.............
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r Baseline Charact
Audiological/Otolo
pr
Audiological/Otolo
App
haracteristics .......
pp
haracteristics .......
comitant Medicatio
App
comitant Medicatio
ior Medication .......
Ap
ior Medication .......
Concomitant Medi
Ap
Concomitant Medi
A
comitant P
A
comitant P


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 6 of 50
9.
Analysis of Pharmacokinetics ......................................................................................... 30
9.1.
PK parameters .................................................................................................... 30
9.2.
Handling of missing and Below Limit of Quantification (BLQ) data ...................... 30
9.3.
Individual PK Data ............................................................................................... 31
9.4.
Summary of PK Data ........................................................................................... 31
10.
Safety Analysis ............................................................................................................... 32
10.1.
Study Drug Administration .............................
................................................. 32
10.2.
Adverse Events ............................................
.... ............................................... 32
10.3.
Clinical Laboratory Tests ....................... ....... .................................................... 32
10.4.
Vital Signs ...................................... ................................................................... 33
10.5.
Physical Examination ............... ....
................................................................... 33
10.6.
Otological Examination ......... ....
................................................................... 33
10.7.
Electrocardiograms ........
....
........................................................................ 33
10.8.
Tympanometry ..............
..... ............................................................................. 33
11.
Interim Analyses ..............
....... ....... ............................................................................ 35
12.
Changes from Analysis Planned in Protocol.................................................................... 36
13.
Reference List ........... .. .................................................................................................. 37
14.
Programming Considerations .......................................................................................... 38
14.1.
General Considerations ....................................................................................... 38
14.2.
Table, Listing, and Figure Format ........................................................................ 38
14.2.1.
General ............................................................................................................... 38
14.2.2.
Headers .............................................................................................................. 38
14.2.3.
Display Titles ...................................................................................................... 39
14.2.4.
Column Headers ................................................................................................ 39
14.2.5.
Body of the Data Display .................................................................................... 39
14.2.6.
Footnotes............................................................................................................ 41
15.
Quality Control ................................................................................................................ 42
16.
Index of Tables ............................................................................................................... 43
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 7 of 50
17.
Index of Figures .............................................................................................................. 47
18.
Index of Listings .............................................................................................................. 48
19.
Shells .............................................................................................................................. 50
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 10 of 50
2. 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
2.1. 
Responsibilities 
 will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings. Pharmacokinetic (PK) analyses will be carried out by 
 
, and the details of analysis are provided in Section 9 of this SAP.   
2.2. 
Timings of Analyses 
The primary analysis of the safety and tolerability profile of PIPE-505, and secondary and exploratory 
preliminary efficacy endpoints will be performed up to 3 months following a single unilateral intratympanic 
injection after all subjects complete the Day 90 visit or terminate early from the study. Unless otherwise 
specified, the analysis includes all data collected in the database through the time of the database lock. 
There is no planned interim analysis in this study. 
An independent Data Monitoring Committee (DMC), will review accumulating safety data periodically 
during the study. Blinded listings will be provided to the DMC and an independent unblinded statistician 
from 
 will be available to provide treatment information to DMC members upon request. 
DMC procedures and the list of blinded listings are outlined in the DMC charter.  
A blinded ad hoc analysis may be performed upon sponsor’s request during the study. The scope of the 
ad hoc analysis will include, but not limited to, the blinded listings to be provided to the DMC with the 
addition of 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
Approved
inate e
d
inate e
atabase thro
d
atabase thro
C), will review accum
ed
C), will review accu
to the DMC and an
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to the DMC and an
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gs are outlined in the
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mited to, the blinded
ro
mited to, the blinded


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 11 of 50
3. 
Study Objectives 
3.1. 
Primary Objective 
The primary objective is to assess the safety and tolerability profile of PIPE-505 when administered as a 
single unilateral intratympanic injection. 
3.2. 
Secondary Objective 
The secondary objective is to assess the single dose plasma PK profile of PIPE-505 following a single 
unilateral intratympanic injection. 
3.3. 
Exploratory Objectives 
The exploratory objectives are: 
1.
  
  
.  
3.4. 
Brief Description 
This is a Phase I/IIa, randomized, double-blind, placebo-controlled, single dose study in subjects with 
sensorineural hearing loss (SNHL) associated 
  
  
 This study plans to enroll subjects at approximately 7 sites 
in the US. Additional site(s) may be recruited to ensure the timely enrollment of study subjects.   
The total duration of subject participation is up to 
.
:

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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 12 of 50

3.5. 
Subject Selection 
Subjects will be screened for eligibility based on t e following inclusion and exclusion criteria. 
3.5.1. 
Inclusion Criteria 
Subjects must meet each of the following inclusion criteria to be eligible for randomization: 
1. Ability to personally provide written, signed, nd dated informed consent to participate in the study.  
2. Subject’s primary languag  is English.  
3. Male or female between 18 and 75 years of age, inclusive, at randomization.  
4. 
  
5. 
  
  
7. Male or female subjects with reproductive potential agree to comply with approved double barrier 
contraceptive method (e.g., condom plus intrauterine device [IUD], condom plus hormonal contraception, 
or double barrier method, i.e., condoms and diaphragms with spermicidal gel or foam) during and for 
3 months after study drug administration.  
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Approv
ased on t e following
ro
ased on t e following
ollowing inclusion cri
pp
ollowing inclusion cri
written, signed, nd
App
written, signed, nd
uag  is English.  
Ap
uag  is English.  
n 18 and 75 yea
A
n 18 and 75 yea
ved


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 13 of 50
Subjects are considered of non-reproductive potential if:  
 
a. Post-menopausal female with ≥12 consecutive months of spontaneous amenorrhea and age 
≥51 years with follicle-stimulating hormone (FSH) >30 mIU/mL at Screening  
 
b. Surgically sterile female and at least 6 weeks post-sterilization (i.e., bilateral oophorectomy or 
hysterectomy)  
 
c. Sterilized male at least 1-year post vasectomy and confirmed that they have obtained 
documentation of the absence of sperm in the ejaculate. 
8. The subject is in general good medical health with no clinically significant or relevant abnormalities, 
including medical history, physical exam, vital signs, electrocardiogram (ECG), and laboratory evaluations 
(hematology, chemistry, and urinalysis) as assessed by the Investigator.  
9. An understanding, ability, and willingness to fully comply with study procedures and restrictions.  
3.5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met:  
1. 
  
2. History of chronic otitis externa or media, other chronic middle ear disorders, or perilymph fistula.  
3. Presence of a genetic, syndromal or developmental auditory disorder.  
4. Presence of an autoimmune or serious neurological disorder that could contribute to auditory loss, as 
determined by the Investigator.  
5. History of herpes zoster oticus, or other infectious etiology of hearing loss as determined by the 
Investigator.  
6. History of barotrauma as determined by the Investigator.  
7. 
  
8. 
  
9. Any prior exposure to platinum-based medications.  
10. Otological disorders that would preclude safe tympanic injection (e.g., history or presence of 
cholesteatoma, tympanic membrane (TM) perforation, otitis media, or middle ear anatomic anomaly) as 
determined by the Investigator.  
11. Presence of a cochlear implant.  
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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with stu
d
with stu
llowing exclusion cri
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llowing exclusion cr
 other chronic middl
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 other chronic middl
developmental audi
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App
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pr
serious neurologica
r oticus, or other in
App
r oticus, or other in
A
s determined b
A
s determined b


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 14 of 50
12. History of Meniere’s disease or endolymphatic hydrops.  
13. History of bothersome tinnitus, as determined by the Investigator.  
14. Past otologic surgical procedures that would preclude safe, intratympanic injection as determined by 
the Investigator.  
15. Intratympanic injection within 6 months of randomization.  
16. Use of an investigational product or intervention other than a non-interventional registry study 
(including vaccine studies) within the greater of 30 days or 5 half-lives (if known) prior to Screening or 
expected during the study.  
17. 
  
18. History of malignancy under current active treatment or considered at substantial risk for progression 
or recurrence during the study interval, as determined by the Investigator. Note, central nervous system 
neoplasms or head and neck cancer are excluded from elig bility regardless of treatment status.  
19. The subject has a QTcF by ECG >450 milliseconds for males or >470 milliseconds for females.  
20. The subject has a history of dysrhythmia (such as atrial fibrillation or ventricular tachycardia, etc.) that 
is considered unstable by the Investigator.  
21. The subject has experienced a significant systemic illness, as judged by the Investigator, within 
30 days prior to Screening.  
22. The subject has a current or relevant history of physical or psychiatric illness, or any medical disorder 
that may require treatment o  make the subject unlikely to fully complete the study, or any condition that 
presents undue risk from the investigational product or procedure, as determined by the Investigator.  
23. Known or suspected intolerance or hypersensitivity to the investigational product or closely-related 
compounds.  
24. The subject is pregnant or breastfeeding or plans to become pregnant during the study.  
25. History of alcohol or other substance abuse within 6 months of Screening as determined by the 
Investigator.  
26. Subject is Hepatitis B positive (Subjects who are surface antibody positive secondary to immunization 
are eligible).  
27. History of Hepatitis C.  
28. Subject is Human Immunodeficiency Virus (HIV) seropositive.  
3.6. 
Determination of Sample Size 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
Approved
nt or considered at 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 16 of 50
 
Deliver the preloaded syringe to the unblinded otologist or neuro-otologist 
  
 
Be identified on the site delegation of responsibility log as the unblinded dose preparer. 
 
Be restricted from participating in any subject assessment  
 
Be restricted from disclosing treatment assignments to any study staff, with the exception of 
otologist/neuro-otologist who administers study drug.  
3.8. 
Administration of Study Medication 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 18 of 50
c
  
  
  
  
speaker. 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 19 of 50
4. 
Endpoints 
4.1. 
Primary Endpoint 
The primary endpoint of the study is the number and severity of adverse events (AEs) up to 3 months 
following a single unilateral intratympanic injection of PIPE-505.  
4.2. 
Secondary Endpoint 
The secondary endpoint of the study is the single dose plasma PK parameters of PIPE-505, including AUCt, 
AUC24, AUC0-∞, Cmax, tmax, t½, CL/F, Vz/F, λz (see SAP Section 9.1 for definitions).  
4.3. 
Exploratory Endpoints   
  
  
  
Approved


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 20 of 50
5. 
Analysis Sets 
5.1. 
Enrolled Set 
  
5.2. 
Randomized Set 
. 
5.3. 
Safety Analysis Set  
Safety Analysis Set includes all randomized subjects who received the study medication. Subjects will be 
analyzed according to treatment received. The Safety Analysis Set will be used for primary analysis and all 
safety analyses.  
5.4. 
Full Analysis Set 
  
5.5. 
Per-Protocol Set 
  
  
5.6. 
Pharmacokinetic Set 
The PK Set includes subjects in the Safety Analysis Set who have no major deviations related to IP intake 
and have at least one quantifiable post-dose PK sample available. The PK Set will be used for PK analysis.  
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Se
d
Se


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 21 of 50
6. 
General Aspects for Statistical Analysis 
6.1. 
General Methods 

  
  
.  
6.2. 
Key Definitions 
6.2.1. 
Baseline 
Baseline will be defined as the last assessment done before study medication administration (considering 
unscheduled visits when available). Change from Baseline will be defined as the measurement at each 
time point minus the Baseline value. 
6.2.2. 
Study Day 
Study Day is calculated relative to the date of study drug administration. Day 0 is defined as the study 
medication administration day. 
6.2.3. 
End of Study 
A subject is considered to have fulfilled the requirements for study completion if/when the subject has 
completed all study periods and Visit 7 (
  
The scheduled End of Study/Early Termination will be the last subject’s visit at Visit 7. 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
A
d
the last as
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able)


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 22 of 50
6.3. 
Missing Data 
6.3.1. 
Birth Dates 
If the date of birth is only partially available, the first of the month will be imputed for any missing days and 
January will be imputed for any missing months. Imputed dates will not be presented in the data listings. 
6.3.2. 
Medication/Procedure Dates 
For prior and concomitant medications/procedures with incomplete dates, the following rules will be used 
to impute start and/or stop dates for the purposes of determining if a medication is prior or concomitant 
only. Imputed dates will not be presented in the data listings. 
For partial start dates: 
 
If day is missing, and the month and year match the month and the year of the study medication 
administration date, the day of the study medication administration date will be imputed. Otherwise, the 
first of the month will be used.  
 
If day and month are missing and the year matches the year of the study medication administration 
date, the month and the day of the study medication administration date will be imputed. Otherwise, 
January 1st will be used.  
 
If the start date is completely missing, and the stop date is on or after study medication administration 
date, the start date should be imputed as the administration date and the medication will be considered 
concomitant medication. If the start date is completely missing and the stop date is before the study 
medication administration date, the medication will be considered to be prior only.  
 
If the stop date is complete and the imputed start date is after the actual stop date, then the start date 
will be imputed as the stop date. 
For partial stop dates: 
 
If the day is missing, then the last day of the month will be used. 
 
If the month is missing, then December will be used.  
 
If the stop date is completely missing then the date of last study visit will be used.  
If the start date for a medication is partially or fully missing, and it is unclear as to whether the medication 
is prior or concomitant, it will be assumed that it is concomitant. 
6.3.3. 
Adverse Events 
For AEs with incomplete dates, the following rules will be used to impute start and/or stop dates for the sole 
purpose of determining if an AE is treatment-emergent. Imputed dates will not appear in the data listings. 
For partial start dates: 
 
If day is missing, and the month and year match the month and the year of the study medication 
administration date, the day of the study medication administration date will be imputed and the AE will 
be considered treatment-emergent. Otherwise, the first of the month will be used and the 
treatment-emergent status will be assessed relative to the study medication administration date. 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 24 of 50
7. 
Demographic, Other Baseline Characteristics and Medication 
7.1. 
Subject Disposition and Discontinuation 
A summary of subject disposition will be provided for the number of subjects screened, number of screen 
failures and reasons for screen failures, as well as the number of subjects in each analysis set (Enrolled 
Set, Randomized Set, Safety Analysis Set, Full Analysis Set, Per-Protocol Set, and PK Set). In addition, 
the number and percent of subjects in each of the following categories will be provided: 
 
Subjects who complete the study 
 
Subjects who discontinue early from study 
 
Reasons for early discontinuation from the study 
Subject disposition information will be provided overall and by treatment group. 
The number of subjects in each analysis set will also be summarized.  
A separate summary will be provided for the number and percentage of subjects attending each visit. 
Percentages will be based on the Safety Analysis Set.  
7.2. 
Inclusion/Exclusion Criteria 
Inclusion/exclusion criteria definitions and violations will be listed. Subjects with inclusion criteria not met or 
exclusion criteria met will be reported. 
7.3. 
Protocol Deviation 
Protocol deviations are pre-defined in the study. Deviations will be categorized as major or minor. Major 
protocol deviations will be summarized by category using the Randomized Set. 
7.4. 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographi  and baseline characteristics will be presented overall and by 
treatment group for the Safety An lysis Set and Full Analysis Set.  
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) for age, height, weight, 
and body mass index (BMI) will be summarized by treatment group and overall. Distribution of subjects by 
sex, race, ethnicity, and child-bearing potential (Yes/No) will be summarized overall and by treatment group. 
Following conversions will be applied where appropriate. 
 
Weight (in kg) = weight (in lbs) * 0.4536.  
 
Height ( in cm) = height (in inch) *2.54  
 
BMI = Weight(kg) / (Height(m)^2) 
7.5. 
Medical History and Audiological/Otological History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 22.1, 
summarized and presented overall and by treatment group based on the Safety Analysis Set. Summaries 
will be ordered alphabetically by system organ class (SOC) and then, within a SOC, alphabetically by 
preferred term (PT).  
Audiological/Otological history including SNHL will be coded and summarized using MedDRA version 22.1 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
Approved
mmarized. 
d
mmarized. 
and percentage of 
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and percentage 
 
tions will be listed. S
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 25 of 50
for the Safety Analysis Set. Categorical summary of audiological/ontological history will be provided. 
Medical history and Audiological/Otological history will be provided separately in separate listings. 
7.6. 
Other Baseline Characteristics 
  
7.7. 
Prior and Concomitant Medication/Procedures 
Medications will be coded using World Health Organization Drug Dictionary (WHO-DD) March 2020 B3. 
Prior and concomitant medications/procedures will be summarized separately by presenting the counts and 
percentage of subjects using medications overall and by each treatment group in the Safety Analysis Set. 
Summaries will be provided by Anatomical Therapeutic Chemical (ATC) classification Level 2 term and PT. 
Medication summaries will be sorted alphabetically by ATC Level 2  and then by PT within each ATC Level 
4. Subjects will be counted only once for each medication class and each preferred drug name.   
7.7.1. 
Prior Medication 
Prior medications will be presented in a summary table overall and by treatment group. Any medications 
(including herbal treatments, vitamins, non-pharmacological treatment such as psychotherapy as 
appropriate) received within 30 days prior to signing the Informed Consent Form (ICF) are considered as 
prior.  
Missing date imputation rules are provided in Section 6.3.2.
7.7.2. 
Concomitant Medication 
Concomitant medications will be presented in a summary table similarly to prior medications. Concomitant 
medication is defined as any medication taken from the date of signing the ICF through the 
y follow-
up visit. 
Missing date imputation rules are provided in Section 6.3.2.
7.7.3. 
Concomitant Procedure 
Concomitant procedure is defined as any procedure operated on or after the study medication 
administration date through the 
 follow-up visit. Concomitant procedures will be presented in a listing. 
Missing date imputation rules are provided in Section 6.3.2.
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 26 of 50
8. 
Efficacy Analysis
8.1. 
Exploratory Efficacy Endpoints 
  
  
 
  
 
  
 
  
  
 
  
 
  
 
  
 
 
 
 
8.1.1. 
  
8.1.2. 
8.1.3. 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 27 of 50
8.1.4. 
8.1.5. 
  
8.1.6. 
.  
8.1.7. 
  
8.1.8. 
  
. 
8.1.9. 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 28 of 50
8.1.10. 
8.1.11. 
8.1.12. 
  
  
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 29 of 50
  
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 30 of 50
9. 
Analysis of Pharmacokinetics 
The blood samples will be collected pre and post dose as shown in the time and events schedule in 
Section 3.9. 
9.1. 
PK parameters 
PK parameters of PIPE-505 will be derived using non-compartmental analysis methods from the 
concentration-time data for all evaluable subjects using a validated Phoenix WinNonlin software version 8 
or higher. Actual sampling times, rather than scheduled sampling times will be used in all computations 
involving sampling times. Table below describes the 
PK parameters that will be determined from 
concentrations of PIPE-505 in plasma.
Plasma PK Parameters for Analysis 
Parameter
Definition
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, 
calculated as AUC∞=AUCt+Clast/λz, where Clast is the last quantifiable 
concentration. 
AUC24 
Area under the plasma concentrati n-time curve from time 0 to 24 hours, 
calculated using the linear trapezoida  rule. 
Cmax
Maximum observed plasma concentration. 
CL/F 
Apparent clearance after extravascular administration, calculated as 
Dose/AUC∞ after a single d se. 
λz 
Terminal elimination rate constant, calculated as the negative of the slope of the 
log-linear regression of the natural logarithm concentration-time curve during the 
terminal phase. 
t1/2z
Terminal elimination half-life, calculated as ln(2)/λz. 
tmax
Time to reach Cmax. 
Vz/F 
Apparent volume of distribution during the terminal phase after extravascular 
administration, calculated as (CL/F)/λz. 
9.2. 
Handling of missing and Below Limit of Quantification (BLQ) data 
Missing concentration data for all patients who received scheduled study treatments will be considered as 
non-informative missing and will not be imputed. No concentration estimates will be provided for missing 
sample values. 
For the derivation of PK parameters and for the individual plasma concentration versus time curves, the 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
Approved
on-time curve from ti
ed
on-time curve from 
λz, where C
ve
λz, where Clast
e
last is the 
e
is the 
d
oncentrati n-time cur
ov
oncentrati n-time cur
ear trapezoida  rule. 
ro
ear trapezoida  rule. 
v
d plasma concentrat
pr
d plasma concentrat
ro
rance after extravas
pp
rance after extravas
∞ after a single d se
App
∞ after a single d se
p
Ap
al elimination rate co
Ap
al elimination rate co
near regression of th
Ap
near regression of th
phase. 
A
phase. 
Ap
t


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 31 of 50
following rules will apply: 
 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose Day 0 
samples will be treated as zero; 
 
The sampling time of pre-dose samples relative to dosing will also be treated as zero; 
 
All BLQ values occurring after dose will be set to missing. 
For plasma concentration summary, the following rules will apply: 
 
All BLQ values will be set to zero. 
9.3. 
Individual PK Data 
The actual and nominal sampling times of PK blood sample collection will be listed for each patient and will 
include the deviation in time from the protocol scheduled time (i e., nominal time), if applicable. 
The individual plasma concentration versus time profiles using the actual sampling time will be presented 
for the given treatment. 
9.4. 
Summary of PK Data 
The plasma concentration data will be summarized by day/time point for the given treatment. 
The PK parameters will be summarized for PIPE-505 group. 
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(i e., 
d
(i e., 
using the actua
d
using the actua
ed by day/time point
ve
ed by day/time point
IPE-505 group. 
ov
IPE-505 group. 


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 32 of 50
10. 
Safety Analysis 
All the safety endpoints will be summarized using Safety Analysis Set. All AEs will be coded using MedDRA 
version 22.1. 
10.1. Study Drug Administration 
A listing of study drug administration will be provided for the Safety Analysis Set. The listing will include the 
ear, the medication injected, date and time, and the volume of drug administration. 
10.2. Adverse Events 
The number of events, incidence, and percentage of treatment-emergent AEs (TEAE) will be calculated 
overall and by treatment group.  
 
Overall TEAEs  
 
Serious TEAEs  
 
Study Drug Related TEAE 
 
Study Drug Related Serious TEAE 
 
Study Procedure Related TEAE 
 
Study Procedure Related Serious TEAE 
 
TEAE by SOC and PT 
 
TEAE by SOC and PT, and Maximum Severity 
 
TEAE leading to Study Discontinuation 

TEAE leading to Death
Selected tables will be presented by SOC and by PT. Events with missing onset dates and end date after 
the study drug exposure or missing will be included as treatment-emergent. TEAEs are considered those 
events occurring or worsening wi h onset d tes on or after study drug exposure through end of study (Day 
90). If a subject experiences more than one occurrence of the same AE, the occurrence with the greatest 
severity and the closest association with the study drug will be summarized. The missing severity will be 
considered as “severe”. TEAEs will be further summarized by severity and relationship to study drug. AE 
listings will be presented.  
10.3. Clinical Laboratory Tests 
Clinical laboratory tests will be summarized by treatment group and visits. Change from baseline values 
will be summarized and shift tables will also be presented separately.  
Laboratory results collected in conventional units will be converted to International System of Units (SI) for 
all summaries and listings. Clinical laboratory test results (hematology, serum chemistry) and their changes 
from baseline will be summarized by visit and treatment group using descriptive statistics. Shift tables for 
hematology and chemistry using categories of low, normal, and high, comparing laboratory test results from 
Baseline to each visit will be presented with percentages based on subjects with a non-missing value at 
baseline and post-baseline visit. Urinalysis laboratory tests will be listed only as it is collected at screening 
only.   
The laboratory tests including pregnancy test results and potentially clinical important findings will be 
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mum Severity 
ro
mum Severity 
nuation 
pr
nuation 
ed by SOC and by P
App
ed by SOC and by P
missing will be inclu
Ap
missing will be inclu
ning wi h onset d te
Ap
ning wi h onset d te
ces more than one
Ap
ces more than one
ociation with 
A
ociation with 
will be 
A
will be


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 33 of 50
provided in a listing. Coagulation panel and other tests will be added in the listings. Serum pregnancy, urine 
pregnancy, FSH, Hepatitis B, Hepatitis C, and HIV tests are performed as other tests; and both coagulation 
panel and other tests will be included in the listings. 
10.4. Vital Signs  
Vital signs (body temperature, respiration rate, pulse rate, systolic and diastolic blood pressure 
measurements, and body weight) are evaluated at the visits. Body weight (without shoes) will be recorded 
whenever vital signs are recorded; height (without shoes) will be recorded at Screening only. 
Vital signs results will be summarized and presented in a listing. 
The following conversion factor will be used to convert any temperatures reported in degrees Fahrenheit to 
Celsius: 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
10.5. Physical Examination 
Complete physical examinations, per each institution’s guidelines, will be performed at Screening and end 
of study, and involves the following body system:  general appear nce; head, neck, eyes, nose and throat; 
respiratory; cardiovascular; abdomen (gastrointestinal); skin; genitourinary system; lymph nodes; 
musculoskeletal; neurological; and other. Any abnormal change from the baseline physical examination 
assessment must be assessed as not clinically significant (NCS) or clinically significant (CS) by the 
Investigator and recorded in the source document and eCRF. Any clinically significant change or new 
diagnosis as a result of a clinically significant change, as determined by the Investigator, will be recorded 
as an AE in the source documentation. 
Physical examination results will be provided in a listing only. 
10.6. Otological Examination 
The otologic examination will include direct examination of the external ear, ear canal, and TM by otoscope, 
as well as standard testing of tympani  mobility. The otological examinations will be conducted by the 
unblinded otologist or neuro-otologist who performs the intratympanic injection and also conducts all 
post-injection otological examinations through at least Day 
, and preferably throughout the study. 
Otological examination listing will be provided. Examination date, otological examination is performed 
(Yes/No), results of each test, and any detailed information for abnormal results will be presented in the 
listing.  
10.7. Electrocardiograms 
Standard 12-lead ECGs will be recorded at Screening, Visit 1, Visit 2, Visit 3, and Visit 7. The Visit 1 (Day 0) 
ECG will only be conducted at 4 hours (±15 minutes) post-dose. The ECG at Screening may be repeated 
at the Investigator’s discretion to confirm the QTcF result. ECG parameters will be evaluated for Heart Rate 
(bpm), PR Interval (msec), RR Interval (msec), QT Interval (msec) Fixed, QRS Interval (msec), and QTcF 
Interval (msec). Descriptive statistics and change from baseline will be summarized and the listing will be 
provided. ECG evaluation will be recorded as normal or abnormal on the eCRF and all abnormal results 
will be evaluated as Normal, Abnormal NCS or Abnormal CS. ECG evaluation shift from baseline table will 
be provided.  
10.8. Tympanometry 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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idelines, will be p
d
idelines, will be
ral appear nce; hea
ed
ral appear nce; h
stinal); skin; genito
ed
stinal); skin; genito
normal change from
ve
normal change from
ly significant (NCS)
ve
ly significant (NCS)
ument and eCRF. A
ov
ument and eCRF. A
nt change, as determ
ov
nt change, as determ
rovided in a listing o
pr
rovided in a listing o
App
nclude direct examina
App
nclude direct examina
of tympani  mobilit
Ap
of tympani  mobilit
uro-otologist who pe
Ap
uro-otologist who pe
examinations throu
A
examinations throu
will be p
A
will be p
a


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 34 of 50
Tympanometry assesses the relationship between the air pressure in the ear canal and the movement of 
the TM. The test measures the compliance of the TM to changes in air pressure, as well as reflex 
contraction of the middle ear muscles. 
  
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 35 of 50
11. 
Interim Analyses 
There are no planned interim analyses. 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
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Filing requirements: TMF 
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12. 
Changes from Analysis Planned in Protocol 
None. 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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13. 
Reference List 
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
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14. 
Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 or higher (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure 
output will adhere to the following specifications.   
14.1. General Considerations 
 
One SAS program can create several outputs. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in RTF format or portable document format (pdf). 
 
Numbering of TFLs will follow ICH E3 guidance  
14.2. Table, Listing, and Figure Format 
14.2.1. 
General 
 
All TFLs will be produced in landscape format.  
 All TFLs will be produced using the Courier New font, size 8. 
 The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides 
 Headers and footers for figures will be in Courier New font, size 8. 
 Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 TFLs will be in black and white (no color). 
 Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used. 
 Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
14.2.2. 
Headers 
 All output should have the following header at the top left of each page: 
 All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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New font, size 8. 
ve
New font, size 8. 
a minimum blank 1-
ov
a minimum blank 1-
be in Courier New f
ro
be in Courier New f
ures with more than 
pr
ures with more than 
white (no color). 
pp
white (no color). 
, such as bolding, ita
App
, such as bolding, ita
not be used in the T
Ap
not be used in the T
A
or 3 may be used. 
Ap
or 3 may be used. 
characte
A
characte
pri


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 39 of 50
 The date output was generated should appear along with the program name as a footer on each 
page. 
14.2.3. 
Display Titles 
 Each TFL should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 
numbering is strongly recommended, but sponsor preferences are obtained before final 
determination. A decimal system (x.y and x.y.z) is used to identify TFLs with related contents. The 
title is centered. The analysis set is identified on the line immediately following the title. The title 
and table designation are single spaced. A solid line spanning the margins will separate the display 
titles from the Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(Safety Analysis Set) 
14.2.4. 
Column Headers 
 Column headings are displayed immediately below the solid line described above in initial upper-
case characters  
 For numeric variables, include “unit” in column or row heading when appropriate. 
 Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
 
The order of treatments in the tables and listings will be Placebo first followed by ‘PIPE-505’ and an 
overall column (if applicable). 
14.2.5. 
Body of the Data Display 
14.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
14.2.5.2. 
Table Conventions 
 Units will be included where available 
 If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
n 
severe 
0 
moderate 
8 
mild 
3 
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et) 
d
et) 
below the solid line 
ve
below the solid line 
 column or row head
ov
 column or row head
d for each treatmen
ro
d for each treatmen
e). This is distinct fro
pr
e). This is distinct fro
ubjects in the analys
pr
ubjects in the analys
he tables and listings
pp
he tables and listings
ble). 
A
ble). 
Data Display 
Ap
Data Display 
tions 
A
tions 
g ar


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
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Filing requirements: TMF 
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 If the categories are not ordered in the CRF (e.g., Medical History, Adverse Events, etc.), then only 
those categories for which there is at least 1 subject represented in 1 or more groups are included. 
Medical history terms and Adverse Events terms are sorted by descending frequency of system 
organ class (SOC) and then by descending frequency of preferred term within each of SOC.  
 Notes are added to the footnote in the TFL shell and each note starts with a new line.  
  If the categories are ordered in the CRF (e.g., Discontinuation from the study etc.), then display all 
the categories in the same order as displayed in the CRF.  
 Unknown and/or Missing categories are added to each parameter for which information is not 
available for 1 or more subjects.  
 Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean (SD) 
XX .X (X.XX) 
Median 
XXX.X 
Min, Max 
XX  XX 
 Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Unle s otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts should not be displayed and percentages equating to 
100% are presented as 100%, without decimal places.  
 For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, foo notes and/or programming notes will identify the selection criteria. 
 Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
14.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
 Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 
 All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
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and 
d
and 
for systolic
d
for systolic
XX
ed
XX
XX .X (X.XX)
ed
XX .X (X.XX)
XXX.X 
e
XXX.X 
XX
XX
ve
XX
XX
cimal place, in pare
ov
cimal place, in pare
4%)). Unle s otherw
ov
4%)). Unle s otherw
set for the treatment 
ro
set for the treatment 
zero counts should n
pro
zero counts should n
without decimal plac
pr
without decimal plac
(number and perce
pp
(number and perce
ry, foo notes and/or 
App
ry, foo notes and/or 
ith a subheading (su
Ap
ith a subheading (su
he subheading follo
Ap
he subheading follo
istics for the su
A
istics for the su


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 41 of 50
 Units will be included where available 
14.2.6. 
Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes.  
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
 Subject specific footnotes are avoided, where possible. 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y z’)  
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eco
d
eco
of the da
d
of the da
ard source line tha
ed
ard source line t
 the program was ru
ed
 the program was r
16.x.y z’)  
ve
16.x.y z’)  


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 42 of 50
15. 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in 
SOP Developing Statistical Programs (3907). 
 SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.   
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Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 43 of 50
16. 
Index of Tables 
Table 14.1.1.1 Subject Disposition  (All Subjects) 
Table 14.1.1.2 Subject Populations  (Enrolled Set) 
Table 14.1.1.3 Subject Visits  (Safety Analysis Set) 
Table 14.1.2.1 Major Protocol Deviations  (Randomized Set) 
Table 14.1.3.1.1 Demographic and Baseline Characteristics  (Safety Analysis Set) 
Table 14.1.3.1.2 Demographic and Baseline Characteristics (Full Analysis Set) 
Table 14.1.3.2.1 Audiological/Otological History (Safety Analysis Set) 
Table 14.1.3.2.2 Audiological/Otological History – Categorical Summary  (Safety Analysis Set) 
Table 14.1.3.3 Medical History  (Safety Analysis Set) 
Table 14.1.4.1 Prior Medications  (Safety Analysis Set) 
Table 14.1.4.2 Concomitant Medications  (Safety Analysis Set) 
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alysis Set) 
ve
alysis Set) 




Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 45 of 50
  
  
Table 14.2.10.1 Summary of PIPE-505 Pharmacokinetics Parameters 
Table 14.2.10.2 Summary of PIPE-505 Plasma Concentration (unit) 
Table 14.3.1.1 Treatment-Emergent Adve se Events - Overall Summary (Safety Analysis Set) 
Table 14.3.1.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.3 Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Maximum Severity  (Safety Analysis Set) 
Table 14.3.1.4. Study Drug Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.5 Study Procedure Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term  (Safety Analysis Set) 
Table 14.3.1.6 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.7. Treatment-Emergent Adverse Events Leading to Study Discontinuation by System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.2.1 Deaths, Listing (All Subjects) 
Table 14.3.2.2 Serious Treatment-Emergent Adverse Events, Listing (All Subjects) 
Table 14.3.4.1.1.1 Hematology: Summary by Visit and Change from Baseline (Safety Analysis Set) 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
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armacokinetics Pa
ro
armacokinetics P
5 Plasma Concentra
pr
5 Plasma Concentra
nt Adve se Events - 
pp
nt Adve se Events - 
rgent Adverse Even
App
rgent Adverse Even
A
nt-Emergent Adver
Ap
nt-Emergent Adver
y Analysis Set) 
A
y Analysis Set) 
ated T
A
ated T


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 46 of 50
Table 14.3.4.1.1.2 Hematology: Shift from Baseline (Safety Analysis Set) 
Table 14.3.4.1.2.1 Blood Chemistry: Summary by Visit and Change from Baseline  (Safety Analysis Set) 
Table 14.3.4.1.2.2 Blood Chemistry: Shift from Baseline  (Safety Analysis Set) 
Table 14.3.4.2.1 Summary of Vital Signs by Visit and Change from Baseline (Safety Analysis Set) 
Table 14.3.4.3.1 ECG Quantitative Parameters: Summary  (Safety Analysis Set) 
Table 14.3.4.3.2 ECG Evaluation Shift from Baseline (Safety Analysis Set) 
 
Table 14.3.4.4.1 Summary and Change from Baseline in Tympanometry Assessments by Visits for Right 
Ear and Left Ear (Safety Analysis Set) 
Table 14.3.4.4.2 Tympanometry Type by Visits for Right Ear and Left Ear  (Safety Analysis Set) 
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Approved


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 47 of 50
17. 
Index of Figures 
  
  
  
 
 
 
 
  
  
  
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A
oved


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 48 of 50
18. 
Index of Listings 
Listing 16.2.1.1 Subject Disposition (Randomized Set) 
Listing 16.2.2.1 Protocol Deviations (Randomized Set) 
Listing 16.2.3.1 Inclusion/Exclusion Criteria – Description (All Subjects) 
Listing 16.2.3.2 Inclusion/Exclusion Criteria Not Met (All Subjects) 
Listing 16.2.3.3 Analysis Set (All Subjects) 
Listing 16.2.3.4 Randomization (Randomized Set) 
Listing 16.2.3.5 Subject Visits (Randomized Set) 
Listing 16.2.4.1 Demographics and Baseline Characteristics (All Subjects) 
Listing 16.2.4.2 Medical History (All Subjects) 
Listing 16.2.4.3.1 Audiological/Otological History (All Subjects) 
Listing 16.2.4.3.2 Audiological/Otological History - Categorical Results (All Subjects) 
Listing 16.2.4.4.1 Prior and Concomitant Medications (Safety Analysis Set) 
Listing 16.2.4.4.2 Concomitant Procedures (Safety Analysis Set) 
Listing 16.2.5.1  Study Drug Administration (Safety Analysis Set) 
Listing 16.2.7.1 Adverse Events (Safety Analysis Set) 
Listing 16.2.8.1.1 Clinical Laboratory Hematology Test Results (Safety Analysis Set) 
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bjects) 
ed
bjects) 
ategorical Results (A
ve
ategorical Results (A
dications (Safety Ana
ov
dications (Safety Ana
Appro
es (Safety Analysis S
ro
es (Safety Analysis S
ration (Safety Analys
pr
ration (Safety Analys


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 49 of 50
Listing 16.2.8.1.2 Clinical Laboratory Chemistry Test Results (Safety Analysis Set) 
Listing 16.2.8.1.3 Clinical Laboratory Urinalysis Test Results (All Subjects) 
Listing 16.2.8.1.4 Clinical Laboratory Coagulation Test Results (All Subjects) 
Listing 16.2.8.1.5 Other Clinical Laboratory Test Results (All Subjects) 
Listing 16.2.8.1.6 Pregnancy Test Results (All Subjects) 
Listing 16.2.8.2.1 Vital Signs (Safety Analysis Set) 
Listing 16.2.8.2.2 Electrocardiogram  (Safety Analysis Set) 
Listing 16.2.8.2.3 Physical Examination (Safety Analysis Set) 
Listing 16.2.8.2.4 Otological Examination (Safety Analysis Set) 
Listing 16.2.8.2.5 Tympanometry (Safety Analysis Set) 
Listing 16.2.8.2.6.1 Listing of PK Sampling and Concentrations (Pharmacokinetics Set) 
Listing 16.2.8.2.6.2 Listing of PIPE-505 PK Parameters  (Pharmacokinetics Set) 
SAP_Final_Body_2.0_22 Apr 2021 | VV-TMF-15663845 | 1.0
Approved
ations (Pharmacok
ed
ations (Pharmac
rs  (Pharmacokinetic
ed
rs  (Pharmacokineti


Statistical Analysis Plan
Sponsor: Pipeline Therapeutics, Inc.; Protocol No.: PTI-505-101 
This document is confidential. 
SAP Version: 2.0, 22Apr2021 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 50 of 50
19. 
Shells 
Tables, listings, and figure shells are provided in a separate file. 
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