Clinical trial NCT04120116
Conditions: Sensorineural Hearing Loss Noise Induced Hearing Loss Sudden Sensorineural Hearing Loss
Keywords: Intratympanic Administration Restoration of Hearing Function
Sponsor: Frequency Therapeutics
Start date: 2019-10-04; Completion date: 2020-12-17
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2a single and repeat dose exploratory efficacy study of intratympanic FX-322 compared to placebo in healthy male and female adults with stable sensorineural hearing loss.

Detailed description:
Sensorineural hearing loss (SNHL) accounts for about 90% of all cases of hearing loss. This phase 2a study will assess the exploratory efficacy, as well as the local and systemic safety of single and repeat intratympanic doses of FX-322 compared to placebo in approximately 96 subjects with stable mild to moderately severe sensorineural hearing loss, with a medical history consistent with either excessive noise exposure or idiopathic sudden sensorineural hearing loss.

Arms: arm 1: Four intratympanic injections of a hydrogel formulation, FX-322 Single Dose, Placebo Three Doses. arm 2: Four intratympanic injections of a hydrogel formulation, FX-322 Two Doses, Placebo Two Doses. arm 3: Four intratympanic injections of a hydrogel formulation, FX-322 Four Doses. arm 4: Four intratympanic injections of a hydrogel formulation, Placebo Four Doses.
Interventions: intervention 1: FX-322 (One Dose) intervention 2: FX-322 (Two Doses) intervention 3: FX-322 (Four Doses) intervention 4: Placebo
Intervention descriptions: intervention 1: Patients will receive one dose of FX-322. intervention 2: Patients will receive two doses of FX-322. intervention 3: Patients will receive four doses of FX-322. intervention 4: Patients will receive Placebo.

Protocol documents:
SAP_002.pdf: 
Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
 
Fr e q u e n c y  T h er a p e uti c s/  
 
S T A TI S TI C A L  A N A L Y SI S  P L A N  
 
 
 
 
A  P h a s e  2 a,  Pr o s p e cti v e,  R a n d o mi z e d,  D o u bl e -Bli n d,  Pl a c e b o -C o ntr oll e d,  Si n gl e 
a n d  R e p e at -D o s e,  M ulti c e nt er,  E x pl or at or y  Effi c a c y  St u d y  of  F X -3 2 2  A d mi ni st er e d 
b y  I ntr at y m p a ni c I nj e cti o n i n A d ult s  wit h  St a bl e  S e n s ori n e ur al  H e ari n g  L o s s  
 
F X -3 2 2 -2 0 2  Pr ot o c ol  ( V er si o n 5. 0,  0 8  F e br u ar y  2 0 2 1)  
 
V E R SI O N:  
4. 0  
D A T E:  
1 0  F e br u ar y  2 0 2 1  
N C T #:  
0 4 1 2 0 1 1 6  
C O M P O U N D  #:  
F X -3 2 2  
S P O N S O R:  
Fr e q u e n c y  T h er a p e uti c s 
1 9  Pr e si d e nti al  W a y  
W o b ur n,  M A  0 1 8 0 1 
U S A  
R E G U L A T O R Y 
A G E N C Y 
I D E N TI FI E R 
N U M B E R( S):  
N C T 0 4 1 2 0 1 1 6  
P R E P A R E D  B Y:   
 
 
 
 
 
 
 
 
 
 
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
 
Fr e q u e n c y  T h er a p e uti c s/  
 
S T A TI S TI C A L  A N A L Y SI S  P L A N  
A C K N O W L E D G M E N T  A N D  SI G N A T U R E  S H E E T  
 
 
 
A  P h a s e  2 a,  Pr o s p e cti v e,  R a n d o mi z e d,  D o u bl e -Bli n d,  Pl a c e b o -C o ntr oll e d,  Si n gl e 
a n d  R e p e at -D o s e,  M ulti c e nt er,  E x pl or at or y  Effi c a c y  St u d y  of  F X -3 2 2  A d mi ni st er e d 
b y  I ntr at y m p a ni c I nj e cti o n i n A d ult s  wit h  St a bl e  S e n s ori n e ur al  H e ari n g  L o s s  
 
 
 
 
 
 
 
A p pr o v e d:  
 
 
A p pr o v e d:  
 
 
A p pr o v e d:  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
 
V er si o n  Hi st or y  
 
 
 
S A P  
V e r si o n  
 
A p pr o v al 
D at e  
 
C h a n g e( s)  
 
R ati o n al e  
1. 0   
2 6 N O V 2 0 1 9   N ot  A p pli c a bl e  
Ori gi n al  V er si o n  
2. 0  
0 8 O C T 2 0 2 0  I n cl u d e c h a n g e  fr o m b a s eli n e  a n al y s e s  f or T FI, 
H SI,  a n d  H HI A.  M a k e  u p d at e s  f or Pr ot o c ol 
V er si o n  3. 0, f or i nt eri m  a n al y si s,  a n d  h a n dli n g 
of  tr e at e d/ u ntr e at e d e ar s  f or F ull  A n al y si s  S et 
a n d  S af et y  A n al y si s  S et  a n al y s e s.  
V er si o n  2. 0  
3. 0  
1 5 J A N 2 0 2 1  
M a k e  u p d at e s f or  Pr ot o c ol  V er si o n  4. 0  a n d f or 
i nt eri m a n al y si s.  
V er si o n  3. 0  
4. 0  
1 0 F E B 2 0 2 1   M a k e  u p d at e s  t o u n bli n d  at  t h e s u bj e ct  l e v el 
aft er  t h e i nt eri m a n al y si s,  a s  s p e cifi e d  i n 
Pr ot o c ol  V er si o n  5. 0.  Cl arif y  c o v ari a n c e 
str u ct ur e  f or H SI  a n d  H HI A  a n al y s e s.  
V er si o n  4. 0  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
 
T a bl e  of  C o nt e nt s  
 
Li st  of  A b br e vi ati o n s  .........................................................................................................................  8 
1.   P ur p o s e  of  t h e A n al y s e s  .......................................................................................................... 1 0  
2.   Pr ot o c ol  S u m m ar y  ................................................................................................................ 1 0  
Pri m ar y  St u d y  O bj e cti v e s  .............................................................................................. 1 0  
St u d y  D e si g n  .............................................................................................................. 1 0  
2. 2. 1.  
S cr e e ni n g  .............................................................................................................. 1 0  
2. 2. 2.  
Tr e at m e nt  .............................................................................................................. 1 1  
2. 2. 3.   
F oll o w -u p  ................................................................................................................ 1 1  
St u d y  p o p ul ati o n  ......................................................................................................... 1 1  
S a m pl e  si z e  ................................................................................................................ 1 2  
3.   G e n er al  A n al y si s  a n d  R e p orti n g  C o n v e nti o n s  ............................................................................. 1 2  
4.  
A n al y si s  S a m pl e s  .................................................................................................................. 1 4  
5.   St u d y  S u bj e ct s  ...................................................................................................................... 1 5  
Di s p o siti o n  of  S u bj e ct s  ................................................................................................. 1 5  
D e m o gr a p hi c  a n d  Ot h er  B a s eli n e  C h ar a ct eri sti c s  ............................................................ 1 7  
6.   St u d y  O p er ati o n s  ................................................................................................................... 1 7  
Pr ot o c ol  D e vi ati o n s  .................................................................................................... 1 7  
R a n d o mi z ati o n  .......................................................................................................... 1 8  
7.   E n d p oi nt  E v al u ati o n  .............................................................................................................. 1 8  
O v er vi e w  of  Effi c a c y  A n al y si s  M et h o d s  ........................................................................... 1 8  
7. 1. 1.  
M ulti c e nt er  St u di e s  ................................................................................................. 1 8  
7. 1. 2.  
A s s e s s m e nt  Ti m e  Wi n d o w s  ........................................................................................ 1 8  
7. 1. 3.   
Ti mi n g  of  A n al y s e s  ................................................................................................... 1 9  
7. 1. 4.  
M ulti pl e  C o m p ari s o n s/ M ulti pli cit y  ........................................................................... 2 0  
7. 1. 5.  
M o d el  Fitti n g  .......................................................................................................... 2 0  
7. 1. 6.   
Mi s si n g  D at a  ........................................................................................................... 2 0  
Pri m ar y  E n d p oi nt  ......................................................................................................... 2 5  
W or d  R e c o g niti o n  i n Q ui et  ............................................................................................ 2 5  
7. 3. 1.   
N u m b er  of  r e c o g ni z e d w or d s  ..................................................................................... 2 6  
7. 3. 2.   
P er c e nt a g e  of  r e c o g ni z e d w or d s  ................................................................................ 2 6  
7. 3. 3.   
A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  ................... 2 7  
7. 3. 4.   
R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  ..................... 2 8  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
7. 3. 5.   
I m pr o v e m e nt > = 1 0 %  ( 5 w or d s)  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  ............................... 2 9  
7. 3. 6.   
Ar c si n e -tr a n sf or m e d W R  .......................................................................................... 2 9  
7. 3. 7.  
W R  C at e g ori e s  ....................................................................................................... 3 0  
7. 3. 8.   
S hift  i n W R  C at e g ori e s  .............................................................................................. 3 0  
7. 3. 9.  
Cli ni c al  I m pr o v e m e nt i n W R,  u si n g  T h or nt o n -R affi n  C o nfi d e n c e  I nt er v al s ( CIT R  ) .............. 3 1  
7. 3. 1 0.  
Cli ni c al  I m pr o v e m e nt i n W R,  u si n g  C ar n e y  S c hl a u c h  C o nfi d e n c e  I nt er v al s ( CIC S ) ......... 3 2  
7. 3. 1 1.   
I n ci d e n c e of  i n c orr e ct p h o n e m e s  ............................................................................ 3 2  
W or d s -I n-N oi s e  ............................................................................................................ 3 3  
7. 4. 1.   
N u m b er  of  r e c o g ni z e d w or d s  ..................................................................................... 3 3  
7. 4. 2.   
P er c e nt a g e  of  r e c o g ni z e d w or d s  ................................................................................ 3 4  
7. 4. 3.   
A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  ................... 3 5  
7. 4. 4.   
R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  ..................... 3 6  
7. 4. 5.   
I m pr o v e m e nt > = 1 0 %  ( 7 w or d s)  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  ..................... 3 7  
7. 4. 6.  
S p e ar m a n -K är b er  e sti m at e s  of  d B  t hr e s h ol d s f or w or d  r e c o g niti o n ( 2 5t h, 5 0 t h ( m e di a n) 
a n d  7 5 t h p er c e ntil e s)  ............................................................................................................ 3 7  
7. 4. 7.   
I m pr o v e m e nt > = 3  d B  s hift s  i n m e di a n  S p e ar m a n -K är b er  e sti m at e s  ............................... 3 8  
7. 4. 8.   
I n ci d e n c e of  i n c orr e ct p h o n e m e s  ............................................................................... 3 9  
P ur e  T o n e  A u di o m etr y  ................................................................................................... 3 9  
7. 5. 1.   
Air  a n d  B o n e  C o n d u cti o n  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s b y  fr e q u e n c y ..................... 4 0  
7. 5. 2.   
A C  a n d  B C  I m pr o v e m e nt > = 1 0  d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s ............ 4 0  
7. 5. 3.   
A C  a n d  B C  I m pr o v e m e nt > = 1 5  d B  fr o m b a s eli n e  f or a n y  fr e q u e n c y ................................ 4 1  
7. 5. 4.  
A C  a n d  B C  C o m p o sit e  I m pr o v e m e nt ............................................................................. 4 2  
7. 5. 5.  
M e a n  o v er all  P T A  ( A C o v er  0. 5,  1,  2,  a n d  4  k H z)  a n d  B C A  ( B C o v er  0. 5,  1,  2  a n d  4  k H z)  .... 4 2  
7. 5. 6.   
M e a n  l o w A C  d B  h e ari n g  t hr e s h ol d ( A C o v er  0. 2 5,  0. 5,  1,  a n d   2 k H z)  ............................. 4 3  
7. 5. 7.   
M e a n  hi g h  A C  d B  h e ari n g  t hr e s h ol d ( A C o v er  3,  4,   6 a n d   8 k H z)  .................................... 4 3  
7. 5. 8.   
Air -B o n e  I m b al a n c e at  0. 5,  1,  2,  3,  a n d   4 k H z  .............................................................. 4 4  
7. 5. 9.   
C o m p o sit e  W R,  WI N  a n d  P ur e  T o n e  A u di o m etr y  E n d p oi nt  ............................................ 4 5  
E xt e n d e d  Hi g h  Fr e q u e n c y  A u di o m etr y  ............................................................................ 4 5  
7. 6. 1.   
Air  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s b y  fr e q u e n c y ..................................................... 4 6  
7. 6. 2.   
A C  I m pr o v e m e nt > = 1 0  d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s ....................... 4 6  
7. 6. 3.   
A C  I m pr o v e m e nt > = 1 5  d B  fr o m b a s eli n e  f or a n y  fr e q u e n c y ........................................... 4 6  
7. 6. 4.  
A C  C o m p o sit e  I m pr o v e m e nt ........................................................................................ 4 7  
7. 6. 5.   
M e a n  d B  h e ari n g  t hr e s h ol d ( A C o v er  9- 1 6  k H z)  ........................................................... 4 7  
7. 6. 6.   
S hift  fr o m n o  si g n al  t o a n y  si g n al  b y  fr e q u e n c y ............................................................ 4 8  
7. 6. 7.   
S hift  fr o m n o  si g n al  t o a n y  si g n al  i n t w o c o nti g u o u s  fr e q u e n ci e s ................................... 4 8  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
7. 6. 8.   
S hift  fr o m n o  si g n al  t o a n y  si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s ................................. 4 8  
Ti n nit u s  F u n cti o n al  I n d e x .............................................................................................. 4 9  
7. 7. 1.   
M e a n  t ot al s c or e,  i n di vi d u al s u b s c al e  s c or e s,  a n d  l o u d n e s s s c or e  .................................. 4 9  
7. 7. 2.   
C h a n g e  fr o m b a s eli n e  i n m e a n  t ot al s c or e,  i n di vi d u al s u b s c al e  s c or e s,  a n d  l o u d n e s s s c or e  
5 0  
H e ari n g  H a n di c a p  I n v e nt or y f or A d ult s  ........................................................................... 5 1  
7. 8. 1.   
M e a n  t ot al s c or e  a n d  i n di vi d u al s u b s c al e  s c or e s  ......................................................... 5 1  
7. 8. 2.   
C h a n g e  fr o m b a s eli n e  i n m e a n  t ot al s c or e  a n d  i n di vi d u al s u b s c al e  s c or e s  ...................... 5 2  
H e ari n g  S cr e e ni n g  I n v e nt or y ........................................................................................... 5 2  
7. 9. 1.  
M e a n  t ot al s c or e  ..................................................................................................... 5 3  
7. 9. 2.   
C h a n g e  fr o m b a s eli n e  i n m e a n  t ot al s c or e  .................................................................. 5 3  
E x a mi n ati o n  of  S u b gr o u p s  ............................................................................................ 5 3  
8.  
S af et y  E v al u ati o n  ................................................................................................................... 5 4  
O v er vi e w  of  S af et y  A n al y si s  M et h o d s  ............................................................................. 5 4  
E xt e nt  of  E x p o s ur e  ...................................................................................................... 5 6  
A d v er s e  E v e nt s  .......................................................................................................... 5 6  
D e at h s,  S eri o u s  A d v er s e  E v e nt s,  a n d  Ot h er  Si g nifi c a nt  A d v er s e  E v e nt s  ............................. 5 8  
8. 4. 1.   
A d v er s e  E v e nt s  of  S p e ci al  I nt er e st ( A E SI) ................................................................... 5 8  
Cli ni c al  L a b or at or y  E v al u ati o n  ....................................................................................... 5 8  
Vit al  Si g n s,  P h y si c al  Fi n di n g s,  a n d  Ot h er  O b s er v ati o n s  R el at e d  t o S af et y  ........................... 5 9  
8. 6. 1.  
Vit al  Si g n s  .............................................................................................................. 5 9  
8. 6. 2.  
P h y si c al  E x a mi n ati o n s  ............................................................................................. 5 9  
8. 6. 3.   
Ot o s c o pi c  E x a mi n ati o n s  .......................................................................................... 5 9  
8. 6. 4.  
T y m p a n o m etr y  ....................................................................................................... 6 0  
8. 6. 5.  
C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  A s s e s s m e nt s  .................................................... 6 1  
8. 6. 6.   
C o n c o mit a nt  M e di c ati o n s  ........................................................................................ 6 2  
9.  
Ot h er  A n al y s e s  ..................................................................................................................... 6 2  
1 0.   
I nt eri m A n al y si s  a n d  D at a  M o nit ori n g  ..................................................................................... 6 2  
1 1.   
C h a n g e s  t o t h e A n al y s e s  Pl a n n e d  i n t h e Pr ot o c ol  .................................................................... 6 3  
1 2.  
R ef er e n c e s  ....................................................................................................................... 6 4  
1 3.  
A p p e n di c e s  ....................................................................................................................... 6 5  
St u d y  Fl o w  C h art  ......................................................................................................... 6 5  
S c h e d ul e  of  E v e nt s  ...................................................................................................... 6 6  
1 4.  
Att a c h m e nt s  ..................................................................................................................... 6 7  
T h or nt o n  a n d  R affi n  ( 1 9 7 8) W or d  R e c o g niti o n  S c ori n g  C h art  ............................................ 6 7  
C ar n e y  S c hl a u c h  ( 2 0 0 7) W or d  R e c o g niti o n  S c ori n g  C h art  ................................................. 6 8  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
T FI  C al c ul ati o n s  .......................................................................................................... 6 9  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
LI S T  O F  A B B R E VI A TI O N S  
 
A C  
Air  C o n d u cti o n  
A E  
A d v er s e  E v e nt  
A E SI  
A d v er s e  E v e nt  of  S p e ci al  I nt er e st 
A R( 1)  
A ut or e gr e s si v e  ( 1) 
A T C  
A n at o mi c al  T h er a p e uti c  C h e mi c al  
B C  
B o n e  C o n d u cti o n  
B C A  
B o n e  C o n d u cti o n  A v er a g e  
BI C  
B a y e si a n  I nf or m ati o n Crit eri a  
C- S S R S  
C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  
CI  
C o nfi d e n c e  I nt er v al 
C N C  
C o n s o n a nt -N u cl e u s -C o n s o n a nt  
C R F  
C a s e  R e p ort  F or m  
C S R  
Cli ni c al  St u d y  R e p ort  
C T M S  
Cli ni c al  Tri al  M a n a g e m e nt  S y st e m  
d B  
D e ci b el  
E H F A  
E xt e n d e d  Hi g h  Fr e q u e n c y  A u di o m etr y  
F A S  
F ull  A n al y si s  S et  
G E E  
G e n er ali z e d  E sti m ati n g  E q u ati o n  
H HI A  
H e ari n g  H a n di c a p  I n v e nt or y f or A d ult s  
H SI  
H e ari n g  S cr e e ni n g  I n v e nt or y 
I A 
I nt eri m A n al y si s  
I C H 
I nt er n ati o n al C o nf er e n c e  o n  H ar m o ni s ati o n  
L S  
L e a st  S q u ar e s  
M A R  
Mi s si n g  At  R a n d o m  
M e d D R A  
M e di c al  Di cti o n ar y  f or R e g ul at or y  A cti viti e s  
M M R M  
Mi x e d -eff e ct  M o d el  f or R e p e at e d  M e a s ur e s  
NI H L  
N oi s e  I n d u c e d H e ari n g  L o s s  
N R  
N o  R e s p o n s e  
P P A S  
P er  Pr ot o c ol  A n al y si s  S et  
P T A  
P ur e  T o n e  A v er a g e  
S A E  
S eri o u s  A d v er s e  E v e nt  
S A P  
St ati sti c al  A n al y si s  Pl a n  
S D  
St a n d ar d  D e vi ati o n  
Sf A S  
S af et y  A n al y si s  S et  
S L  
S e n s ati o n  L e v el  
S P L  
S o u n d  Pr e s s ur e  L e v el  
S S N H L  
S u d d e n  S e n s ori n e ur al  H e ari n g  L o s s  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
T E A E  
Tr e at m e nt -E m er g e nt  A d v er s e  E v e nt  
T FI  
Ti n nit u s  F u n cti o n al  I n d e x 
T M  
T y m p a ni c  M e m br a n e  
T R  
T h or nt o n -R affi n  
U N  
U n str u ct ur e d  
W R  
W or d  R e c o g niti o n  i n q ui et  
WI N  
W or d s -I n-N oi s e  t e sti n g 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
1.  P U R P O S E  O F  T H E  A N A L Y S E S  
 
T h e  p ur p o s e  of t hi s  st ati sti c al  a n al y si s  pl a n ( S A P) i s t o  pr o vi d e  d et ail e d i nf or m ati o n t o  ai d i n 
t h e i m pl e m e nt ati o n of  t h e st ati sti c al  a n al y si s  a n d r e p orti n g  of  t h e  st u d y d at a  f or u s e  i n t h e 
i nt eri m a n al y si s  (I A) a n d  cli ni c al  st u d y  r e p ort ( C S R). It bri efl y  s u m m ari z e s  t h e pr ot o c ol, 
d e s cri b e s t h e  a n al y si s  s et s t h at  will  b e  a n al y z e d,  a n d  d e s cri b e s t h e  a n al y s e s t o  b e 
p erf or m e d.   T h e  d et ail s  of  t h e s p e cifi c  st ati sti c al  m et h o d s  t h at will  b e  u s e d  ar e  pr o vi d e d.   If 
a d diti o n al  a n al y s e s  ar e r e q uir e d t o  s u p pl e m e n t t h e  pl a n n e d  a n al y s e s  d e s cri b e d i n t hi s  S A P, 
t h e y m a y  b e  c o m pl et e d  a n d  will  b e  i d e ntifi e d i n t h e C S R  a s  p o st  h o c.  T a bl e,  fi g ur e, a n d 
li sti n g s p e cifi c ati o n s  ar e  i n s e p ar at e  d o c u m e nt s.  
 
Pl a n s  f or t h e I A ar e  s p e cifi e d  i n S e cti o n  1 0 . 
 
T hi s  S A P  w a s  writt e n  wit h  d u e  c o n si d er ati o n  of t h e r e c o m m e n d ati o n s  o utli n e d i n t h e  m o st 
r e c e nt I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni s ati o n (I C H)  E 9  G ui d eli n e  e ntitl e d  G ui d a n c e f or 
I n d u str y: St ati sti c al  Pri n ci pl e s f or  Cli ni c al  Tri al s  a n d t h e  m o st r e c e nt I C H  E 3  G ui d eli n e, 
e ntitl e d  G ui d a n c e  f or I n d u str y: Str u ct ur e  a n d  C o nt e nt  of  Cli ni c al  St u d y  R e p ort s  a n d  w a s 
fi n ali z e d pri or  t o u n bli n di n g  f or t h e i nt eri m a n al y si s.  
 
2.  P R O T O C O L  S U M M A R Y  
 
Pri m ar y  St u d y  O bj e cti v e s  
 
1.  T o  a s s e s s t h e  e x pl or at or y  effi c a c y  b y  a u di ol o gi c r e s p o n s e f oll o wi n g  si n gl e  a n d r e p e at 
d o s e s  of  F X -3 2 2 i n  s u bj e ct s  wit h  st a bl e  s e n s ori n e ur al  h e ari n g l o s s.  
 
2.  T o  a s s e s s  t h e l o c al a n d  s y st e mi c  s af et y  of  si n gl e  a n d  r e p e at d o s e s  at  of  F X -3 2 2  i n 
s u bj e ct s  wit h  st a bl e  s e n s ori n e ur al  h e ari n g l o s s.  
 
St u d y  D e si g n  
 
T hi s i s  a  P h a s e  2 a,  pr o s p e cti v e, r a n d o mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d,  si n gl e  a n d 
r e p e at-d o s e,  m ulti c e nt er,  e x pl or at or y  effi c a c y  st u d y  of  F X -3 2 2,  a d mi ni st er e d  b y 
i ntr at y m p a ni c i nj e cti o n, i n  a dult s  wit h  st a bl e  s e n s ori n e ur al  h e ari n g l o s s.  
 
T h e  st u d y  will  h a v e  3  p h a s e s:  S cr e e ni n g,  Tr e at m e nt,  a n d  F oll o w -u p.  T h e  S cr e e ni n g  p h a s e 
c a n  o c c ur  u p t o  3 0  d a y s  pri or t o  st u d y  dr u g  a d mi ni str ati o n ( B a s eli n e/ Tr e at m e nt  D a y  1).  T h e 
Tr e at m e nt  p h a s e  will  b e  2 1  d a y s ( 4 tr e at m e nt  vi sit s  7  d a y s  a p art)  a n d t h e  F oll o w -u p  p h a s e 
will  b e   7 m o nt h s  fr o m B a s eli n e  ( D a y 1).  
 
2. 2. 1.  S cr e e ni n g  
 
D ur i n g t h e  S cr e e ni n g  p h a s e,  all  s u bj e ct s  will  b e  s cr e e n e d t o  d et er mi n e  st u d y  eli gi bilit y. All 
s u bj e ct s  will  r et ur n f or t h e B a s eli n e  vi sit  a n d  will  b e  e v al u at e d  t o e n s ur e  t h e y c o nti n u e  t o 
m e et  a p pr o pri at e  i n cl u si o n/ e x cl u si o n crit eri a  a p pli c a bl e  at  t h at vi sit.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
2. 2. 2.  Tr e at m e nt  
 
A p pr o xi m at el y  9 6  s u bj e ct s  ar e  pl a n n e d t o  b e  e nr oll e d i n t hi s  st u d y.  T h e  s u bj e ct s  will  b e 
r a n d o mi z e d t o r e c ei v e  F X-3 2 2  or  pl a c e b o  a c c or di n g  t o t h e diff er e nt tr e at m e nt  gr o u p 
s c h e d ul e s li st e d  b el o w:  
 
Gr o u p  D o si n g  S c h e d ul e  
Tr e at m e nt  
G r o u p  
 
#  of  S u bj e ct s  
 
D a y   1 
 
D a y   8 
 
D a y  1 5  
 
D a y  2 1  
1  
2 4  
F X -3 2 2   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
2  
2 4  
F X -3 2 2  
F X -3 2 2   
Pl a c e b o   
Pl a c e b o  
3  
2 4  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
4  
2 4   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
 
O n c e  a  s u bj e ct  h a s  b e e n i d e ntifi e d  a s  m e eti n g  all i n cl u si o n/ e x cl u si o n  crit eri a, t h e  q u alif yi n g 
e ar  wit h  t h e w or s e  h e ari n g  will  b e  s el e ct e d,  u nl e s s   a r ati o n al e e xi st s  t o tr e at t h e ot h er  e ar 
( e. g., t h e w or s e  h e ari n g  e ar  d o e s  n ot  m e et  t h e st u d y  crit eri a).  T h e  st u d y  tr e at m e nt or 
pl a c e b o  will  b e  a d mi ni st er e d  o n  D a y  1,  D a y  8,  D a y  1 5,  a n d  D a y  2 1.   T h e  pl a c e b o  will  b e 
m at c h e d  t o F X -3 2 2  i n c o n si st e n c y  a n d  c ol or.  
 
E a c h  s u bj e ct  will  b e  pl a c e d  i n t h e s u pi n e  p o siti o n.  T o pi c al  a n e st h e si a  will  b e  a d mi ni st er e d 
t o t h e t y m p a ni c m e m br a n e.  U n d er   a mi cr o s c o p e,   a 2 5 -g a u g e  n e e dl e  will  b e  u s e d  t o i nj e ct 
F X -3 2 2  or  pl a c e b o  i nt o t h e mi d dl e  e ar  at  t h e j u n cti o n of  t h e p o st eri or  i nf eri or a n d  p o st eri or 
s u p eri or  q u a dr a nt  wit h  t h e n e e dl e  ti p dir e ct e d  t o w ar d s t h e r o u n d wi n d o w.   T h e  p o st eri or 
s u p eri or  q u a dr a nt  s h o ul d  b e  a v oi d e d  t o pr e v e nt  i nj ur y t o t h e o s si cl e s.  Aft er  i nj e cti o n, t h e 
s u bj e ct  will  c o nti n u e  t o li e wit h  t h e i nj e ct e d e ar  f a ci n g u p  f or 1 0 -1 5  mi n ut e s.  T h e  i nj e cti o n s 
will  b e  p erf or m e d  at  a n  a p pr o pri at e  l o c ati o n d e si g n at e d  b y   a B o ar d -c ertifi e d 
Ot ol ar y n g ol o gi st tr ai n e d  a n d  e x p eri e n c e d i n  p erf or mi n g i ntr at y m p a ni c i nj e cti o n s.   S af et y 
m o nit ori n g  will i n cl u d e r e c or di n g  of  a d v er s e  e v e nt s ( A E s),  s af et y l a b or at or y  a s s e s s m e nt s, 
a n d  m o nit ori n g  of  t y m p a n om etr y  a n d  ot o s c o pi c  e x a m s.  
 
2. 2. 3.  F oll o w -u p  
 
S u bj e ct s  will  b e  r e q uir e d t o  r et ur n f or  s af et y,  ot ol o gi c,  a n d  a u di ol o gi c  a s s e s s m e nt s  at  D a y s 
1 5,  6 0,  9 0,  1 5 0,  a n d  2 1 0  aft er  t h e i niti al i nj e cti o n. S u bj e ct s  will  b e  c o nt a ct e d  b y  p h o n e  f or 
s af et y  a s s e s s m e nt s  at  D a y s  3 0,  1 2 0,  a n d  1 8 0.  
 
St u d y  p o p ul ati o n  
 
T h e  st u d y  p o p ul ati o n  will  i n cl u d e m al e  a n d  f e m al e a d ult s  ( 1 8 t o 6 5  y e ar s  i n cl u si v e), 
ot h er wi s e  h e alt h y  wit h  st a bl e  s e n s ori n e ur al  h e ari n g l o s s.  Pr ot o c ol  S e cti o n s  8. 4. 2  a n d  8. 4. 3 
d efi n e  t h e i n cl u si o n a n d  e x cl u si o n  crit eri a  f or t h e st u d y.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
S a m pl e  si z e  
 
T h e  s a m pl e  si z e  of  a p pr o xi m at el y  2 4  s u bj e ct s  p er  gr o u p  w a s  c o n si d er e d  a d e q u a t e t o 
e x pl or e t h e  p ot e nti al  effi c a c y  of  F X -3 2 2  a s s o ci at e d  wit h  v ari o u s  d o si n g  s c h e d ul e s  a n d  w a s 
n ot  b a s e d  o n  f or m al st ati sti c al  e v al u ati o n.  
 
3.  G E N E R A L  A N A L Y SI S  A N D  R E P O R TI N G  C O N V E N TI O N S  
 
T h e f oll o wi n g i s  a li st  of  g e n er al  a n al y si s  a n d r e p orti n g  c o n v e nti o n s t o  b e  a p pli e d f or t hi s 
st u d y.  
 
• 
C at e g ori c al  v ari a bl e s  will  b e  s u m m ari z e d  u si n g  c o u nt s ( n)  a n d  p er c e nt a g e s ( %)  a n d 
will  b e  pr e s e nt e d  i n t h e f or m  n ( %). If  a c o u nt  i s 0,  n o  p er c e nt a g e  will  b e  s h o w n.   T o 
e n s ur e  c o m pl et e n e s s,  s u m m ari e s f or  c at e g ori c al  a n d  di s cr et e  v ari a bl e s  will i n cl u d e 
all  c at e g ori e s,  e v e n  if n o  s u bj e ct s  h a d   a r e s p o n s e i n  a p arti c ul ar  c at e g or y.  Mi s si n g 
d at a f or  c at e g ori c al  v ari a bl e s  will  h a v e  a ‘ Mi s si n g’  c at e g or y  a d d e d  at t h e  e n d  a n d t h e 
c o u nt  will  b e  pr e s e nt e d  wit h o ut  a  p er c e nt a g e.   P er c e nt a g e s  f or c at e g ori c al  v ari a bl e s 
will  e x cl u d e  t h e ‘ Mi s si n g’ c at e g or y.  
 
• 
C o nti n u o u s  v ari a bl e s  will  b e  s u m m ari z e d  u si n g  m e a n,  st a n d ar d  d e vi ati o n ( S D), 
mi ni m u m,  m a xi m u m,  m e di a n,  a n d  n u m b er  of  s u bj e ct s.  T h e  m e a n,  m e di a n,  a n d 
c o nfi d e n c e  i nt er v al s ( CI) will  b e  r o u n d e d a n d  r e p ort e d t o  1 m or e  l e v el of  pr e ci si o n 
t h a n t h e ori gi n al  o b s er v ati o n s,  a n d  t h e S D  will  b e  r o u n d e d a n d  r e p ort e d t o  2 m or e 
l e v el s  of  pr e ci si o n t h a n t h e  ori gi n al  o b s er v ati o n s. T h e  mi ni m u m  a n d  m a xi m u m  will 
b e  t h e s a m e  pr e ci si o n  a s  t h e ori gi n al  d at a.  
 
• 
F oll o wi n g  S A S  d ef a ult r ul e s, t h e  m e di a n  will  b e r e p ort e d  a s t h e r o u n d e d  a v er a g e  of 
t h e t w o mi d dl e  n u m b er s  if t h e d at a s et  c o nt ai n s  e v e n  n u m b er s.  
 
• P- v al u e s  will  b e  r o u n d e d a n d  r e p ort e d t o  3 d e ci m al  pl a c e s if  gr e at er t h a n  0. 0 0 1.   If 
t h e r o u n d e d  p-v al u e i s  l e s s t h a n  0. 0 0 1, ‘ < 0. 0 0 1’  will  b e r e p ort e d.  If t h e r o u n d e d  p- 
v al u e  i s > 0. 9 9 9,  ‘ > 0. 9 9 9’ will  b e  r e p ort e d.   P-v al u e s  a n d  si g nifi c a nt  l e v el s will  b e 
r e p ort e d a s  0. 0 5  r at h er t h a n . 0 5. 
 
• N o  pr eli mi n ar y  r o u n di n g will  b e  p erf or m e d;  r o u n di n g will  o nl y  o c c ur  aft er  a n al y si s. 
T o  r o u n d, c o n si d er  di git  t o ri g ht of  l a st si g nifi c a nt  di git:   if  <  5 t h e n r o u n d d o w n,  if 
> = 5  t h e n r o u n d u p.  
 
• All  li sti n g s will  b e  s ort e d  i n or d er  of  tr e at m e nt gr o u p,  s u bj e ct,  a n d  ti m e of 
a s s e s s m e nt  ( e. g., vi sit,  ti m e, a n d/ or  e v e nt).  
 
• 
D at e s  i n li sti n g s will  b e  di s pl a y e d  a s  y y y y -m m -d d  ( e. g., 2 0 1 9 -0 8 -2 2).  
 
• A g e  (i n y e ar s)  will  b e  c al c ul at e d  u si n g  t h e d at e  of  birt h  a n d  t h e Vi sit   1 ( S cr e e ni n g) 
d at e  i n t h e f oll o wi n g S A S  al g orit h m:   fl o or((i nt c k(‘ m o nt h’, d at e  of  birt h,  Vi sit   1 d at e)  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
–  ( d a y( Vi sit  1 d at e)   < d a y( d at e  of  birt h))))/ 1 2.   I n t h e a n al y si s  d at a s et s,  t a bl e s, a n d 
li sti n g s, a g e  will  b e  r e p ort e d a s  t h e i nt e g er p art  of  t h e d eri v e d  a g e,  wit h  n o  r o u n di n g. 
 
• 
All  a n al y si s  will  b e  p erf or m e d  u si n g  t h e S A S  S y st e m  v er si o n  9. 4.  
 
• 
All t a bl e s t h at  s u m m ari z e r e s ult s  b y tr e at m e nt  gr o u p f or  s u bj e ct s i n t h e  F ull  A n al y si s 
S et  ( F A S) or  P er  Pr ot o c ol  A n al y si s  S et  ( P P A S), d efi n e d  i n S e cti o n  4 , will  i n cl u d e e a c h 
of t h e  F X -3 2 2 tr e at m e nt  gr o u p s,  a  p o ol e d  F X -3 2 2 tr e at m e nt  gr o u p,  a n d t h e  pl a c e b o 
tr e at m e nt gr o u p.   S u bj e ct s  i n t h e F A S  or  P P A S  will  b e  cl a s sifi e d  i nt o r a n d o mi z e d 
tr e at m e nt  gr o u p s b a s e d  o n  t h eir r a n d o mi z e d tr e at m e nt. 
 
R a n d o mi z e d  Tr e at m e nt  
G r o u p  
 
#  of  S u bj e ct s  
 
D a y   1 
 
D a y   8 
 
D a y  1 5  
 
D a y  2 1  
F X -3 2 2  1 x  
2 4  
F X -3 2 2   Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
F X -3 2 2  2 x  
2 4  
F X -3 2 2  
F X -3 2 2   
Pl a c e b o   
Pl a c e b o  
F X -3 2 2  4 x  
2 4  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  P o ol e d  
7 2  
F X -3 2 2   Pl a c e b o  
or  F X -3 2 2  
Pl a c e b o  
or  F X -3 2 2  
Pl a c e b o  or  
F X -3 2 2  
Pl a c e b o  
2 4   
Pl a c e b o   Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
 
F or  a s s e s s m e nt s  c o m pl et e d  b y  e ar  f or e a c h  s u bj e ct,  t h e u nit  of  a n al y si s  will  b e  t h e 
e ar  a n d tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  s u m m ari z e d  s e p ar at el y.  Tr e at e d  e ar s  will 
b e  d efi n e d  a s  t h e q u alifi e d  e ar s  f or tr e at m e nt t h at r e c ei v e d at  l e a st o n e  d o s e  of 
st u d y  tr e at m e nt p er  t h e r a n d o mi z e d tr e at m e nt s c h e d ul e,  a n d  u ntr e at e d  e ar s  will  b e 
t h e e ar s  n ot  q u alifi e d  f or tr e at m e nt.  F or  a n al y s e s  b y  e ar,  t h e tr e at m e nt gr o u p  f or 
e a c h  e ar  will  b e  t h e s u bj e ct’ s  r a n d o mi z e d tr e at m e nt gr o u p,  r e g ar dl e s s of  a ct u al 
a d mi ni str ati o n  i n t h e gi v e n  e ar.  All  tr e at e d ( q u alifi e d) e ar  d at a  will  b e  a n al y z e d, 
i n cl u di n g t h o s e wit h  d o si n g  a d mi ni str ati o n  err or s.   All  u ntr e at e d  ( n ot q u alifi e d)  e ar 
d at a  will  b e  a n al y z e d  u p  u ntil  a n y  d o si n g  a d mi ni str ati o n  err or  ( wr o n g e ar  i nj e cti o n). 
F or  a n al y s e s  b y  e ar,  d at a  f or u ntr e at e d  ( n ot q u alifi e d)  e ar s  aft er   a d o si n g 
a d mi ni str ati o n  err or  will  b e  e x cl u d e d fr o m  F A S  a n d  P P A S  a n al y s e s.  
 
• All t a bl e s  t h at  s u m m ari z e r e s ult s b y  tr e at m e nt  gr o u p f or s u bj e ct s i n  t h e  S af et y 
A n al y si s  S et  ( Sf A S) will  i n cl u d e 1  F X -3 2 2  d o s e r e c ei v e d,   2 F X -3 2 2  d o s e s  r e c ei v e d, 4 
F X -3 2 2  d o s e s r e c ei v e d,  a n d  pl a c e b o ( 0  F X -3 2 2  d o s e s r e c ei v e d).  F or  Sf A S  a n al y s e s  b y  
s u bj e ct,  all  s u bj e ct s i n t h e  Sf A S  will  b e  cl a s sifi e d i nt o  a ct u al tr e at m e nt  gr o u p s  b a s e d  
o n t h e  a ct u al  n u m b er  of  F X -3 2 2  d o s e s r e c ei v e d i n  a n y  e ar ( q u alifi e d  or  n ot  q u alifi e d). 
I n t h e  e v e nt t h at a n y  s u bj e ct( s)  r e c ei v e  3 F X -3 2 2  d o s e s,  s e p ar at e  li sti n g s f or 
s u bj e ct( s) r e c ei vi n g  3  F X -3 2 2  d o s e s  will  b e  cr e at e d.  S u bj e ct s r e c ei vi n g  3  F X -3 2 2 
d o s e s  will  b e  i n cl u d e d i n t h e t ot al c ol u m n.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
A ct u al  Tr e at m e nt  Gr o u p  
#  of  S u bj e ct s  
Pl a n n e d  
 
D a y s   1-2 1  
F X -3 2 2  1 x  
2 4  
1  d o s e  of  F X -3 2 2  
F X -3 2 2  2 x  
2 4  
2  d o s e s  of  F X -3 2 2  
F X -3 2 2  4 x  
2 4  
4  d o s e s  of  F X -3 2 2  
Pl a c e b o  
2 4  
0  d o s e s  of  F X -3 2 2  
 
F or  a s s e s s m e nt s  c o m pl et e d  b y  e ar f or  e a c h  s u bj e ct, t h e  u nit  of  a n al y si s  will  b e t h e 
e ar  a n d  tr e at e d a n d  u ntr e at e d  e ar s  will  b e  s u m m ari z e d  s e p ar at el y.   A n  e ar  will  b e 
c o n si d er e d  tr e at e d fr o m t h e ti m e it r e c ei v e s a n y  d o s e,  w h et h er  t h e q u alif yi n g  e ar  or 
n ot.   A s u bj e ct’ s  tr e at e d e ar  will  b e  cl a s sifi e d  i nt o a n  a ct u al  tr e at m e nt gr o u p  b a s e d 
o n  t h e a ct u al  n u m b er  of  F X -3 2 2  d o s e s  r e c ei v e d i n t h at e ar.   A n  e ar  will  b e 
c o n si d er e d  n ot  tr e at e d u p  u ntil  t h e ti m e it r e c ei v e s a n y  d o s e,  w h et h er  t h e q u alif yi n g 
e ar  or  n ot.   U ntr e at e d  e ar s  will  b e  cl a s sifi e d  i n t h e Pl a c e b o  gr o u p  u p  u ntil  t h e ti m e it 
r e c ei v e s  a n y d o s e,  aft er  w hi c h t h e  e ar  will  b e  cl a s sifi e d  i nt o  a n  a ct u al tr e at m e nt 
gr o u p  b a s e d  o n t h e  a ct u al  n u m b er  of  F X -3 2 2  d o s e s r e c ei v e d i n t h at  e ar.  Pr e -d o si n g 
m e a s ur e m e nt s  will  b e  m a p p e d  t o tr e at e d or  u ntr e at e d  b a s e d  o n  d o si n g  at  D a y  1.  
S u bj e ct s  wit h  tr e at m e nt r e c ei v e d i n t h e n o n -q u alifi e d  e ar  m a y  c o ntri b ut e  m or e  t h a n 
1  tr e at e d e ar  t o Sf A S  a n al y s e s.  I n t h e e v e nt  t h at a n y  s u bj e ct/ e ar  c o m bi n ati o n( s) 
r e c ei v e  3  F X-3 2 2  d o s e s,  s e p ar at e r e p ort s f or  s u bj e ct/ e ar  c o m bi n ati o n( s) r e c ei vi n g  3 
F X -3 2 2  d o s e s  will  b e  cr e at e d,  a s  a p pli c a bl e.  S u b je c t/e ar  c o m bi n ati o n( s ) r e c ei vi n g 3 
F X -3 2 2  d o s e s  will  b e i n cl u d e d i n t h e  F X -3 2 2  t ot al e ar s  c ol u m n.  
 
F or  e x a m pl e,  a  s u bj e ct tr e at e d  wit h  F X -3 2 2  2 x i n t h e  q u alifi e d  e ar  at  D a y s  1  a n d  8 
a n d  tr e at e d wit h  F X -3 2 2  2 x  i n t h e n ot  q u alifi e d  e ar  at  D a y s  1 5  a n d  2 1  will  b e 
s u m m ari z e d  a s  f oll o w s: 
a.   F or  s u m m ari e s  b y  s u bj e ct:  T hi s  s u bj e ct  will  b e i n cl u d e d i n t h e  F X -3 2 2  4 x  s e cti o n 
of t h e t a bl e.  
b.   F or  s u m m ari e s  b y  e ar:  
i. T h e  q u alifi e d  e ar  d at a  will  b e r e p ort e d  at  all  vi sit s i n t h e  F X -3 2 2  2 x  s e cti o n 
of  t h e t a bl e i n t h e  Tr e at e d  c ol u m n. 
ii. T h e  n ot  q u alifi e d  e ar  d at a  u p  t o  a n d i n cl u di n g D a y  1 5  will  b e  r e p ort e d i n 
t h e Pl a c e b o  s e cti o n  of  t h e t a bl e i n t h e U ntr e at e d  c ol u m n.  
iii. T h e  n ot  q u alifi e d  e ar  d at a  aft er  D a y  1 5  will  b e r e p ort e d  at  vi sit s  aft er  D a y 
1 5  i n t h e F X -3 2 2  2 x  s e cti o n  of  t h e t a bl e i n t h e Tr e at e d  c ol u m n.  
 
4.  A N A L Y SI S  S A M P L E S  
 
T h e  f oll o wi n g d efi niti o n s  will  b e  u s e d  t o d eri v e  t h e a n al y si s  s et s  f or t hi s st u d y.  
 
• F ull  A n al y si s  S et  
 
T h e  F ull  A n al y si s  S et i s  d efi n e d  a s  all r a n d o mi z e d  s u bj e ct s  w h o r e c ei v e  at l e a st  o n e  d o s e  of 
st u d y  dr u g (r e g ar dl e s s  of  w h et h er  a f ull  d o s e  w a s  a d mi ni st er e d)  i n t h e  q u alifi e d e ar  p er t h e  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
r a n d o mi z e d tr e at m e nt  s c h e d ul e. S u bj e ct s  will  b e  a n al y z e d  a c c or di n g t o t h eir r a n d o mi z e d 
tr e at m e nt gr o u p,  a s  d e s cri b e d  i n S e cti o n  3 .  F or  a s s e s s m e nt s  c o m pl et e d  b y  e ar  f or e a c h 
s u bj e ct,  tr e at e d ( q u alifi e d) a n d  u ntr e at e d  ( n ot q u alifi e d)  e ar s  will  b e  s u m m ari z e d 
s e p ar at el y,  a s  d e s cri b e d i n  S e cti o n  3 . T h e  F A S  will  b e  u s e d t o  e x pl or e  effi c a c y.  
 
• P er  Pr ot o c ol  A n al y si s  S et  
 
T h e  P er  Pr ot o c ol  A n al y si s  S et  i s  d efi n e d a s  s u bj e ct s r e c ei vi n g  all  f o ur d o s e s  of  st u d y  dr u g  or 
pl a c e b o  i n t h e q u alifi e d  e ar  t o b e  tr e at e d p er  t h e r a n d o mi z ati o n tr e at m e nt s c h e d ul e  a n d 
wit h o ut  m aj or  pr ot o c ol  d e vi ati o n s  t h at c o ul d  i nt erf er e wit h  i nt er pr et ati o n of  t h e r e s ult s. 
T h e s e  m aj or  pr ot o c ol  d e vi ati o n s  will  b e  i d e ntifi e d pri or  t o br e a ki n g  t h e st u d y  bli n d  f or t h e 
I A.  Pr ot o c ol  d e vi ati o n s  t h at o c c ur  aft er  u n bli n di n g  f or t h e I A will  b e  e v al u at e d  f or 
m aj or/ mi n or  cl a s sifi c ati o n  b y  t h e bli n d e d  m e di c al  a n d  st u d y  t e a m pri or  t o br e a ki n g  t h e 
st u d y  bli n d  f or t h e C S R.   If  diff er e nt fr o m t h e F A S,  t h e P P A S  m a y  b e  u s e d  i n a d diti o n al 
s e n siti vit y  a n al y s e s f or  effi c a c y.  P P A S  s u bj e ct s  will  b e  a n al y z e d  a c c or di n g t o t h eir 
r a n d o mi z e d tr e at m e nt  gr o u p,  a s  d e s cri b e d i n  S e cti o n 3 . F or  a s s e s s m e nt s  c o m pl et e d  b y  e ar 
f or e a c h  s u bj e ct, tr e at e d  ( q u alifi e d) a n d  u ntr e at e d  ( n ot q u alifi e d)  e ar s  will  b e  s u m m ari z e d 
s e p ar at el y,  a s  d e s cri b e d  i n S e cti o n  3 . 
 
• S af et y  A n al y si s  S et  
 
T h e  S af et y  A n al y si s  S et  will i n cl u d e  all  s u bj e ct s  e x p o s e d t o  st u d y  dr u g  or  pl a c e b o i n  a n y  e ar 
a n d  will  b e  a n al y z e d  a c c or di n g t o t h e  a ct u al tr e at m e nt  gr o u p r e g ar dl e s s  of t h eir r a n d o mi z e d  
tr e at m e nt  a s si g n m e nt,  a s  d e s cri b e d i n  S e cti o n 3 . F or  s af et y  a s s e s s m e nt s  b y  s u bj e ct, t h e  
t ot al n u m b er  of  F X -3 2 2  r e c ei v e d i n a n y  e ar  will  b e  u s e d  t o a s si g n  a ct u al  tr e at m e nt gr o u p.  
F or  s af et y  a s s e s s m e nt s  c o m pl et e d  b y  e ar f or  e a c h  s u bj e ct, tr e at e d  a n d  u ntr e at e d  e ar s  will 
b e  s u m m ari z e d  s e p ar at el y,  a s  d e s cri b e d  i n S e cti o n  3 . T h e  Sf A S  will  b e  u s e d  f or t h e a n al y si s 
of  s af et y. 
 
5.  S T U D Y  S U B J E C T S  
 
Di s p o siti o n  of  S u bj e ct s  
 
T h e  di s p o siti o n  of  all  c o n s e nt e d  s u bj e ct s  will  b e  s u m m ari z e d i n t a bl e s  b y tr e at m e nt  gr o u p 
a n d  o v er all  p er  S e cti o n  3 . S u bj e ct s  w h o f ail e d  s cr e e ni n g  or  w er e  n ot r a n d o mi z e d  will  o nl y 
b e  i n cl u d e d i n t h e o v er all  c ol u m n.   T h e  f oll o wi n g di s p o siti o n  i nf or m ati o n wil l b e 
s u m m ari z e d:  
 
• T h e  n u m b er  of  s u bj e ct s  c o n s e nt e d  ( si g n e d I nf or m e d C o n s e nt).  
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o f ail e d  s cr e e ni n g  a n d t h e r e a s o n s f or 
f ail ur e ( Di d n ot  m e et  crit eri a,  Wit h dr e w  c o n s e nt,  L o st  t o f oll o w-u p,  Ot h er).  
 
• T h e  n u m b er  of  s u bj e ct s  n ot r a n d o mi z e d  v er s u s r a n d o mi z e d  a n d t h e  n u m b er  a n d 
p er c e nt a g e  of  s u bj e ct s f or  e a c h r a n d o mi z ati o n  str atifi c ati o n f a ct or ( Eti ol o g y  of  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
h e ari n g  l o s s: S u d d e n  s e n s ori n e ur al  h e ari n g  l o s s ( S S N H L), N oi s e -i n d u c e d h e ari n g  l o s s 
( NI H L);  W or d  R e c o g niti o n  S c or e  at  S cr e e ni n g: > = 5 0 %  c orr e ct,  < 5 0 %  c orr e ct).  
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  i n e a c h  a n al y si s  s et  ( F A S, P P A S,  Sf A S).  
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s r e c ei vi n g  st u d y tr e at m e nt  at  e a c h tr e at m e nt 
vi sit ( D a y  1,  8,  1 5,   2 1). 
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  c o m pl et e d t h e  st u d y t hr o u g h  Vi sit  9 
( D a y  2 1 0). 
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  di s c o nti n u e d t h e  st u d y  e arl y  a n d t h e 
r e a s o n s f or  wit h dr a w al ( A d v er s e  E v e nt,  D e at h,  L a c k  of  Effi c a c y,  L o st t o  F oll o w-u p, 
N o n -C o m pli a n c e  Wit h  St u d y  Dr u g,  P h y si ci a n  D e ci si o n,  Pr e g n a n c y,  Pr o gr e s si v e 
Di s e a s e,  Pr ot o c ol  Vi ol ati o n,  R e c o v er y,  St u d y  T er mi n at e d  b y  S p o n s or,  T e c h ni c a l 
Pr o bl e m,  Wit h dr a w al  b y  S u bj e ct,  Ot h er).  
 
• T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  di s c o nti n u e d  t h e st u d y  e arl y  f or 
r e a s o n s r el at e d t o C O VI D -1 9  ( S u bj e ct h a s  c o nfir m e d  C O VI D -1 9,  S u bj e ct  d e ci si o n,  Sit e 
d e ci si o n).  
 
P er c e nt a g e s f or t h e  n u m b er  of  s u bj e ct s  w h o f ail e d  s cr e e ni n g  a n d t h e r e a s o n s f or f ail ur e  will 
b e  b a s e d  o n  t h e n u m b er  of  s u bj e ct s  w h o  si g n e d  i nf or m e d c o n s e nt.  All  ot h er  p er c e nt a g e s 
will  u s e  t h e n u m b er  of  r a n d o mi z e d s u bj e ct s  a s  t h e d e n o mi n at or.  All  r o w s will  b e 
s u m m ari z e d  b y  r a n d o mi z e d tr e at m e nt gr o u p.  
 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  att e n d e d  e a c h  vi sit  will  b e  s u m m ari z e d  b y 
r a n d o mi z e d tr e at m e nt gr o u p  f or t h e F A S.  
 
A  K a pl a n -M ei er  pl ot  of  ti m e fr o m t h e d at e  of  r a n d o mi z ati o n t o t h e d at e  of  st u d y  c o m pl eti o n 
or  e arl y  di s c o nti n u ati o n  will  b e  pr o vi d e d  b y  r a n d o mi z e d tr e at m e nt gr o u p  f or all  s u bj e ct s 
r a n d o mi z e d.  S u bj e ct s  w h o  c o m pl et e d  t h e st u d y  will  b e  c e n s or e d  at  t h eir st u d y  c o m pl eti o n 
d at e.   F or  t h e I A, o n g oi n g  s u bj e ct s  will  b e  c e n s or e d  at  t h eir D a y  9 0  d at e,  if a v ail a bl e,  or  t h e 
d at a  s n a p s h ot  d at e  if t h e D a y  9 0  d at e  i s n ot  a v ail a bl e.  
 
S u bj e ct  di s p o siti o n  d at a f or  all  s u bj e ct s r a n d o mi z e d  will  al s o  b e li st e d.  A  s e p ar at e li sti n g  of 
s u bj e ct s  w h o  f ail e d  s cr e e ni n g  wit h t h e r e a s o n f or s cr e e n f ail ur e  will  b e  pr o vi d e d.  
 
A li sti n g  of  all  s u bj e ct s  aff e ct e d  b y t h e  C O VI D -1 9  p a n d e mi c ( di s c o nti n u e d t h e  st u d y  e arl y, 
h a d r e m ot e  vi sit s  p erf or m e d,  or  mi s s e d  vi sit s f or r e a s o n s r el at e d  d u e t o  C O VI D -1 9)  will  b e 
pr o vi d e d  b y  sit e  a n d  s u bj e ct t o  d o c u m e nt  h o w  t h e  s u bje ct’ s  p arti ci p ati o n  w a s i m p a ct e d  b y 
C O VI D -1 9.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
D e m o gr a p hi c  a n d  Ot h er  B a s eli n e  C h ar a ct eri sti c s  
 
S u m m ar y  d e s cri pti v e  st ati sti c s  f or d e m o gr a p hi c  a n d  ot h er  b a s eli n e  c h ar a ct eri sti c s  will  b e 
r e p ort e d f or t h e  F A S  a n d  Sf A S  a n al y si s  s et s  b y tr e at m e nt  gr o u p  a n d  o v er all. T h e  s u m m ar y 
f or  F A S  s u bj e ct s  will  b e  b y r a n d o mi z e d tr e at m e nt  gr o u p  a n d t h e  s u m m ar y f or  Sf A S  s u bj e ct s 
will  b e  b y  a ct u al  tr e at m e nt  gr o u p.  C h ar a ct eri sti c s  t o b e  s u m m ari z e d i n cl u d e:  
 
• D e m o gr a p hi c:  a g e,  r a c e, et h ni cit y,  a n d  s e x.  
 
• T ar g et e d  h e ari n g l o s s  hi st or y:  w h e n  h e ari n g l o s s  st art e d,  e ar( s)  wit h  h e ari n g l o s s, 
eti ol o g y  of  h e ari n g  l o s s, ot h er  s y m pt o m s  of  h e ari n g  l o s s, a n d  h e ari n g  ai d  u s e.  
 
• Vit al  Si g n s:  h ei g ht,  b o d y  w ei g ht,  a n d  B MI  at  s cr e e ni n g.  
 
• P ur e  T o n e  A v er a g e  ( 0. 5, 1,  2,  a n d  4  k H z)  at  s cr e e ni n g  f or t h e q u alifi e d  e ar.  
• B o n e  C o n d u cti o n  A v er a g e  ( 0. 5, 1,  2,  a n d  4  k H z)  at  s cr e e ni n g  f or t h e q u alifi e d  e ar.  
• W or d  R e c o g niti o n  n u m b er  of  r e c o g ni z e d w or d s  at  s cr e e ni n g  f or t h e q u alifi e d  e ar.  
D e m o gr a p hi c  a n d  ot h er  b a s eli n e  c h ar a ct eri sti c  d at a  will  al s o  b e li st e d f or  s u bj e ct s i n t h e 
F A S.  
 
M e di c al  hi st or y  a n d  uri n e  dr u g  s cr e e n  d at a  will  b e  li st e d f or s u bj e ct s  i n t h e F A S.  
 
6.  S T U D Y  O P E R A TI O N S  
 
Pr ot o c ol  D e vi ati o n s  
 
All  pr ot o c ol  d e vi ati o n s  will  b e r e c or d e d i n  
  cli ni c al tri al  m a n a g e m e nt  s y st e m ( C T M S) 
a n d  r e p ort e d i n li sti n g s f or r a n d o mi z e d s u bj e ct s.   T h e  li sti n g s will  i n cl u d e t h e s u bj e ct  I D, 
tr e at m e nt  gr o u p, d at e  of  t h e  d e vi ati o n, pr ot o c ol  d e vi ati o n  t e xt, a n d  pr ot o c ol  d e vi ati o n 
t y p e. T h e  m e di c al  a n d  st u d y  t e a m will  p erf or m   a bli n d e d  r e vi e w of  t h e pr ot o c ol  d e vi ati o n s 
pri or t o t h e I A  u n bli n di n g  a n d  d at a b a s e  s n a p s h ot t o  cl a s sif y t h e  pr ot o c ol  d e vi ati o n s  a s  m aj or  
or  mi n or.   Pr ot o c ol  d e vi ati o n s  t h at o c c ur  aft er  u n bli n di n g  f or t h e I A will  b e  e v al u at e d  f or 
m aj or/ mi n or  cl a s sifi c ati o n  b y t h e  bli n d e d  m e di c al  a n d  st u d y t e a m  pri or t o  st u d y  u n bli n di n g 
a n d  d at a b a s e  l o c k. T h e  i n di c at or i d e ntif yi n g t h e d e vi ati o n  a s  m aj or  or  mi n or  will  b e 
i n cl u d e d i n t h e li sti n g s. 
 
If t h e n u m b er  of  m aj or  pr ot o c ol  d e vi ati o n s  i s 1 0  or  m or e,  m aj or  pr ot o c ol  d e vi ati o n s  will  b e 
s u m m ari z e d  i n t a b ul ar f or m at b y  tr e at m e nt gr o u p,  i n cl u di n g o v er all,  a n d  t y p e of  d e vi ati o n 
f or r a n d o mi z e d  s u bj e ct s. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
R a n d o mi z ati o n  
 
S u bj e ct s  will  b e r a n d o mi z e d  1: 1: 1: 1 t o  f o ur tr e at m e nt  gr o u p s t o r e c ei v e m ulti pl e  d o s e s  of 
F X -3 2 2  ( 0. 2 m L)  a n d/ or  pl a c e b o  ( 0. 2 m L).    A si n gl e  i nj e cti o n of  F X -3 2 2  or  pl a c e b o  will  b e 
a d mi ni st er e d  o n  D a y  1  b y i ntr at y m p a ni c i nj e cti o n f oll o w e d  b y  s u b s e q u e nt i nj e cti o n s  of 
eit h er  F X -3 2 2  or  pl a c e b o  o n  D a y  8,  D a y  1 5  a n d  D a y  2 1  a s  p er  tr e at m e nt  gr o u p. R a n d o mi z e d 
s u bj e ct s  will  b e  all o c at e d  t o e a c h  of   4 tr e at m e nt  gr o u p s ( 2 4 i n  e a c h  gr o u p). 
 
Tr e a t m e nt 
Gr o u p  N u m b er  
( L a b el) 
 
#  of 
S u bj e ct s  
 
 
D a y   1 
 
 
D a y   8 
 
 
D a y  1 5  
 
 
D a y  2 1  
1  ( F X-3 2 2  1 x)   
2 4  
F X -3 2 2   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
2  ( F X-3 2 2  2 x)   
2 4  
F X -3 2 2  
F X -3 2 2   
Pl a c e b o   
Pl a c e b o  
3  ( F X-3 2 2  4 x)   
2 4  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
F X -3 2 2  
4  ( Pl a c e b o)  
2 4   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o   
Pl a c e b o  
 
7.  E N D P OI N T  E V A L U A TI O N  
 
O v er vi e w  of  Effi c a c y  A n al y si s  M et h o d s  
 
7. 1. 1.  M ulti c e nt er  St u di e s  
 
St u d y  s u bj e ct s  will  b e  e nr oll e d fr o m  m ulti pl e  st u d y  sit e s.  F or t h e  pri m ar y  effi c a c y  a n d  s af et y 
a n al y s e s,  st u d y  d at a  will  b e  a n al y z e d  a n d  s u m m ari z e d  a s   a w h ol e,  a n d  n o  f or m al 
a c c o m m o d ati o n  f or sit e -t o-sit e  v ari ati o n  will  b e  m a d e.  
 
S e n siti vit y  a n al y s e s  will  b e  p erf or m e d f or  s el e ct  w or d r e c o g niti o n  e n d p oi nt s ( p er c e nt a g e  of  
r e c o g ni z e d  w or d s,  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e, r el ati v e  p er c ent  c h a n g e fr o m 
b a s eli n e)  t o a s s e s s t h e  p o s si bl e  pr e s e n c e  a n d  eff e ct  of  sit e -t o-sit e  h et er o g e n eit y.   B a si c 
d e s cri pti v e  a n al y s e s  of  d e m o gr a p hi c s,  b a s eli n e  c h ar a ct eri sti c s  or  ot h er  a s s e s s m e nt s  m a y  b e 
r e p e at e d f or  e a c h  sit e i n di vi d u all y t o  s u p p ort t h e  w or d r e c o g niti o n  s e n siti vit y  a n al y s e s. 
 
7. 1. 2.  A s s e s s m e nt  Ti m e  Wi n d o w s 
T h e f oll o wi n g  st u d y  vi sit s  ar e  s c h e d ul e d.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  1 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T a bl e   7- 1    
St u d y  Vi sit Wi n d o w s  
 
 
Vi sit  
 
Vi sit  N u m b er  
A s s e s s m e  
nt/ D a y  
T ar g et  
D a y  
 
T ar g et  Wi n d o w  
A n al y si s  
Wi n d o w
a  
S cr e e ni n g  
1  
-3 0  t o  0 
0  
0  
< 0  
B a s eli n e/  
Tr e at m e nt  
2 a  
1  
1  
1  
1  
Tr e at m e nt  
2 b  
8  
8  
6- 1 0  ( +/- 2  d a y s)  
2- 1 1  
2 c  
1 5   
1 5  
1 3 -1 7  ( +/- 2  d a y s)  
1 2 -1 7  
2 d  
2 1   
2 1  
1 9 -2 3  ( +/- 2  d a y s)  
1 8 -2 4  
F oll o w -u p  
3  
3 0   
3 0  
2 5 -4 5  ( +/- 1 5  d a y s)  
2 5 -4 5  
4  
6 0   
6 0  
4 5 -7 5  ( +/- 1 5  d a y s)  
4 6 -7 5  
5  
9 0   
9 0  
7 5 -1 0 5  ( +/- 1 5  d a y s)  
7 6 -1 0 5  
6  
1 2 0   
1 2 0  
1 0 5 -1 3 5  ( +/- 1 5  d a y s)  
1 0 6 -1 3 5  
7  
1 5 0   
1 5 0  
1 3 5 -1 6 5  ( +/- 1 5  d a y s)  
1 3 6 -1 6 5  
8  
1 8 0   
1 8 0  
1 6 5 -1 9 5  ( +/- 1 5  d a y s)  
1 6 6 -1 9 5  
9  
2 1 0   
2 1 0  
1 9 5 -2 2 5  ( +/- 1 5  d a y s)  
1 9 6 -2 2 5  
a A n al y si s  wi n d o w s  ar e  d efi n e d  u si n g  t h e mi d -p oi nt s  b et w e e n  e a c h  s c h e d ul e d  vi sit,  a n d  will  b e  
u s e d  t o m a p  e arl y  t er mi n ati o n or  u n s c h e d ul e d  vi sit  d at a  t o s c h e d ul e d  vi sit s.  
 
All  s c h e d ul e d  vi sit  d at a  p er  Pr ot o c ol  V er si o n  4. 0, i n cl u di n g  a s s e s s m e nt s  p erf or m e d  o ut si d e 
t h e t ar g et  wi n d o w,  will b e i n cl u d e d i n  s u m m ar y  t a bl e s, fi g ur e s, a n d li sti n g s.   S c h e d ul e d  vi sit 
d at a  will  b e  pr e s e nt e d  a c c or di n g  t o t h e n o mi n al  c a s e  r e p ort f or m ( C R F) r e c or d e d vi sit  a n d 
n ot  r e-m a p p e d  a c c or di n g  t o t h e a n al y si s  wi n d o w s  i n T a bl e   7- 1.  E arl y  t er mi n ati o n vi sit  a n d 
u n s c h e d ul e d  vi sit  effi c a c y  d at a  will  b e  m a p p e d t o  s c h e d ul e d  vi sit s  u si n g t h e  a n al y si s 
wi n d o w s  i n T a bl e   7- 1.  E arl y  t er mi n ati o n vi sit  a n d  u n s c h e d ul e d  vi sit  effi c a c y  d at a  will  b e 
i n cl u d e d i n t a bl e s  a n d fi g ur e s if  n o  s c h e d ul e d  vi sit  d at a i s  a v ail a bl e f or t h e  no mi n al  C R F 
r e c or d e d vi sit.   If m or e  t h a n o n e  u n s c h e d ul e d  a s s e s s m e nt  ( e arl y t er mi n ati o n or 
u n s c h e d ul e d) i s  p erf or m e d  wit hi n  a n  a n al y si s  wi n d o w, t h e  a s s e s s m e nt  p erf or m e d  cl o s e st t o 
t h e t ar g et d a y  will  b e  u s e d.   F or  s af et y  t a bl e s a n d  fi g ur e s, e arl y  t er mi n ati o n  vi sit a n d 
u n s c h e d ul e d  s af et y  d at a  will  n ot  b e  m a p p e d t o  s c h e d ul e d  vi sit s  u si n g  a n al y si s  wi n d o w s.  
D at a  f or a s s e s s m e nt s  t h at  w er e pl a n n e d t o  b e  p erf or m e d  at  o n -sit e  st u d y  vi sit s i n  Pr ot o c ol 
V er si o n  2. 0  a n d  w er e r e m o v e d i n  Pr ot o c ol  V er si o n  3. 0  d u e  t o t h e  s wit c h t o t el e p h o n e  vi sit s 
will  b e  e x cl u d e d  fr o m t a bl e s a n d  fi g ur e s.  All  d at a,  s c h e d ul e d  a n d  u n s c h e d ul e d,  will  b e 
i n cl u d e d i n li sti n g s. 
 
7. 1. 3.  Ti mi n g  of  A n al y s e s  
 
T h e I A  will  b e  p erf or m e d  aft er  all  e nr oll e d  s u bj e ct s  c o m pl et e  Vi sit  5 ( D a y  9 0)  a n d t h e 
d at a b a s e  s n a p s h ot  i s c o m pl et e d.  
 
All  C S R  a n al y s e s  will  b e  p erf or m e d  aft er  t h e st u d y  i s c o m pl et e d  a n d  t h e d at a b a s e  i s l o c k e d. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
7. 1. 4.  M ulti pl e  C o m p ari s o n s/ M ulti pli cit y  
 
N o  a dj u st m e nt s f or  m ulti pl e  c o m p ari s o n s  will  b e  m a d e.  All  p -v al u e s  will  b e  c o n si d er e d 
d e s cri pti v e.  
 
7. 1. 5.  M o d el  Fitti n g  
 
T h e  f oll o wi n g t y p e s of  m o d el s  m a y  b e  fit f or t h e effi c a c y  e n d p oi nt s:   Mi x e d -eff e ct  m o d el  f or 
r e p e at e d m e a s ur e s  ( M M R M), g e n er ali z e d  e sti m ati n g  e q u ati o n s  ( G E E), or  l o gi sti c r e gr e s si o n. 
 
F or t h e  M M R M  m o d el s,  a  si n gl e  c o v ari a n c e  str u ct ur e  will  b e  a p pli e d t o  all  M M R M  a n al y s e s 
f or a n  effi c a c y  e n d p oi nt.   Diff er e nt  c o v ari a n c e  str u ct ur e s  m a y  b e  a p pli e d  t o diff er e nt 
effi c a c y  e n d p oi nt s.   F or  t h e  W or d  R e c o g niti o n i n  Q ui et ( W R)  a n d  W or d s-i n-N oi s e ( WI N) 
a n al y s e s, t h e  c o v ari a n c e  str u ct ur e f or  e a c h  e n d p oi nt  will  b e i d e ntifi e d  b y  c o m p ari n g  m o d el  
fit f or t h e r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  u si n g 
t w o diff er e nt  c o v ari a n c e  str u ct ur e s  ( u n str u ct ur e d [ U N] a n d  a ut or e gr e s si v e  ( 1) [ A R( 1)]), a s 
d e s cri b e d  i n S e cti o n  7. 3. 4 . F or  t h e a u di o m etr y  a n al y s e s,  t h e c o v ari a n c e  str u ct ur e  will  b e 
i d e ntifi e d  b y  c o m p ari n g m o d el fit f or t h e  m e a n  o v er a ll  P ur e  T o n e  A v er a g e ( P T A)  u si n g t h e 
t w o diff er e nt  c o v ari a n c e  str u ct ur e s,  a s  d e s cri b e d  f or W R  a n d  WI N.   F or  t h e Ti n nit u s 
F u n cti o n al I n d e x ( T FI)  a n al y s e s, t h e  T FI t ot al  s c or e  will  b e  u s e d t o i d e ntif y t h e  c o v ari a n c e 
str u ct ur e  f or all  T FI  e n d p oi nt  a n al y s e s.  C o v ari a n c e  str u ct ur e s  will  al s o  b e  i d e ntifi e d f or t h e 
H e ari n g  H a n di c a p I n v e nt or y f or  A d ult s ( H HI A)  a n d t h e  H e ari n g  S cr e e ni n g I n v e nt or y ( H SI) 
a n al y s e s,  s e p ar at el y,  u si n g t h e t ot al  s c or e s.  T h e  c o v ari a n c e  str u ct ur e s i d e ntifi e d f or t h e I A 
m a y  b e  diff er e nt  t h a n t h e  c o v ari a n c e str u ct ur e s f or t h e  C S R  a n al y s e s,  b a s e d  o n  t h e 
e v al u ati o n  f or m o d el  fit.  F urt h er  d et ail s  f or e a c h  of  t h e pl a n n e d  m o d el s  a n d  a n al y s e s  ar e 
pr o vi d e d  i n s u b s e q u e nt  s e cti o n s.  
 
M o d el s  a n d  d e s cri pti v e  s u m m ari e s f or t h e I A  will  o nl y i n cl u d e  d at a t hr o u g h  Vi sit  5  ( D a y  9 0). 
D at a t hr o u g h  Vi sit  9  ( D a y  2 1 0)  will  b e i n cl u d e d i n t h e  m o d el s  a n d  s u m m ari z e d  d e s cri pti v el y 
f or t he  C S R. 
 
7. 1. 6.  Mi s si n g  D at a  
 
D u e  t o t h e e x pl or at or y  n at ur e  of  t h e st u d y,  n o  f or m al i m p ut ati o n o n  mi s si n g  d at a  will  b e 
p erf or m e d.  Mi s si n g  d at a  d u e t o t h e  C O VI D -1 9  p a n d e mi c  will r e m ai n  mi s si n g i n t h e  pl a n n e d 
st ati sti c al  s u m m ari e s  a n d  a n al y s e s.  U nl e s s  ot h er wi s e  s p e cifi e d,  i n c o m pl et e d at a  f or t h e 
effi c a c y  e n d p oi nt s  will  b e  a s s u m e d  mi s si n g  at r a n d o m ( M A R)  a n d  a n al y z e d  u si n g t h e  
M M R M  a p pr o a c h. 
 
F or t h e  W R  a n d  WI N, t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  c o m pl eti n g  e a c h  w or d li st  at 
e a c h  vi sit  will  b e  s u m m ari z e d f or tr e at e d  e ar s  b y r a n d o mi z e d tr e at m e nt  gr o u p f or  s u bj e ct s  
i n t h e F A S.   F or  t h e a u di o m etr y  e n d p oi nt s,  t h e n u m b er  a n d  p er c e nt a g e  of   su bj e ct s  wit h 
n o n -mi s si n g,  n o  r e s p o n s e,  or n ot  d o n e  at  e a c h fr e q u e n c y  a n d  vi sit  will  b e  s u m m ari z e d f or 
tr e at e d e ar s  b y  r a n d o mi z e d tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
W h er e r e c or d e d,  vi sit s i m p a ct e d  b y t h e  C O VI D -1 9  p a n d e mi c  will  b e i d e ntifi e d i n  d at a 
li sti n g s. 
 
T a bl e   7- 2    
Effi c a c y  V ari a bl e s a n d  A n al y si s  M et h o d s  
 
Effi c a c y  E n d p oi nt  
A n al y si s  M et h o d( s)  
S e cti o n  
W o r d  R e c o g niti o n  i n Q ui et  
7. 3  
N u m b er  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
M M R M i n  tr e at e d e ar s.  
• 
Ri s k r ati o s  of tr e at e d  e ar s t o  u ntr e at e d  e ar s f or  all  s u bj e ct s, 
s u bj e ct s  wit h  bil at er al  h e ari n g  l o s s, a n d  s u bj e ct s  wit h o ut 
bil at er al  h e ari n g  l o s s. 
7. 3. 1  
P er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
M M R M i n  tr e at e d e ar s.  
• 
S e n siti vit y:  D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s  b y  sit e.  
7. 3. 2  
A b s ol ut e  p er c e nt 
c h a n g e  fr o m b a s eli n e 
i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  o b s er v e d  m e a n s 
f or tr e at e d  e ar s. 
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  a dj u st e d (l e a st 
s q u ar e s)  m e a n s  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
• 
S e n siti vit y:  D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s  b y  sit e.  
7. 3. 3  
R el ati v e  p er c e nt 
c h a n g e  fr o m b a s eli n e 
i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  o b s er v e d  m e a n s 
f or tr e at e d  e ar s. 
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  a dj u st e d (l e a st 
s q u ar e s)  m e a n s  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
• 
S e n siti vit y:  D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s  b y  sit e.  
7. 3. 4  
I m pr o v e m e nt > = 1 0 %  • 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 3. 5  
( 5 w or d s)  i n 
• 
G E E  i n tr e at e d e ar s.  
 
p er c e nt a g e  of  
 
r e c o g ni z e d w or d s  
 
Ar c si n e -tr a n sf or m e d 
W R  
• 
D e s cri pti v e  s u m m ar y f or tr e at e d  e ar s. 
M M R M i n tr e at e d  e ar s.  
7. 3. 6  
W R  c at e g ori e s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
B ar  c h art s  f or tr e at e d e ar s.  
7. 3. 7  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
Effi c a c y  E n d p oi nt  
A n al y si s  M et h o d( s)  
S e cti o n  
S hift  i n W R  c at e g ori e s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 3. 8  
Cli ni c al I m pr o v e m e nt 
i n  W R,  u si n g 
T h or nt o n -R affi n 
C o nfi d e n c e  I nt er v al s 
( CIT R  ) 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
S c att er pl ot s  f or tr e at e d e ar s.  
• 
G E E  i n tr e at e d e ar s.  
7. 3. 9  
Cli ni c al I m pr o v e m e nt 
i n W R,  u si n g  C ar n e y 
S c hl a u c h  C o nfi d e n c e 
I nt er v al s ( CIC S ) 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
S c att er pl ot s f or  tr e at e d e ar s.  
• 
G E E  i n tr e at e d e ar s.  
7. 3. 1 0  
I n ci d e n c e  of i n c orr e ct 
p h o n e m e s  
• 
H e at  m a p s  f or tr e at e d e ar s.  
7. 3. 1 1  
W o r d s -I n-N oi s e  
 
7. 4  
N u m b er  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
• 
Ri s k r ati o  of tr e at e d  e ar s t o  u ntr e at e d  e ar s f or  all  s u bj e ct s, 
s u bj e ct s  wit h  bil at er al  h e ari n g  l o s s, a n d  s u bj e ct s  wit h o ut 
bil at er al  h e ari n g  l o s s. 
7. 4. 1  
P er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  o b s er v e d  m e a n s 
f or tr e at e d e ar s  ( at e a c h  si g n al -t o-n oi s e  r ati o). 
• 
M M R M  i n tr e at e d  e ar s. 
7. 4. 2  
A b s ol ut e  p er c e nt 
c h a n g e  fr o m b a s eli n e 
i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  o b s er v e d  m e a n s 
f or tr e at e d  e ar s. 
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  a dj u st e d (l e a st 
s q u ar e s)  m e a n s  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
7. 4. 3  
R el ati v e  p er c e nt 
c h a n g e  fr o m b a s eli n e 
i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  o b s er v e d  m e a n s 
f or tr e at e d  e ar s. 
• 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or  a dj u st e d (l e a st 
s q u ar e s)  m e a n s  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
7. 4. 4  
I m pr o v e m e nt > = 1 0 %  • 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 4. 5  
( 5 w or d s)  i n 
• 
G E E  i n tr e at e d e ar s.  
 
p er c e nt a g e  of  
 
 
r e c o g ni z e d w or d s   
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
Effi c a c y  E n d p oi nt  
A n al y si s  M et h o d( s)  
S e cti o n  
S p e ar m a n -K är b er 
e sti m at e s  of  d B 
t hr e s h ol d s f or  w or d 
r e c o g niti o n ( 2 5t h, 5 0 t h 
( m e di a n)  a n d  7 5t h 
p er c e ntil e s)  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
S c att er  pl ot s  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
7. 4. 6  
I m pr o v e m e nt > = 3  d B  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 4. 7  
s hift s  i n m e di a n  
• 
G E E  i n tr e at e d e ar s.  
 
S p e ar m a n -K är b er  
 
 
e sti m at e s  
 
 
I n ci d e n c e  of i n c orr e ct 
p h o n e m e s  
• 
H e at  m a p s  f or tr e at e d e ar s.  
7. 4. 8  
P u r e  T o n e  A u di o m etr y   
7. 5  
Air  C o n d u cti o n  ( A C) 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
7. 5. 1  
a n d  B o n e  C o n d u cti o n  • 
M M R M  i n tr e at e d  e ar s. 
 
( B C) a u di o m etr y  d B  
 
 
h e ari n g  t hr e s h ol d s b y   
 
fr e q u e n c y 
 
 
A C  a n d  B C  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 5. 2  
I m pr o v e m e nt > = 1 0  
• 
G E E  i n tr e at e d e ar s.  
 
d B  fr o m b a s eli n e  f or 
 
 
t w o c o nti g u o u s  
 
 
fr e q u e n ci e s 
 
 
A C  a n d  B C  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 5. 3  
I m pr o v e m e nt > = 1 5  
• 
G E E  i n tr e at e d e ar s.  
 
d B  fr o m b a s eli n e  f or 
 
 
a n y  fr e q u e n c y 
 
 
A C  a n d  B C  C o m p o sit e 
I m pr o v e m e nt 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
G E E  i n tr e at e d e ar s.  
7. 5. 4  
M e a n  o v er all  P ur e 
T o n e  A v er a g e  ( P T A) 
( A C o v er  0. 5,  1,  2,  a n d 
4  k H z)  a n d  B o n e 
C o n d u cti o n  A v er a g e 
( B C A) ( B C o v er  0. 5,  1,  
2  a n d   4 k H z)  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
M M R M  i n tr e at e d  e ar s. 
• 
D e s cri pti v e  s u m m ar y  of  s hift fr o m  b a s eli n e i n  P T A 
c at e g ori e s  f or tr e at e d e ar s.  
7. 5. 5  
M e a n  l o w A C  d B  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 5. 6  
h e ari n g  t hr e s h ol d ( A C • 
M M R M  i n tr e at e d  e ar s. 
 
o nl y  o v er  0. 2 5,  0. 5,  1,   
 
a n d  2  k H z  
 
 
fr e q u e n ci e s) 
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
Effi c a c y  E n d p oi nt  
A n al y si s  M et h o d( s)  
S e cti o n  
M e a n  hi g h  A C  d B  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 5. 7  
h e ari n g  t hr e s h ol d ( A C • 
M M R M  i n tr e at e d  e ar s. 
 
o nl y  o v er  3,  4,  6,  a n d  
 
 
8  k H z  fr e q u e n ci e s) 
 
 
Air -B o n e   I m b al a n c e 
at  0. 5,  1,  2,  3,  a n d  4 
k H z  
• 
D e s cri pti v e  s u m m ari e s  f or tr e at e d e ar s.  
7. 5. 8  
C o m p o sit e  E n d p oi nt  
C o m p o sit e  W R,  WI N 
a n d  P ur e  T o n e 
A u di o m etr y  E n d p oi nt  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
L o gi sti c  R e gr e s si o n  i n tr e at e d e ar s.  
7. 5. 9  
E xt e n d e d  Hi g h  F r e q u e n c y  A u di o m etr y  ( E H F A) 
7. 6  
A C  a u di o m etr y  d B 
h e ari n g t hr e s h ol d s  b y 
fr e q u e n c y 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d a n d  u ntr e at e d  e ar s.  
• 
M M R M i n  tr e at e d e ar s.  
7. 6. 1  
A C  I m pr o v e m e nt 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 6. 2  
> = 1 0  d B  fr o m 
• 
G E E  i n tr e at e d e ar s.  
 
b a s eli n e  f or t w o 
 
 
c o nti g u o u s  
 
 
fr e q u e n ci e s 
 
 
A C  I m pr o v e m e nt 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 6. 3  
> = 1 5  d B  fr o m 
• 
G E E  i n tr e at e d e ar s.  
 
b a s eli n e  f or a n y  
 
 
fr e q u e n c y 
 
 
A C  C o m p o sit e 
I m pr o v e m e nt 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
G E E  i n tr e at e d e ar s.  
7. 6. 4  
M e a n  d B  h e ari n g 
t hr e s h ol d ( A C o v er   9- 
1 6  k H z)  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
• 
M M R M i n  tr e at e d e ar s.  
7. 6. 5  
S hift  fr o m n o  si g n al 
t o  a n y  si g n al  b y 
fr e q u e n c y 
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 6. 6  
S hift  fr o m n o  si g n al  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 6. 7  
t o a n y  si g n al  i n t w o 
 
 
c o nti g u o u s  
 
 
fr e q u e n ci e s 
 
 
S hift  fr o m n o  si g n al  
• 
D e s cri pti v e  s u m m ar y  f or tr e at e d e ar s.  
7. 6. 8  
t o a n y  si g n al  i n t hr e e 
 
 
c o nti g u o u s  
 
 
fr e q u e n ci e s 
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
Effi c a c y  E n d p oi nt  
A n al y si s  M et h o d( s)  
S e cti o n  
Ti n nit u s  F u n cti o n al  I n d e x 
7. 7  
M e a n  t ot al s c or e,  
• 
D e s cri pti v e  s u m m ar y.  
7. 7. 1  
i n di vi d u al s u b s c al e  
• 
M M R M  f or t ot al s c or e  a n d  l o u d n e s s s c or e.  
 
s c or e s,  a n d  l o u d n e s s 
 
s c or e  
 
C h a n g e  fr o m b a s eli n e 
i n m e a n  t ot al s c or e, 
i n di vi d u al s u b s c al e 
s c or e s,  a n d  l o u d n e s s 
s c or e  
• 
D e s cri pti v e  s u m m ar y.  
• 
M M R M  f or t ot al s c or e  a n d  l o u d n e s s s c or e.  
• 
C orr el ati o n  a n al y s e s.  
7. 7. 2  
H e a ri n g  H a n di c a p  I n v e nt o r y f o r A d ult s  
7. 8  
M e a n  t ot al s c or e  a n d 
i n di vi d u al s u b s c al e 
s c or e s  
• 
D e s cri pti v e  s u m m ar y.  
• 
M M R M.  
7. 8. 1  
C h a n g e  fr o m b a s eli n e 
i n  m e a n t ot al  s c or e 
a n d  i n di vi d u al 
s u b s c al e  s c or e s  
• 
D e s cri pti v e  s u m m ar y.  
• 
M M R M.  
• 
C orr el ati o n  a n al y s e s.  
7. 8. 2  
H e ari n g  S cr e e ni n g  I n v e nt or y 
7. 9  
M e a n  t ot al s c or e  
• 
D e s cri pti v e  s u m m ar y.  
• 
M M R M.  
7. 9. 1  
C h a n g e  fr o m b a s eli n e 
i n  m e a n t ot al  s c or e 
• 
D e s cri pti v e  s u m m ar y.  
• 
M M R M.  
• 
C orr el ati o n  a n al y s e s.  
7. 9. 2  
 
Pri m ar y  E n d p oi nt  
 
T h er e  i s n o  si n gl e  pri m ar y  e n d p oi nt  f or t hi s st u d y.  
 
W or d  R e c o g niti o n  i n Q ui et  
 
W or d  R e c o g niti o n  i s m e a s ur e d  u si n g  t h e i n ci d e n c e of  c orr e ctl y  r e c o g ni z e d w or d s  fr o m 
r e c or d e d  c o n s o n a nt-n u cl e u s -c o n s o n a nt ( C N C)  w or d li st s.  T h e  W R t e st  c o n si st s  of  5 0  w or d s 
a n d t h e  n u m b er  of  a n d  a s s e s s e d  p er c e nt a g e  of  c orr e ctl y r e c o g ni z e d  w or d s  o ut  of  5 0  will  b e 
r e c or d e d. If all  5 0  w or d s  ar e  n ot  a s s e s s e d  i n e a c h  e ar,  t h e W R  t e st s c or e  will  n ot  b e 
c al c ul at e d.  
 
W R  will  b e  p erf or m e d  at  S cr e e ni n g,  D a y  1 5,  6 0,  9 0,  1 5 0,  a n d  2 1 0  vi sit s.   T e sti n g  will  b e 
p erf or m e d  at  3 0  d B  s e n s ati o n l e v el ( S L) r e g ar di n g  t h e  p ur e t o n e  a v er a g e  of  0. 5,  1,  a n d  2  k H z 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
at  S cr e e ni n g.  W or d  li st s will  b e  r ot at e d at  e a c h  vi sit.  A d diti o n al  d et ail s  c a n  b e  f o u n d i n t h e 
st u d y  A u di ol o g y  M a n u al  of  Pr o c e d ur e s.  
 
B a s eli n e  s c or e s f or  a n al y si s  will  b e  c o m p ut e d fr o m t h e  S cr e e ni n g  vi sit.  T h er e  will  b e  n o 
i m p ut ati o n f or mi s si n g  s c or e s.  
 
7. 3. 1.  N u m b er  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar  (l eft,  ri g ht), t h e  n u m b er  of  w or d s  cl a s sifi e d  a s  c orr e ctl y  r e c o g ni z e d 
o ut  of  5 0  will  b e  r e c or d e d. L eft  a n d  ri g ht e ar s  will  b e  m a p p e d  t o tr e at e d a n d  u ntr e at e d  f or 
a n al y si s,  a s  d e s cri b e d  i n S e cti o n  3 . 
 
I n  s u bj e ct s i n t h e  F A S  wit h  h e ari n g l o s s i n  b ot h  e ar s  p er t h e  T ar g et e d  H e ari n g  L o s s  Hi st or y 
C R F  p a g e, t h e r ati o  of t h e  n u m b er  of r e c o g ni z e d  w or d s f or tr e at e d  e ar  v er s u s  u ntr e at e d  e ar 
will  b e  c o m p ut e d. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  n u m b er  of r e c o g ni z e d  w or d s  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d 
u ntr e at e d  e ar s  s e p ar at el y  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  will  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  
7. 3. 4  f or s u bj e ct s  i n t h e  F A S. T h e  c o v ari a n c e  str u ct ur e ( U N  or  A R( 1)) t h at  pr o vi d e s  t h e  b e st 
m o d el fit  f or t h e r el ati v e  p er c e nt c h a n g e fr o m  b a s eli n e  i n p er c e nt a g e  of r e c o g ni z e d  w or d s, 
a s  d e s cri b e d i n  S e cti o n  7. 3. 4 ,  will  b e i m pl e m e nt e d  wit h  a r e p e at e d  st at e m e nt i n  S A S. 
 
T h e  r ati o of  t h e n u m b er  of  r e c o g ni z e d w or d s  f or tr e at e d e ar s  v er s u s  u ntr e at e d  e ar s  will  b e 
s u m m ari z e d  d e s cri pti v el y  b y  vi sit  a n d tr e at m e nt  gr o u p f or  all  s u bj e ct s i n t h e  F A S,  s u bj e ct s i n 
t h e  F A S  wit h bil at er al  h e ari n g l o s s,  a n d  s u bj e ct s  i n t h e  F A S  wit h o ut  bil at er al  h e ari n g l o s s. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 3. 2.  P er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
U si n g t h e  n u m b er  of r e c o g ni z e d  w or d s i n  S e cti o n  7. 3. 1 , t h e  p er c e nt a g e  of r e c o g ni z e d  w or d s 
will  b e  c o m p ut e d  b y  vi sit  a s  t h e n u m b er  of  r e c o g ni z e d w or d s  di vi d e d  b y  5 0  a n d  m ulti pli e d 
b y  1 0 0,  s e p ar at el y  f or e a c h  e ar.  
 
• 
A n al y si s  of  t h e E n d p oi nt  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T h e  p er c e nt a g e  of r e c o g ni z e d  w or d s  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d 
u ntr e at e d  e ar s  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 3. 1  f or  s u bj e ct s i n t h e  F A S. 
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  will  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  
7. 3. 4  f or  s u bj e ct s i n t h e  F A S. T h e  c o v ari a n c e  str u ct ur e ( U N  or  A R( 1)) t h at  pr o vi d e s  t h e  b e st 
m o d el fit  f or t h e r el ati v e  p er c e nt c h a n g e fr o m  b a s eli n e  i n p er c e nt a g e  of r e c o g ni z e d  w or d s, 
a s  d e s cri b e d i n  S e cti o n  7. 3. 4 ,  will  b e i m pl e m e nt e d  wit h  a r e p e at e d  st ate m e nt i n  S A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
T h e  p o s si bl e  pr e s e n c e  of  sit e -t o-sit e  h et er o g e n eit y  will  b e  e v al u at e d  b y  d e s cri pti v el y 
s u m m ari zi n g  t h e p er c e nt a g e  of  r e c o g ni z e d w or d s  f or tr e at e d e ar s  b y  sit e,  vi sit,  a n d 
tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 3. 3.  A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e n t a g e of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  will  b e  c o m p ut e d  a s  1 0 0*[( w/ 5 0)   – ( b/ 5 0)] w h er e  “ w” i s t h e fr e q u e n c y of 
w or d s r e c o g ni z e d  at t h e  p o st -b a s eli n e  vi sit  a n d “ b” i s t h e fr e q u e n c y  of  w or d s r e c o g ni z e d  at 
b a s eli n e.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  will  b e 
s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d  e ar s  u si n g t h e  a p pr o a c h  d e s cri b e d i n 
S e cti o n  7. 3. 1  f or s u bj e ct s  i n t h e F A S.  
 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s)  will  b e  cr e at e d f or t h e  a dj u st e d (l e a st  s q u ar e s)  m e a n 
a b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  f or tr e at e d e ar s 
b y  p o st -b a s eli n e  vi sit  a n d tr e at m e nt  gr o u p f or  s u bj e ct s i n t h e  F A S.  P o st -b a s eli n e  vi sit  will  b e 
pl ott e d  o n  t h e  x-a xi s  a n d t h e  a dj u st e d (l e a st  s q u ar e s)  m e a n  a b s ol ut e  p er c e nt  c h a n g e fr o m 
b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  f or tr e at e d e ar s  will  b e  pl ott e d  o n  t h e  y-a xi s.  
E a c h  tr e at m e nt gr o u p  will  b e  pr e s e nt e d  a s   a s e p ar at e  li n e i n t h e pl ot.   T h e  li n e gr a p h s  will 
b e r e p e at e d f or t h e  o b s er v e d  m e a n  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  f or tr e at e d e ar s.  
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  will  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  
7. 3. 4  f or  s u bj e ct s i n t h e  F A S. T h e  c o v ari a n c e  str u ct ur e ( U N  or  A R( 1)) t h at  pr o vi d e s  t h e  b e st 
m o d el fit  f or t h e r el ati v e  p er c e nt c h a n g e fr o m  b a s eli n e  i n p er c e nt a g e  of r e c o g ni z e d  w or d s, 
a s  d e s cri b e d i n  S e cti o n  7. 3. 4 ,  will  b e i m pl e m e nt e d  wit h  a r e p e at e d  st at e m e nt i n  S A S. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e li n e gr a p h s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
T h e  p o s si bl e  pr e s e n c e  of  sit e -t o-sit e  h et er o g e n eit y  will  b e  e v al u at e d  u si n g t h e  a p pr o a c h 
d e s cri b e d  i n S e cti o n  7. 3. 2  f or s u b j e ct s i n t h e F A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 3. 4.  R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  t o e a c h  p o st -b a s eli n e  vi sit  i n p er c e nt a g e  of 
r e c o g ni z e d w or d s  will  b e  c o m p ut e d  a s  1 0 0*[( w -b)/ b]  w h er e  “ w” i s t h e fr e q u e n c y of  w or d s 
r e c o g ni z e d at  t h e p o st -b a s eli n e  vi sit  a n d  “ b” i s t h e fr e q u e n c y of  w or d s  r e c o g ni z e d at 
b a s eli n e.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  will  b e 
s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d  e ar s  u si n g t h e  a p pr o a c h  d e s cri b e d i n 
S e cti o n  7. 3. 1  f or s u bj e ct s  i n t h e F A S.  
 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or t h e  a dj u st e d (l e a st  s q u ar e s)  m e a n s  a n d  o b s er v e d 
m e a n s  will  b e  cr e at e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  7. 3. 3  f or s u bj e ct s  i n t h e F A S.  
 
I n tr e at e d e ar s  o nl y  f or s u bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or t h e r el ati v e 
p er c e nt  c h a n g e  fr o m b a s eli n e i n  p er c e nt a g e  of  r e c o g ni z e d  w or d s will  b e  a n al y z e d  u si n g  a 
mi x e d -eff e ct,  r e p e at e d m e a s ur e s  m o d el  u si n g  fi x e d c o v ari at e s  f or tr e at m e nt gr o u p,  W R 
s c or e  at  b a s eli n e  ( < 5 0 % v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g  l o s s ( S S N H L v er s u s  NI H L),  vi sit, 
a n d  i nt er a cti o n b et w e e n  vi sit  a n d  tr e at m e nt gr o u p.  S e p ar at e  m o d el s  will  b e  fit s p e cif yi n g 
U N  a n d  A R( 1)  c o v ari a n c e  str u ct ur e s (i m pl e m e nt e d  wit h  a r e p e at e d  st at e m e nt i n  S A S).  T h e 
c o v ari a n c e  str u ct ur e  pr o vi di n g t h e l o w e st  c orr e ct e d  A k ai k e’ s I nf or m ati o n  Crit eri a ( AI C c)  a n d 
B a y e si a n  I nf or m ati o n Crit eri a  ( BI C) v al u e s  fr o m t h e m o d el  will  b e  i m pl e m e nt e d f or t h e 
r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  a n d  all  ot h er  W R  e n d p oi nt s.   T h e  tr e at m e nt gr o u p 
diff er e n c e s  a n al y z e d  will  b e  b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  
gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g  
t h e  p o ol e d  F X-3 2 2  gr o u p).  C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L e a st  s q u ar e s 
( L S)  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all ( e. g.,  T y p e III  S u m s  of  S q u ar e s). 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e li n e gr a p h s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  2 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T h e  p o s si bl e  pr e s e n c e  of  sit e -t o-sit e  h et er o g e n eit y  will  b e  e v al u at e d  u si n g t h e  a p pr o a c h 
d e s cri b e d  i n S e cti o n  7. 3. 2  f or s u bj e ct s  i n t h e F A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 3. 5.  I m pr o v e m e nt > = 1 0 %  ( 5 w or d s)  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
I m pr o v e m e nt  > = 1 0 % i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  at  e a c h  p o st-b a s eli n e  vi sit f or 
tr e at e d e ar s  will  b e  c o m p ut e d  a s   1 if t h e a b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n 
p er c e nt a g e  of r e c o g ni z e d  w or d s  > = 1 0 %  a n d  a s  0,  ot h er wi s e  w h er e  a b s ol ut e  p er c e nt  c h a n g e 
fr o m b a s eli n e  i s n o n -mi s si n g.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of i m pr o v e m e nt  > = 1 0 %  i n p er c e nt a g e  of  r e c o g ni z e d  w or d s at  e a c h  p o st - 
b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y  vi sit 
a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
I n tr e at e d e ar s  o nl y  f or s u bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or i n ci d e n c e of 
i m pr o v e m e nt  > = 1 0 % i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  m a y  b e  a n al y z e d  u si n g  a 
g e n er ali z e d  e sti m ati n g  e q u ati o n  b a s e d  o n  t h e bi n o mi al  di stri b uti o n  wit h  l o git li n k. T h e  fi x e d 
c o v ari at e s  m a y i n cl u d e tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  
eti o l o g y  of  h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d 
tr e at m e nt gr o u p.  C o v ari at e s  f or W R  s c or e  at  b a s eli n e  a n d  eti ol o g y  of  h e ari n g  l o s s m a y  b e 
dr o p p e d  if t h e m o d el  f ail s t o c o n v er g e.    A r a n d o m eff e ct  f or wit hi n -s u bj e ct,  r e p e at e d 
m e a s ur e s  v ari a bilit y  m a y  b e  i n cl u d e d.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
O d d s r ati o s,  9 5 %  CI s,  a n d  p -v al u e s  m a y  b e r e p ort e d  a n d  c o m p ari s o n s  will  b e  m a d e  b y  vi sit 
a n d  o v er all. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 3. 6.  Ar c si n e -tr a n sf or m e d W R  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  ar c si n e -tr a n sf or m e d  W R ( St u d e b a k er,  1 9 8 5)  will  b e  c o m p ut e d  b y  vi sit f or tr e at e d  e ar s 
a s  
 
𝑅 𝑅 =  𝑎 𝑎 𝑎 𝑎𝑎 𝑎𝑠 𝑠 𝑠 𝑠𝑠 𝑠
𝑤 𝑤⁄
( 𝑠 𝑠 +  1 ) + 𝑎 𝑎 𝑎 𝑎𝑎 𝑎𝑠 𝑠𝑠 𝑠 𝑠 𝑠
( 𝑤 𝑤 + 
1)⁄
( 𝑠 𝑠 +  1 ) 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
w h er e  “ R” i s t h e tr a n sf or m e d r a di a n s, “ w” i s t h e fr e q u e n c y of  w or d s  r e c o g ni z e d, a n d  “ n” i s 
t h e n u m b er  of  w or d s  i n t h e w or d  t e st ( n  = 5 0  f or W R  a s s e s s m e nt s).  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  ar c si n e -tr a n sf or m e d  W R  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  e ar s  u si n g t h e 
a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 3. 1  f or  s u bj e ct s i n t h e  F A S. 
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  will  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  
7. 3. 4  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 3. 7.  W R  C at e g ori e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
U si n g t h e  p er c e nt a g e  of r e c o g ni z e d  w or d s i n  S e cti o n  7. 3. 2  b y  vi sit  a n d f or  e a c h  e ar, 
p er c e nt a g e s  will  b e  c at e g ori z e d  a s  f oll o w s, u si n g  t h e S c h o e pfli n  ( 2 0 1 2) j u stifi c ati o n: 
 
○ 
E x c ell e nt:   
> 8 5 %  
○ 
G o o d:  
6 8  t o 8 5 %  
○ 
F air:  
5 1  t o 6 7 %  
○ 
P o or  
3 3  t o 5 0 %  
○ 
V er y  P o or:  
1 5  t o 3 2 %  
○ 
E xtr e m el y  P o or:   
< 1 5 %  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  di stri b uti o n  of  W R  c at e g ori e s  at  e a c h  b a s eli n e  a n d  p o st -b a s eli n e  vi sit f or tr e at e d  e ar s 
will  b e  s u m m ari z e d  u si n g  fr e q u e n ci e s a n d  p er c e nt a g e s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or 
s u bj e ct s  i n t h e F A S.  
 
B ar  c h art s  will  b e  cr e at e d f or t h e  di stri b uti o n  of  W R  c at e g ori e s  at  e a c h  b a s eli n e  a n d  p o st - 
b a s eli n e  vi sit  f or tr e at e d e ar s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e b ar  c h art s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 3. 8.  S hift  i n W R  C at e g ori e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
U si n g t h e  W R  C at e g ori e s i n  S e cti o n  7. 3. 7  b y  vi sit f or tr e at e d  e ar s,  s hift s fr o m  b a s eli n e t o 
e a c h  p o st  b a s eli n e -vi sit  will  b e  c o m p ut e d  ( e. g., F air  t o G o o d).  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  di stri b uti o n  i n t h e s hift  i n W R  c at e g ori e s  fr o m b a s eli n e  t o e a c h  p o st -b a s eli n e  vi sit  f or 
tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y  vi sit  a n d tr e at m e nt 
gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 3. 9.  Cli ni c al  I m pr o v e m e nt i n W R,  u si n g  T h or nt o n -R affi n  C o nfi d e n c e  I nt er v al s ( CIT R ) 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
Cli ni c al  i m pr o v e m e nt i n W R  at  p o st -b a s eli n e  vi sit s  f or tr e at e d e ar s  will  b e  d efi n e d  b y 
c o m p ari n g  T h or nt o n -R affi n ( 1 9 7 8)  9 5 %  c o nfi d e n c e i nt er v al s ( CI T R ) ( S e cti o n 1 4. 1 )  at t h e 
b a s eli n e  vi sit  v er s u s  t h e p er c e nt a g e  of  r e c o g ni z e d w or d s  at  t h e p o st -b a s eli n e  vi sit s.   It will 
b e  d efi n e d  a s ‘I m pr o v e d’ if t h e  s u bj e ct’ s  p o st -b a s eli n e  s c or e i s  hi g h er t h a n t h e  u p p er li mit  of  
t h e  s u bj e ct’ s  b a s eli n e  9 5 %  CIT R ,  a s ‘ N o  c h a n g e’ if t h e  p o st-b a s eli n e  s c or e f all s  wit hi n  or  o n  
t h e  b o u n d s  of t h e  b a s eli n e  9 5 %  CIT R ,  a n d ‘ R e d u cti o n’ if t h e  p o st- ba s eli n e  s c or e i s l o w er t h a n 
t h e b a s eli n e  l o w er li mit of  t h e 9 5 %  CI T R.  
 
T h e  T h or nt o n -R affi n  9 5 %  CI T R  r e p ort e d i n  S e cti o n 1 4. 1  will  b e  u s e d  dir e ctl y  a n d  n ot 
c o m p ut e d.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of  cli ni c al i m pr o v e m e nt i n  W R (I m pr o v e m e nt,  N o  C h a n g e,  R e d u cti o n)  b a s e d  
o n  CI T R  at  e a c h  p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d 
p er c e nt a g e s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
S c att er   pl ot s  will b e  u s e d  t o s u m m ari z e  cli ni c al i m pr o v e m e nt  i n t h e p er c e nt a g e  of 
r e c o g ni z e d  w or d s ( S e cti o n 7. 3. 2 ) i n tr e at e d e ar s.   T h e  p er c e nt a g e  of  r e c o g ni z e d  w or d s at 
b a s eli n e  will  b e  pl ott e d  o n t h e  x -a xi s  a n d t h e  p er c e nt a g e  of r e c o g ni z e d  w or d s  p o st -b a s eli n e 
will  b e  pl ott e d  i n t h e  y-a xi s,  wit h   a s e p ar at e  pl ot  f or e a c h  p o st -b a s eli n e  vi sit.   T h e  b a s eli n e 
T h or nt o n -R affi n  9 5 %  c o nfi d e n c e  i nt er v al s i n S e cti o n  1 4. 1  will  b e  o v er l ai d i n t h e pl ot.  
 
I n tr e at e d e ar s  o nl y  f or s u bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or i n ci d e n c e of 
cli ni c al i m pr o v e m e nt i n  W R  m a y  b e  a n al y z e d  u si n g  a  g e n er ali z e d  e sti m ati n g  e q u ati o n  b a s e d 
o n  t h e m ulti n o mi al  di stri b uti o n  wit h  g e n er ali z e d  l o git ( n o mi n al) li n k.  T h e  fi x e d c o v ari at e s 
m a y i n cl u d e tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti o l o g y  of 
h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. 
C o v ari at e s  f or  W R s c or e  at  b a s eli n e  a n d  eti ol o g y  of  h e ari n g l o s s  m a y  b e  dr o p p e d if t h e 
m o d el  f ail s t o c o n v er g e.    A r a n d o m eff e ct  f or wit hi n -s u bj e ct,  r e p e at e d m e a s ur e s  v ari a bilit y 
m a y  b e i n cl u d e d.   T h e  tr e at m e nt  gr o u p  diff er e n c e s  a n al y z e d  will  b e b et w e e n  e a c h  F X -3 2 2 
gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n t h e 
i n di vi d u al  F X-3 2 2  gr o u p s  ( e x cl u di n g t h e p o ol e d  F X -3 2 2  gr o u p).   Pr o p orti o n al  o d d s r ati o s, 
9 5 %  CI s,  a n d  p -v al u e s  m a y  b e r e p ort e d  a n d  c o m p ari s o n s  will  b e  m a d e  b y  vi sit  a n d  o v er all.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h t h e  e x c e pti o n  of t h e  s c att er  pl ot s, t h e  a n al y s e s  will  b e r e p e at e d f or  s u bj e ct s  i n t h e 
P P A S.  
 
7. 3. 1 0.  Cli ni c al  I m pr o v e m e nt i n W R,  u si n g  C ar n e y  S c hl a u c h  C o nfi d e n c e  I nt er v al s ( CIC S ) 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
Cli ni c al  i m pr o v e m e nt i n W R  at  p o st -b a s eli n e  vi sit s  f or tr e at e d e ar s  will  b e  d efi n e d  b y 
c o m p ari n g  C ar n e y  S c hl a u c h ( 2 0 0 7)  9 5 %  c o nfi d e n c e i nt er v al s ( CI C S ) ( S e cti o n 1 4. 2 )  at t h e 
b a s eli n e  vi sit  v er s u s  t h e p er c e nt a g e  of  r e c o g ni z e d w or d s  at  t h e p o st -b a s eli n e  vi sit s.   It will 
b e  d efi n e d  a s ‘I m pr o v e d’ if t h e  s u bj e ct’ s  p o st -b a s eli n e  s c or e i s  hi g h er t h a n t h e  u p p er li mit  of  
t h e  s u bj e ct’ s  b a s eli n e  9 5 %  CIC S ,  a s ‘ N o  c h a n g e’ if t h e  p o st-b a s eli n e  s c or e f all s  wit hi n  or  o n  
t h e  b o u n d s  of t h e  b a s eli n e  9 5 %  CIc s,  a n d ‘ R e d u cti o n’ if t h e  p o st- ba s eli n e  s c or e i s l o w er t h a n 
t h e b a s eli n e  l o w er li mit of  t h e 9 5 %  CI c s.  
 
T h e  C ar n e y  S c hl a u c h  9 5 %  CI c s  r e p ort e d i n S e cti o n  1 4. 2  will  b e  u s e d  dir e ctl y  a n d  n ot 
c o m p ut e d.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s,  s c att er  pl ot s,  a n d tr e at m e nt  gr o u p  c o m p ari s o n s  m a y  b e  p erf or m e d 
f or  cli ni c al i m pr o v e m e nt i n  W R (I m pr o v e m e nt,  N o  C h a n g e,  R e d u cti o n)  b a s e d  o n  CI C S  a s 
d e s cri b e d i n  S e cti o n  7. 3. 9 . T h e  C ar n e y  S c hl a u c h  9 5 %  c o nfi d e n c e i nt er v al s  will  b e  util i z e d 
i n st e a d  of t h e  T h or nt o n-R affi n  9 5 %  c o nfi d e n c e i nt er v al s.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h t h e  e x c e pti o n  of t h e  s c att er  pl ot s, t h e  a n al y s e s  will  b e r e p e at e d f or  s u bj e ct s  i n t h e 
P P A S.  
 
7. 3. 1 1.  I n ci d e n c e of  i n c orr e ct p h o n e m e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
I n e a c h  w or d  r e c o g niti o n li st, t h er e ar e  1 5 0  p h o n e m e s  r e pr e s e nt e d a cr o s s  t h e 5 0  w or d s 
wit h  e x a ctl y   3 p h o n e m e s  p er  w or d.  T h e  1 5 0  p h o n e m e s  ar e  n ot  u nif or ml y  or  u ni q u el y 
r e pr e s e nt e d, b ut  di stri b ut e d  wit h  fr e q u e n ci e s e m piri c all y  a p pr o xi m ati n g  r e al-w orl d  u s e 
( C a u s e y  et  al.,  1 9 8 4). F or  e a c h  u ni q u e  p h o n e m e, t h e  p er c e nt a g e  n ot r e c o g ni z e d  c orr e ctl y 
will  b e  c o m p ut e d  b y  s u bj e ct,  vi sit,  a n d  e ar.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
H e at  m a p s  will  b e  pr o d u c e d  b y  vi sit  a n d  tr e at m e nt  gr o u p f or tr e at e d e ar s  t o gr a p hi c all y 
di s pl a y t h e i n ci d e n c e  of i n c orr e ct  p h o n e m e s f or  s u bj e ct s i n t h e  F A S.  T h e  x -a xi s  will i n cl u d e  a 
c ol u m n  f or e a c h  u ni q u e  p h o n e m e  a n d  t h e  y-a xi s  will  i n cl u d e  a r o w f or e a c h  s u bj e ct.   T h e 
s h a di n g  f or  e a c h  c ell of t h e  m a p  will r e pr e s e nt t h e  p er c e nt a g e  of  p h o n e m e s  n ot r e c o g ni z e d 
c orr e ctl y.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
S h a di n g  C ol or  
P er c e nt a g e   I n c orr e ct 
> = 9 0 %  
8 0  t o < 9 0 %  
7 0  t o < 8 0 %  
6 0  t o < 7 0 %  
5 0  t o < 6 0 %  
4 0  t o < 5 0 %  
3 0  t o < 4 0 %  
2 0  t o < 3 0 %  
1 0  t o < 3 2 %  
< = 1 0 %  
P o st  h o c  a n al y s e s  m a y  b e  p erf or m e d  o n  s el e ct  u ni q u e  p h o n e m e s  of i nt er e st,  b a s e d  o n t h e 
fi n al r e s ult s of  t h e h e at  m a p  d e s cri b e d  a b o v e.  T h e  p o st  h o c  a n al y s e s  m a y  i n cl u d e h e at 
m a p s  b y  vi sit  f or tr e at e d e ar s  al s o  t a ki n g i nt o a c c o u nt  t h e l o c ati o n of  t h e p h o n e m e  wit hi n 
t h e w or d  ( p h o n e m e/l o c ati o n) f or s u bj e ct s  i n t h e F A S.  P o st  h o c  tr e at m e nt gr o u p 
c o m p ari s o n s  m a y  al s o  b e  p erf or m e d.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
N o n e.  
 
W or d s -I n-N oi s e  
 
WI N i s  m e a s ur e d  u si n g  t h e i n ci d e n c e  of  c orr e ctl y r e c o g ni z e d  w or d s i n t h e  pr e s e n c e  of 
b a c k gr o u n d  n oi s e  u si n g  m ultit al k er  b a b bl e ( Wil s o n  et  al.,  2 0 0 3).  M at eri al s  ar e r e c or d e d  at  7 
si g n al -t o-n oi s e r ati o s ( 0,  4,  8,  1 2,  1 6,  2 0,  2 4  d B) t h at  ar e  pr e s e nt e d i n  a  d e s c e n di n g  m a n n er. 
T h e  te st  c o n si st s  of   2 li st s of  3 5  r e c or d e d w or d s  ( 7 0 t ot al) f or e a c h  e ar  a n d  t h e n u m b er  of 
a n d  p er c e nt a g e  of  c orr e ctl y r e c o g ni z e d  w or d s  at  e a c h  si g n al -t o-n oi s e r ati o  will  b e r e c or d e d 
s e p ar at el y  b y  e ar.  T h e  o v er all  WI N  s c or e  will  b e  r e c or d e d a s  t h e p er c e nt a g e   of c orr e ctl y 
r e c o g ni z e d w or d s  a cr o s s  all  si g n al -t o-n oi s e  r ati o s b y  vi sit  a n d  e ar.  If all  7 0  w or d s  ar e  n ot 
a s s e s s e d  i n e a c h  e ar,  t h e WI N  t e st s c or e  will  n ot  b e  c al c ul at e d.  
 
T h e  WI N  t e st will  b e  p erf or m e d  at  S cr e e ni n g,  D a y  1 5,  6 0,  9 0,  1 5 0,  a n d  2 1 0  vi sit s.   T e sti n g 
will  b e  p erf or m e d  at  8 0  d B  s o u n d  pr e s s ur e l e v el ( S P L)  a n d  w or d li st s  will  b e r ot at e d  at  e a c h 
vi sit.   A d diti o n al  d et ail s  c a n  b e  f o u n d i n t h e  A u di ol o g y M a n u al  of  Pr o c e d ur e s.  
 
B a s eli n e  s c or e s f or  a n al y si s  will  b e  c o m p ut e d fr o m t h e  S cr e e ni n g  vi sit.  T h er e  will  b e  n o 
i m p ut ati o n f or mi s si n g  s c or e s.  
 
7. 4. 1.  N u m b er  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar  (l eft, ri g ht), t h e  n u m b er  of  w or d s cl a s sifi e d  a s  c orr e ctl y r e c o g ni z e d 
at  e a c h  si g n al -t o-n oi s e r ati o  will  b e  r e c or d e d. T h e  o v er all  WI N  s c or e  will  al s o  b e  c o m p ut e d 
a s t h e  n u m b er  of  w or d s  c orr e ctl y  r e c o g ni z e d  a cr o s s  all  si g n al -t o-n oi s e  r ati o s.  L eft  a n d  ri g ht 
e ar s  will  b e  m a p p e d  t o tr e at e d a n d  u ntr e at e d  f or a n al y si s,  a s  d e s cri b e d  i n S e cti o n  3 . 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
I n  s u bj e ct s i n t h e  F A S  wit h  h e ari n g l o s s i n  b ot h  e ar s  p er t h e  T ar g et e d  H e ari n g  L o s s  Hi st or y 
C R F  p a g e, t h e r ati o  of t h e  n u m b er  of r e c o g ni z e d  w or d s f or tr e at e d  e ar  v er s u s  u ntr e at e d  e ar 
will  b e   c o m p ut e d. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  n u m b er  of  r e c o g ni z e d w or d s  at  e a c h  si g n al -t o-n oi s e  r ati o a n d  o v er all  will  b e 
s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d  e ar s  s e p ar at el y  b y  vi sit  a n d tr e at m e nt  
gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  f or t h e  n u m b er of  r e c o g ni z e d  w or d s o v er all  will  b e 
p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 4. 4  f or s u bj e ct s  i n t h e F A S.   T h e 
c o v ari a n c e  str u ct ur e ( U N  or  A R( 1)) t h at  pr o vi d e s t h e  b e st  m o d el fit f or t h e r el ati v e  p er c e nt 
c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s,  a s  d e s cri b e d i n  S e cti o n  7. 4. 4 ,  will 
b e  i m pl e m e nt e d wit h   a r e p e ate d  st at e m e nt  i n S A S.   Tr e at m e nt  gr o u p  c o m p ari s o n s  will  n ot 
b e  p erf or m e d  f or e a c h  si g n al -t o-n oi s e  r ati o. 
 
T h e  r ati o of  t h e n u m b er  of  r e c o g ni z e d w or d s  f or tr e at e d e ar s  v er s u s  u ntr e at e d  e ar s  will  b e 
s u m m ari z e d  d e s cri pti v el y  b y  vi sit  a n d tr e at m e nt  gr o u p f or  all  s u bj e ct s i n t h e  F A S,  s u bj e ct s i n 
t h e  F A S  wit h  bil at er al  h e ari n g l o s s,  a n d  s u bj e ct s i n t h e  F A S  wit h o ut  bil at er al  h e ari n g l o s s. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 4. 2.  P er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
U si n g t h e  n u m b er  of r e c o g ni z e d  w or d s i n  S e cti o n  7. 4. 1 , th e  p er c e nt a g e  of r e c o g ni z e d  w or d s 
will  b e  c o m p ut e d  f or e a c h  si g n al -t o-n oi s e  r ati o b y  vi sit  a s  t h e n u m b er  of  r e c o g ni z e d w or d s 
di vi d e d  b y  1 0  a n d  m ulti pli e d  b y  1 0 0,  s e p ar at el y f or  e a c h  e ar.  T h e  p er c e nt a g e  of r e c o g ni z e d 
w or d s  o v er all  b y  vi sit  will  b e  c o m p ut e d  a s  t h e n u m b er  of  r e c o g ni z e d w or d s  di vi d e d  b y  7 0 
a n d  m ulti pli e d  b y  1 0 0,  s e p ar at el y  f or e a c h  e ar.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  p er c e nt a g e  of  r e c o g ni z e d w or d s  at  e a c h  si g n al -t o-n oi s e  r ati o a n d  o v er all  will  b e 
s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d  e ar s  u si n g t h e  a p pr o a c h  d e s cri b e d i n 
S e cti o n  7. 4. 1  f or s u bj e ct s  i n t h e F A S.  
 
Li n e  gr a p h s  ( wit h st a n d ar d  err or  b ar s)  will  b e  cr e at e d  f or t h e o b s er v e d  p er c e nt a g e  of 
r e c o g ni z e d  w or d s  at  e a c h  si g n al-t o-n oi s e r ati o f or tr e at e d  e ar s  b y  vi sit  a n d tr e at m e nt  gr o u p 
f or s u bj e ct s  i n t h e F A S.   T h e  si g n al -t o-n oi s e  r ati o will  b e  pl ott e d  o n  t h e  x-a xi s  a n d  t h e 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
p er c e nt a g e  of  r e c o g ni z e d  w or d s  will  b e  pl ott e d  o n t h e  y -a xi s.  T h er e  will  b e  s e p ar at e li n e s 
f or e a c h  tr e at m e nt gr o u p  a n d  p o s si bl y  s e p ar at e  pl ot s  f or e a c h  vi sit.  All  tr e at m e nt gr o u p s 
a n d  vi sit s  m a y  b e  i n cl u d e d i n  a si n gl e  pl ot,  if t h e li n e s ar e  n ot  t o o cr o w d e d.  
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  f or t h e p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  will  b e 
p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 4. 4  f or s u bj e ct s  i n t h e F A S.   T h e 
c o v ari a n c e  str u ct ur e ( U N  or  A R( 1)) t h at  pr o vi d e s t h e  b e st  m o d el fit f or t h e r el ati v e  p er c e nt 
c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s,  a s  d e s cri b e d i n  S e cti o n  7. 4. 4 ,  will 
b e  i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S.   Tr e at m e nt  gr o u p  c o m p ari s o n s  will  n ot 
b e  p erf or m e d  f or e a c h  si g n al -t o-n oi s e  r ati o. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e li n e gr a p h s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 4. 3.  A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit i n  p er c e nt a g e  of 
r e c o g ni z e d w or d s  at  e a c h  si g n al -t o-n oi s e  r ati o will  b e  c o m p ut e d  a s  1 0 0*[( w/ 1 0)   – ( b/ 1 0)] 
w h er e  “ w” i s t h e fr e q u e n c y of  w or d s  r e c o g ni z e d at  t h e p o st -b a s eli n e  vi sit  a n d  “ b” i s t h e 
fr e q u e n c y  of  w or d s r e c o g ni z e d  at  b a s eli n e. T h e  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e t o 
e a c h  p o st -b a s eli n e  vi sit i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all  will  b e  c o m p ut e d  u si n g 
t h e s a m e  al g orit h m,  b ut  wit h  7 0  w or d s  i n t h e d e n o mi n at or  i n st e a d of  1 0.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  a b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e i n  p er c e nt a g e  of  r e c o g ni z e d w or d s  at  e a c h 
si g n al -t o-n oi s e r ati o  a n d  o v er all  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d 
e ar s  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 4. 1  f or  s u bj e ct s i n t h e  F A S. 
 
Li n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s)  will  b e  cr e at e d f or t h e  a dj u st e d (l e a st  s q u ar e s)  m e a n 
a b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  f or 
tr e at e d e ar s  b y  p o st -b a s eli n e  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S .  P o st - 
b a s eli n e  vi sit  will  b e  pl ott e d  o n  t h e  x-a xi s  a n d  t h e a dj u st e d  (l e a st s q u ar e s)  m e a n  a b s ol ut e 
p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  f or tr e at e d e ar s 
will  b e  pl ott e d  o n  t h e  y-a xi s.   E a c h  tr e at m e nt gr o u p  will  b e  pr e s e nt e d  a s   a s e p ar at e  li n e i n 
t h e pl ot.   T h e  li n e  gr a p h s will  b e  r e p e at e d f or t h e o b s er v e d  m e a n  a b s ol ut e  p er c e nt  c h a n g e 
fr o m b a s eli n e i n  p er c e nt a g e  of  r e c o g ni z e d  w or d s o v er all  f or tr e at e d e ar s.  
 
Tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  a b s ol ut e  p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  
of  r e c o g ni z e d w or d s  o v er all  will  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  7. 4. 4  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
f or  s u bj e ct s i n t h e  F A S. T h e  c o v ari a n c e  str u ct ur e ( U N  or  A R( 1 )) t h at  pr o vi d e s t h e  b e st  m o d el 
fit f or t h e r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all, 
a s  d e s cri b e d i n  S e cti o n  7. 4. 4 ,  will  b e i m pl e m e nt e d  wit h  a r e p e at e d  st at e m e nt i n  S A S. 
Tr e at m e nt  gr o u p  c o m p ari s o n s  will  n ot  b e  p erf or m e d f or  e a c h  si g n al -t o-n oi s e r ati o.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e li n e gr a p h s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 4. 4.  R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  t o e a c h  p o st -b a s eli n e  vi sit  i n p er c e nt a g e  of 
r e c o g ni z e d  w or d s  at  e a c h  si g n al-t o-n oi s e r ati o  will  b e  c o m p ut e d  a s  1 0 0*[( w -b)/ b]  w h er e 
“ w” i s t h e fr e q u e n c y  of w or d s r e c o g ni z e d  at t h e  p o st -b a s eli n e  vi sit  a n d “ b” i s t h e fr e q u e n c y 
of  w or d s  r e c o g ni z e d at  b a s eli n e.  T h e  r el ati v e p er c e nt  c h a n g e  fr o m b a s eli n e  t o e a c h  p o st - 
b a s eli n e  vi sit  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  will  b e  c o m p ut e d  u si n g  t h e s a m e 
al g orit h m , b ut  wit h  “ w” a n d  “ b” s c or e s  f or all  7 0  w or d s  at  e a c h  vi sit.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e r el ati v e  p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  at  e a c h  si g n al - 
t o-n oi s e r ati o  a n d  o v er all  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  a n d  u ntr e at e d  e ar s 
u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 4. 1  f or  s u bj e ct s i n t h e  F A S. 
 
L i n e  gr a p h s ( wit h  st a n d ar d  err or  b ar s) f or t h e  a dj u st e d (l e a st  s q u ar e s)  m e a n s  a n d  o b s er v e d 
m e a n s  will  b e  cr e at e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  7. 4. 3  f or s u bj e ct s  i n t h e F A S.  
 
I n tr e at e d e ar s  o nl y  f or s u bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or t h e r el ati v e 
p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all  will  b e  a n al y z e d 
u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g fi x e d  c o v ari at e s f or tr e at m e nt  gr o u p, 
W R  s c or e  at  b a s eli n e  ( < 5 0 % v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g  l os s  ( S S N H L v er s u s  NI H L), 
vi sit,  a n d  i nt er a cti o n b et w e e n  vi sit  a n d  tr e at m e nt gr o u p.   A s  d e s cri b e d  i n S e cti o n  7. 3. 4 , 
s e p ar at e  m o d el s  will  b e fit  s p e cif yi n g  U N  a n d  A R( 1)  c o v ari a n c e  str u ct ur e s  (i m pl e m e nt e d 
wit h  a r e p e at e d  st at e m e nt i n  S A S).  T h e  c o v ari a n c e  str u ct ur e  pr o vi di n g t h e l o w e st  c orr e ct e d 
AI C c  a n d  BI C  v al u e s  fr o m t h e m o d el  will  b e  i m pl e m e nt e d f or t h e r el ati v e p er c e n t c h a n g e 
fr o m b a s eli n e  a n d  all  ot h er  WI N  e n d p oi nt s.   T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will 
b e  b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all 
( e. g., T y p e  III S u m s  of  S q u ar e s).  Tr e at m e nt  gr o u p  c o m p ari s o n s  will  n ot  b e  p erf or m e d  f or 
e a c h  si g n al -t o-n oi s e  r ati o. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
Wit h  t h e e x c e pti o n  of  t h e li n e gr a p h s,  t h e a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 4. 5.  I m pr o v e m e nt > = 1 0 %  ( 7 w or d s)  i n p er c e nt a g e  of  r e c o g ni z e d w or d s  o v er all  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
I m pr o v e m e nt  > = 1 0 % i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all  at  e a c h  p o st-b a s eli n e  vi sit 
f or tr e at e d e ar s  will  b e  c o m p ut e d  a s  1 if  t h e a b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e i n 
p er c e nt a g e  of  r e c o g ni z e d  w or d s o v er all  > = 1 0 %  a n d  a s  0,  ot h er wi s e  w h er e  t h e  a b s ol ut e 
p er c e nt  c h a n g e i s  n ot  mi s si n g.  I m pr o v e m e nt  > = 1 0 % ( 7  w or d s) i n  p er c e nt a g e  of r e c o g ni z e d 
w or d s  will  n ot  b e  c o m p ut e d  f or e a c h  si g n al -t o-n oi s e  r ati o. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of i m pr o v e m e nt  > = 1 0 % i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all  at  e a c h 
p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s 
b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
I n tr e at e d e ar s  o nl y  f or  su bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or i n ci d e n c e of 
i m pr o v e m e nt  > = 1 0 % i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all  m a y  b e  a n al y z e d  u si n g  a 
g e n er ali z e d  e sti m ati n g  e q u ati o n  b a s e d  o n  t h e bi n o mi al  di stri b uti o n  wit h  l o git li n k. T h e  fi x e d 
c o v ari at e s  m a y i n cl u d e tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  
eti ol o g y  of  h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d 
tr e at m e nt gr o u p.  C o v ari at e s  f or W R  s c or e  at  b a s eli n e  a n d  eti ol o g y  of  h e ari n g  l o s s m a y   be 
dr o p p e d  if t h e m o d el  f ail s t o c o n v er g e.    A r a n d o m eff e ct  f or wit hi n -s u bj e ct,  r e p e at e d 
m e a s ur e s  v ari a bilit y  m a y  b e  i n cl u d e d.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
O d d s r ati o s,  9 5 %  CI s,  a n d  p -v al u e s  m a y  b e r e p ort e d  a n d  c o m p ari s o n s  will  b e  m a d e  b y  vi sit 
a n d  o v er all. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 4. 6.  S p e ar m a n -K är b er  e sti m at e s  of  d B t hr e s h ol d s f or  w or d r e c o g niti o n ( 2 5 t h,  5 0t h 
( m e di a n) a n d  7 5 t h p er c e ntil e s)  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  S p e ar m a n -K är b er  e sti m at e s ( 2 5 t h,  5 0t h ( m e di a n)  a n d  7 5t h p er c e ntil e s)  of  d B t hr e s h ol d s 
f or w or d  r e c o g niti o n ( Wil s o n et  al.,  1 9 7 3)  at  e a c h  vi sit  f or tr e at e d e ar s  will  b e  c o m p ut e d  a s  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
𝑅 𝑅 𝑎 𝑎 =  𝑎 𝑎 +  (𝑎 𝑎𝑠 𝑠 ∗ 𝑠 𝑠) − (𝑠 𝑠 ∗ 𝑤 𝑤)/ 𝑠 𝑠 
 
w h er e “ p c” i s t h e p er c e ntil e  of i nt er e st,  “I” i s t h e i niti al d B  pr e s e nt ati o n  l e v el (fi x e d at  2 4), 
“ d” i s t h e att e n u ati o n  d B  st e p  si z e  (fi x e d at  4),  “ c” i s t h e n u m b er  of  w or d s  p er  d e cr e m e nt 
(fi x e d  at  1 0), a n d “ w”  i s t h e fr e q u e n c y of  w or d s  r e c o g ni z e d  o v er all at  e a c h  vi sit.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
S p e ar m a n -K är b er  e sti m at e s  ( 2 5 t h,  5 0t h ( m e di a n)  a n d  7 5t h p er c e ntil e s )  will  b e  s u m m ari z e d 
d e s cri pti v el y  f or tr e at e d e ar s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
F or  e a c h  p o st -b a s eli n e  vi sit,  s c att er  pl ot s  of t h e  m e di a n  S p e ar m a n -K är b er  e sti m at e s  at 
b a s eli n e  v er s u s t h e  p o st -b a s eli n e  vi sit  will  b e  pr o d u c e d  b y tr e at m e nt  gr o u p f or  s u bj e ct s i n 
t h e  F A S. 
 
I n tr e at e d e ar s  o nl y  f or s u bj e ct s  i n t h e F A S,  tr e at m e nt gr o u p  c o m p ari s o n s  f or t h e m e di a n 
S p e ar m a n -K är b er  e sti m at e  will  b e  a n al y z e d  u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el 
u si n g fi x e d  c o v ari at e s f or tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %), 
eti ol o g y  of  h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d 
tr e at m e nt gr o u p.   T h e  c o v ari a n c e  str u ct ur e  ( U N or  A R( 1))  t h at pr o vi d e s  t h e b e st  m o d el  fit 
f or t h e r el ati v e  p er c e nt  c h a n g e fr o m  b a s eli n e i n  p er c e nt a g e  of r e c o g ni z e d  w or d s  o v er all,  a s 
d e s cri b e d  i n S e cti o n  7. 4. 4 , will  b e  i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S.  T h e 
tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e  b et w e e n  e a c h  F X -3 2 2  gr o u p  (i n cl u di n g t h e 
p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2 
gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g., 
e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all ( e. g.,  T y p e III  S u m s  of  S q u a r e s). 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 4. 7.  I m pr o v e m e nt > = 3  d B  s hift s  i n m e di a n  S p e ar m a n -K är b er  e sti m at e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
I m pr o v e m e nt  > =  3  d B  s hift s i n  m e di a n  S p e ar m a n-K är b er  e sti m at e s  at  e a c h  p o st -b a s eli n e  
vi sit f or tr e at e d  e ar s  will  b e  c o m p ut e d  a s  1 if t h e  p o st -b a s eli n e  S p e ar m a n -K är b er  e sti m at e  – 
b a s eli n e  S p e ar m a n -K är b er  e sti m at e i s  > = 3  a n d  a s  0,  ot h er wi s e  w h er e t h e  b a s eli n e  a n d  p o st - 
b a s eli n e  S p e ar m a n -K är b er  e sti m at e s  ar e  n ot  mi s si n g.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of i m pr o v e m e nt  > = 3  d B  s hift s i n  m e di a n  S p e ar m a n -K är b er  e sti m at e s  at  e a c h 
p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  
b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  3 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
Tr e at m e nt  gr o u p  c o m p ari s o n s  m a y  b e  p erf or m e d  u si n g  t h e a p pr o a c h  d e s cri b e d  i n S e cti o n  
7. 4. 5  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 4. 8.  I n ci d e n c e of  i n c orr e ct p h o n e m e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
F or  e a c h  u ni q u e  p h o n e m e, t h e  p er c e nt a g e  n ot r e c o g ni z e d  c orr e ctl y  o v er  all  si g n al -t o-n oi s e 
r ati o s will  b e  c o m p ut e d  b y  s u bj e ct,  vi sit,  a n d  e ar.  
 
P o st  h o c  e n d p oi nt s  m a y  b e  d eri v e d f or  p h o n e m e s  n ot r e c o g ni z e d  c orr e ctl y  at  e a c h  si g n al - 
t o- n oi s e r ati o. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
H e at  m a p s  will  b e  pr o d u c e d f or t h e  p er c e nt a g e  of  p h o n e m e s  n ot  r e c o g ni z e d  c orr e ctl y  b y 
vi sit  a n d tr e at m e nt  gr o u p f or tr e at e d  e ar s  u si n g t h e  s a m e  a p pr o a c h  d e s cri b e d i n  S e cti o n 
7. 3. 1 1 . 
 
H e at  m a p s  at  e a c h  si g n al -t o-n oi s e r ati o  m a y  al s o  b e  pr o d u c e d  p o st -h o c.  A d diti o n al  p o st  h o c 
a n al y s e s  m a y  b e  pr o d u c e d  o n  s el e ct  u ni q u e  p h o n e m e s  of i nt er e st,  b a s e d  o n t h e fi n al r e s ult s 
i n t h e  h e at  m a p  d e s cri b e d  a b o v e. T h e  p o st  h o c  a n al y s e s  m a y i n cl u d e  h e at  m a p s  b y  vi sit f or 
tr e at e d e ar s  al s o  t a ki n g i nt o a c c o u nt  t h e l o c ati o n of  t h e p h o n e m e  wit h  i n t h e w or d 
( p h o n e m e/l o c ati o n) f or s u bj e ct s  i n t h e F A S.  P o st  h o c  tr e at m e nt gr o u p  c o m p ari s o n s  m a y 
al s o  b e  p erf or m e d. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
N o n e.  
 
P ur e  T o n e  A u di o m etr y  
 
T h e  p ur e t o n e  a u di o m etr y t e st  will  b e  u s e d t o  d et er mi n e  a  s u bj e ct’ s t hr e s h ol d f or  h e ari n g  at 
t h e f oll o wi n g fr e q u e n ci e s tr a n s mitt e d vi a  air  a n d  b o n e:  air  t e st e d at  0. 2 5,  0. 5,  1,  2,  3,  4,  6 
a n d   8 k H z;  a n d  b o n e  t e st e d at  0. 5,  1,  2,   3 a n d   4 k H z.   If b ot h  m a s k e d  a n d  u n m a s k e d  r e s ult s 
ar e  a v ail a bl e f or t h e  s a m e  vi sit,  d at e,  e ar,  a n d fr e q u e n c y, t h e  m a s k e d r e s ult s  will  b e  u s e d f or 
a n al y si s.   T hi s  t e st will  b e  p erf or m e d  at  S cr e e ni n g,  D a y  1 5,  6 0,  9 0,  1 5 0,  a n d  2 1 0.  
 
B a s eli n e  s c or e s  f or a n al y si s   will b e  c o m p ut e d fr o m  t h e  S cr e e ni n g vi sit.   F or  m e a s ur e m e nt s 
p o st -S cr e e ni n g,  mi s si n g r e s p o n s e  v al u e s f or  a  gi v e n  fr e q u e n c y,  wit h cl a s sifi c ati o n  of “ N R”  
( n o r e s p o n s e  d u e t o  s u bj e ct  a u di o m etri c t hr e s h ol d s  gr e at er t h a n t h e  m a xi m al  c ali br at e d  d B 
of  t h e e q ui p m e nt),  will  b e  i m p ut e d u si n g  t h e m a xi m u m  d B  f or t h e a u di o m etr y  e q ui p m e nt  of 
a  gi v e n  sit e  pl u s  5  d B  a n d  cl a s sifi e d  a s  n o  si g n al  at t h at fr e q u e n c y.  Mi s si n g r e s p o n s e  v al u e s 
at  S cr e e ni n g  will  r e m ai n mi s si n g.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
7. 5. 1.  Air  a n d  B o n e  C o n d u cti o n  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s b y  fr e q u e n c y 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar (l eft, ri g ht), t h e  A C  a n d  B C  a u di o m etr y  d B  h e ari n g t hr e s h ol d s  will  b e 
r e c or d e d f or e a c h  fr e q u e n c y ( Air: 0. 2 5,  0. 5,  1,  2,  3,  4,  6,  a n d  8  k H z;  B o n e:  0. 5,  1,  2,  3,  a n d  4 
k H z).  L eft  a n d  ri g ht  e ar s will  b e  m a p p e d  t o tr e at e d  a n d u ntr e at e d  f or  a n al y si s, a s  d e s cri b e d 
i n S e cti o n  3 .  Mi s si n g  v al u e s  will  b e  i m p ut e d p er  S e cti o n  7. 5 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
S e p ar at el y f or  A C  a n d  B C, t h e  h e ari n g t hr e s h ol d  at  e a c h fr e q u e n c y  will  b e  s u m m ari z e d 
d e s cri pti v el y  f or tr e at e d a n d  u ntr e at e d  e ar s  s e p ar at el y  b y  vi sit  a n d  tr e at m e nt gr o u p  f or 
s u bj e ct s  i n t h e F A S.  
 
I n tr e at e d  e ar s  o nl y f or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or  A C  h e ari n g 
t hr e s h ol d at  e a c h  fr e q u e n c y will  b e  a n al y z e d  u si n g  s e p ar at e  mi x e d -eff e ct,  r e p e at e d 
m e a s ur e s  m o d el s  u si n g fi x e d  c o v ari at e s f or tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 % 
v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g  l o s s ( S S N H L v er s u s  NI H L),  vi sit,  a n d  i nt er a cti o n b et w e e n 
vi sit  a n d  tr e at m e nt gr o u p.   T h e  c o v ari a n c e  str u ct ur e  ( U N or  A R( 1))  t h at pr o vi d e s  t h e b e st 
m o d el  fit f or t h e P T A,  a s  d e s cri b e d  i n S e cti o n  7. 5. 5 , will  b e  i m pl e m e nt e d wit h   a r e p e at e d 
st at e m e nt i n  S A S.  T h e tr e at m e nt  gr o u p  diff er e n c e s  a n al y z e d  will  b e  b et w e e n  e a c h  F X -3 2 2 
gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n t h e 
i n di vi d u al  F X-3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  g r o u p). C o m p ari s o n s  will  b e  m a d e 
b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all ( e. g.,  T y p e III  S u m s  of 
S q u ar e s) f or  e a c h fr e q u e n c y.  T h e  a n al y si s  will  b e r e p e at e d f or  B C  h e ari n g t hr e s h ol d s.  
 
A  s c att er  pl ot  of  t h e  m e a n  A C a u di o m etr y  t hr e s h ol d s  b y fr e q u e n c y will  b e  pr e p ar e d  f or 
tr e at e d a n d  u ntr e at e d  e ar s  f or e a c h  tr e at m e nt gr o u p  wit h  li n e s c o n n e cti n g  e a c h  p oi nt.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 5. 2.  A C  a n d  B C  I m pr o v e m e nt > = 1 0  d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
A C I m pr o v e m e nt  > = 1 0  d B fr o m  b a s eli n e f or t w o  c o nti g u o u s fr e q u e n ci e s  at  e a c h  p o st - 
b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  c o m p ut e d  a s  1 if t h e  p o st -b a s eli n e t hr e s h ol d  –  b a s eli n e 
t hr e s h ol d i s  > = 1 0 d B f or  t w o  c o nti g u o u s fr e q u e n ci e s  a n d  a s 0,  ot h er wi s e.   T h e  e n d p oi nt  will 
utili z e  i m p ut e d v al u e s  p er  S e cti o n  7. 5 .  T h e  B C  I m pr o v e m e nt > = 1 0  d B  will  b e  d eri v e d  u si n g 
t h e  s a m e  a p pr o a c h. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of  A C i m pr o v e m e nt  > = 1 0  d B fr o m  b a s eli n e f or t w o  c o nti g u o u s fr e q u e n ci e s  at 
e a c h  p o st -b a s eli n e  vi sit  f or tr e at e d e ar s  will  b e  s u m m ari z e d  u si n g  fr e q u e n ci e s a n d 
p er c e nt a g e s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  T h e  s u m m ar y  will  b e 
r e p e at e d f or  B C i m pr o v e m e nt. 
 
I n tr e at e d  e ar s  o nl y f or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or i n ci d e n c e  of 
A C i m pr o v e m e nt  > = 1 0  d B fr o m  b a s eli n e f or t w o  c o nti g u o u s fr e q u e n ci e s  m a y  b e  a n al y z e d 
u si n g  a  g e n er ali z e d  e sti m ati n g  e q u a ti o n  b a s e d o n  t h e  bi n o mi al  di stri b uti o n wit h  l o git li n k. 
T h e fi x e d  c o v ari at e s  m a y i n cl u d e tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  
> = 5 0 %),  eti ol o g y  of  h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit 
a n d tr e at m e nt  gr o u p.  C o v ari at e s f or  W R  s c or e  at  b a s eli n e  a n d  eti ol o g y  of  h e ari n g l o s s  m a y 
b e  dr o p p e d  if t h e m o d el  f ail s t o c o n v er g e.    A r a n d o m eff e ct  f or wit hi n -s u bj e ct,  r e p e at e d 
m e a s ur e s  v ari a bilit y  m a y  b e  i n cl u d e d.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
O d d s r ati o s,  9 5 %  CI s,  a n d  p -v al u e s  m a y  b e r e p ort e d  a n d  c o m p ari s o n s  will  b e  m a d e  b y  vi sit  
a n d  o v er all.   T h e  a n al y si s  will  b e  r e p e at e d f or B C  i m pr o v e m e nt. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 5. 3.  A C  a n d  B C  I m pr o v e m e nt > = 1 5  d B  fr o m b a s eli n e  f or a n y  fr e q u e n c y 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
A C I m pr o v e m e nt  > = 1 5  d B fr o m  b a s eli n e f or  a n y fr e q u e n c y  at  e a c h  p o st -b a s eli n e  vi sit f or 
tr e at e d  e ar s  will  b e  c o m p ut e d  a s  1 if t h e  p o st-b a s eli n e t hr e s h ol d  –  b a s eli n e t hr e s h ol d i s  
> = 1 5  d B f or  a n y fr e q u e n c y  a n d  a s  0,  ot h er wi s e.  T h e  e n d p oi nt  will  utili z e i m p ut e d  v al u e s  p er 
S e cti o n  7. 5 . T h e  B C I m pr o v e m e nt  > = 1 5  d B  will  b e  d eri v e d  u si n g t h e  s a m e  a p pr o a c h.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of  A C i m pr o v e m e nt  > = 1 5  d B fr o m  b a s eli n e f or  a n y fr e q u e n c y  at  e a c h  p o st - 
b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  
7. 5. 2  f or s u bj e ct s  i n t h e F A S.  T h e  s u m m ar y  will  b e  r e p e at e d f or B C  i m pr o v e m e nt. 
 
Tr e at m e nt  gr o u p  c o m p ari s o n s f or  A C i m pr o v e m e nt  a n d  B C i m pr o v e m e nt  m a y  b e  p erf or m e d 
u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 5. 2  f or  s u bj e ct s i n t h e  F A S. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
7. 5. 4.  A C  a n d  B C  C o m p o sit e  I m pr o v e m e nt 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  A C  C o m p o sit e I m pr o v e m e nt  e n d p oi nt i s  d efi n e d  a s t h e  o c c urr e n c e  of  eit h er  or  b ot h  of 
t h e f oll o wi n g  c o n diti o n s f or  a  gi v e n  s u bj e ct’ s  e ar f or  a  gi v e n  vi sit:  1)  A C I m pr o v e m e nt  > = 1 0 
d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s a s  d e s cri b e d i n  S e cti o n  7. 5 . 2 or  2)  A C 
i m pr o v e m e nt > = 1 5  d B  fr o m b a s eli n e  f or a n y  fr e q u e n c y a s  d efi n e d  i n S e cti o n  7. 5. 3 .  B C 
C o m p o sit e  I m pr o v e m e nt i s d efi n e d  u si n g  t h e s a m e  a p pr o a c h.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of  A C  C o m p o sit e I m pr o v e m e nt  at  e a c h  p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will 
b e  s u m m ari z e d  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 5. 2  f or  s u bj e ct s i n t h e  F A S. T h e 
s u m m ar y  will  b e  r e p e at e d f or B C  C o m p o sit e  I m pr o v e m e nt. 
 
Tr e at m e nt  gr o u p  c o m p ari s o n s f or  A C  C o m p o sit e I m pr o v e m e nt  a n d  B C  C o m p o sit e 
I m pr o v e m e nt  m a y  b e  p erf or m e d  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n 7. 5. 2  f or  s u bj e ct s 
i n t h e  F A S. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 5. 5.  M e a n  o v er all  P T A  ( A C o v er  0. 5,  1,  2,  a n d  4  k H z)  a n d  B C A  ( B C o v er  0. 5,  1,  2  a n d  
4  k H z)  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar (l eft, ri g ht), t h e  m e a n  o v er all  P T A  will  b e  d eri v e d  b y  a v er a gi n g t h e 
A C  a u di o m etr y  d B  h e ari n g t hr e s h ol d s  o v er  0. 5,  1,  2,  a n d  4  k H z fr e q u e n ci e s.  L eft  a n d ri g ht 
e ar s  will  b e  m a p p e d  t o tr e at e d a n d  u ntr e at e d  f or a n al y si s,  a s  d e s cri b e d  i n S e cti o n  3 . 
Mi s si n g  v al u e s  will  b e  i m p ut e d p er  S e cti o n  7. 5 .  T h e  B C A  will  b e  d eri v e d  u si n g  t h e s a m e 
a p pr o a c h.  If  h e ari n g t hr e s h ol d s  ar e  mi s si n g f or  a n y  of t h e  0. 5,  1,  2,  a n d  4  k H z fr e q u e n ci e s 
( aft er i m p ut ati o n of  r e c or d s wit h  cl a s sifi c ati o n  of  “ N R”), P T A  or  B C A  will  b e  mi s si n g, 
r e s p e cti v el y. 
 
M e a n  o v er all  P T A f or  e a c h  e ar  will  b e  c at e g ori z e d i nt o  < 2 6,  2 6 -4 0,  4 1 -5 5 ,  5 6-7 0,  a n d  > 7 0 f or 
e a c h  vi sit  a n d  s hift s  fr o m b a s eli n e  t o e a c h  p o st -b a s eli n e  vi sit  will  b e  c o m p ut e d  ( e. g., 2 6 -4 0 
t o  4 1- 5 5). 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  m e a n  o v er all  P T A  will  b e  s u m m ari z e d  d e s cri pti v el y f or tr e at e d  e ar s  s e p ar at el y  b y  vi sit 
a n d tr e at m e nt  gr o u p f or  s u bj e ct s  i n t h e  F A S. T h e  s u m m ar y  will  b e r e p e at e d f or  B C A.  
 
I n tr e at e d  e ar s  o nl y f or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or  m e a n  o v er all 
P T A  will  b e  a n al y z e d  u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g fi x e d  c o v ari at e s 
f or tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g l o s s 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. A s  d e s cri b e d 
i n  S e cti o n 7. 3. 4 ,  s e p ar at e  m o d el s  will  b e fit  s p e cif yi n g  U N  a n d  A R( 1)  c o v ari a n c e  str u ct ur e s 
(i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S).   T h e  c o v ari a n c e  str u ct ur e  pr o vi di n g  t h e 
l o w e st  c orr e ct e d  AI C c  a n d  BI C  v al u e s fr o m t h e  m o d el  will b e i m pl e m e nt e d  f or t h e P T A  a n d 
all  ot h er  a u di o m etr y  e n d p oi nt s.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e  b et w e e n 
e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s 
b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  C o m p ari s o n s  
will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all ( e. g.,  T y p e III 
S u m s  of  S q u ar e s).   T h e  tr e at m e nt gr o u p  c o m p ari s o n s  will  al s o  b e  p erf or m e d  f or B C A.  
 
T h e  di stri b uti o n i n t h e  s hift i n  m e a n  o v er all  P T A  c at e g ori e s f or tr e at e d  e ar s fr o m  b a s eli n e t o 
e a c h  p o st -b a s eli n e  vi sit  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y  vi sit  a n d 
tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 5. 6.  M e a n  l o w A C  d B  h e ari n g  t hr e s h ol d ( A C o v er  0. 2 5,  0. 5,  1,  a n d  2  k H z)  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar (l eft, ri g ht), t h e  m e a n l o w  A C  d B  h e ari n g t hr e s h ol d  will  b e  d eri v e d 
b y  a v er a gi n g t h e  A C  a u di o m etr y  d B  h e ari n g t hr e s h ol d s  o v er  0. 2 5,  0. 5,  1,  a n d  2  k H z 
fr e q u e n ci e s. L eft  a n d  ri g ht e ar s  will  b e  m a p p e d  t o tre at e d  a n d  u ntr e at e d  f or a n al y si s,  a s 
d e s cri b e d  i n S e cti o n  3 . Mi s si n g  v al u e s  will  b e  i m p ut e d p er  S e cti o n  7. 5 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  m e a n l o w  A C  d B  h e ari n g t hr e s h ol d  will  b e  s u m m ari z e d  d e s cri pti v el y f or  s u bj e ct s i n t h e 
F A S  a s  d e s cri b e d i n  S e cti o n  7. 5. 5 . Tr e at m e nt  gr o u p  c o m p ari s o n s  will  al s o  b e  p erf or m e d  a s 
d e s cri b e d  i n S e cti o n  7. 5. 5 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr eat e d  a n d  u ntr e at e d  e ar  d at a.  
 
7. 5. 7.  M e a n  hi g h  A C  d B  h e ari n g  t hr e s h ol d ( A C o v er  3,  4,   6 a n d   8 k H z)  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
At  e a c h  vi sit  a n d  b y  e ar (l eft, ri g ht), t h e  m e a n  hi g h  A C  d B  h e ari n g t hr e s h ol d  will  b e  d eri v e d 
b y  a v er a gi n g t h e  A C  a u di o m etr y  d B  h e ari n g t hr e s h ol d s  o v er  3,  4,  6  a n d  8  k H z fr e q u e n ci e s. 
L eft  a n d  ri g ht e ar s  will  b e  m a p p e d  t o tr e at e d a n d  u ntr e at e d  f or a n al y si s,  a s  d e s cri b e d  i n 
S e cti o n  3 .  Mi s si n g  v al u e s  will  b e  i m p ut e d p er  S e cti o n  7. 5 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  m e a n  hi g h  A C  d B  h e ari n g t hr e s h ol d  will  b e  s u m m ari z e d  d e s cri pti v el y f or  s u bj e ct s i n t h e 
F A S  a s  d e s cri b e d i n  S e cti o n  7. 5. 5 . Tr e at m e nt  gr o u p  c o m p ari s o n s  will  al s o  b e  p erf or m e d  a s 
d e s cri b e d  i n S e cti o n  7. 5. 5 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 5. 8.  Air -B o n e  I m b al a n c e at  0. 5,  1,  2,  3,  a n d   4 k H z  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar (l eft, ri g ht),  Air -B o n e i m b al a n c e i s  c o m p ut e d  a s  A C -B C  d B  h e ari n g 
t hr e s h ol d s at  0. 5,  1,  2,  3,  a n d   4 k H z.   L eft  a n d  ri g ht e ar s  will  b e  m a p p e d  t o tr e at e d a n d 
u ntr e at e d f or  a n al y si s,  a s  d e s cri b e d i n  S e cti o n  3 . Mi s si n g t hr e s h ol d  v al u e s  will  b e i m p ut e d 
p er   S e cti o n 7. 5  pri or  t o t h e  d eri v ati o n. 
 
Air -b o n e i m b al a n c e  at  e a c h fr e q u e n c y  will  b e  c at e g ori z e d i nt o  < = 1 0  d B  v er s u s  > 1 0  d B f or 
e a c h  vi sit  a n d  s hift s fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit  will  b e  c o m p ut e d ( e. g.,  < = 1 0 
d B  t o  > 1 0  d B). 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  Air -B o n e i m b al a n c e  at  e a c h fr e q u e n c y  ( 0. 5, 1,  2,  3,  a n d  4  k H z)  will  b e  s u m m ari z e d 
d e s cri pti v el y  f or tr e at e d e ar s  b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
T h e  di stri b uti o n  i n t h e s hift  i n air -b o n e  i m b al a n c e f or tr e at e d e ar s  at  e a c h  fr e q u e n c y fr o m 
b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s 
b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
7. 5. 9.  C o m p o sit e  W R,  WI N  a n d  P ur e  T o n e  A u di o m etr y  E n d p oi nt  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  c o m p o sit e  e n d p oi nt  will  b e  a s s e s s e d i n tr e at e d  e ar s  a n d  d efi n e d  a s  si m ult a n e o u sl y 
m e eti n g  b ot h  of  t h e f oll o wi n g c o n diti o n s  at  a n y  vi sit  ( D a y 9 0  or  2 1 0):  
 
o  A  p o st -b a s eli n e  > = 1 0 %  W R  i m pr o v e m e nt O R   a > = 1 0 %  WI N  i m pr o v e m e nt, a n d  
 
o  A  p o st -b a s eli n e  1 0  d B i m pr o v e m e nt i n  2  c o nti g u o u s fr e q u e n ci e s  or  a  p o st -b a s eli n e 
1 5  d B  i m pr o v e m e nt i n  a n y fr e q u e n c y f or A C  t hr e s h ol d s 
 
P o st -b a s eli n e  > = 1 0 %  W R i m pr o v e m e nt i s  d efi n e d i n  S e cti o n  7. 3. 5  a n d  > = 1 0 %  WI N 
i m pr o v e m e nt i s d efi n e d  i n S e cti o n  7. 4. 5 . P o st -b a s eli n e  > =  1 0  d B  i m pr o v e m e nt i n 2 
c o nti g u o u s fr e q u e n ci e s f or  A C t hr e s h ol d s i s  d efi n e d i n  S e cti o n  7. 5. 2  a n d  p o st -b a s eli n e  > =  1 5 
d B  i n a n y  fr e q u e n c y f or A C  t hr e s h ol d s i s d efi n e d  i n S e cti o n  7. 5. 3 . 
 
T h e  c o m p o sit e  e n d p oi nt  will  b e  c o m p ut e d  a s  1 if  b ot h  c o n diti o n s  ar e  m et  i n t h e tr e at e d  e ar 
at t h e  s a m e  vi sit f or  a n y  of t h e  p o st -b a s eli n e  vi sit s ( D a y  9 0  a n d  2 1 0)  a n d  a s  0,  ot h er wi s e.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  i n ci d e n c e of  t h e c o m p o sit e  W R,  WI N  a n d  p ur e  t o n e a u di o m etr y  e n d p oi nt  f or tr e at e d 
e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y tr e at m e nt  gr o u p f or  s u bj e ct s 
i n t h e  F A S. 
 
I n tr e at e d  e ar s  o nl y f or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  c o m p o sit e 
e n d p oi nt  will  b e  a n al y z e d  u si n g  a l o gi sti c r e gr e s si o n  m o d el.  T h e fi x e d  c o v ari at e s  will i n cl u d e 
tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  a n d  eti ol o g y  of  h e ari n g l o s s 
( S S N H L  v er s u s  NI H L). T h e tr e at m e nt  gr o u p  diff er e n c e s  a n al y z e d  will  b e  b et w e e n  e a c h  F X - 
3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n 
t h e i n di vi d u al  F X-3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  O d d s r ati o s, t h eir  9 5 % 
CI s,  a n d   p-v al u e s  will  b e  r e p ort e d. 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
E xt e n d e d  Hi g h  Fr e q u e n c y  A u di o m etr y  
 
E H F A  will  b e  p erf or m e d t o  d et er mi n e  a  s u bj e ct’ s t hr e s h ol d  d B f or  h e ari n g  at fr e q u e n ci e s 
b e y o n d  t h o s e i n st a n d ar d  p ur e  t o n e a u di o m etr y.   O v er -air  fr e q u e n ci e s u s e d  ( n o b o n e 
t e sti n g) ar e  9,  1 0,  1 1. 2,  1 2. 4,  1 4,  a n d  1 6  k H z.   If b ot h  m a s k e d  a n d  u n m a s k e d  r e s ult s ar e 
a v ail a bl e f or t h e  s a m e  vi sit,  d at e,  e ar,  a n d fr e q u e n c y, t h e  m a s k e d r e s ult s  will  b e  u s e d f or 
a n al y si s.   T hi s  t e st will  b e  p erf or m e d  at  S cr e e ni n g,  D a y  1 5,  6 0,  9 0,  1 5 0,  a n d  2 1 0.  
 
B a s eli n e  s c or e s  f or a n al y si s  will  b e  c o m p ut e d fr o m  t h e  S cr e e ni n g vi sit.   F or  m e a s ur e m e nt s 
p o st -S cr e e ni n g,  mi s si n g r e s p o n s e  v al u e s f or  a  gi v e n fr e q u e n c y  wit h  cl a s sifi c ati o n  of “ N R” ( n o  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
r e s p o n s e d u e  t o s u bj e ct  a u di o m etri c  t hr e s h ol d s gr e at er  t h a n t h e m a xi m al  c ali br at e d  d B  of 
t h e e q ui p m e nt),  will  b e  i m p ut e d u si n g  t h e m a xi m u m  d B  f or t h e a u di o m etr y  e q ui p m e nt  of  a 
gi v e n  sit e  pl u s  5  d B  a n d  cl a s sifi e d  a s  n o  si g n al  at t h at  fr e q u e n c y. Mi s si n g r e s p o n s e  v al u e s  at 
S cr e e ni n g  will  r e m ai n mi s si n g.  
 
7. 6. 1.  Air  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s b y  fr e q u e n c y 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar  (l eft, ri g ht), t h e A C  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s will  b e 
r e c or d e d f or e a c h  fr e q u e n c y ( 9, 1 0,  1 1. 2,  1 2. 4,  1 4,  a n d  1 6  k H z).  L eft  a n d  ri g ht e ar s  will  b e 
m a p p e d t o tr e at e d  a n d  u ntr e at e d f or  a n al y si s,  a s  d e s cri b e d i n  S e cti o n  3 . Mi s si n g  v al u e s  will 
b e  i m p ut e d p er   S e cti o n 7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s, tr e at m e nt  gr o u p  c o m p ari s o n s,  a n d t h e  s c att er  pl ot  will  b e 
p erf or m e d  f or A C  a u di o m etr y  d B  h e ari n g  t hr e s h ol d s a s  d e s cri b e d  i n S e cti o n  7. 5. 1 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 6. 2.  A C  I m pr o v e m e nt > = 1 0  d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
A C I m pr o v e m e nt  > = 1 0  d B fr o m  b a s eli n e f or t w o  c o nti g u o u s fr e q u e n ci e s  at  e a c h  p o st - 
b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  c o m p ut e d  a s  1 if t h e  p o st -b a s eli n e t hr e s h ol d  –  b a s eli n e 
t hr e s h ol d i s  > = 1 0 d B f or  t w o  c o nti g u o u s fr e q u e n ci e s  a n d  a s 0,  ot h er wi s e.   T h e  e n d p oi nt  will 
utili z e  i m p ut e d v al u e s  p er  S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s  a n d tr e at m e nt  gr o u p  c o m p ari s o n s  m a y  b e  p erf or m e d f or  A C 
i m pr o v e m e nt  > = 1 0  d B fr o m  b a s eli n e f or t w o  c o nti g u o u s fr e q u e n ci e s  a s  d e s cri b e d i n  S e cti o n 
7. 5. 2 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 6. 3.  A C  I m pr o v e m e nt > = 1 5  d B  fr o m b a s eli n e  f or a n y  fr e q u e n c y 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
A C I m pr o v e m e nt  > = 1 5  d B fr o m  b a s eli n e f or  a n y fr e q u e n c y  at  e a c h  p o st -b a s eli n e  vi sit f or 
tr e at e d  e ar s  will  b e  c o m p ut e d  a s  1 if t h e  p o st-b a s eli n e t hr e s h ol d  –  b a s eli n e t hr e s h ol d i s  
> = 1 5  d B f or  a n y fr e q u e n c y  a n d  a s  0,  ot h er wi s e.  T h e  e n d p oi nt  will  utili z e i m p ut e d  v al u e s  p er 
S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s  a n d tr e at m e nt  gr o u p  c o m p ari s o n s  m a y  b e  p erf or m e d f or  A C 
i m pr o v e m e nt  > = 1 5  d B fr o m  b a s eli n e f or  a n y fr e q u e n c y  a s  d e s cri b e d i n  S e cti o n 7. 5. 3 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 6. 4.  A C  C o m p o sit e  I m pr o v e m e nt 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  A C  C o m p o sit e I m pr o v e m e nt  e n d p oi nt i s  d efi n e d  a s t h e  o c c urr e n c e  of  eit h er  or  b ot h  of 
t h e f oll o wi n g  c o n diti o n s f or  a  gi v e n  s u bj e ct’ s  e ar f or  a  gi v e n  vi sit:  1)  A C I m pr o v e m e nt  > = 1 0 
d B  fr o m b a s eli n e  f or t w o c o nti g u o u s  fr e q u e n ci e s a s  d e s cri b e d i n  S e cti o n  7. 6 . 2  or  2)  A C 
i m pr o v e m e nt  > = 1 5  d B fr o m  b a s eli n e f or  a n y fr e q u e n c y  a s  d efi n e d i n  S e cti o n 7. 6. 3 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e i n ci d e n c e  of  A C  C o m p o sit e I m pr o v e m e nt  at  e a c h  p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will 
b e  s u m m ari z e d  u si n g t h e  a p pr o a c h  d e s cri b e d i n  S e cti o n  7. 6. 2  f or  s u bj e ct s i n t h e  F A S. 
 
D e s cri pti v e  s u m m ari e s  a n d tr e at m e nt  gr o u p  c o m p ari s o n s  m a y  b e  p erf or m e d f or  A C 
C o m p o sit e  I m pr o v e m e nt a s  d e s cri b e d  i n S e cti o n  7. 5. 4 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 6. 5.  M e a n  d B  h e ari n g  t hr e s h ol d ( A C o v er  9- 1 6  k H z)  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit  a n d  b y  e ar  (l eft, ri g ht), t h e m e a n  d B  h e ari n g  t hr e s h ol d  will b e  d eri v e d  b y 
a v er a gi n g t h e  A C  a u di o m etr y  d B  h e ari n g t hr e s h ol d s  o v er  9 -1 6  k H z fr e q u e n ci e s.  L eft  a n d 
ri g ht  e ar s  will  b e  m a p p e d t o tr e at e d  a n d  u ntr e at e d f or  a n al y si s,  a s  d e s cri b e d i n  S e cti o n 3 . 
Mi s si n g  v al u e s  will  b e  i m p ut e d p er  S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s  a n d tr e at m e nt  gr o u p  c o m p ari s o n s  will  b e  p erf or m e d f or  m e a n  d B  
h e ari n g  t hr e s h ol d a s  d e s cri b e d  i n S e cti o n  7. 5. 5 . 
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
If t h er e  ar e  a n y d o si n g  a d mi ni str ati o n s  err or s  s u c h  t h at  a  n ot q u alifi e d  e ar i s  tr e at e d, t h e 
d e s cri pti v e  s u m m ari e s  b y tr e at e d  a n d  u ntr e at e d  e ar s  will  b e  r e p e at e d f or  s u bj e ct s i n t h e 
F A S  i n cl u di n g all  tr e at e d a n d  u ntr e at e d  e ar  d at a.  
 
7. 6. 6.  S hift  fr o m n o  si g n al  t o a n y  si g n al  b y  fr e q u e n c y 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
F or  e a c h fr e q u e n c y,  s hift s fr o m  n o  si g n al t o  a n y  si g n al  will  b e  c o m p ut e d i n  s u bj e ct s i n t h e 
F A S  wit h  n o  si g n al ( mi s si n g/i m p ut e d  h e ari n g r e s p o n s e)  at  b a s eli n e i n t h e tr e at e d  e ar.  At 
e a c h  p o st -b a s eli n e  vi sit,  s u bj e ct s  wit h  a n y  si g n al  ( a n y n o n -mi s si n g/ n ot  i m put e d  h e ari n g 
r e s p o n s e) i n t h e tr e at e d e ar  will  b e  fl a g g e d a s   1 a n d  a s  0,  ot h er wi s e.   T h e  e n d p oi nt  will 
utili z e  i m p ut e d v al u e s  p er  S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
F or  e a c h fr e q u e n c y, t h e i n ci d e n c e  of  s hift s fr o m  n o  si g n al  at  b a s eli n e t o  a n y  si g n al  at  e a c h 
p o st -b a s eli n e  vi sit f or tr e at e d  e ar s  will  b e  s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s 
b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  wit h  n o  si g n al  at  b a s eli n e  i n th e  F A S.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
7. 6. 7.  S hift  fr o m n o  si g n al  t o a n y  si g n al  i n t w o c o nti g u o u s  fr e q u e n ci e s 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
S hift s  fr o m n o  si g n al  i n t w o c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  t o a n y  si g n al  i n t w o 
c o nti g u o u s  fr e q u e n ci e s  at  e a c h  p o st-b a s eli n e  vi sit  will  b e  c o m p ut e d i n  s u bj e ct s i n t h e  F A S 
wit h  n o  si g n al  ( mi s si n g/i m p ut e d h e ari n g r e s p o n s e)  at  b a s eli n e i n  t h e tr e at e d  e ar f or  a n y t w o 
c o nti g u o u s  fr e q u e n ci e s. At  e a c h  p o st -b a s eli n e  vi sit,  s u bj e ct s  wit h  a n y  si g n al  ( a n y n o n - 
mi s si n g/ n ot i m p ut e d  h e ari n g r e s p o n s e) i n t h e  tr e at e d  e ar at t h e  s a m e  t w o c o nti g u o u s 
fr e q u e n ci e s will  b e  fl a g g e d a s   1 a n d  a s  0,  ot h er wi s e.   T h e  e n d p oi nt  will  utili z e  i m p ut e d 
v al u e s  p er  S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  i n ci d e n c e of  s hift s  fr o m n o  si g n al  i n t w o c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  t o a n y 
si g n al  i n t w o c o nti g u o u s  fr e q u e n ci e s at  e a c h  p o st -b a s eli n e  vi sit  f or tr e at e d e ar s  will  b e 
s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y  vi sit  a n d tr e at m e nt  gr o u p f or  s u bj e ct s i n 
t h e F A S  wit h  n o  si g n al  i n a n y  t w o c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  i n t h e tr e at e d e ar.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S  
 
7. 6. 8.  S hift  fr o m n o  si g n al  t o a n y  si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  4 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
S hift s  fr o m n o  si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  t o a n y  si g n al  i n t hr e e 
c o nti g u o u s  fr e q u e n ci e s  at  e a c h  p o st-b a s eli n e  vi sit  will  b e  c o m p ut e d i n  s u bj e ct s i n t h e  F A S 
wit h  n o  si g n al  ( mi s si n g/i m p ut e d h e ari n g  r e s p o n s e) at  b a s eli n e  i n t h e tr e at e d  e ar f or a n y 
t hr e e  c o nti g u o u s fr e q u e n ci e s. At  e a c h  p o st -b a s eli n e  vi sit,  s u bj e ct s  wit h  a n y  si g n al ( a n y  n o n - 
mi s si n g/ n ot i m p ut e d  h e ari n g  r e s p o n s e) i n t h e tr e at e d e ar  i n t h e  s a m e t hr e e  c o nti g u o u s 
fr e q u e n ci e s will  b e  fl a g g e d a s   1 a n d  a s  0,  ot h er wi s e.   T h e  e n d p oi nt  will  utili z e  i m p ut e d 
v al u e s  p er  S e cti o n  7. 6 . 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  i n ci d e n c e of  s hift s  fr o m n o  si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  t o a n y 
si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s at  e a c h  p o st -b a s eli n e  vi sit  f or tr e at e d e ar s  will  b e 
s u m m ari z e d  u si n g fr e q u e n ci e s  a n d  p er c e nt a g e s  b y  vi sit  a n d tr e at m e nt  gr o u p f or  s u bj e ct s i n 
t h e F A S  wit h  n o  si g n al  i n t hr e e c o nti g u o u s  fr e q u e n ci e s at  b a s eli n e  i n t h e tr e at e d e ar.  
 
• 
S e n siti vit y  A n al y s e s  of  t h e E n d p oi nt  
T h e  a n al y s e s  will  b e  r e p e at e d f or s u bj e ct s  i n t h e P P A S.  
 
Ti n nit u s  F u n cti o n al  I n d e x 
 
T h e  T FI  i s  a 2 5 -it e m q u e sti o n n air e  t h at c a n  b e  u s e d t o  q u a ntif y  t h e tr e at m e nt-r el at e d 
c h a n g e i n ti n nit u s.  T h e  T FI i n cl u d e s i n di vi d u al it e m  s c or e s,  a  t ot al  s c or e,  a n d  ei g ht  s u b s c al e s 
a d dr e s si n g:   t h e i ntr u si v e n e s s of  ti n nit u s, t h e s e n s e  of  c o ntr ol  t h e p ati e nt  h a s,  c o g niti v e 
i nt erf er e n c e, sl e e p  di st ur b a n c e,  a u dit or y  i s s u e s, r el a x ati o n i s s u e s, q u alit y  of  lif e, a n d 
e m oti o n al  di str e s s.   All  i n str u m e nt it e m s, e x c e pt  it e m s  1 a n d  3,  ar e  o n  a n  i n v ert e d  0-1 0 
s c al e  wit h   0 b ei n g  m o st  f a v or a bl e a n d  1 0  b ei n g  l e a st f a v or a bl e. It e m s  1 a n d   3 ar e  o n  a n 
i n v ert e d  0 % t o  1 0 0 %  s c al e  wit h  0 %  b ei n g  m o st f a v or a bl e  a n d  1 0 0 %  b ei n g l e a st f a v or a bl e. 
T h e  t ot al s c or e  a n d i n di vi d u al  s u b s c al e  s c or e s  ar e  t h e a v er a g e  it e m r e s p o n s e ( all s u b s c al e s 
c o n si st  of   3 or   4 it e m s) t h at i s t h e n s c al e d  t o  0-1 0 0.   D et ail e d  s c ori n g  i n stru cti o n s  ar e  i n 
S e cti o n  1 4. 3 .  T h e  s u bj e ct  will  c o m pl et e  t h e i n str u m e nt ( eit h er dir e ctl y  o nt o  t h e 
q u e sti o n n air e  i n p er s o n,  vi a  w e b,  or  o v er  t h e p h o n e)  at  t h e D a y  1,  6 0,  1 2 0,  a n d  2 1 0  vi sit s.  
 
B a s eli n e  s c or e s  f or a n al y si s  will  b e  c o m p ut e d  fr o m t h e D a y   1 vi sit.   N o  i m p ut ati o n will  b e 
p erf or m e d f or  mi s si n g  d at a  a n d  S e cti o n  1 4. 3  pr o vi d e s f urt h er  d et ail r e g ar di n g t h e i m p a ct  of  
mi s si n g  d at a  o n  T FI  s c or e s.  N o  s e n siti vit y  a n al y s e s  will  b e  p erf or m e d f or t h e  T FI  e n d p oi nt s.  
 
7. 7. 1.  M e a n  t ot al s c or e,  i n di vi d u al s u b s c al e  s c or e s,  a n d  l o u d n e s s s c or e  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit, t h e  m e a n t ot al  T FI  s c or e  a n d i n di vi d u al  s u b s c al e  s c or e s  will  b e  c o m p ut e d  p er 
S e ct i o n 1 4. 3 . T h e  l o u d n e s s s c or e  will  b e  t h e r e s p o n s e fr o m it e m 2.  
 
• 
A n al y si s  of  t h e E n d p oi nt  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T h e  m e a n  t ot al T FI  s c or e,  i n di vi d u al s u b s c al e  s c or e s,  a n d l o u d n e s s  s c or e  will  b e  s u m m ari z e d 
d e s cri pti v el y  b y  vi sit  a n d  tr e at m e nt  gr o u p f or s u bj e ct s  i n t h e  F A S. 
 
F or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  m e a n t ot al  T FI  s c or e  will  b e 
a n al y z e d  u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g  fi x e d  c o v ari at e s f or 
tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g l o s s 
( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. A s  d e s cri b e d 
i n  S e cti o n 7. 3. 4 ,  s e p ar at e  m o d el s  will  b e fit  s p e cif yi n g  U N  a n d  A R( 1)  c o v ari a n c e  str u ct ur e s 
(i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S).   T h e  c o v ari a n c e  str u ct ur e  pr o vi di n g  t h e 
l o w e st c orr e ct e d  AI C c  a n d  BI C  v al u e s  fr o m t h e m o d el  will  b e  i m pl e m e nt e d f or t h e T FI  t ot al 
s c or e  a n d  all  ot h er  T FI  e n d p oi nt s.   T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v e r all 
( e. g.,  T y p e III  S u m s  of  S q u ar e s). T h e  a n al y si s  will  b e r e p e at e d f or t h e l o u d n e s s  s c or e.  
 
7. 7. 2.  C h a n g e fr o m  b a s eli n e i n  m e a n t ot al  s c or e, i n di vi d u al  s u b s c al e  s c or e s,  a n d 
l o u d n e s s  s c or e 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  c h a n g e fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit  will  b e  c o m p ut e d  a s  w  –  b  w h er e “ w” i s 
t h e p o st -b a s eli n e  s c or e  a n d “ b”  i s t h e  s c or e  at  b a s eli n e. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  c h a n g e  fr o m  b a s eli n e t o e a c h  p o st -b a s eli n e  vi sit i n  m e a n t ot al  T FI  s c or e, i n di vi d u al 
s u b s c al e  s c or e s,  a n d l o u d n e s s  s c or e  will  b e  s u m m ari z e d  d e s cri pti v el y  b y  vi sit  a n d tr e at m e nt 
gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
F or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  c h a n g e fr o m  b a s eli n e i n  m e a n 
t ot al  T FI  s c or e  will  b e  a n al y z e d  u si n g  a  mi x e d-eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g fi x e d 
c o v ari at e s f or tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti ol o g y  of 
h e ari n g l o s s ( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. 
T h e  c o v ari a n c e  str u ct ur e  ( U N or  A R( 1))  t h at pr o vi d e s  t h e b e st  m o d el  fit f or t h e T FI  t ot al 
s c or e,  a s  d e s cri b e d i n  S e cti o n  7. 7. 1 ,  will  b e i m pl e m e nt e d  wit h  a r e p e at e d  st at e m e nt i n  S A S. 
T h e tr e at m e nt  gr o u p  diff er e n c e s  a n al y z e d  will  b e  b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e 
p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d  c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2 
gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g., 
e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all ( e. g.,  T y p e III  S u m s  of  S q u ar e s).  T h e 
a n al y si s  will  b e  r e p e at e d f or t h e l o u d n e s s s c or e.  
 
C orr el ati o n  a n al y s e s  b et w e e n t h e  m e a n  c h a n g e fr o m  b a s eli n e i n t ot al  T FI  s c or e, i n di vi d u al 
s u b s c al e  s c or e s,  a n d  t h e l o u d n e s s s c or e  v er s u s  t h e f oll o wi n g W R,  WI N  a n d  P T A  c o nti n u o u s 
e n d p oi nt s  f or tr e at e d e ar s  will  b e  p erf or m e d  f or s u bj e ct s  i n t h e F A S:  
 
• W R:  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
o  P er c e nt a g e  of  r e c o g ni z e d w or d s  ( S e cti o n 7. 3. 2 ) 
o  A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n w or d  r e c o g niti o n ( S e cti o n 7. 3. 3 ) 
o  R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n w or d  r e c o g niti o n ( S e cti o n 7. 3. 4 ) 
o  Ar c si n e -tr a n sf or m e d w or d  r e c o g niti o n ( S e cti o n 7. 3. 6 ) 
• WI N:  
o  P er c e nt a g e  of  r e c o g ni z e d w or d s  ( S e cti o n 7. 4. 2 ) 
o  A b s ol ut e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n w or d  r e c o g niti o n ( S e cti o n 7. 4. 3 ) 
o  R el ati v e  p er c e nt  c h a n g e  fr o m b a s eli n e  i n w or d  r e c o g niti o n ( S e cti o n 7. 4. 4 ) 
o  M e di a n  S p e ar m a n -K är b er  e sti m at e s  of  d B t hr e s h ol d s f or  w or d r e c o g niti o n 
( S e cti o n 7. 4. 6 ) 
• P T A:  
o  M e a n  o v er all  P T A  ( A C o v er  0. 5,  1,  2,  a n d   4 k H z)  ( S e cti o n 7. 5. 5 ) 
P e ar s o n  c orr el ati o n  c o effi ci e nt s f or t h e  s p e cifi e d  c orr el ati o n s  will  b e  s u m m ari z e d  b y  vi sit 
a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
S c att er  pl ot s  will  al s o  b e  u s e d t o  di s pl a y t h e  c orr el ati o n s.  T h e  c h a n g e fr o m  b a s eli n e i n  T FI 
s c or e  (t ot al, s u b s c al e,   or l o u d n e s s) will  b e  pl ott e d  o n  t h e  x-a xi s  a n d  t h e effi c a c y  e n d p oi nt 
( W R,  WI N,  P T A) f or tr e at e d  e ar s  will  b e  pl ott e d  o n t h e  y-a xi s,  wit h  a  s e p ar at e  pl ot f or  e a c h 
p o st -b a s eli n e  vi sit.  Tr e at m e nt  gr o u p s  will  b e  diff er e nti at e d  u si n g  diff er e nt  s y m b ol s.  
 
P o st  h o c  c orr el ati o n  a n al y s e s  m a y  b e  p erf or m e d  o n  s el e ct  q u alit ati v e  W R,  WI N  a n d  P T A 
e n d p oi nt s  of i nt er e st. 
 
H e ari n g  H a n di c a p  I n v e nt or y f or A d ult s  
 
T h e  H HI A i s  a  2 5 -it e m  s elf-a s s e s s m e nt  s c al e s  c o m p o s e d  of t w o  s u b s c al e s ( 1 3 it e m s f or 
E m oti o n al  a n d  1 2 it e m s  f or  S o ci al/ Sit u ati o n al). All it e m s  ar e  o n  a  3 -l e v el  s c al e  of  0 t o  4 ( N o 
=  0,  S o m eti m e s  =  2,  Y e s  =  4).  T h e t ot al  a n d  s u b s c al e  s c or e s r a n g e fr o m  0 ( n o  h a n di c a p) t o 
1 0 0  (t ot al h a n di c a p)  a n d  will  b e  c o m p ut e d  a s  t h e s u m  of  it e m r e s p o n s e s c or e s  f or e a c h 
s c al e  di vi d e d  b y t h e  m a xi m u m  p o s si bl e  s c or e f or t h e  s c al e.  T h e t ot al  a n d  s u b s c al e  s c or e s  
will  b e  mi s si n g  if a n y  it e m r e s p o n s e s c or e s  ar e  mi s si n g.   T h e  s u bj e ct  will  c o m pl et e  t h e 
a s s e s s m e nt ( eit h er  dir e ctl y  o nt o t h e  q u e sti o n n air e i n  p er s o n,  vi a  w e b,  or  o v er t h e  p h o n e)  at  
t h e D a y  1,  6 0,  1 2 0,  a n d  2 1 0  vi sit s.  
 
B a s eli n e  s c or e s f or  a n al y si s  will  b e  c o m p ut e d fr o m t h e  D a y  1  vi sit.  N o i m p ut ati o n  will  b e 
p erf or m e d  f or mi s si n g  d at a  a n d  n o  s e n siti vit y  a n al y s e s  will  b e  p erf or m e d  f or t h e H HI A 
e n d p oi nt s.  
 
7. 8. 1.  M e a n  t ot al s c or e  a n d  i n di vi d u al s u b s c al e  s c or e s  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit, t h e  m e a n t ot al  H HI A  s c or e  will  b e  c o m p ut e d  a s t h e  s u m  of  all it e m r e s p o n s e s 
a n d  di vi d e d  b y  1 0 0.  T h e  E m oti o n al  a n d  S o ci al/ Sit u ati o n al  s c or e s  will  b e  t h e s u m  of  all 
s u b s c al e it e m s,  di vi d e d  b y t h e  m a xi m u m  p o s si bl e  s c or e ( 5 2 f or  E m oti o n al  a n d  4 8 f or 
S o ci al/ Sit u ati o n al).  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  m e a n t ot al  H HI A  s c or e  a n d i n di vi d u al  s u b s c al e  s c or e s  will  b e  s u m m ari z e d  d e s cri pti v el y 
b y  vi sit  a n d  tr e at m e nt gr o u p  f or s u bj e ct s  i n t h e F A S.  
 
F or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  m e a n t ot al  H HI A  s c or e  will  b e 
a n al y z e d  u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g fi x e d  c o v ari at e s f or  
tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g l o s s 
( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. A s  d e s cri b e d 
i n  S e cti o n 7. 3. 4 ,  s e p ar at e  m o d el s  will  b e fit  s p e cif yi n g  U N  a n d  A R( 1)  c o v ari a n c e str u ct ur e s 
(i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S).   T h e  c o v ari a n c e  str u ct ur e  pr o vi di n g  t h e 
l o w e st c orr e ct e d  AI C c  a n d  BI C  v al u e s  fr o m t h e m o d el  will  b e  i m pl e m e nt e d f or t h e H HI A 
t ot al s c or e  a n d  all  ot h er  H HI A  e n d p oi nt s.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v er all 
( e. g., T y p e  III S u m s  of  S q u ar e s).  T h e  a n al y si s  will  b e  r e p e at e d f or e a c h  H HI A  s u b s c al e  s c or e.  
 
7. 8. 2.  C h a n g e  fr o m b a s eli n e  i n m e a n  t ot al s c or e  a n d  i n di vi d u al s u b s c al e  s c o r e s 
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  c h a n g e fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit  will  b e  c o m p ut e d  a s  w  –  b  w h er e “ w” i s 
t h e p o st -b a s eli n e  s c or e  a n d “ b”  i s t h e  s c or e  at  b a s eli n e. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s,  tr e at m e nt gr o u p  c o m p ari s o n s,  a n d  c orr el ati o n  a n al y s e s  will  b e 
p erf or m e d f or  c h a n g e fr o m  b a s eli n e i n  m e a n t ot al  H HI A  s c or e  a n d  c h a n g e fr o m  b a s eli n e i n 
m e a n  H HI A  s u b s c al e  s c or e s  a s  d e s cri b e d i n  S e cti o n  7. 7. 2 . T h e  c o v ari a n c e  str u ct ur e 
i d e ntifi e d i n S e cti o n  7. 8. 1  will  b e  utili z e d.  
 
H e ari n g  S cr e e ni n g  I n v e nt or y 
 
T h e  H SI i s  a  1 2 -it e m  q u e sti o n n air e  a s s e s si n g h e ari n g i m p air m e nt.  It e m s 1 t o  8  ar e  s c or e d  o n 
a  5 -p oi nt  or di n al  s c al e:  N e v er  =  1,  S el d o m,  O c c a si o n all y,  Fr e q u e ntl y,  a n d  Al w a y s  =  5.  It e m s 
9 t o  1 2  ar e  o n  diff er e nt   5-p oi n t  s c al e:  G o o d   = 1,  A v er a g e,  Sli g htl y  B el o w  A v er a g e,  P o or, 
V er y  P o or  =  5.  T h e t ot al  s c or e i s  o n  a  0 t o  6 0  s c al e  a n d i s  t h e  s u m  of  all  1 2 r e s p o n s e  s c or e s, 
wit h it e m s  2,  3,  4,  7,  a n d  8  b ei n g r e v er s e -s c or e d (i n v ert e d).  T h e t ot al  s c or e  will  b e  mi s si n g if 
a n y it e m r e s p o n s e  s c or e s  ar e  mi s si n g.  L o w er  s c or e s  ar e f a v or a bl e  a n d  hi g h er  s c or e s  ar e 
u nf a v or a bl e.  T h e  H SI i s  d e si g n e d t o  a s s e s s  s u bj e cti v e  c h a n g e  d uri n g t h e  st u d y  a n d  will  b e 
gi v e n  t o t h e s u bj e ct  t o c o m pl et e  at  t h e D a y   1 a n d  2 1 0  vi sit s.  
 
B a s eli n e  s c or e s f or  a n al y si s  will  b e  c o m p ut e d fr o m t h e  D a y  1  vi sit.  N o i m p ut ati o n  will  b e 
p erf or m e d  f or mi s si n g  d at a  a n d  n o  s e n siti vit y  a n al y s e s  will  b e  p erf or m e d  f or t h e H SI 
e n d p oi nt s.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
7. 9. 1.  M e a n  t ot al s c or e  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
At  e a c h  vi sit,  t h e  m e a n t ot al  H SI s c or e  will  b e  c o m p ut e d  a s t h e  s u m  of  all  1 2  r e s p o n s e s 
s c or e s.  It e m s  1,  5,  6,  9,  1 0,  1 1,  a n d  1 2  will  m ai nt ai n t h e  ori gi n al  5-p oi nt  s c ori n g  a n d it e m s  2,  
3,  4,  7,  a n d  8  will  b e  r e v er s e-s c or e d  (i n v ert e d). T h e  t ot al s c or e  i s o n  a  0  t o 6 0  s c al e.  
 
• 
A n al y si s  of  t h e E n d p oi nt  
T h e  m e a n t ot al  H SI  s c or e  will  b e  s u m m ari z e d  d e s cri pti v el y  b y  vi sit  a n d tr e at m e nt  gr o u p f or 
s u bj e ct s  i n t h e F A S.  
 
F or  s u bj e ct s i n t h e  F A S, tr e at m e nt  gr o u p  c o m p ari s o n s f or t h e  m e a n t ot al  H SI  s c or e  will  b e 
a n al y z e d  u si n g  a  mi x e d -eff e ct, r e p e at e d  m e a s ur e s  m o d el  u si n g fi x e d  c o v ari at e s f or  
tr e at m e nt  gr o u p,  W R  s c or e  at  b a s eli n e ( < 5 0 %  v er s u s  > = 5 0 %),  eti ol o g y  of  h e ari n g l o s s 
( S S N H L  v er s u s  NI H L),  vi sit,  a n d i nt er a cti o n  b et w e e n  vi sit  a n d tr e at m e nt  gr o u p. A s  d e s cri b e d 
i n  S e cti o n 7. 3. 4 ,  s e p ar at e  m o d el s  will  b e fit  s p e cif yi n g  U N  a n d  A R( 1)  c o v ari a n c e  str u ct ur e s 
(i m pl e m e nt e d wit h   a r e p e at e d st at e m e nt  i n S A S).   T h e  c o v ari a n c e  str u ct ur e  pr o vi di n g  t h e 
l o w e st  c orr e ct e d  AI C c  a n d  BI C  v al u e s fr o m t h e  m o d el  will  b e i m pl e m e nt e d f or t h e  H SI t ot al 
s c or e  a n d  all  ot h er  H SI  e n d p oi nt s.  T h e  tr e at m e nt gr o u p  diff er e n c e s  a n al y z e d  will  b e 
b et w e e n  e a c h  F X -3 2 2  gr o u p (i n cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p)  v er s u s  pl a c e b o,  a n d 
c o m p ari s o n s  b et w e e n t h e i n di vi d u al  F X -3 2 2  gr o u p s ( e x cl u di n g t h e  p o ol e d  F X -3 2 2  gr o u p).  
C o m p ari s o n s  will  b e  m a d e  b y  vi sit ( e. g.,  e sti m at e d  L S  M e a n  diff er e n c e s  b y  vi sit)  a n d  o v e r all 
( e. g., T y p e  III S u m s  of  S q u ar e s).  
 
7. 9. 2.  C h a n g e  fr o m b a s eli n e  i n m e a n  t ot al s c or e  
 
• 
C o m p ut ati o n  of  t h e E n d p oi nt  
T h e  c h a n g e fr o m  b a s eli n e t o  e a c h  p o st -b a s eli n e  vi sit  will  b e  c o m p ut e d  a s  w  –  b  w h er e “ w” i s 
t h e p o st -b a s eli n e  s c or e  a n d “ b”  i s t h e  s c or e  at  b a s eli n e. 
 
• 
A n al y si s  of  t h e E n d p oi nt  
D e s cri pti v e  s u m m ari e s,  tr e at m e nt gr o u p  c o m p ari s o n s,  a n d  c orr el ati o n  a n al y s e s  wil l b e 
p erf or m e d f or  c h a n g e fr o m  b a s eli n e i n  m e a n t ot al  H SI  s c or e  a s  d e s cri b e d i n  S e cti o n  7. 7. 2. 
T h e  c o v ari a n c e  str u ct ur e  i d e ntifi e d i n S e cti o n  7. 9. 1  will  b e  utili z e d.  
 
E x a mi n ati o n  of  S u b gr o u p s  
 
D e s cri pti v e  s u m m ari e s  will  b e  pr e p ar e d  f or t h e e n d p oi nt s  d efi n e d  i n S e cti o n s  7. 3. 2 
( P er c e nt a g e  of  W R r e c o g ni z e d  w or d s)  a n d 7. 4. 2  ( P er c e nt a g e  of  WI N r e c o g ni z e d  w or d s) f or 
t h e f oll o wi n g  s u b gr o u p s u si n g  t h e F A S:  
 
• 
S u bj e ct  D e m o gr a p hi c s  
o  S e x  
o  R a c e  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
o  Et h ni cit y  
o  A g e  ( c at e g ori e s: 1 8  t o < 3 5,  3 5  t o < 5 0,  5 0  t o 6 5,  > 6 5)  
• 
B a s eli n e  Di s e a s e  C h ar a ct eri sti c s  
o  W R  s c or e  at  b a s eli n e  ( < 5 0 % v er s u s  > = 5 0 %)  
o  Eti ol o g y  of  h e ari n g  l o s s ( S S N H L v er s u s  NI H L)  
 
8.  S A F E T Y  E V A L U A TI O N  
 
O v er vi e w  of  S af et y  A n al y si s  M et h o d s  
 
T h e  a s s e s s m e nt  of l o c al  a n d  s y st e mi c  s af et y  of  si n gl e  a n d r e p e at e d  d o s e s  of  F X -3 2 2 i n 
s u bj e ct s  wit h  st a bl e  s e n s ori n e ur al  h e ari n g  l o s s i s a n  o bj e cti v e  of  t hi s st u d y.  T h e  s af et y 
a n al y s e s  will  b e  p erf or m e d  f or t h e s af et y  a n al y si s  s et  a n d  will  i n cl u d e tr e at m e nt-e m er g e nt 
a d v er s e  e v e nt s ( T E A E s),  s eri o u s  a d v er s e  e v e nt s ( S A E s),  cli ni c al l a b or at or y  m e a s ur e m e nt s, 
vit al  si g n s,  p h y si c al  e x a mi n ati o n,  ot o s c o pi c  e x a mi n ati o n,  t y m p a n o m etr y, c o n c o mit a nt 
m e di c ati o n s,  a n d  C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  ( C-S S R S)  a s s e s s m e nt s.  T a b ul ar 
s u m m ari e s  of  d e s cri pti v e  st ati sti c s  will  b e  pr e s e nt e d  f or all  s u bj e ct s  i n cl u d e d i n t h e S af et y 
A n al y si s  S et  a n d  s u bj e ct s  will  b e  cl a s sifi e d i nt o  a ct u al tr e at m e nt  gr o u p s  b a s e d  o n t h e  a ct u al 
n u m b er  of  F X -3 2 2  d o s e s  r e c ei v e d i n a n y  e ar  ( q u alifi e d or  n ot  q u alifi e d).  
 
W h er e  a p pr o pri at e, tr e at e d  will  b e  di sti n g ui s h e d fr o m t h e  u ntr e at e d  e ar,  a s  d e s cri b e d i n  
S e cti o n  3 . F or  u n q u alifi e d  e ar s  t h at r e c ei v e st u d y  tr e at m e nt i n err or,  t h e d at e  a n d  ti m e of 
t h e  st u d y  dr u g  a d mi ni str ati o n,  or  d at e if ti m e i s  mi s si n g,  or  vi sit if  d at e i s  mi s si n g ( e x c e pt f or 
e ar -r el at e d A E s,  a s  pr o vi d e d  b el o w),  will  b e  u s e d  t o i d e ntif y a s s e s s m e nt s  t h at will  b e 
cl a s sifi e d  a s  tr e at e d f or s af et y  a n al y s e s  b y  e ar.  
 
If  a n  a s s e s s m e nt  o c c ur s o n t h e  s a m e  d at e t h at  a n  u n q u alifi e d  e ar r e c ei v e s  st u d y tr e at m e nt 
i n err or,  a n d  a s s e s s m e nt  ti m e or  tr e at m e nt st art  ti m e i s mi s si n g,  t h e a s s e s s m e nt  will  b e 
pr e s u m e d  t o h a v e  o c c urr e d  pri or  t o st u d y  dr u g  a d mi ni str ati o n  f or p ur p o s e s  of  d efi ni n g  t h e 
e ar  a s  tr e at e d (i. e., t h e e ar  w o ul d  b e  c o n si d er e d  u ntr e at e d  at  t h at a s s e s s m e nt),  wit h  t h e 
e x c e pti o n  of  e ar -r el at e d  A E s, i n  w hi c h  c a s e t h e  e ar  w o ul d  b e  c o n si d er e d tr e at e d. T h e  s a m e 
l o gi c  w o ul d  b e  a p pli e d t o  a s s e s s m e nt s  ot h er t h a n  e ar-r el at e d A E s if t h e  a s s e s s m e nt  
o c c urr e d  o n  t h e  s a m e  vi sit t h at a n  u n q u alifi e d  e ar  r e c ei v e s  st u d y tr e at m e nt i n err o r  a n d o n e 
or  b ot h  d at e s  ar e  mi s si n g.  F or  e ar -r el at e d  A E s,  p arti al  d at e s  will  b e i m p ut e d f or  p ur p o s e s  of 
i d e ntif yi n g tr e at e d  e ar s i n t h e  s a m e  m a n n er t h e y ar e f or  p ur p o s e s  of  d efi ni n g  T E A E s,  a s 
pr o vi d e d  b el o w. 
 
F or  all  s af et y  e n d p oi nt s,  b a s eli n e  will  b e t h e l a st  n o n -mi s si n g  v al u e  b ef or e fir st 
a d mi ni str ati o n  of   st u d y  dr u g. 
 
F or  all  s hift fr o m  b a s eli n e  a n al y s e s,  p er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of  s u bj e ct s i n 
e a c h  b a s eli n e  c at e g or y.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
S af et y  d at a  will  n ot  b e i m p ut e d,  e x c e pt f or  p arti al  a n d  mi s si n g  d at e s,  w hi c h  will  b e i m p ut e d 
o nl y f or  d efi ni n g  T E A E s  a n d  c o n c o mit a nt  m e di c ati o n s.  I m p ut e d  d at e s  will  n ot  b e  pr e s e nt e d 
i n  d at a li sti n g s. 
 
P arti al  d at e s  will  b e  i m p ut e d f or t h e p ur p o s e s  of  d efi n i n g T E A E s  a s  f oll o w s: 
 
• 
F or  a  mi s si n g  st art  d a y  w h er e t h e  m o nt h  a n d  y e ar  ar e  pr e s e nt, t h e  st art  d a y  will  b e 
s et  t o t h e fir st d a y  of  t h e m o nt h,  u nl e s s  t h e f oll o wi n g t w o c o n diti o n s  ar e  m et:  
 
1.  t h e fir st  d a y of  t h e m o nt h i s  b ef or e  t h e d at e  of  fir st  a d mi ni str ati o n of  st u d y  dr u g 
a n d t h e  m o nt h  a n d  y e ar  ar e  t h e  s a m e a s  t h e m o nt h  a n d  y e ar  of t h e  d at e  of  fir st 
a d mi ni str ati o n  of   st u d y  dr u g, a n d  
 
2.  t h e e n d  d at e  i s o n  or  aft er  t h e d at e  of  fir st a d mi ni str ati o n  of  st u d y  dr u g  or  t h e 
e n d  d at e  i s c o m pl et el y  mi s si n g.  
 
If t h e t w o a b o v e  c o n diti o n s  ar e  m et,  t h e st art  d a y  will  b e  s et  t o t h e d a y  of  fir st 
a d mi ni str ati o n  of   st u d y  dr u g. 
 
• F or   a mi s si n g  st art  d a y  a n d  m o nt h  w h er e  t h e y e ar  i s pr e s e nt,  t h e st art  d a y  a n d 
m o nt h  will  b e  s et  t o J a n u ar y  1 st,  u nl e s s  1)  J a n u ar y  1 st  i s b ef or e  t h e d at e  of  fir st 
a d mi ni str ati o n  of  st u d y  dr u g  a n d  t h e y e ar  i s t h e s a m e  a s  t h e y e ar  of  t h e d at e  of  fir st 
a d mi ni str ati o n  of  st u d y  dr u g,  a n d  2)  t h e e n d  d at e  i s o n  or  aft er  t h e d at e  of  fir st 
a d mi ni str ati o n  of  st u d y  dr u g  or t h e  e n d  d at e i s  c o m pl et el y  mi s si n g, i n  w hi c h  c a s e t h e 
st art  d a y  a n d  m o nt h  will  b e  s et  t o t h at of  t h e d at e  of  fir st a d mi ni str ati o n  of  st u d y 
dr u g.  
 
• 
F or  a  mi s si n g  e n d  d a y  w h er e t h e  m o nt h  a n d  y e ar  ar e  pr e s e nt, t h e  e n d  d a y  will  b e  s et 
t o t h e l a st d a y  of  t h e m o nt h,  u nl e s s  t h e m o nt h  a n d  y e ar  ar e  t h e s a m e  a s  t h e m o nt h 
a n d  y e ar  of  t h e l a st c o nt a ct  d at e  f or t h e s u bj e ct,  i n  w hi c h  c a s e t h e e n d  d a y  will  b e 
s et  t o t h at of  t h e  s u bj e ct' s l a st  c o nt a ct d at e.  
 
• 
F or  a  mi s si n g  e n d  d a y  a n d  m o nt h  w h er e t h e  y e ar i s  pr e s e nt, t h e  e n d  d a y  a n d  m o nt h 
will  b e  s et  t o t h e  s u bj e ct' s l a st  c o nt a ct d at e,  u nl e s s t h e  y e ar  of  t h e  s u bj e ct' s l a st 
c o nt a ct  d at e i s  gr e at er  t h a n t h e  e n d y e ar,  i n  w hi c h  c a s e t h e e n d  d a y  a n d  m o nt h  will 
b e   s et t o  D e c e m b er  3 1 st. 
 
P arti al  a n d  c o m pl et el y  mi s si n g  d at e s  will  b e i m p ut e d f or t h e  p ur p o s e s  of  cl a s sif yi n g 
c o n c o mit a nt  m e di c ati o n s  a s  f oll o w s: 
 
• 
P arti al  d at e s  will  b e  i m p ut e d f oll o wi n g t h e s a m e  al g orit h m  a s  a b o v e  f or T E A E s.  
 
• F or  a n  e ntir el y  mi s si n g  st art  d at e  (i. e., d a y,  m o nt h,  a n d  y e ar  ar e  mi s si n g),  t h e st art 
d at e  will  b e  s et  t o t h e d at e  of  fir st a d mi ni str ati o n  of  st u d y  dr u g  u nl e s s  t h e st o p  d at e 
i s pri or  t o t h e d at e  of  fir st  a d mi ni str ati o n of  st u d y  dr u g,  i n w hi c h  c a s e  t h e st art  d at e 
will  b e   s et t o t h e  st o p d at e.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
• 
F or  a n  e ntir el y  mi s si n g  st o p  d at e (i. e.,  d a y,  m o nt h,  a n d  y e ar  ar e  mi s si n g), t h e 
m e di c ati o n  will  b e  tr e at e d a s  o n g oi n g.  
 
E xt e nt  of  E x p o s ur e  
 
T h e  di stri b uti o n  of  a ct u al  F X -3 2 2  d o s e s  r e c ei v e d b y  r a n d o mi z e d tr e at m e nt gr o u p  will  b e 
s u m m ari z e d  a s t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s r e c ei vi n g  0,  1,  2,  3,  or  4  d o s e s  of  F X - 
3 2 2  i n a n y  e ar  a n d  s e p ar at el y,  i n t h e q u alif yi n g  e ar  t o b e  tr e at e d.  T h e  s u m m ar y  will  b e  b y 
r a n d o mi z e d tr e at m e nt gr o u p  a n d  o v er all  f or s u bj e ct s  i n t h e F A S.  
 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  r e c ei vi n g st u d y  tr e at m e nt at  e a c h  tr e at m e nt vi sit 
( D a y  1,  8, 1 5,  2 1)  p er  t h e r a n d o mi z e d tr e at m e nt  s c h e d ul e i n t h e q u alif yi n g  e ar t o  b e  tr e at e d 
will  b e  s u m m ari z e d  b y r a n d o mi z e d tr e at m e nt  gr o u p  a n d  o v er all f or  s u bj e ct s i n t h e  F A S.  T h e 
q u alif yi n g  e ar  t o b e  tr e at e d ( L eft  E ar  or  Ri g ht  E ar) will  b e  c a pt ur e d  o n t h e  T ar g et e d  H e ari n g 
L o s s  Hi st or y  C R F  p a g e  a n d  i s t h e e ar  t o b e  tr e at e d at  all  f o ur tr e at m e nt vi sit s.  
 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  r e c ei vi n g i n c orr e ct  st u d y tr e at m e nt  at  e a c h 
tr e at m e nt vi sit  i n t h e q u alif yi n g  e ar  t o b e  tr e at e d will  b e  s u m m ari z e d  b y  r a n d o mi z e d 
tr e at m e nt gr o u p  a n d  o v er all  f or s u bj e ct s  i n t h e F A S.  
 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s tr e at e d i n t h e  n o n -q u alif yi n g  e ar  at  e a c h  vi sit  will 
b e  s u m m ari z e d  b y  r a n d o mi z e d tr e at m e nt gr o u p  a n d  o v er all  f or s u bj e ct s  i n t h e F A S.  
 
D o si n g i nt er v al  p att er n s  f or t h e  q u alif yi n g  e ar  e a c h tr e at m e nt  gr o u p  will  b e  e v al u at e d  u si n g 
t h e d ur ati o n  of  d a y s  b et w e e n  e a c h  st u d y  tr e at m e nt a d mi ni str ati o n  at  D a y s  8,  1 5  a n d  2 1.  
T h e  n u m b er  of  d a y s  b et w e e n  t h e c urr e nt  tr e at m e nt a d mi ni str ati o n  a n d  t h e pri or  tr e at m e nt 
a d mi ni str ati o n  will  b e  c o m p ut e d.  T h e  d ur ati o n  of  d a y s  b et w e e n  e a c h  st u d y  tr e at m e nt 
a d mi ni str ati o n  will  b e  s u m m ari z e d  c at e g ori c all y ( < 2  d a y s,  2 -4  d a y s,  5 -7  d a y s,  8 -1 0  d a y s,  > 1 0 
d a y s)  b y  tr e at m e nt gr o u p  a n d  o v er all  f or t h e q u alif yi n g  e ar  f or s u bj e ct s  i n t h e F A S.  
 
If t h er e ar e  a n y  d o si n g  a d mi ni str ati o n s  err or s  s u c h t h at   a n ot  q u alifi e d  e ar  i s tr e at e d,  a 
s e n siti vit y  a n al y si s  m a y  b e  p erf or m e d  s u m m ari zi n g t h e  d o si n g i nt er v al  p att er n s f or  a n y  e ar. 
St u d y  tr e at m e nt a d mi ni str ati o n  at  e a c h  tr e at m e nt vi sit  will  al s o  b e  li st e d f or s u bj e ct s  i n t h e 
F A S; t hi s  li sti n g will  i n cl u d e  a ct u al tr e at m e nt a d mi ni st er e d i n  e a c h  e ar  a ct u all y  tr e at e d. 
 
A d v er s e  E v e nt s  
 
All  A E s  will  b e  r e c or d e d fr o m t h e ti m e of  t h e fir st tr e at m e nt t hr o u g h t h e e n d  of  t h e f oll o w 
u p  p eri o d.  A d v er s e  e v e nt s  o c c urri n g  f or t h e fir st ti m e, or  w or s e ni n g  i n s e v erit y,  o n  or  aft er 
t h e fir st  d o s e  of  st u d y  dr u g  or  pl a c e b o  will  b e  c o n si d er e d t o  b e  T E A E s. O nl y  T E A E s  will  b e 
pr e s e nt e d  i n s u m m ar y  t a bl e s, b ut  all  A E s  will  b e  li st e d wit h   a fl a g i n di c ati n g if t h e A E  w a s 
tr e at m e nt-e m er g e nt.  A d v er s e  e v e nt s  will  b e  c o d e d  u si n g  t h e M e di c al  Di cti o n ar y  f or 
R e g ul at or y  A cti viti e s ( M e d D R A) t o i d e ntif y t h e  s y st e m  or g a n  cl a s s  a n d  pr ef err e d t er m.  T h e 
M e d D R A  v er si o n  u s e d  will  b e  wit hi n   1 f ull v er si o n  of  t h e l at e st v er si o n  at  st u d y  e n d.   A n y 
e ar -r el at e d A E,  w h et h er  o c c urri n g  i n  1 or  b ot h  e ar s,  will  o nl y  b e  c o u nt e d  o n c e  i n s u bj e ct 
i n ci d e n c e c o u nt s  p er  s y st e m  or g a n  cl a s s  a n d  pr ef err e d  t er m. 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
Tr e at m e nt -e m er g e nt  A E s  will  b e  s u m m ari z e d  b y tr e at m e nt  gr o u p  a n d  o v er all f or  all  s u bj e ct s  
i n t h e Sf A S.   T h e  s u m m ar y  will  di s pl a y  t h e t ot al n u m b er  of  T E A E s  a s  w ell  a s  t h e c o u nt  a n d 
p er c e nt a g e  of  s u bj e ct s  e x p eri e n ci n g  a n y  T E A E.  T h e t ot al  n u m b er  of  T E A E s  a n d t h e  c o u nt 
a n d  p er c e nt a g e  of  s u bj e ct s  e x p eri e n ci n g  at l e a st  1  T E A E i n  e a c h  s y st e m  or g a n  cl a s s  a n d 
pr ef err e d  t er m will  al s o  b e  s h o w n.  All  p er c e nt a g e s  will  u s e  t h e n u m b er  of  s u bj e ct s  i n t h e 
Sf A S  b y  tr e at m e nt gr o u p  a s  t h e d e n o mi n a t or. T h er ef or e,  if  a s u bj e ct  h a s  m or e  t h a n  1 A E 
wit hi n   a s y st e m  or g a n  cl a s s,  t h e s u bj e ct  will  b e  c o u nt e d  o nl y  o n c e  i n t h at s y st e m  or g a n 
cl a s s.  If  a s u bj e ct  h a s  m or e  t h a n  1 A E  t h at c o d e s  t o t h e s a m e  pr ef err e d  t er m, t h e s u bj e ct 
will  b e  c o u nt e d  o nl y  o n c e  f or t h at pr ef err e d  t er m.  T h e  t a b ul ar s u m m ar y  will  b e  s ort e d  b y 
d e s c e n di n g  fr e q u e n c y of  s y st e m  or g a n  cl a s s  a n d  pr ef err e d  t er m f or o v er all  i n ci d e n c e. 
 
Tr e at m e nt -e m er g e nt  A E s  will  al s o  b e  s u m m ari z e d  b y  m a xi m u m r el ati o n s hi p t o  st u d y  dr u g 
a n d  m a xi m u m  s e v erit y.   R el ati o n s hi p t o  t h e dr u g  will  b e  s c or e d  a s  R el at e d,  P o s si bl e, 
U nli k el y  or  N ot  R el at e d.  R el at e d  A E s  will  b e  cl a s sifi e d  a s t h o s e  s c or e d  a s  R el at e d  a n d 
P o s si bl e.  S e v erit y  will  b e  r at e d a s  Mil d,  M o d er at e,  or  S e v er e.   All  p er c e nt a g e s  will  u s e  t h e 
n u m b er  of  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p  a s  t h e d e n o mi n at or.  S u m m ar y  t a bl e s 
will r efl e ct  a  c o u nt  a n d  p er c e nt a g e  of  s u bj e ct s  e x p eri e n ci n g  at l e a st  1  T E A E i n  e a c h  s y st e m 
or g a n  cl a s s,  pr ef err e d  t er m a n d  gr o u pi n g,  r el ati o n s hi p, or  s e v erit y.  If  a s u bj e ct  e x p eri e n c e s 
m or e  t h a n  1 A E  wit hi n  s y st e m  or g a n  cl a s s  or  pr ef err e d  t er m, t h at s u bj e ct  will  b e  c o u nt e d 
o nl y  o n c e  f or t h at e v e nt  u n d er  t h e m a xi m u m  s e v erit y  or  m o st  r el at e d c at e g or y  f or t h e st u d y 
dr u g.  Si mil arl y, i n t h e  e v e nt t h at r el ati o n s hi p  or  s e v erit y  d at a  ar e  mi s si n g, t h e  st u d y  a n al y si s 
will  i n cl u d e  a c at e g or y  f or mi s si n g  r el ati o n s hi p or  s e v erit y  i n t h e s u m m ar y  t a bl e s.  T h e 
t a b ul ar  s u m m ari e s will  b e  s ort e d  b y  d e s c e n di n g  fr e q u e n c y of  s y st e m  or g a n  cl a s s  a n d 
pr ef err e d  t er m b a s e d  o n  t h e o v er all  i n ci d e n c e. 
 
F or  e ar -r el at e d  T E A E  a n al y s e s  w h er e t h e  e ar i s t h e  u nit  of  a n al y si s,  e ar s  will  b e  s u m m ari z e d 
a c c or di n g  t o w h et h er  it w a s  t h e tr e at e d (ti m e p eri o d  aft er  e ar  r e c ei v e d a n y  tr e at m e nt), 
u ntr e at e d  e ar  (ti m e p eri o d  b ef or e  e ar  r e c ei v e d a n y  tr e at m e nt), or  b ot h  e ar s  ( c o u nt of 
s u bj e ct s  i n e a c h  tr e at m e nt gr o u p).   E ar s  will  b e  pr e s e nt e d  b y  a ct u al  tr e at m e nt gr o u p  a n d 
o v er all  a s  d e s cri b e d  i n S e cti o n  3 . P er c e nt a g e s  f or t h e tr e at e d e ar  s u m m ar y  will  u s e  t h e 
n u m b er  of  e ar s  tr e at e d i n t h e Sf A S  b y  tr e at m e nt gr o u p  a s  t h e d e n o mi n at or.  P er c e nt a g e s 
f or t h e u ntr e at e d  e ar  s u m m ar y  will  u s e  t h e n u m b er  of  e ar s  n ot  tr e at e d i n t h e  Sf A S b y 
tr e at m e nt gr o u p  a s  t h e d e n o mi n at or.  P er c e nt a g e s  f or t h e b ot h  e ar  s u m m ar y  will  u s e  t h e 
n u m b er  of  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p  a s  t h e d e n o mi n at or.   I n e a c h 
cl a s sifi c ati o n  of  e ar  t y p e (tr e at e d, u ntr e at e d,  b ot h), if  a n  e ar  h a s  m or e  t h a n  1 A E  wit hi n  a 
s y st e m  or g a n  cl a s s,  t h e e ar  will  b e  c o u nt e d  o nl y  o n c e i n  t h at s y st e m  or g a n  cl a s s.   If  a n e ar 
h a s  m or e  t h a n  1 A E  t h at c o d e s  t o t h e s a m e  pr ef err e d  t er m, t h e e ar  will  b e  c o u nt e d  o nl y 
o n c e  f or t h at pr ef err e d  t er m.  F or  u n q u alifi e d  e ar s  t h at r e c ei v e st u d y  tr e at m e nt i n err or, 
a n y  e ar -r el at e d A E s  will  b e  m a p p e d  t o u ntr e at e d  or  tr e at e d e ar( s)  b a s e d  o n  w h e n  st u d y 
dr u g  a d mi ni str ati o n  o c c urr e d i n t h e  u n q u alifi e d  e ar,  a s  d e s cri b e d i n  S e cti o n  8. 1 . B e c a u s e  a n 
e ar  i s d e e m e d  tr e at e d aft er  r e c ei vi n g a n y  st u d y  tr e at m e nt a s  d e s cri b e d  i n S e cti o n  3 , it i s 
p o s si bl e f or  b ot h  e ar s  t o  b e  d e e m e d tr e at e d f or  e ar-r el at e d  T E A E  a n al y s e s. 
 
All  A E s  will  b e  pr e s e nt e d i n  d at a li sti n g s f or  s u bj e ct s i n t h e  Sf A S.  A  c ol u m n  will  b e i n cl u d e d 
i n t h e li sti n g s f or w h et h er  t h e A E  i s tr e at m e nt-e m er g e nt.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
D e at h s,  S eri o u s  A d v er s e  E v e nt s,  a n d  Ot h er  Si g nifi c a nt  A d v er s e  E v e nt s  
 
Tr e at m e nt -e m er g e nt  S A E s,  T E A E s  l e a di n g t o st u d y  wit h dr a w al,  a n d  T E A E s  r e s ulti n g i n d e at h 
will  b e  s u m m ari z e d  s e p ar at el y  f or all  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p  a n d  o v er all.  
All  p er c e nt a g e s  will  u s e  t h e n u m b er  of  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p  a s  t h e 
d e n o mi n at or.  S u m m ar y t a bl e s  will r efl e ct  a  c o u nt  a n d  p er c e nt a g e  of  s u bj e ct s  e x p eri e n ci n g  
at l e a st  1  T E A E i n  e a c h  s y st e m  or g a n  cl a s s  a n d  pr ef err e d t er m  wit hi n  e a c h  A E  s u b s et 
(s eri o u s,  l e a di n g t o st u d y  wit h dr a w al,  d e at h).  I n a d diti o n,  t h e n u m b er  of  s u bj e ct s 
e x p eri e n ci n g  a n y  T E A E s i n t h e r e s p e cti v e  s u b s et  will  b e r e p ort e d.  T h e t a b ul ar  s u m m ar y  will 
b e  s ort e d  b y  d e s c e n di n g fr e q u e n c y  of  s y st e m  or g a n  cl a s s  a n d  pr ef err e d t er m  b a s e d  o n  t h e 
o v er all i n ci d e n c e. 
 
A d v er s e  e v e nt s l e a di n g t o  st u d y  wit h dr a w al,  A E s r e s ulti n g i n  d e at h,  a n d  S A E s  will  b e 
pr e s e nt e d  i n d at a  li sti n g s f or s u bj e ct s  i n t h e Sf A S.  
 
8. 4. 1.  A d v er s e  E v e nt s  of  S p e ci al I nt er e st ( A E SI)  
Pr ot o c ol  S e cti o n  1 3  d efi n e s  a d v er s e  e v e nt s  of  s p e ci al i nt er e st.  
A E SI s  will  b e  s u m m ari z e d  b y  tr e at m e nt gr o u p  a n d  o v er all  f or all  s u bj e ct s  i n t h e Sf A S.   T h e 
s u m m ar y  will  di s pl a y  t h e t ot al n u m b er  of  A E SI s  a s  w ell  a s  t h e c o u nt  a n d  p er c e nt a g e  of 
s u bj e ct s  e x p eri e n ci n g  a n y  A E SI.  T h e  t ot al  n u m b er  of  A E SI s  a n d t h e  c o u nt a n d  p er c e nt a g e  of 
s u bj e ct s  e x p eri e n ci n g  at  l e a st  1  A E SI i n  e a c h  s y st e m  or g a n  cl a s s  a n d  pr ef err e d t er m  will  al s o 
b e  s h o w n.  All  p er c e nt a g e s  will  u s e  t h e n u m b er  of  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p 
a s t h e  d e n o mi n at or.  T h er ef or e, if  a  s u bj e ct  h a s  m or e t h a n  1  A E  wit hi n  a  s y st e m  or g a n  cl a s s, 
t h e s u bj e ct  will  b e  c o u nt e d  o nl y  o n c e  i n t h at s y st e m  or g a n  cl a s s.   If  a s u bj e ct  h a s  m or e  t h a n 
1  A E  t h at c o d e s  t o t h e s a m e  pr ef err e d  t er m, t h e s u bj e ct  will  b e  c o u nt e d  o nl y  o n c e  f or t h at 
pr ef err e d  t er m.  T h e  t a b ul ar s u m m ar y  will  b e  s ort e d  b y  d e s c e n di n g  fr e q u e n c y of  s y st e m 
or g a n  cl a s s  a n d  pr ef err e d  t er m f or o v er all  i n ci d e n c e. 
 
A E SI s  will  b e  pr e s e nt e d  i n a  d at a  li sti n g f or s u bj e ct s  i n t h e Sf A S.  
 
Cli ni c al  L a b or at or y  E v al u ati o n  
 
Cli ni c al l a b or at or y  e v al u ati o n  d at a  will  b e  pr e s e nt e d  b y l a b or at or y  p ar a m et er  a s  d e s cri pti v e  
st ati sti c s  f or t h e  c h a n g e fr o m  b a s eli n e t o  e a c h  vi sit  a n d  s hift s fr o m  b a s eli n e t o  e a c h  vi sit  b y 
tr e at m e nt gr o u p  a n d  o v er all  f or s u b j e ct s i n t h e Sf A S.  U n s c h e d ul e d  vi sit  a n d  e arl y 
t er mi n ati o n  vi sit  d at a  will  n ot  b e  m a p p e d t o s c h e d ul e d  vi sit s  p er  S e cti o n  7. 1. 2.  
U n s c h e d ul e d  vi sit  a n d  e arl y  t er mi n ati o n vi sit  d at a  will  b e  e x cl u d e d  fr o m s u m m ar y  t a bl e s 
a n d  i n cl u d e d i n li sti n g s.  T h e  a n al y s e s  f or s hift s  fr o m b a s eli n e  t o e a c h  vi sit  will  u s e 
l a b or at or y-pr o vi d e d  v al u e s  of  hi g h  ( H), n or m al  ( N) or  l o w ( L) t o cl a s sif y  l a b or at or y r e s ult s. 
R e s ult s t h at  ar e r e p ort e d  a s  hi g h  p a ni c ( H P)  or  hi g h  n or m al ( H N)  will  b e  cl a s sifi e d  a s  H,  a n d 
r e s ult s t h at  ar e r e p ort e d  a s l o w  p a ni c ( L P)  or l o w n or m al ( L N)  will  b e  cl a s sifi e d  a s  L.  Mi s si n g 
v al u e s  will  r e m ai n mi s si n g.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  5 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
Pr e g n a n c y r e s ult s  will  n ot  b e  s u m m ari z e d,  b ut  will  b e  i n cl u d e d i n li sti n g s  wit h  all  ot h er 
l a b or at or y d at a  f or s u bj e ct s  i n t h e Sf A S.  
 
Vit al  Si g n s,  P h y si c al  Fi n di n g s,  a n d  Ot h er  O b s er v ati o n s  R el at e d  t o S af et y  
 
8. 6. 1.  Vit al  Si g n s  
 
Vit al  si g n  e v al u ati o n  d at a  will  b e  pr e s e nt e d  b y  p ar a m et er  a s  d e s cri pti v e  st ati sti c s  f or t h e 
c h a n g e fr o m  b a s eli n e t o  e a c h  vi sit  a n d  s hift s fr o m  b a s eli n e t o  e a c h  vi sit  b y tr e at m e nt  gr o u p 
a n d  o v er all  f or s u bj e ct s  i n t h e Sf A S.   U n s c h e d ul e d  vi sit  a n d  e arl y  t er mi n ati o n vi sit  d at a  will 
n ot  b e  m a p p e d  t o s c h e d ul e d  vi sit s  p er  S e cti o n  7. 1. 2 . U n s c h e d ul e d  vi sit  a n d  e arl y 
t er mi n ati o n vi sit  d at a  will  b e  e x cl u d e d  fr o m s u m m ar y  t a bl e s a n d  i n cl u d e d i n li sti n g s. T h e 
a n al y s e s  f or s hift s  fr o m b a s eli n e  t o e a c h  vi sit  will  u s e  pr e d efi n e d  cli ni c all y  r el e v a nt 
c at e g ori e s t o  cl a s sif y r e s ult s i nt o l o w,  n or m al  a n d  hi g h.  Mi s s i n g  v al u e s  will r e m ai n  mi s si n g. 
 
T a bl e   8- 1  Vit al  Si g n  C at e g ori e s f or Cli ni c al  R el e v a n c e  
 
Vit al  Si g n  
L o w  
N or m al  
Hi g h  
S y st oli c  Bl o o d  Pr e s s ur e  ( m m H g)  
< 9 0  
9 0 -1 2 0   
> 1 2 0  
Di a st oli c  Bl o o d  Pr e s s ur e  ( m m H g)  < 6 0  
6 0 -8 0  
> 8 0  
H e art  R at e  ( b e at s p er  mi n ut e)   
< 6 0  
6 0 -1 0 0   
> 1 0 0  
 
Vit al  si g n  e v al u ati o n  d at a  will  al s o  b e  i n cl u d e d i n li sti n g s f or s u bj e ct s  i n t h e Sf A S.  
 
8. 6. 2.  P h y si c al  E x a mi n ati o n s  
 
B a s eli n e  p h y si c al  e x a mi n ati o n r e s ult s  of  N or m al,  A b n or m al  a n d  N ot  D o n e  will  b e  pr e s e nt e d 
b y  b o d y  s y st e m  a s  d e s cri pti v e  st ati sti c s  b y  tr e at m e nt gr o u p  a n d  o v er all  f or s u bj e ct s  i n t h e 
Sf A S.  Mi s si n g  v al u e s  will r e m ai n  mi s si n g.  
 
P h y si c al  e x a mi n ati o n  d at a  will  a l s o b e  i n cl u d e d i n li sti n g s f or s u bj e ct s  i n t h e Sf A S.  
 
8. 6. 3.  Ot o s c o pi c  E x a mi n ati o n s  
 
Ot o s c o pi c  e x a mi n ati o n  d at a  will  b e  pr e s e nt e d  b y  vi sit f or tr e at e d  e ar s (ti m e  p eri o d  aft er  e ar 
r e c ei v e d  a n y tr e at m e nt) a n d  u ntr e at e d  e ar s  (ti m e p eri o d  b ef or e  e ar  r e c ei v e d  a n y 
tr e at m e nt),  s e p ar at el y,  a s  d e s cri pti v e  st ati sti c s f or  e a c h  cl a s sifi c ati o n  of t h e  e x a mi n ati o n  b y 
tr e at m e nt gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d  o v er all  f or s u bj e ct s  i n t h e Sf A S,  a s 
d e s cri b e d i n  S e cti o n  3 .  F or  u n q u alifi e d  e ar s  t h at r e c ei v e  st u d y tr e at m e nt i n  err or,  ot o s c o pi c 
e x a mi n ati o n  r e s ult s will  b e  m a p p e d  t o u ntr e at e d  or  tr e at e d e ar( s)  b a s e d  o n  w h e n  st u d y 
dr u g  a d mi ni str ati o n  o c c urr e d i n t h e  u n q u alifi e d  e ar,  a s  d e s cri b e d i n  S e cti o n  8. 1 . B e c a u s e  a n 
e ar  i s d e e m e d  tr e at e d aft er  r e c ei vi n g a n y  st u d y  tr e at m e nt a s  d e s cri b e d  i n S e cti o n  3 , it i s 
p o s si bl e  f or b ot h  e ar s  t o b e  d e e m e d  tr e at e d at   a vi sit.   U n s c h e d ul e d  vi sit  a n d  e arl y 
t er mi n ati o n  vi sit  d at a  will  n ot  b e  m a p p e d t o s c h e d ul e d  vi sit s  p er  S e cti o n  7. 1. 2 . 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
U n s c h e d ul e d  vi sit  a n d  e arl y t er mi n ati o n  vi sit  d at a  will  b e  e x cl u d e d fr o m  s u m m ar y t a bl e s 
a n d  i n cl u d e d i n li sti n g s. Mi s si n g  v al u e s  f or e a c h  c o m p o n e nt  will  r e m ai n mi s si n g.  
 
Ot o s c o pi c  e x a mi n ati o n s  will  i n cl u d e t h e f oll o wi n g cl a s sifi c ati o n s:  
 
• 
Tr e at e d  E ar:  Ri g ht  or  L eft.  F or  s u bj e ct s  wit h  a  n o n -q u alifi e d  e ar t h at r e c ei v e d  st u d y 
tr e at m e nt, b ot h  e ar s  will  b e  cl a s sifi e d  a s  tr e at e d aft er  t h e a d mi ni str ati o n  of  st u d y 
tr e at m e nt i n t h e n o n -q u alifi e d   e ar. 
 
• 
E xt er n al I n s p e cti o n,  A uri cl e  a n d  M e at u s:  N or m al,  A b n or m al ( Er yt h e m a,  C er u m e n, 
Ot orr h e a,  Ot h er). 
 
• 
I nt er n al E ar  E x a mi n ati o n:  
o  T y m p a ni c  M e m br a n e:  N or m al,  A b n or m al ( Er yt h e m a,  B ul gi n g,  S c arri n g, 
Gr a n ul ati o n,  P erf or ati o n,  Ot h er)  
 
o  T y m p a ni c  M e m br a n e  –  P erf or ati o n:  N ot  Pr e s e nt,  Pr e s e nt ( Si z e  of  P erf or ati o n: 
Pi n h ol e,  < =  2 5 %  of t h e  T M,  >  2 5 %  a n d  < =  5 0 %  of t h e  T M,  >  5 0 %  of t h e  T M)  
 
o  Mi d dl e  E ar:  N or m al,  A b n or m al  ( Eff u si o n, Ot orr h e a,  Ot h er)  
 
T h e  n u m b er  a n d  p er c e nt a g e  of  e ar s  pr e s e nti n g  wit h  e a c h  ot o s c o pi c  cl a s sifi c ati o n  will  b e 
pr o vi d e d  f or tr e at e d e ar s  (ti m e p eri o d  aft er  e ar  r e c ei v e d a n y  tr e at m e nt) a n d  u ntr e at e d  e ar s 
(ti m e p eri o d  b ef or e  e ar  r e c ei v e d a n y  tr e at m e nt), s e p ar at el y,  f or e a c h  vi sit  b y  tr e at m e nt 
gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d  o v er all  f or s u bj e ct s  i n t h e Sf A S,  a s  d e s cri b e d  i n 
S e cti o n  3 .  T h e  n u m b er  a n d  p er c e nt a g e  of  e ar s  wit h  s hift s  i n t h eir ot o s c o pi c  cl a s sifi c ati o n 
fr o m b a s eli n e  t o e a c h  vi sit  will  al s o  b e  pr o vi d e d  b y  e ar (tr e at e d  a n d  u ntr e at e d)  f or e a c h 
tr e at m e nt  gr o u p ( a ct u al tr e at m e nt r e cei v e d)  a n d  o v er all.  
 
Ot o s c o pi c  e x a mi n ati o n  d at a,  s c h e d ul e d  a n d  u n s c h e d ul e d,  will  b e  pr e s e nt e d i n  a  d at a li sti n g 
f or s u bj e ct s  i n t h e Sf A S.  
 
8. 6. 4.  T y m p a n o m etr y  
 
T y m p a n o m etr y  d at a  will  b e  pr e s e nt e d  b y  vi sit  f or tr e at e d e ar s  (ti m e p eri o d  aft er  e ar 
r e c ei v e d  a n y tr e at m e nt) a n d  u ntr e at e d  e ar s  (ti m e p eri o d  b ef or e  e ar  r e c ei v e d  a n y 
tr e at m e nt),  s e p ar at el y,  a s  d e s cri pti v e  st ati sti c s f or  e a c h  c o m p o n e nt  of t h e t y m p a n o gr a m  b y 
tr e at m e nt gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d  o v er all  f or s u bj e ct s  i n t h e Sf A S,  a s 
d e s cri b e d i n  S e cti o n  3 .  F or  u n q u alifi e d  e ar s  t h at r e c ei v e  st u d y tr e at m e nt i n  err or,  ot o s c o pi c 
e x a mi n ati o n  r e s ult s will  b e  m a p p e d  t o u ntr e at e d  or  tr e at e d e ar( s)  b a s e d  o n  w h e n  st u d y 
dr u g  a d mi ni str ati o n  o c c urr e d i n t h e  u n q u alifi e d  e ar,  a s  d e s cri b e d i n  S e cti o n  8. 1 . B e c a u s e  a n 
e ar  i s d e e m e d  tr e at e d aft er  r e c ei vi n g a n y  st u d y  tr e at m e nt a s  d e s cri b e d  i n S e cti o n  3 , it i s 
p o s si bl e  f or b ot h  e ar s  t o b e  d e e m e d  tr e at e d at   a vi sit.   U n s c h e d ul e d  vi sit  a n d  e arl y 
t er mi n ati o n  vi sit  d at a  will  n ot  b e  m a p p e d t o s c h e d ul e d  vi sit s  p er  S e cti o n  7. 1. 2 . 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
U n s c h e d ul e d  vi sit  a n d  e arl y t er mi n ati o n  vi sit  d at a  will  b e  e x cl u d e d fr o m  s u m m ar y t a bl e s 
a n d  i n cl u d e d i n li sti n g s. Mi s si n g  v al u e s  f or e a c h  c o m p o n e nt  will  re m ai n  mi s si n g.  
 
T y m p a n o gr a m  d at a  will  i n cl u d e t h e f oll o wi n g cl a s sifi c ati o n s:  
 
• 
Tr e at e d  E ar:  Ri g ht  or  L eft.  F or  s u bj e ct s  wit h  a  n o n -q u alifi e d  e ar t h at r e c ei v e d  st u d y 
tr e at m e nt, b ot h  e ar s  will  b e  cl a s sifi e d  a s  tr e at e d aft er  t h e a d mi ni str ati o n  of  st u d y 
tr e at m e nt i n t h e n o n -q u alifi e d   e ar. 
 
• 
T y p e  of  T y m p a n o gr a m  ( A, B,  C)  
• 
T y p e  B  –  V ol u m e  ( < 2. 0 m L,  > = 2. 0  m L)  
 
• 
E ar  C a n al  V ol u m e  ( m L) 
• 
P e a k  A d mitt a n c e  ( m L) 
• 
P e a k  Pr e s s ur e  ( d a P a) 
Tr e at e d  E ar,  T y p e  of  T y m p a n o gr a m  a n d  T y p e  B  –  V ol u m e  d at a  will  b e  s u m m ari z e d  a s t h e 
n u m b er  a n d  p er c e nt a g e  of  e ar s  wit h  e a c h  c at e g or y  a n d  E ar  C a n al  V ol u m e,  P e a k  A d mitt a n c e 
a n d  P e a k  Pr e s s ur e  will  b e  s u m m ari z e d  a s  c o nti n u o u s  v ari a bl e s  p er  S e cti o n  3 . S u m m ari e s  
will  b e  f or tr e at e d e ar s  (ti m e p eri o d  aft er  e ar  r e c ei v e d a n y  tr e at m e nt) a n d  u ntr e at e d  e ar s 
(ti m e p eri o d  b ef or e  e ar  r e c ei v e d a n y  tr e at m e nt), s e p ar at el y,  f or e a c h  vi sit  b y  tr e at m e nt 
gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d  o v er all  f or s u bj e ct s  i n t h e Sf A S,  a s  d e s cri b e d  i n 
S e cti o n  3 . 
 
T h e  n u m b er  a n d  p er c e nt a g e  of  e ar s  wit h  s hift s  fr o m b a s eli n e  t o e a c h  vi sit  i n t y p e a n d 
v ol u m e  of t y m p a n o gr a m ( A,  B -s m all  v ol u m e  a n d/ or  n or m al,  B -l ar g e  v ol u m e,  or  C)  will  al s o 
b e  pr o vi d e d  b y  e ar  (tr e at e d a n d  u ntr e at e d)  f or e a c h  tr e at m e nt gr o u p  ( a ct u al tr e at m e nt 
r e c ei v e d) a n d   o v er all. 
 
All t y m p a n o gr a m  d at a,  s c h e d ul e d  a n d  u n s c h e d ul e d,  will  b e  p r e s e nt e d i n  a  d at a li sti n g f or 
s u bj e ct s  i n t h e Sf A S.  
 
8. 6. 5.  C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  A s s e s s m e nt s  
 
T h e  B a s eli n e  v er si o n  of  t h e  C-S S R S  will  b e  a d mi ni st er e d  at  D a y   1 a n d  t h e Si n c e  L a st  Vi sit 
v er si o n  will  b e  a d mi ni st er e d  at  D a y s  6 0,  1 2 0  a n d  2 1 0.  U n s c h e d ul e d  vi sit  a n d  e arl y 
t er mi n ati o n  vi sit  d at a  will  n ot  b e  m a p p e d t o s c h e d ul e d  vi sit s  p er  S e cti o n  7. 1. 2 . 
U n s c h e d ul e d  vi sit  a n d  e arl y  t er mi n ati o n vi sit  d at a  will  b e  e x cl u d e d  fr o m s u m m ar y  t a bl e s 
a n d  i n cl u d e d i n li sti n g s.  All  s ui ci d al  i d e ati o n a n d  b e h a vi or al  v ari a bl e s  c oll e ct e d  will  b e 
s u m m ari z e d  d e s cri pti v el y f or  e a c h  vi sit  b y tr e at m e nt  gr o u p ( a ct u al tr e at m e nt r e c ei v e d)  a n d  
o v er all  f or s u bj e ct s  i n t h e Sf A S,  a s  d e s cri b e d  i n S e cti o n  3 .  Mi s si n g  v al u e s  will  r e m ai n 
mi s si n g.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 2  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
All   C-S S R S  d at a,  s c h e d ul e d  a n d  u n s c h e d ul e d,  will  b e  i n cl u d e d i n d at a  li sti n g s f or all  s u bj e ct s 
i n t h e  Sf A S. 
 
8. 6. 6.  C o n c o mit a nt  M e di c ati o n s  
 
All  m e di c ati o n s t a k e n i n  t h e 1 4  d a y s  pri or  t o t h e S cr e e ni n g  vi sit  t hr o u g h t h e  e n d of  t h e 
f oll o w-u p  p eri o d  will  b e  r e c or d e d o n  t h e C o n c o mit a nt  M e di c ati o n s  l o g.  Pri or  a n d 
c o n c o mit a nt  m e di c ati o n s  will  b e  c o d e d  u si n g  t h e l at e st  v er si o n  of  W orl d  H e alt h 
Or g a ni z ati o n  Dr u g  Di cti o n ar y  E n h a n c e d  w h e n t h e  st u d y  st art e d t o i d e ntif y t h e  dr u g  cl a s s 
a n d   pr ef err e d  dr u g  n a m e. 
 
C o n c o mit a nt  m e di c ati o n s  will  i n cl u d e all  m e di c ati o n s  t h at st art e d,  or  w er e  c o nti n ui n g, 
d uri n g  or  aft er  a d mi ni str ati o n  of  st u d y  dr u g.   Pri or  m e di c ati o n s  will  i n cl u d e all  m e di c ati o n s 
t h at st art e d  a n d  st o p p e d  pri or  t o t h e d a y  of  a d mi ni str ati o n  of  t h e st u d y  dr u g.   I n t h e e v e nt 
t h at  a  s u bj e ct  b e gi n s a  pri or  m e di c ati o n f oll o wi n g  fir st  d o s e of  st u d y  dr u g  or  pl a c e b o,  t h e 
p o st -d o s e  u s e  will  b e  c o n si d er e d  c o n c o mit a nt  w hil e  t h e pri or  u s e  m e di c ati o n  will  still  b e 
r e p ort e d. 
 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  u si n g  c o n c o mit a nt  m e di c ati o n s  will  b e t a b ul at e d  b y 
A n at o mi c al  T h er a p e uti c  C h e mi c al ( A T C)  a n d  pr ef err e d t er m f or  all  s u bj e ct s i n t h e  Sf A S  b y 
tr e at m e nt gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d  o v er all.  If  a s u bj e ct  h a s  m or e  t h a n 1 
m e di c ati o n  wit hi n  a n  a n at o mi c  cl a s s, t h e  s u bj e ct  will  b e  c o u nt e d  o nl y  o n c e i n t h at  a n at o mi c 
cl a s s.   Si mil arl y,  if  a s u bj e ct  h a s  m or e  t h a n  1 m e di c ati o n  t h at c o d e s  t o t h e s a m e  pr ef err e d 
t er m, t h e s u bj e ct  will  b e  c o u nt e d  o nl y  o n c e  f or t h at pr ef err e d  t er m.  All  p er c e nt a g e s  will  u s e 
t h e n u m b er  of  s u bj e ct s  i n t h e Sf A S  b y  tr e at m e nt gr o u p  ( a ct u al tr e at m e nt r e c ei v e d) a n d 
o v er all,  a s  d e s cri b e d  i n S e cti o n  3,  a s  t h e d e n o mi n at or.  T h e  t a b ul ar s u m m ar y  will  b e  s ort e d 
b y  d e s c e n di n g  or d er  b a s e d  o n  t h e o v er all  fr e q u e n c y. 
 
Pri or  a n d  c o n c o mit a nt  m e di c ati o n  d at a  will  al s o  b e  pr e s e nt e d i n  a  d at a li sti n g f or  s u bj e ct s i n 
t h e  Sf A S. 
 
9.  O T H E R  A N A L Y S E S  
 
T h e  bi o m ar k er  a n al y s e s  s p e cifi e d  i n t h e st u d y  pr ot o c ol  ar e  o ut si d e  t h e s c o p e  of  t hi s S A P.  
 
1 0.  I N T E RI M A N A L Y SI S  A N D  D A T A  M O NI T O RI N G  
 
T h e  bli n d e d  d at a  will  b e  c o nti n u o u sl y  m o nit or e d  f or s af et y.   I nt er v e nti o n al l e v el a g gr e g at e d 
d at a  m o nit ori n g  will  b e  c o n d u ct e d  o n c e  all  e nr oll e d  s u bj e ct s  h a v e  c o m pl et e d t h e  D a y  9 0  vi sit 
( Vi sit 5)  or  w er e  e arl y  di s c o nti n u ati o n s.   A n  i nt eri m a n al y si s  of  all  D a y  9 0  d at a  m a y  b e 
p erf or m e d t o  a s si st i n  d at a i nt er pr et ati o n  or t o  u n d er st a n d  p att er n s  of  mi s si n g n e s s i n r e al - 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 3  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
ti m e or  t o m o nit or  d at a  i nt e grit y. T h e  st u d y  will  c o nti n u e  a s  pl a n n e d  t o fi n al a n al y si s  w h e n 
all  p ati e nt s  h a v e  c o m pl et e d  t h eir d a y  2 1 0  vi sit.  
 
T h e  pl a n n e d i nt eri m  a n al y si s  will i n cl u d e  s el e ct t a bl e s  a n d fi g ur e s  pl a n n e d  f or t h e  C S R,  wit h 
s u bj e ct s  gr o u p e d i nt o r a n d o mi z e d  or  a ct u al tr e at m e nt  gr o u p s  b a s e d  o n  u n bli n d e d tr e at m e nt  
a s si g n m e nt s.   D at a s et s  s u p p orti n g  t h e s el e ct t a bl e s  a n d fi g ur e s  will  al s o  b e  pr o vi d e d  al o n g 
wit h  t h e r a w r a n d o mi z ati o n c o d e s.   I n t h e t a bl e s a n d  fi g ur e s, m o d el  r e s ult s a n d  d e s cri pti v e 
st ati sti c s  t hr o u g h  Vi sit  5 ( D a y 9 0)  will  b e  pr e s e nt e d,  a s  a p pr o pri at e.   Wit h  t h e e x c e pti o n  of 
t h e s u bj e ct  di s p o siti o n  s u m m ar y  a n d  K a pl a n -M ei er  pl ot  of  ti m e fr o m t h e d at e  of 
r a n d o mi z ati o n t o t h e d at e  of  st u d y  c o m pl eti o n  or  e arl y  di s c o nti n u ati o n,  all  d at a  aft er  D a y  9 0 
will  b e  e x cl u d e d. 
 
T h e f oll o wi n g t a bl e s  a n d  fi g ur e s  pl a n n e d f or t h e  C S R  a n al y s e s  ar e  pl a n n e d f or t h e I A:  S u bj e ct 
Di s p o s iti o n f or  C o n s e nt e d  s u bj e ct s ( S e cti o n 5. 1 ),  D e m o gr a p hi c  a n d  B a s eli n e  C h ar a ct eri sti c s 
f or t h e F A S  ( S e cti o n 5. 2 ), S u bj e ct  Vi sit  A c c o u nt a bilit y  f or t h e F A S  ( S e cti o n 5. 1 ), W R,  WI N,  a n d 
A u di o m etr y  a c c o u nt a bilit y  ( S e cti o n 7. 1. 6 ), M aj or  Pr ot o c ol  D e vi ati o n s  f or R a n d o mi z e d 
S u bj e ct s ( S e cti o n  6. 1 ),  St u d y  Tr e at m e nt  E x p o s ur e f or t h e  F A S ( S e cti o n 8. 2 ),  W or d 
R e c o g niti o n i n  Q ui et f or t h e  F A S  a n d  P P S  e x cl u di n g  a n al y s e s  b y  sit e  or  s u b gr o u p ( S e cti o n 
7. 3 ),  W or d s-I n-N oi s e f or t h e  F A S  a n d  P P S  e x cl u di n g  a n al y s e s  b y  sit e  or  s u b gr o u p ( S e cti o n 
7. 4 ), P ur e  T o n e  A u di o m etr y  a n al y s e s  f or t h e  F A S a n d  P P S  ( S e cti o n 7. 5 ), C o m p o sit e  E n d p oi nt 
f or t h e F A S  a n d  P P S  ( S e cti o n 7. 5. 9 ), T FI  f or t h e F A S  ( S e cti o n 7. 7 ), H HI  f or t h e F A S  ( S e cti o n 
7. 8 ),  H SI f or t h e  F A S ( S e cti o n 7. 9 ),  A d v er s e E v e nt s  f or t h e  Sf A S ( S e cti o n 8. 3 ),  Ot o s c o pi c 
E x a mi n ati o n  f or t h e Sf A S  ( S e cti o n 8. 6. 3 ), T y m p a n o m etr y  f or t h e Sf A S  ( S e cti o n 8. 6. 4 ),  C-S S R S 
f or t h e  Sf A S ( S e cti o n 8. 6. 5 ),  a n d  c o n c o mit a nt  m e di c ati o n s f or t h e  Sf A S ( S e cti o n 8. 6. 6) . 
P h o n e m e  a n al y s e s,  W R  a n d  WI N  a n al y s e s  b y  sit e  or  s u b gr o u p,  a s  w ell  a s  a n y  s e n siti vit y 
a n al y s e s  f or t h e  F A S  d u e t o st u d y tr e at m e nt  a d mi ni str ati o n i n t h e  n ot  q u alifi e d  e ar  ar e 
e x cl u d e d fr o m  t h e I A. 
 
T h e  st u d y  t e a m will  r e m ai n bli n d e d  t o t h e d at a  d uri n g  t h e I A. A n  u n bli n d e d  st ati sti ci a n  a n d 
st ati sti c al  pr o gr a m m er,  s e p ar at e  fr o m t h e bli n d e d  st u d y  t e a m, will  pr o vi d e  u n bli n d e d  r e s ult s 
of t h e I A t o t h e  Fr e q u e n c y  T h er a p e uti c s  Dir e ct or  of  Bi o st ati sti c s,  S a m  Wil s o n.  Aft er r e c ei vi n g 
t h e u n bli n d e d  I A r e s ult s, t h e Fr e q u e n c y  Dir e ct or  of  Bi o st ati sti c s  a n d  a n y  ot h er  Fr e q u e n c y 
t e a m m e m b er s  w h o  ar e  u n bli n d e d  at  t h e ti m e of  t h e i nt eri m a n al y si s  will  b e  r e m o v e d fr o m 
a n y  bli n d e d  di s c u s si o n s  or  d e ci si o n  m a ki n g r e g ar di n g t h e  F X -3 2 2 -2 0 2 fi n al  a n al y s e s.  
 
1 1.  C H A N G E S  T O  T H E  A N A L Y S E S  P L A N N E D  I N T H E  P R O T O C O L  
 
Pr ot o c ol  S e cti o n  1 4. 1. 5  s p e cifi e s t h at  a dj u st e d  p -v al u e s  a n d  c o nfi d e n c e i nt er v al s  m a y  b e 
c o m p ut e d f or  p air wi s e tr e at m e nt  c o m p ari s o n s f or  a  gi v e n  e n d p oi nt.  S u c h  a dj u st e d  a n al y s e s 
ar e  n o l o n g er  pl a n n e d i n  t h e S A P  a n d t h er e  will  b e  n o  a dj u st m e nt s  f or m ulti pli cit y  of  gr o u p 
c o m p ari s o n s.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 4  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
1 2.  R E F E R E N C E S  
 
C a u s e y,  G.  D.,  H o o d,  L.  J.,  H er m a n s o n,  C.  L.,  &  B o wli n g,  L.  S. ( 1 9 8 4).  T h e  M ar yl a n d  C N C t e st:  
n or m ati v e  st u di e s.  A u di ol o g y , 2 3 ( 6),  5 5 2-5 6 8.  
 
F D A  ( 2 0 2 0). St ati sti c al  C o n si d er ati o n s  f or Cli ni c al  Tri al s  D uri n g  t h e C O VI D -1 9  P u bli c  H e alt h 
E m er g e n c y.  G ui d a n c e f or I n d u str y.  P u bli s h e d  J u n e  2 0 2 0.  A v ail a bl e fr o m: 
htt p s:// w w w.f d a. g o v/ m e di a/ 1 3 9 1 4 5/ d o w nl o a d.  
 
S c h o e pf li n, J.  R.  ( 2 0 1 2). B a c k  t o b a si c s:  S p e e c h  a u di o m etr y.  A d el p hi  U ni v er sit y.  R etri e v e d 
o n,   2 3( 1 2), 2 0 1 4.  
 
St u d e b a k er,  G.  A. ( 1 9 8 5).  A "r ati o n ali z e d"  ar c si n e  tr a n sf or m.  J o ur n al  of  S p e e c h,  L a n g u a g e, 
a n d  H e ari n g  R e s e ar c h,  2 8( 3),  4 5 5 -4 6 2.  
 
T h or nt o n,  A.  R.,  &  R affi n,  M.  J. ( 1 9 7 8).  S p e e c h -di s cri mi n ati o n  s c or e s  m o d el e d  a s  a  bi n o mi al 
v ari a bl e.  J o ur n al  of  s p e e c h  a n d  h e ari n g r e s e ar c h,  2 1( 3),  5 0 7 -5 1 8.  
 
Wil s o n,  R.  H.,  M or g a n,  D.  E.,   & Dir k s,  D.  D.  ( 1 9 7 3).  A pr o p o s e d  S R T  pr o c e d ur e  a n d  it s 
st ati sti c al  pr e c e d e nt.  J o ur n al  of  S p e e c h  a n d  H e ari n g  Di s or d er s,  3 8( 2),  1 8 4 -1 9 1.  
 
Wil s o n  R H,  A br a m s,  H B,  Pilli o n  A L. ( 2 0 0 3).  A  w or d -r e c o g niti o n t a s k i n  m ultit al k er  b a b bl e 
u si n g   a d e s c e n di n g  pr e s e nt ati o n  m o d e  fr o m 2 4  d B  t o  0 d B  si g n al  t o b a b bl e.   J R e h a bil  R e s 
D e v.  2 0 0 3  J ul -A u g;  4 0( 4): 3 2 1 -7.  


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 5  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
1 3.  A P P E N DI C E S  
 
St u d y  Fl o w  C h art  
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 6  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
S c h e d ul e  of  E v e nt s  
 
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 7  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
1 4.  A T T A C H M E N T S  
 
T h or nt o n  a n d  R affi n  ( 1 9 7 8) W or d  R e c o g niti o n  S c ori n g  C h art  
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 8  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
C ar n e y  S c hl a u c h  ( 2 0 0 7) W or d  R e c o g niti o n  S c ori n g  C h art  
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  6 9  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T FI  C al c ul ati o n s  
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  7 0  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
 
 
 


Fr e q u e n c y  T h er a p e uti c s  
Pr ot o c ol  N o.  F X -3 2 2 -2 0 2  
C O N FI D E N TI A L  
St ati sti c al  A n al y si s  Pl a n  
1 0  F e br u ar y  2 0 2 1  
P a g e  7 1  of  7 1  
V er si o n  D at e:  2 0 2 1 -0 2 -1 0  
V er si o n:  4. 0  
 
 
 
 
T h e  p o s si bl e  r e s p o n s e s t o it e m s e x c e pt   1 a n d   3 ar e  0,  1,  2,  3,  4,  5,  6,  7,  8,  9,  a n d  1 0.  T h e  
p o s si bl e  r e s p o n s e s t o it e m s  1 a n d   3 ar e  0 %,  1 0 %,  2 0 %,  3 0 %,  4 0 %,  5 0 %,  6 0 %,  7 0 %,  8 0 %, 
9 0 %,  a n d  1 0 0 %.  Pri or t o  c o m p uti n g t h e  T FI t ot al  s c or e, t h e r e s p o n s e s f or it e m s  1  a n d  3  ar e 
tr a n sf or m e d fr o m  a p er c e nt a g e  s c al e  t o  a  0 t o 1 0  s c al e,  b y  di vi di n g  t h e v al u e s  b y  1 0.  
 
T h e  T FI  t ot al s c or e  i s t h e n d efi n e d  a s   a s u m  of  t h e 2 5  it e m s, aft er  it e m s  1 a n d   3 ar e 
tr a n sf or m e d. T h e  t ot al T FI  s c or e  i s c al c ul at e d  a s  t h e s u m  of  t h e 2 5  s c or e s,  di vi d e d  b y  t h e 
n u m b er  of  n o n -mi s si n g  s c or e s,  m ulti pli e d  b y  1 0.  T h e t ot al  s c or e r a n g e s fr o m  0 t o  1 0 0,  wit h 
hi g h er  s c or e s  r e pr e s e nti n g gr e at er  p er c ei v e d  h a n di c a p.  
 
T h e  T FI t ot al  s c or e i s  n ot  v ali d if  7  or  m or e it e m s  ar e  o mitt e d.  T o  b e  v ali d  a s  a  m e a s ur e  of 
ti n nit u s s e v erit y,  at  l e a st 1 9  it e m s m u st  b e  c o m pl et e d.  
 
T FI  S u b s c al e s  
 
T h e  2 5 it e m s  c a n  al s o  b e  gr o u p e d i nt o  8  s u b s c al e s: i ntr u si v e,  s e n s e  of  c o ntr ol,  c o g niti v e, 
sl e e p,  a u dit or y,  r el a x ati o n,  q u alit y of  lif e,  a n d e m oti o n al.  
 
• 
T h e  i ntr u si v e gr o u p  i n cl u d e s it e m s 1,  2,  a n d  3.  
• 
T h e  s e n s e  of  c o ntr ol  gr o u p  i n cl u d e s it e m s 4,  5,  a n d  6.  
 
• 
T h e  c o g niti v e  gr o u p  i n cl u d e s it e m s 7,  8,  a n d  9.  
• 
T h e  sl e e p  gr o u p  i n cl u d e s it e m s 1 0,  1 1,  a n d  1 2.  
• 
T h e  a u dit or y  gr o u p  i n cl u d e s it e m s 1 3,  1 4,  a n d  1 5.  
 
• 
T h e  r el a x ati o n gr o u p  i n cl u d e s it e m s 1 6,  1 7,  a n d  1 8.  
• 
T h e  q u alit y  of  lif e gr o u p  i n cl u d e s it e m s 1 9,  2 0,  2 1,  a n d  2 2.  
 
• 
T h e  e m oti o n al  gr o u p  i n cl u d e s it e m s 2 3,  2 4,  a n d  2 5.  
T h e  s u b s c al e  s c or e s  will  b e  c o m p ut e d  b y  s u m mi n g t h e  p oi nt s f or  e a c h  q u e sti o n  i n cl u d e d i n 
t h e r el e v a nt s u b s c al e,  di vi di n g  b y  t h e n u m b er  of  n o n -mi s si n g  s c or e s  wit hi n  t h e s u b s c al e, 
m ulti pli e d  b y  1 0.  E a c h  s u b s c al e  s c or e  h a s   a r a n g e of   0 t o 1 0 0.  E a c h  T FI  s u b s c al e  s c or e  i s n ot 
v ali d  if  2 or  m or e  it e m s ar e  o mitt e d.   T o  b e  v ali d  s u b s c al e  s c or e s,  n o  m or e  t h a n  1 it e m c a n 
b e  o mitt e d. 

Prot_000.pdf: 
Page 1 of 50 
FX-322-202 V5.0 8Feb2021 
 
CLINICAL STUDY PROTOCOL 
A Phase 2a, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Single and Repeat-Dose, Multicenter, Exploratory Efficacy 
Study of FX-322 Administered by Intratympanic Injection in Adults 
with Stable Sensorineural Hearing Loss 
 
 
Protocol Number: 
FX-322-202 
EudraCT Number: 
N/A 
National Clinical Trial (NCT) 
Identified Number 
NCT04120116 
 
Investigational Product: 
FX-322 
Phase: 
2a 
Sponsor: 
 
Frequency Therapeutics 
19 Presidential Way 
Woburn. MA 01801 
USA 
 
 
Protocol Date: 
8 February 2021 
Protocol Version: 
5.0 
 
 
CONFIDENTIAL 
 
 
This protocol may not be reproduced or communicated to a third party without the 
written permission of Frequency Therapeutics


 
Page 2 of 50 
FX 322 202 V5 0 8Feb2021
1 
PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Phase 2a, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Single and Repeat-Dose, Multicenter, Exploratory Efficacy 
Study of FX-322 Administered by Intratympanic Injection in Adults with 
Stable Sensorineural Hearing Loss 
 
Protocol Number: 
 
FX-322-202 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the sponsor and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  All changes to the 
consent form will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
Page 3 of 50 
FX 322 202 V5 0 8Feb2021
2 
SYNOPSIS 
Protocol Number: 
FX-322-202 
Title: 
A Phase 2a, Prospective, Randomized, Double-Blind, Placebo-Controlled, Single and Repeat-
Dose, Multicenter, Exploratory Efficacy Study of FX-322 Administered by Intratympanic 
Injection in Adults with Stable Sensorineural Hearing Loss 
Investigational Product: 
FX-322 
Study Centers: 
Approximately 15 centers in the US 
Phase: 
Phase 2a 
 
Objectives: 
Primary Objective(s) 
1. To assess the exploratory efficacy by audiologic response following single and repeat 
doses of FX-322 in subjects with stable sensorineural hearing loss. 
2. To assess the local and systemic safety of single and repeat doses at of FX-322 in 
subjects with stable sensorineural hearing loss. 
 
Endpoints: 
 
Efficacy Endpoint(s) 
• Mean changes from Screening in: 
o Word Recognition in quiet (WR) 
o Words-In-Noise testing (WIN) 
o Standard Pure Tone Audiometry (air 0.25-8 kHz; bone 0.5-4 kHz) 
 
Additional Exploratory Efficacy Endpoint(s) 
• Mean changes from Screening in: 
o Extended High Frequency Audiometry (air 9-16 kHz) 
o Tinnitus Functional Index (TFI) 
o Hearing Handicap Inventory for Adults (HHIA) 
o Hearing Screening Inventory (HSI) 
 
Safety Endpoint(s) 
• Adverse events 
• Changes from Screening in: 
o Otoscopy 
o Tympanometry 


 
Page 4 of 50 
FX 322 202 V5 0 8Feb2021
Study Design: 
This is a Phase 2a, prospective, randomized, double-blind, placebo-controlled, single and 
repeat-dose, multicenter, exploratory efficacy study of FX-322, administered by 
intratympanic injection, in adults with stable sensorineural hearing loss (no changes in air 
conduction greater than 10 dB at a single frequency or greater than 5dB at two contiguous 
frequencies from the prior audiogram to the Screening audiogram).  
The study will have 3 phases: Screening, Treatment, and Follow-up. 
Screening:  Can occur up to 30 days prior to study drug administration (Baseline/Treatment 
Day 1). All subjects will be screened to determine study eligibility. As part of recording the 
medical history of subjects, concurrent use of hearing aids during the study will be 
documented.  All subjects will return for the Baseline visit and evaluated to ensure they 
continue to meet appropriate inclusion/exclusion criteria applicable at that visit. 
Baseline/Treatment: Approximately 96 subjects are planned to be enrolled in this study.  The 
subjects will be randomized to receive FX-322 or placebo according to the different treatment 
group schedules listed below: 
Group Dosing Schedule 
Treatment 
Group 
# of 
Subjects 
Day 1 
Day 8 
Day 15 
Day 21 
1 
24 
FX-322 
Placebo 
Placebo 
Placebo 
2 
24 
FX-322 
FX-322 
Placebo 
Placebo 
3 
24 
FX-322 
FX-322 
FX-322 
FX-322 
4 
24 
Placebo 
Placebo 
Placebo 
Placebo 
 
Once a subject has been identified as meeting all inclusion/exclusion criteria, the qualifying 
ear with the worse hearing (ear with the worst Screening pure tone average) will be selected, 
unless a rationale exists to treat the other ear (e.g. the worse hearing ear does not meet the study 
criteria).  The study treatment or placebo will be administered on Day 1, Day 8, Day 15, and 
Day 21. The placebo will be matched to FX-322 in consistency and color.  
Each subject will be placed in the supine position. Topical anesthesia will be administered to 
the tympanic membrane. Under a microscope, a 25-gauge needle will be used to inject FX-322 
or placebo into the middle ear at the junction of the posterior inferior and posterior superior 
quadrant with the needle tip directed towards the round window. The posterior superior 
quadrant should be avoided to prevent injury to the ossicles.  After injection, the subject will 
continue to lie with the injected ear facing up for 10-15 minutes. The injections will be 
performed at an appropriate location designated by a Board-certified Otolaryngologist  trained 
and experienced in performing intratympanic injections. Safety monitoring will include 
recording of adverse events (AEs), safety laboratory assessments, and monitoring of 
tympanometry and otoscopic exams. 
Follow up: Subject will be required to return to clinic for safety, otologic, and audiologic 
assessments at Days 15, 60, 90, 150, and 210 after the initial injection.  Subjects will be 
contacted by phone for safety assessments at Days 30, 120, and 180. 
Number of Subjects:  
Approximately 96 evaluable subjects 
Study Duration: 
Screening phase: up to 30 days before first study drug administration (Baseline Visit). 


 
Page 5 of 50 
FX 322 202 V5 0 8Feb2021
Treatment phase: 21 days (4 treatment visits 7 days apart) 
Follow-up phase: 7 months from Baseline (Day 1). 
 
Study Population: 
Male and female adults (18 to 65 years inclusive), otherwise healthy with stable sensorineural 
hearing loss.  
Statistical Analysis: 
Sample Size:  The sample size of approximately 24 subjects per group was considered 
adequate to explore the potential efficacy of FX-322 associated with various dosing schedules 
and was not based on formal statistical evaluation. 
Statistical Methods:  Descriptive summaries will be provided for patient disposition, 
demographic and baseline disease data.  Summary statistics for efficacy endpoints will be 
provided for each randomized treatment group  and timepoint.  Comparisons of each FX-322 
group to placebo along with 95% confidence intervals of the difference will also be 
calculated.  Additionally, comparisons among the 3 FX-322 groups will also be conducted as 
well as a pooled FX-322 group comparison to placebo group.  The Full Analysis Set defined 
as all randomized subjects exposed to at least one dose of study drug, will comprise the 
analysis set for the exploratoration of efficacy.  Additional sensitivity analyses will be 
conducted using a Per Protocol Analysis Set.  Subjects will be analysed by their randomized 
treatment group for both the Full Analysis and Per Protocol Analysis Set analyses.   
The incidence of  treatment-emergent adverse events will be presented by preferred term and 
body system using the Medical Dictionary for Regulatory Activities (MedDRA®).  
Tabulations will be provided by seriousness, severity, and relationship to study drug.  
Laboratory, tympanometry and otologic data will be presented as summary statistics at each 
timepoint as well as changes from baseline and/or shift tables.  All subjects exposed to study 
drug will be included in the Safety Analysis Set and included in the safety analyses according 
to the actual treatment group regardless of the randomized assignment.   
Details of the planned statistical analyses and methods will be provided in the Statistical 
Analysis Plan (SAP) which will be finalized prior to database lock and study blind break 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 6 of 50 
FX 322 202 V5 0 8Feb2021
PROTOCOL Version 5.0 Amendments 
 
Item No. 
Change 
Section and Page Number(s) 
1 
Updated date and version of protocol. Title Page, pg.1 
Footer, every page 
2 
Updated language regarding data 
monitoring at the Day-90 Interim 
Analysis 
Section 14.1.6 Interim Analysis pg. 
41. 
 
PROTOCOL Version 4.0 Amendments 
Item No. 
Change 
Section and Page Number(s) 
1 
Updated date and version of protocol. Title Page, pg.1 
Footer, every page 
2 
Updated information regarding 
blinding roles on the study 
 
Section 8.7.1 Blinding pg. 27. 
3 
Updated language to conduct data 
monitoring following the Day 90 visit 
Section 14.1.6 Interim Analysis pg. 
41. 
 
PROTOCOL Version 3.0 Amendments 
Item No. 
Change 
Section and Page Number(s) 
1 
Updated date and version of protocol. Title Page, pg.1 
Footer, every page 
2 
Updated visit type from clinic to 
phone. 
Synopsis, pg. 4 
Section 8.1 Overall Study Design and 
Plan, pg. 17. 
Section 8.1.2 Schedule of 
Assessments, pg. 18. 
Section 10.1.4 – 10.1.9 Visits, pgs. 
30-31. 
 
3 
Removed assessments from visits 
Section 11 Efficacy Measures pg. 32. 
Section 12.1.7 Otoscopy, pg 34. 
Section 12.1.8 Tympanometry, pg 34. 
 
4 
Updated language around interim 
analysis 
Section 14.1.6 Interim Analysis pg. 
41. 
5 
Updated how missing data will be 
handled 
Section 14.2 Handling of Missing 
Subject Data and Subject Withdrawls 
pg. 42. 
6 
Updated text for grammatical and 
capitalization consistency   
Throughout Protocol 
 
 
 
 
 
 
 
 


 
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FX 322 202 V5 0 8Feb2021
 
 
 
 
 
 
 
 
 
 
PROTOCOL Version 2.0 Amendments 


 
Page 8 of 50 
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Item No. 
Change 
Section and Page Number(s) 
1 
Updated date and version of protocol. Title Page, pg.1 
Footer, every page 
2 
Added information and signature for 
Sponsor Chief Medical Officer 
Sponsor Signature, pg. 2 
3 
Defined “ear with worst hearing” as 
ear with the worst Screening pure 
tone average 
Section 2  Synopsis, pg. 4 
Section 8.1, Overall Study Design 
and Plan, pg. 15 
Section 8.7.5, Selection and Timing 
of Dose for Each Subject, pg. 26 
4 
Clarified randomization should be 
>50% correct, <50% correct for the 
WR scores 
Section 8.1 Overall Study Design and 
Plan, pg. 15 
Section 8.7.3 Method of Assigning 
Subjects to Treatment Groups, pg. 25 
5 
Updated stability criteria for 
clarification 
Section 8.1 Overall Study Design and 
Plan, pg. 15 
Section 8.4.2. Inclusion Criteria, pg. 
19 
6 
Updated Exclusion Criteria #4 to 
allow for clarification of definition of 
conductive hearing loss 
Section 8.4.3. Exclusion Criteria, pg. 
20 
7 
Removed EMLA brand name to 
allow for use of generic topical 
anesthesia 
Section 2  Synopsis, pg. 4 
Section 8.5.1, Investigational Product 
Administered, pg. 22 
Section 8.6.1 Packaging and 
Labeling, pg. 24 
 
8 
Updated language to allow for 
subjects to be rescreened 
Section 8.4.5. Screen Failures, pg. 22 
9 
Added guidance for which prior 
audiogram should be used to confirm 
Inclusion/Exclusion criteria 
Secition 10.1.1 Screening, pg. 28 
10 
Removed alcohol from urine drug 
testing 
Section 10.1.1 Screening, pg. 28 
Section 12.1.2 Clinical Laboratory 
Evaluation, pg 33 
11 
Clarified that the WR AESI should be 
recorded for the treated ear only 
Section 13  Adverse Events, Adverse 
Events of Special Interest, pg. 36 
12 
Updated descriptive statistics to 
reflect change in Inclusion Criteria 
Section 14.1.1.  Descriptive Statistics, 
pg. 37 
13 
Updated text for grammatical and 
capitalization consistency   
Throughout Protocol 
 
 
 
 


 
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3 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures .................................................................................. 2 
2 
Synopsis ...................................................................................................................... 3 
3 
Table of Contents ....................................................................................................... 8 
4 
List of Abbreviations and Definition of Terms ..................................................... 13 
5 
Introduction .............................................................................................................. 14 
6 
Risk/Benefit Assessment .......................................................................................... 15 
6.1 
Known Potential Benefits ........................................................................................ 15 
6.2 
Known Potential Risks ............................................................................................ 16 
6.3 
Assessment of Potential Risks and Benefits ........................................................... 16 
7 
Study Objectives and Endpoints ............................................................................ 16 
7.1 
Primary Objective(s) ............................................................................................... 16 
7.2 
Endpoints .................................................................................................................. 16 
8 
Investigational Plan ................................................................................................. 17 
8.1 
Overall Study Design and Plan: Description ......................................................... 17 
8.1.1 
Study Design ............................................................................................. 18 
8.1.2 
Schedule of Assessments .......................... Error! Bookmark not defined. 
8.2 
Scientific Rationale for Study Design .................................................................... 21 
8.3 
End of Study Definition ........................................................................................... 21 
8.4 
Selection of Study Population ................................................................................. 21 
8.4.1 
Number of Planned Subjects .................................................................... 21 
8.4.2 
Inclusion Criteria ...................................................................................... 21 
8.4.3 
Exclusion Criteria ..................................................................................... 22 
8.4.4 
Withdrawal of Subjects From Study Drug and/or Study 
Assessments .............................................................................................. 22 
8.4.5 
Screen Failures .......................................................................................... 23 
8.5 
Investigational Products .......................................................................................... 24 
8.5.1 
Investigational Products Administered ..................................................... 24 
8.5.2 
Identity of Investigational Products .......................................................... 24 
8.6 
Preparation and Dispensing .................................................................................... 24 
8.6.1 
Packaging and Labeling ............................................................................ 26 
8.6.2 
Supply, Storage and Handling .................................................................. 26 
8.6.3 
Compliance and Drug Accountability ...................................................... 26 
8.6.4 
Disposal, Return or Retention of Study Drug ........................................... 26 
8.7 
Randomization and Blinding .................................................................................. 27 


 
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8.7.1 
Blinding .................................................................................................... 27 
8.7.2 
Un-blinding ............................................................................................... 27 
8.7.3 
Method of Assigning Subjects to Treatment Groups ............................... 27 
8.7.4 
Selection of Doses in the Study ................................................................ 27 
8.7.5 
Selection and Timing of Dose for Each Subject ....................................... 28 
8.8 
Prior and Concomitant Therapy ............................................................................ 28 
8.8.1 
Prohibited Medication/Therapy ................................................................ 28 
8.8.2 
Rescue Medication .................................................................................... 28 
8.8.3 
Treatment Compliance .............................................................................. 29 
9 
Discontinuation and lost to follow-up .................................................................... 29 
9.1 
Discontinuation of Study Intervention ................................................................... 29 
9.2 
Lost to Follow-up ..................................................................................................... 29 
10 
Timing of Study Procedures ................................................................................... 29 
10.1 Pre-treatment ........................................................................................................... 30 
10.1.1 
Screening Visit (Visit 1; Day -30 to 0) ..................................................... 30 
10.1.2 
Baseline/Treatment Visit (Visit 2a, [Day 1]) ............................................ 30 
10.1.3 
Additional Treatment Visits (Visits 2b, 2c, 2d, [Days 8, 15 and 
21] +/- 2 days) ........................................................................................... 30 
10.1.4 
Follow-up (Visit 3, [Day 30 +/- 15 days]) ................................................ 31 
10.1.5 
Follow-up (Visit 4, [Day 60 +/- 15 days]) ................................................ 31 
10.1.6 
Follow-up (Visit 5, [Day 90 +/- 15 days]) ................................................ 31 
10.1.7 
Follow-up (Visit 6, [Day 120 +/- 15 days]) .............................................. 32 
10.1.8 
Follow-up (Visit 7, [Day 150 +/- 15 days]) .............................................. 32 
10.1.9 
Follow-up (Visit 8, [Day 180 +/- 15 days]) .............................................. 32 
10.1.10 
Follow-up (Visit 9. [Day 210 +/- 15 days]) .............................................. 32 
10.2 Duration of Treatment ............................................................................................ 33 
11 
Efficacy Assessments ............................................................................................... 33 
11.1 Efficacy Measurements Assessed ........................................................................... 33 
11.1.1 
Word Recognition in Quiet (WR) ............................................................. 33 
11.1.2 
Words-In-Noise Testing (WIN) ................................................................ 33 
11.1.3 
Standard Pure Tone Audiometry .............................................................. 33 
11.2 Exploratory Efficacy Measurements Assessed ..................................................... 33 
11.2.1 
Extended High Frequency Audiometry .................................................... 33 
11.2.2 
Tinnitus Functional Index (TFI) ............................................................... 34 
11.2.3 
Hearing Handicap Inventory for Adults (HHIA) ...................................... 34 
11.2.4 
Hearing Screening Inventory (HSI)) ........................................................ 34 
12 
Safety Assessments ................................................................................................... 34 
12.1 Safety Measurements Assessed ............................................................................... 34 
12.1.1 
Concomitant Medication .......................................................................... 34 
12.1.2 
Clinical Laboratory Evaluation ................................................................. 34 


 
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FX 322 202 V5 0 8Feb2021
12.1.3 
Vital Signs ................................................................................................ 35 
12.1.4 
Physical Exam (PE) .................................................................................. 35 
12.1.5 
Columbia Suicide and Severity Rating Scale (C-SSRS) .......................... 35 
12.1.6 
Body Mass Index (BMI) ........................................................................... 35 
12.1.7 
Otoscopy ................................................................................................... 35 
12.1.8 
Tympanometry .......................................................................................... 35 
13 
Adverse Events ......................................................................................................... 36 
13.1 Serious Adverse Events ........................................................................................... 38 
13.2 Expedited Safety Reporting .................................................................................... 39 
14 
Statistical Methods ................................................................................................... 40 
14.1 Statistical and Analytical Plans .............................................................................. 40 
14.1.1 
Descriptive Statistics ................................................................................ 40 
14.1.2 
Sample Size .............................................................................................. 40 
14.1.3 
Analysis Sets ............................................................................................. 40 
14.1.4 
Subject Disposition, Demographics and Baseline Disease Status ............ 41 
14.1.5 
Efficacy Exploration ................................................................................. 41 
14.1.6 
Interim Analyses ....................................................................................... 42 
14.1.7 
Safety Analyses ........................................................................................ 43 
14.1.7.1 Adverse Events ......................................................................................... 43 
14.1.7.2 Clinical Laboratory Evaluations ............................................................... 43 
14.1.7.3 Vital Signs and Physical Examation ......................................................... 43 
14.1.7.4 Prior and Concomitant Medications ......................................................... 43 
14.1.7.5 Tympanometry and Otoscopy ................................................................... 43 
14.2 Handling of Missing Data and Subject Withdrawals ........................................... 43 
15 
Quality Assurance and Quality Control ................................................................ 44 
15.1 Audit and Inspection ............................................................................................... 44 
15.2 Monitoring ................................................................................................................ 44 
15.3 Data Management and Coding ............................................................................... 44 
16 
Records and Supplies .............................................................................................. 45 
16.1 Drug Accountability ................................................................................................ 45 
16.2 Financing and Insurance ......................................................................................... 45 
17 
Ethics ......................................................................................................................... 45 
17.1 Independent Ethics Committee or Institutional Review Board .......................... 45 
17.2 Regulatory Authorities ............................................................................................ 45 
17.3 Ethical Conduct of the Study .................................................................................. 45 
17.4 Informed Consent .................................................................................................... 46 
17.5 Subject Confidentiality ............................................................................................ 46 


 
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18 
References ................................................................................................................. 48 
19 
Appendix 1 ................................................................................................................ 49 
Word Recognition Scoring Chart .............................................................................. 49 
20 
Investigator Signature Page .................................................................................... 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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FX 322 202 V5 0 8Feb2021
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ASHA 
American Speech-Language-Hearing Association 
BMI 
Body mass index 
BPPV 
Benign Paroxysmal Positional Vertigo 
NIHL 
Noise induced hearing loss 
CONSORT 
Consolidation Standards of Reporting Trials 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide and Severity Rating Scale 
dB 
Decibel 
DMSO 
Dimethyl sulfoxide 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FAS 
Full Analysis Set 
FDA 
Federal Drug Administration 
GCP 
Good Clinical Practice 
GLMM 
Generalized Linear Mixed Models 
GSK 
Glycogen Synthase Kinase 
HDAC 
Histone deacetylase 
HCG 
Human chorionic gonadotrophin 
HHIA 
Hearing Handicap Inventory in Adults 
HSI 
Hearing Screening Inventory 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LGR5+ 
Leucine-rich repeat-containing G-protein coupled receptor 5 
positive 
MAR 
Missing at Random 
MedDRA Ò 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
PE 
Physical exam 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PPAS 
Per Protocol Analysis Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SfAS 
Safety Analysis Set 
SNHL 
Sensorineural hearing loss  
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexcepted Serious Adverse Reaction 
TFI 
Tinnitus Functional Index 
TM 
Tympanic membrane 
WHO 
World Health Organization 
WIN 
Words-In-Noise Testing 
WR 
Word Recognition in quiet 
 
 


 
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FX 322 202 V5 0 8Feb2021
5 
INTRODUCTION 
Worldwide, an estimated 1.1 billion people are at risk for hearing loss due to exposure to 
damaging levels of sound (WHO, 2015). The WHO also reported that 16% of the disabling 
hearing loss in adults is attributable to occupational noise exposure (Nelson et al, 2005). The 
hearing loss population shows higher rates of dementia, depression, and other mental health 
disorders, especially in the elderly (Choi et al, 2016; McGilton et al, 2016; Deal et al, 2016). 
Sensorineural hearing loss (SNHL) accounts for about 90% of all cases of hearing loss (Li et 
al, 2017). Leading causes include noise exposure, ototoxic medications, advanced age, 
inherited, and autoimmune disorders. Noise is a major occupational and environmental 
hazard, causing hearing loss, sleep disturbance, fatigue, and hypertension (Hong et al, 2013). 
SNHL has long been recognized as the primary and direct health effect of excessive noise 
exposure (Basner et al, 2015). In the United States, an estimated 48 million people or 20.3% 
of the population 12 years or older has hearing loss in one or both ears (Lin et al, 2011).  
Excessive sound levels or loud sounds for extended periods time hyperstimulate cochlear hair 
cells, which can lead to increased production of reactive oxygen species and oxidative cell 
death. Presently, no curative treatments exist, but rather assistive devices such as hearing aids 
and cochlear implants are used to address the symptoms of SNHL. These options, however, 
do not address the underly biological deficit of SNHL and are not sufficient for normal 
quality of life in individuals with SNHL. 
FX-322 is a fixed ratio dose combination of two small molecules: a glycogen synthase kinase 
(GSK) inhibitor, FX03, and Valproate Sodium (an HDAC inhibitor approved in multiple 
countries including the US for human use as Depacon®). 
The active ingredients in FX-322 target two cellular mechanisms, histone deacetylase 
(HDAC) inhibition and GSK-3 inhibition, which act synergistically to induce a regenerative 
response in cochlear tissue. The combination of the mechanisms was shown to enable 
Leucine-rich repeat-containing G-protein coupled receptor 5 positive (Lgr5+) progenitor cells 
to asymmetricly divide to create a copy of themselves and a daughter cell that can become a 
hair cell (McLean et al, 2017). Thus, FX-322 could serve as a treatment for hearing loss by 
restoring lost hair cells. 
In preclinical experiments, a fixed ratio dose combination of FX03 and Valproate Sodium 
demonstrates: 
• Expansion of the Lgr5+ progenitor cells and subsequent conversion into hair cells 
using newborn and adult cells. Substantial Lgr5+ cell expansion occurs with the 
combination of agents but not with the individual agents.  
• Expansion of progenitor cells from adult primate inner ear, and expansion and 
subsequent conversion of progenitor cells into hair cells from the adult human inner 
ear. 
• Formation of new hair cells in ototoxin damaged mouse cochlear explants. 
• Significant improvement in hearing and hair cell numbers in an adult mouse model of 
noise-induced hearing loss. 
Based on these findings, FX-322 is formulated as a fixed ratio dose combination, which also 
contains 
 
 
 


 
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FX 322 202 V5 0 8Feb2021
FX-322 will be 
administered by an intratympanic injection into the middle ear onto the round window 
membrane area, enabling the active ingredients to locally diffuse into the cochlea. 
Minimal systemic exposure occurred after a single intratympanic injection of FX-322 in two 
previous clinical trials. In the first of these trials, FX-322-103, nine patients undergoing 
cochlear implantation surgery received a single unilateral intratympanic injection of FX-322 
(6 patients) or placebo (3 patients) to study tolerability, systemic drug exposure, and cochlear 
drug exposure.  The results demonstrated acceptable local and systemic acute tolerability and 
very limited systemic exposure that was unmeasurable within 24 hours post injection.  In 
addition, the cochlear FX-322 drug concentration data demonstrated the drug was present at 4 
hours after intratympanic injection in one patient but unmeasurable after 24 hours in the 
perilymph in two subjects. 
The second clinical trial was a Phase 1/2  (FX-322-201) randomized, double-blind, placebo-
controlled single-dose study in adults with stable sensorineural hearing loss.  The objectives of 
this study were to assess: 1) the systemic safety of two dose levels of FX-322; 2) the plasma 
pharmacokinetic profile of FX-322; and 3) the effect of FX-322 on otologic and audiologic 
measures. After intratympanic injection of FX-322, there were no serious adverse events 
(SAEs) or AEs that led to a subject withdrawal or death and the most common AEs were 
considered associated with the intratympanic injection procedure. No clinically significant 
safety issues were observed on otologic or audiologic measures.  Additionally, the systemic 
PK profile of FX-322 was minimal and dose-proportionate with both drugs cleared from the 
circulation within approximately 24 hours. Over the course of the study, a post-hoc analysis 
showed a statistically significant improvement in WR for patients treated with FX-322 versus 
patients given placebo.  FX-322 patients showed an improvement in WR scores from baseline 
to Day 90. In addition, the FX-322 group showed a clinically meaningful improvement in WIN 
scores from baseline to Day 90 as determined by Wilson and McArdle, 2007. Four of the FX-
322 patients showed a clinically meaningful improvement in WR according to established 
audiological definitions (Thorton and Raffin, 1978), with two of these patients demonstrating 
WIN improvements that are defined as clinically meaningful (Wilson and McArdle, 2007).  
The notable improvements in these measures of hearing function were generally observed in 
FX-322 patients within 15-30 days of treatment and were sustained for 90 days.  There was no 
difference in treatment effect observed between the two dose volumes of FX-322. 
 
6 
RISK/BENEFIT ASSESSMENT 
6.1 
Known Potential Benefits 
The active ingredients in FX-322 target two cellular mechanisms, histone deacetylase 
(HDAC) inhibition and GSK-3 inhibition, which act synergistically to induce a regenerative 
response in cochlear tissue. FX-322 could serve as a treatment for patients with SNHL 
because the active ingredients have demonstrated 1) the ability to induce progenitor cell 
expansion and subsequent conversion into new hair cells across species, including human, 2) 
restoration of hair cells in ototoxin-damaged mouse cochlear implants, and 3) a significant 
improvement in hearing and hair cell numbers in an adult mouse model of noise-induced 
hearing loss. 
Most recently it has been shown that in humans with stable SNHL, a single intratympanic 
dose of FX-322 was associated with improvements in speech intelligibility as measured by 


 
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FX 322 202 V5 0 8Feb2021
WR and WIN, data that suggest FX-322 may restore hearing function to some degree in 
humans. 
6.2 
Known Potential Risks 
The risks of intratympanic injection of FX-322 have been carefully studied in nonclinical 
toxicology studies, as well as in two separate clinical trials. Based on these studies, the risks 
appear to be similar to those experienced with intratympanic injections of other materials, 
such as steroids, that are not FDA-approved. The risks are characterized as persistent eardrum 
perforation, pain or bleeding with injection, temporary dizziness, middle ear infection, and 
conductive or sensorineural hearing loss. A published clinical trial using multiple 
intratympanic injections of a steroid in SSNHL patients has shown the majority of adverse 
events to be associated with the injection procedure, with eardrum perforations reported at 
less than 4% (Rauch et al., 2011). 
6.3 
Assessment of Potential Risks and Benefits 
Based on the very low potential for risk, which is primarily associated with the intratympanic 
injection procedure, compared to the potential benefit which is the possibility of restoration 
of hearing, the risk/benefit profile is considered acceptable to conduct the study described 
herein. 
7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary Objective(s) 
1. To assess the exploratory efficacy by audiologic response following single and 
repeated doses of FX-322 in subjects with stable sensorineural hearing loss. 
2. To assess the local and systemic safety of single and repeat doses at of FX-322 in 
subjects with stable sensorineural hearing loss. 
 
7.2 
Endpoints 
Efficacy Endpoint(s) 
• Mean changes from Screening in: 
o Word Recognition in quiet (WR) 
o Words-In-Noise testing (WIN) 
o Standard Pure Tone Audiometry (air 0.25-8 kHz; bone 0.5-4 kHz) 
 
Additional Exploratory Efficacy Endpoint(s) 
• Mean changes from Screening in: 
o Extended High Frequency Audiometry (air 9-16 kHz) 
o Tinnitus Functional Index (TFI) 
o Hearing Handicap Inventory for Adults (HHIA) 
o Hearing Screening Inventory (HSI)  
 
Safety Endpoint(s) 
• Adverse events  
• Changes from Screening in: 
o Otoscopy 
o Tympanometry 


 
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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a Phase 2a, prospective, randomized, double-blind, placebo-controlled, single and 
repeat-dose, multicenter, exploratory efficacy study of FX-322, administered by 
intratympanic injection, in adults with stable sensorineural hearing loss (no changes in air 
conduction greater than 10 dB at a single frequency or greater than 5dB at two contiguous 
frequencies from the prior audiogram to the Screening audiogram in the study ear). 
 
In a previous human study, Study FX-322-201, it was demonstrated that a single dose FX-
322 was well-tolerated in patients with hearing loss with no drug-related serious adverse 
events.  The only ear related adverse events in the study were consistent with those 
experienced with a standard intratympanic injection. Additionally, FX-322 was shown to be 
associated with improvements in hearing function in some patients that were considered 
clinically meaningful, as defined by several key measures of audibility and intelligibility. 
 
Screening:  Can occur up to 30 days prior to study drug administration (Baseline/Treatment 
Day 1). All subjects will be screened to determine study eligibility. As part of recording the 
medical history of subjects, concurrent use of hearing aids will be documented.  All subjects 
will return for the Baseline visit and evaluated to ensure they continue to meet 
inclusion/exclusion criteria applicable at that visit. 
 
Baseline/Treatment: Approximately 96 subjects are planned to be enrolled in this study.  
The subjects will be randomized to receive FX-322 or placebo according to the different 
treatment group schedules listed below: 
 
Group Dosing Schedule 
Treatment 
Group 
# of 
Subjects 
Day 1 
Day 8 
Day 15 
Day 21 
1 
24 
FX-322 
Placebo 
Placebo 
Placebo 
2 
24 
FX-322 
FX-322 
Placebo 
Placebo 
3 
24 
FX-322 
FX-322 
FX-322 
FX-322 
4 
24 
Placebo 
Placebo 
Placebo 
Placebo 
 
Subjects will be stratified at randomization by baseline (last assessment before study drug 
administration Word Recognition (>=50% correct, <50% correct) and etiology of hearing 
loss (Sudden vs Noise). 
 
Once a subject has been identified as meeting all inclusion/exclusion criteria, the qualifying 
ear with the worse hearing (ear with the worst Screening pure tone average) will be selected, 
unless a rationale exists to treat the other ear.  The study treatment or placebo will be 
administered on Day 1, Day 8, Day 15, and Day 21. The placebo will be matched to FX-322 
in consistency and color.  
 


 
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Each subject will be placed in the supine position. Topical anesthetic cream will be 
administered to the tympanic membrane. Under a microscope, a 25-gauge needle will be used 
to inject FX-322 or placebo into the middle ear at the junction of the posterior inferior and 
posterior superior quadrant with the needle tip directed towards the round window. The 
posterior superior quadrant should be avoided to prevent injury to the ossicles.  After 
injection, the subject will continue to lie with the injected ear facing up for 10-15 minutes. 
The injections will be performed at an appropriate location designated by a Board-certified 
Otolaryngologist trained and experienced in performing intratympanic injections.  Safety 
monitoring will include recording of adverse events (AEs), safety laboratory assessments,  
and monitoring of tympanometry and otoscopic exams. 
 
Follow up:  
Subjects will be required to return to clinic for safety, otologic, and audiologic assessments at 
Days 15, 60, 90, 150, and 210 after the initial injection.  Subjects will be contacted by phone 
for safety assessments at Days 30, 120, and 180. 
Unscheduled visits may occur as needed.  See the Schedule of Assessments for more 
information. 
 
8.1.1 Study Design 
   
  
 
 
 
 


 
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FX 322 202 V5 0 8Feb2021
8.1.2 Schedule of Assessments 
 
 
Visit  
Screening 
Baseline/ 
Treatment 
Additional  
Treatments e 
Phone 
Follow-up e, f 
In-Clinic 
Follow-up e 
Unscheduled 
Visit 
Visit Number 
1 
2a 
2b, 2c, 2d 
3, 6, 8 
4, 5, 7, 9 
UNS 
Assessment/Day 
-30 to 0 
(Day 1)   Day 8, Day 15, 
Day 21 
30, 120, 
 180 
60, 90, 150, 
210  
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
Xb 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History  
X 
Xb 
 
 
 
 
Concomitant Medication  
X 
Xb, c 
Xb, c 
X 
X 
X 
Physical Examination including 
weight and height 
X 
 
 
 
 
 
Vital Signs (body temperature, 
pulse rate, bp) 
X 
Xb 
 
Xb 
 
X 
Xi 
Tympanometry  
X 
 
Xb, d 
 
X 
Xi 
Standard Pure Tone Audiometry 
X 
 
Xb, d 
 
X 
Xi 
Extended High Frequency 
Audiometry 
X 
 
Xb, d 
 
X 
Xi 
Word recognition, quiet  
X 
 
Xb, d 
 
X 
Xi 
Words-In-Noise testing 
X 
 
Xb, d 
 
X 
Xi 
Tinnitus Functional Index 
 
Xb 
 
X g 
X g 
Xi 
Hearing Handicap Inventory for 
Adults 
 
Xb 
 
X g 
X g 
Xi 
Hearing Screening Inventory  
 
Xb 
 
 
X h 
Xi 
Columbia Suicide and Severity 
Rating Scale 
 
Xb 
 
X g 
X g 
Xi 
Otoscopy 
X 
Xb 
Xb 
 
X 
Xi 
Urine Pregnancy Test (women of 
child bearing potential only) 
X 
Xb 
Xb 
 
 
Xi 
Urine Drug Screen 
Xa 
 
 
 
 
 
Safety Laboratory Assessments 
X 
 
 
 
X h 
Xi 
Blood sample for biomarker 
analysis 
 
Xb 
 
 
Xh 
 
Study Medication (FX-322 or 
placebo) 
 
X 
X 
 
 
 
Adverse Events 
 
Xc 
Xb, c 
X 
X 
X 
 
 
 
 
 
 
 


 
Page 20 of 50 
FX 322 202 V5 0 8Feb2021
a- See exclusion regarding positive drug tests    
b- Assessment performed prior to injection. 
c- Assessments performed after injection. 
d- Perform only at Day 15 visit.  
e- Visit windows: +/- 2 days for treatment visits, +/- 15 days for follow up visits. 
f- Subjects will be administered questionnaires over the phone or the internet depending on site’s preference. 
g- Perform only at Day 60, 120, and 210 visits. 
h- Perform only at Day 210 visit. 
i- Perform at Investigator Discretion 
 


 
FX 322 202 V5 0 8Feb2021
Page 21 of 50
 
8.2 
Scientific Rationale for Study Design 
The active ingredients in FX-322 target two cellular mechanisms, histone deacetylase 
(HDAC) and GSK-3 inhibition, which act synergistically to induce progenitor cell expansion 
and new hair cell formation in several ex vivo test systems. In vivo, significant improvements 
in hearing and increases in hair cell counts were observed in an adult mouse model of noise-
induced hearing loss after a single treatment. Most recently, it has been shown that in humans 
with stable SNHL, a single intratympanic dose of FX-322 was associated with improvements 
in speech intelligibility as measured by WR and WIN, data that suggest FX-322 may restore 
hearing function to some degree in humans. Taken together, these data provide justification 
to evaluate the safety and efficacy of multiple intratympanic injections of FX-322 in patients 
with stable SNHL. 
 
8.3 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases 
of the study including the last visit or the last scheduled procedure shown in the Schedule of 
Assessments, Section 8.1.2. 
8.4 
Selection of Study Population 
8.4.1 Number of Planned Subjects  
Approximately 96 subjects are planned to enter the study, and 96 subjects are expected to 
complete the study.   
8.4.2 Inclusion Criteria 
To be eligible for study entry subjects must satisfy all of the following criteria: 
1. Subject has read and voluntarily signed the Informed Consent Form (ICF) after all 
questions have been answered and prior to any study-mandated procedure. 
2. Adult aged 18-65 years inclusive. 
3. Established diagnosis of stable sensorineural hearing loss by standard audiometric 
measures for ≥ 6 months prior to the Screening visit (no changes in air conduction greater 
than 10 dB at a single frequency or greater than 5dB at two contiguous frequencies from 
the prior audiogram to the Screening audiogram in the study ear).  
4. Documented medical history consistent with hearing loss being caused by noise exposure 
or sudden sensorineural hearing loss (documented audiogram at least 6 months prior to 
screening required).  
5. A pure tone average of 26-70 dB at 500Hz, 1000Hz, 2000Hz, and 4000Hz in the ear to be 
injected. 
6. Subjects with a 15% - 85% correct score on Word Recognition test (8 – 42 words correct 
out of 50) at Screening in the study ear. 
7. Ability to communicate well with the Investigator and is willing to comply with and 
complete all the study procedures. 
8. Female subjects must be of non-childbearing potential or will need to utilize two methods 
of highly effective contraception during the study participation (e.g. hormonal 
contraception or an intrauterine device and condoms) or remain abstinent.  Male subjects 


 
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should use condoms with spermicide during the course of the study or remain abstinent.  
Subjects should not donate sperm or ova during the study period. 
8.4.3 Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following criterion are 
applicable: 
1. Subject has previously participated in a FX-322 clinical trial. 
2. Subjects currently on any medication consisting of valproic acid, valproate sodium, or 
divalproex sodium. 
3. Perforation of tympanic membrane or other tympanic membrane disorders that would 
interfere with the delivery and safety assessment of an intratympanic medication or 
reasonably be suspected to affect tympanic membrane healing after injection in study ear.  
This includes a current tympanostomy tube. 
4. Any conductive hearing loss of greater than 15 dB at a single frequency or greater than 
10dB at two or more contiguous octave frequencies in the study ear at the Screening visit 
or on the prior audiogram (if the Investigator feels there is not a true conductive hearing 
loss, the Medical Montior should be consulted). 
5. Active chronic middle ear disease or a history of major middle ear surgery, as an adult, in 
the ear to be injected. 
6. Subject has had an intratympanic injection in either ear within 6 months of the screening 
visit. 
7. History of clinically significant vestibular symptoms at the discretion of the investigator.  
For example, BPPV may be considered acceptable whereas Meniere’s would not.   
8. History of clinically significant systemic autoimmune disease (e.g. rheumatoid arthritis, 
Sjogren's syndrome, multiple sclerosis, psoriasis). 
9. History of head or neck radiation treatment or exposure. 
10. History of platinum-based chemotherapy treatment. 
11. Exposure to another investigational drug within 28 days prior to injection of study drug. 
12. Evidence of any active or chronic disease or condition that could interfere with, or for 
which the treatment of might interfere with, the conduct of the study, or that would pose 
an unacceptable risk to the subject in the opinion of the investigator following a detailed 
medical history, physical examination, and vital signs (systolic and diastolic blood 
pressure, pulse rate, body temperature). 
13. History of substance abuse within 2 years of the Screening Visit. 
14. Positive test for drugs of abuse at screening. In cases when the Investigator feels the 
subject should not be excluded for a positive drug test, the Sponsor will be consulted and 
determine final eligibility. 
15. Positive urine pregnancy test or breast-feeding. 
16. Any known factor, condition or disease that, in the view of the Investigator, might 
interfere with treatment compliance, study conduct or interpretation of the results (e.g. 
previous high-dose aminoglycoside treatment). 
 
8.4.4 Withdrawal of Subjects From Study Drug and/or Study Assessments 
Subjects may discontinue study drug or withdraw from the study for any of the following 
reasons: 
• Adverse Event,  


 
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• Death,  
• Lack of Efficacy,  
• Lost to Follow-up,  
• Non-Compliance with Study Drug,  
• Other,  
• Physician Decision,  
• Pregnancy,  
• Progressive Disease,  
• Protocol Violation,  
• Recovery,  
• Study Terminated by Sponsor,  
• Technical Problem,   
• Withdrawal by Subject 
 
Subjects are free to discontinue study drug and/or withdraw from the study at any time 
without providing reason(s) for withdrawal and without prejudice to further treatment. 
Subjects who discontinue study drug should be encouraged to continue to remain in the study 
and follow the per protocol assessments.  Should a subject withdraw early from the study the 
reason(s) for study withdrawal will be documented in the electronic case report form (eCRF).  
All reasonable efforts will be made to have the subject return for one final assessment. 
Subjects withdrawing from the study will be encouraged to complete the same final 
evaluations as subjects completing the study according to this protocol, particularly safety 
evaluations. The aim is to record data in the same way as for subjects who completed the 
study. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These efforts 
must be documented in the subject’s file. Refer to Section 8.4.4 for details. 
Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the study, in 
subjects or female partners of male subjects, should be confirmed and reported to the 
investigator.  All subjects will be followed until the end of the study, completing study 
assessments as appropriate during pregnancy. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject is subsequently found to be pregnant after inclusion in the study, any 
pregnancy will be followed to term, and the status of mother and child will be reported to the 
sponsor after delivery. 
Full details will be recorded on the pregnancy page of the eCRF if the subject has completed 
the study. 
8.4.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 


 
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information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
Rescreening is allowed for subjects in the Phase 2a study FX-322-202.  Rescreening must 
occur on a different day than the original Screening Visit.  Subjects will need to sign a new 
Informed Consent Form and will be assigned a new Screening number.  All assessments will 
need to be performed again at the new Screening visit. 
 
8.5 
Investigational Products 
8.5.1 Investigational Products Administered 
Subjects will be randomized 1:1:1:1 to four treatment groups to receive multiple doses of 
 A single injection of FX-322 or placebo will be 
administered on Day 1 by intratympanic injection followed by subsequent injections of either 
FX-322 or placebo on Day 8, Day 15 and Day 21 as per treatment group. Randomized 
subjects will be allocated to each of 4 treatment groups (24 in each group).   
 
Group Dosing Schedule 
Treatment 
Group 
# of 
Subjects 
Day 1 
Day 8 
Day 15 
Day 21 
1 
24 
FX-322 
Placebo 
Placebo 
Placebo 
2 
24 
FX-322 
FX-322 
Placebo 
Placebo 
3 
24 
FX-322 
FX-322 
FX-322 
FX-322 
4 
24 
Placebo 
Placebo 
Placebo 
Placebo 
 
Topical anesthetic cream will be administered to the tympanic membrane.  After 10 minutes, 
under a microscope, a 25-gauge needle will be used to inject of FX-322 or placebo into the 
middle ear at the junction of the posterior inferior and posterior superior quadrant with the 
needle tip directed towards the round window. The posterior superior quadrant should be 
avoided to prevent injury to the ossicles.  
 
After injection, the subject will continue to lie with the injected ear facing up for 10-15 
minutes. The injections will be performed at an appropriate location designated by a Board 
Certified Otolaryngologist trained and experienced in performing intratympanic injections.   
 
8.5.2 Identity of Investigational Products 
The investigational drug is FX-322 which is a fixed ratio dose combination of 2 small 
molecules: a glycogen synthase kinase (GSK) inhibitor (FX03) and valproate sodium (FX00), 
a histone deacetylase (HDAC) inhibitor. 
 
8.6 
Preparation and Dispensing 
The FX-322 investigational product is a sterile liquid for intratympanic injection only. 
 
 
 
 


 
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An osmolarity matched placebo for FX-322 is a sterile liquid for intratympanic injection 
only. 
 
 
 
The components in the study drug and placebo are shown in the following tables: 
 
Table FX-322 Study Drug: 
 
Active Ingredients 
Total 
 
FX03 
 
Valproate Sodium 
 
Inactive Ingredients 
 
 
 
 
 
 
 
 
The matched placebo has been developed with similar pH, osmolality and gelation as FX-
322.  
 
 
  
 
Dosages of Active Agents to be Injected in Humans  
 
 
FX-322 
Total 
 
 
FX03 
 
 
FX00 
 
 
 
Frequency Therapeutics will supply sterile FX-322 and placebo, as a sealed sterile vial 
containing 
 and another sterile vial containing 
. The placebo 
or FX-322 is prepared by 
 
  
Each box will be labelled Study drug in compliance with applicable local regulations. FX-
322/Placebo and 
vials will be packaged in separate boxes.  
 
Detailed instructions on compounding the study drug will be provided in the pharmacy 
manual.  
 
All study drug will be transported, received, stored and handled strictly in accordance with 
the product label, the instructions provided to the investigational sites, the sites standard 
operation procedures and applicable regulations.   


 
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8.6.1 Packaging and Labeling 
For the injection, the study drug or placebo will be provided in a kit with 4 study vials 
labelled for each injection (Injection 1, Injection 2, Injection 3, and Injection 4).  The subject 
will be assigned just one kit for all of the study treatments.  The 
 will be taken from 
general stock at the site.  Topical anesthetic cream will be provided to the site.  More 
information can be found in the Pharmacy Manual.  The study drug and placebo will be 
prepared in a sterile 1 mL tuberculin syringe with a sterile cap.  The syringe will be labelled 
clearly with the details for each randomized patient.  Two syringes per patient will be 
provided in case a back-up syringe is needed for injection.  The dose 
 will be filled 
to the 
 mark.  The FX-322 and placebo preparations drawn into the syringes must be 
warmed in a heating unit. Refer to the Pharmacy Manual for further instructions. 
 
The label(s) for the investigational product will include sponsor name, address and telephone 
number, the protocol number, investigational product name, dosage form, amount of 
investigational product per container, lot number, unique kit number, storage conditions, and 
required caution statements and/or regulatory statements, as applicable. 
 
8.6.2 Supply, Storage and Handling 
The vials must be stored as indicated in the Pharmacy Manual. Empty vials and containers 
may be destroyed at the conclusion of the study, after the site monitor has performed 
accountability and in compliance with the site’s SOP.  
8.6.3 Compliance and Drug Accountability 
Accountability for the study drug at the study site is the responsibility of the Investigator, or 
their designee. The Investigator will ensure that the study drug is used only in accordance 
with this protocol. In order to maintain the blinding of the study drug, the Investigator may 
choose to assign some of the drug accountability responsibilities to a unblinded pharmacist or 
other appropriate individual. This individual will not perform any other study procedures 
other than study drug preparation and accountability.  Drug accountability records indicating 
the drug’s delivery date to the site, inventory at the site, use by each subject, and return (of 
unused vials) to Frequency Therapeutics (or destruction, if approved by Frequency 
Therapeutics) will be maintained by the clinical site. These records will adequately document 
that the subjects were provided the doses as specified in the protocol and should reconcile all 
study drug received from Frequency Therapeutics or its designee. Accountability records will 
include dates, quantities, batch/serial numbers, and subject identification numbers. The site 
monitor will review drug accountability at the site on an ongoing basis during monitoring 
visits. 
8.6.4 Disposal, Return or Retention of Study Drug 
All unused and used study drug will be retained at the site until inventoried by the site 
monitor. All used, unused or expired study drug will be returned to Frequency Therapeutics 
or if authorized, disposed off at the study site in accordance with governing regulations and 
documented.  


 
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8.7 
Randomization and Blinding 
8.7.1 Blinding 
The subjects, all Frequency Therapeutics staff and representatives, Investigators and site 
personnel involved in administering study assessments will be blinded to the study drug 
assignment. The otolaryngologist will be blinded to treatment. The pharmacy staff who 
prepare the study drug will be unblinded and will not perform any other roles on the study 
other than drug preparation and accountability.  The independent statistician and/or 
independent statistical programmer who is not otherwise involved with the study will 
generate the randomization schedule, will be un-blinded, and will perform the Day 90 data 
monitoring review.  There will be a designated unblinded team from Frequency Therapeutics 
that will manage the implementation and distribution of the Interim Analysis. This team will 
not perform any other roles on the study at the time of this analysis or for the rest of the 
study. 
8.7.2 Un-blinding 
Only in the case of emergency, when knowledge of the study drug administered is essential 
for the clinical management or welfare of the subject, may the Investigator un-blind a 
subject’s treatment group assignment. Under such conditions, the identity of the study drug 
will be obtained either via the unblinding functionality within the IRT system or by 
contacting the CRO. 
 
If possible, the Medical Monitor and Frequency Therapeutics should be consulted prior to 
breaking the blind. If the blind is broken for any reason, the Investigator must notify 
Frequency Therapeutics and the Medical Monitor immediately of the un-blinding incident 
without revealing the subject’s study treatment group assignment to Frequency Therapeutics 
and the Medical Monitor. In the event that the treatment group assignment is broken, the date, 
the signature of the person who broke the code and the reason for breaking the code must be 
recorded on the source documents.  Any code-breaks that occur must be immediately 
reported to the Medical Monitor.  Any subject whose treatment group assignment has been 
un-blinded will be followed up for safety purposes.  
 
8.7.3 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized 1:1:1:1 to one of four treatment groups.  To protect the blind, all 
subjects will receive four injections.  A single injection of FX-322 or placebo will be 
administered on Day 1 by intratympanic injection followed by subsequent injections of either 
FX-322 or placebo on Day 8, Day 15 and Day 21 as per treatment group.    
The randomization will be stratified for baseline Word Recognition Score (>=50% correct, 
<50% correct) and etiology of hearing loss (SSNHL vs. NIHL). 
8.7.4 Selection of Doses in the Study 
In this Phase 2a study (FX-322-202), four intratympanic injections will be administered as 
either placebo or the investigational product FX-322 and given on Days 1, 8, 15, and 21. 
 
 
 


 
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Weekly dosing of FX-
322 did not produce any significant toxicological findings that were different from controls in 
the study. Additionally, study FX-322-201 demonstrated that a single dose of FX-322 was 
well-tolerated in patients with stable SNHL. Given that FX-322 drug product is formulated at 
maximally achievable concentration and that the systemic circulation and cochlear fluid 
pharmacokinetics show short half-lives for each of the FX-322 components, the weekly 
dosing schedule was selected as it allows for audiometric evaluations between doses and 
determination of the number of doses that provides the maximum progenitor cell effect and 
consequent improvement in hearing function.  
 
The data from Phase 1/2 Study FX-322-201 support the hypothesis that activation of 
progenitor cells and consequent sensory hair cell formation and restoration of hearing 
function are driven by the concentration of the drug product applied to the round window 
membrane via intratympanic injection, and not by the volume of drug product delivered to 
the middle ear.  
 
Based on the above, 
 will be used as the standard dose volume for all future clinical 
trials that study intratympanic administration of FX-322. 
 
8.7.5 Selection and Timing of Dose for Each Subject 
Once a subject has been identified who meets all inclusion/exclusion criteria, the ear with the 
worse hearing (ear with the worst Screening pure tone average) will be selected, unless a 
rationale exists to treat the other ear.  The Investigator will need to discuss that rationale with 
the Sponsor prior to randomization. Subjects will be administered a total of 4 doses of FX-
322 and/or placebo. Injections will take place on Days 1, 8, 15, and 21 as per treatment 
group. 
  
8.8 
Prior and Concomitant Therapy 
At each study visit the study personal will question the subject about any medication taken, 
including vitamin supplements and herbal remedies. Any concurrent medications will be 
recorded in the subject's records and the eCRF. Any changes in doses or introduction of a 
new medication during the course of the study will be recorded. Any medications taken in the 
14 days prior to the Screening visit will be recorded on the Concomitant Medication log. 
8.8.1 Prohibited Medication/Therapy 
Concomitant medications that are not allowed during the study are valproic acid (brand name 
(e.g. Depacon®, Depakote®, Depakene, Epival®, Valpro, and Epilim) or derivatives. 
Intratympanic injections of anything other than study medication are prohibited during the 
course of the study or within 14 days prior to the Screening Visit.  Oral and intratympanic 
steroids are prohibited during the study, including the follow up period.  Aminoglycosides 
and platinum-based chemotherapies are excluded during the study. 
 
8.8.2 Rescue Medication 
No rescue medication will be provided as no FDA approved treatment for sensorineural 
hearing loss exists.  The Investigator should treat any adverse events as medically appropriate 
and per their standard of care.   


 
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8.8.3 Treatment Compliance 
Treatment will be administered by the Investigator to each subject on Day 1, 8, 15 and 21 as 
per the treatment schedule for each of the subjects randomized to one of four groups.  If a 
subject misses a treatment, that treatment will not be made up and subject will return for the 
next scheduled treatment. 
 
9 
DISCONTINUATION AND LOST TO FOLLOW-UP 
9.1 
Discontinuation of Study Intervention 
Discontinuation from FX-322 does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse 
event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• All efforts will be made for the subject to complete all of the follow up visits. 
• If the subject does not wish to continue the follow up period, all efforts will be made 
for the subject to complete all assessments collected at the last follow up visit (see 
Section 8.4.4). 
 
9.2 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she fails to return for 2 scheduled visits 
(or the final visit) and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 
5 days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
10 TIMING OF STUDY PROCEDURES 
Subjects will provide written informed consent before any study related procedures are 
performed. 
The planned study assessments are in Section Error! Reference source not found.. 


 
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10.1 Pre-treatment 
10.1.1 Screening Visit (Visit 1; Day -30 to 0) 
The following procedures will be performed at the Screening Visit: 
• Obtain signed Informed Consent. 
• Assess for eligibility (against the inclusion and exclusion criteria). 
• Obtain prior audiogram.  The audiogram must be performed at least 6 months prior to 
the Screening Visit.  If there are multiple audiograms present in the subject’s records, 
the most recently performed audiogram at least 6 months old should be used. 
• Collect full medical history, including targeted hearing loss history, concomitant 
illnesses/diseases, and concomitant medications. 
• Record demographic data, including ethnic origin, date of birth, and sex. 
• Perform a physical examination, including body weight and height. 
• Record vital signs (supine blood pressure, body temperature, and heart rate). 
• Collect blood sample for safety laboratory assessments. 
• Collect urine sample for pregnancy test, if applicable. 
• Collect urine sample for drug screening (cocaine, narcotics, benzodiazepines, 
tetrahydrocannabinol, barbiturates, and amphetamines). 
• Perform otoscopy, standard pure tone audiometry, extended high frequency 
audiometry, word recognition testing, WIN testing, and tympanometry  
 
10.1.2 Baseline/Treatment Visit (Visit 2a, [Day 1]) 
The following procedures will be performed at the Baseline/Treatment Visit: 
• Before injection of study drug:  
o Reassess for eligibility against the inclusion and exclusion criteria. 
o Collect blood sample for biomarker analysis. 
o Collect concomitant medications. 
o Record vital signs. 
o Perform a urine pregnancy test, if applicable. 
o Perform otoscopy. 
o Record any changes in medical history that have occurred since the previous 
visit. 
o Administer the Tinnitus Functional Index, C-SSRS, Hearing Handicap 
Inventory for Adults, and Hearing Screening Inventory. 
o When all the above baseline procedures have been performed and the 
Investigator has confirmed the subject’s eligibility for the study, the subject 
will be randomized. Each subject will receive a unique randomization number. 
• Inject FX-322 or placebo via intratympanic injection to the study ear. 
• After study drug injection: 
o Record any adverse events that have occurred since study treatment. 
o Collect concomitant medications. 
 
10.1.3 Additional Treatment Visits (Visits 2b, 2c, 2d, [Days 8, 15 and 21] +/- 2 days) 
The additional treatment visits (Visits 2b, 2c, and 2d) will take place 7 days apart on Days 8, 
15 and 21 after the Baseline/Treatment visit. The following procedures will be performed at 
these visits: 


 
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• Before injection of study drug: 
o Collect concomitant medications. 
o Record any adverse events that have occurred since last study visit. 
o Record vital signs. 
o Perform otoscopy. 
o Perform urine pregnancy test. 
• Inject FX-322 or placebo via intratympanic injection to the study ear as per treatment 
group. 
• After study drug injection: 
o Record any adverse events that have occurred since study treatment. 
o Collect concomitant medications. 
 
In addition to the above the following procedures will be performed only at Visit 2c, Day 15 
prior to study injection: 
• Perform standard pure tone audiometry, extended high frequency audiometry, word 
recognition testing, WIN testing, and tympanometry.  
 
 
10.1.4 Follow-up (Visit 3, [Day 30 +/- 15 days]) 
The Phone Call Follow-up Visit (Visit 3) will take place at Day 30 (± 15 days). The 
following procedures will be assessed via phone at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
 
10.1.5 Follow-up (Visit 4, [Day 60 +/- 15 days]) 
The Follow-up Visit (Visit 4) will take place at Day 60 (± 15 days). The following 
procedures will be performed at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
• Perform otoscopy, standard pure tone audiometry, extended high frequency 
audiometry, word recognition testing, WIN testing, and tympanometry. 
• Administer the Tinnitus Functional Index, C-SSRS, and Hearing Handicap Inventory 
for Adults. 
• Record vital signs. 
 
If the subject is not able to return to clinic for this visit due to any reason, a phone call visit 
will be performed.  Any AEs and concomitant medication changes will be recorded along 
with the questionniares. 
 
10.1.6 Follow-up (Visit 5, [Day 90 +/- 15 days]) 
The Follow-up Visit (Visit 5) will take place at Day 90 (± 15 days). The following 
procedures will be performed at the Follow-up Visit: 


 
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• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
• Perform otoscopy, standard pure tone audiometry, extended high frequency 
audiometry, word recognition testing, WIN testing, and tympanometry. 
• Record vital signs. 
 
If the subject is not able to return to clinic for this visit due to any reason, a phone call visit 
will be performed.  Any AEs and concomitant medication changes will be recorded. 
 
 
10.1.7 Follow-up (Visit 6, [Day 120 +/- 15 days]) 
The Phone Call Follow-up Visit (Visit 6) will take place at Day 120 (± 15 days). The 
following procedures will be assessed via phone at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
• Administer the Tinnitus Functional Index, C-SSRS, and Hearing Handicap Inventory 
for Adults. 
 
10.1.8 Follow-up (Visit 7, [Day 150 +/- 15 days]) 
The Follow-up Visit (Visit 7) will take place at Day 150 (± 15 days). The following 
procedures will be performed at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
• Perform otoscopy, standard pure tone audiometry, extended high frequency 
audiometry, word recognition testing, WIN testing, and tympanometry. 
• Record vital signs. 
 
If the subject is not able to return to clinic for this visit due to any reason, a phone call visit 
will be performed.  Any AEs and concomitant medication changes will be recorded. 
 
 
10.1.9 Follow-up (Visit 8, [Day 180 +/- 15 days]) 
The Phone Call Follow-up Visit (Visit 8) will take place at Day 180 (± 15 days). The 
following procedures will be assessed via phone at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 
 
10.1.10  Follow-up (Visit 9, [Day 210 +/- 15 days]) 
The Follow-up Visit (Visit 9) will take place at Day 210 (± 15 days). The following 
procedures will be performed at the Follow-up Visit: 
• Record any AEs that have occurred since the last visit and any changes in concomitant 
medication. 


 
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• Perform otoscopy, standard pure tone audiometry, extended high frequency 
audiometry, word recognition testing, WIN testing, and tympanometry. 
• Administer the Tinnitus Functional Index, C-SSRS, Hearing Handicap Inventory for 
Adults, and Hearing Screening Inventory.  
• Collect blood sample for safety laboratory assessments. 
• Collect blood sample for biomarker analysis. 
• Record vital signs. 
 
10.2 Duration of Treatment 
The duration of treatment will be 4 weeks with 6 months of follow up after the treatment 
period. 
11 EFFICACY ASSESSMENTS 
11.1 Efficacy Measurements Assessed 
11.1.1 Word Recognition in Quiet (WR) 
Word recognition in quiet will be measured with recorded CNC word lists.  The test will 
consist of 50 words presented to the subject and the percentage of words correctly identified 
will be recorded.  Word recognition will be performed at Screening, Day 15, 60, 90,  150, and 
210 Visits.  Testing will be performed at 30dB SL regarding the pure tone average of 0.5, 1, 
and 2 kHz at Screening.  Word lists will be rotated at each visit.  Additional details can be 
found in the Audiology Manual of Procedures.   
11.1.2 Words-In-Noise Testing (WIN) 
The Words-in-Noise Test (WIN) was developed as an instrument to quantify the ability of 
listeners to understand monosyllabic words in background noise using multitalker babble 
(Wilson, 2003). Materials are recorded at 7 signal-to-noise ratios (0, 4, 8, 12, 16, 20, 24 dB) 
that are presented in a descending manner. This test is conducted by presenting 2 lists of 35 
recorded words to each ear.  Overall accuracy will be recorded as the number of words 
identified correctly.  This test will occur at Screening, Day 15, 60, 90, 150, and 210.  Testing 
will be performed at 80dB SPL.  Word lists will be rotated at each visit.  Additional details 
can be found in the Audiology Manual of Procedures.   
 
11.1.3 Standard Pure Tone Audiometry 
Standard Pure Tone Audiometry will be measured to determine a subject’s threshold for 
hearing at various frequencies and will be performed at the Screening visit and Day 15, 60, 
90, 150, and 210.  This will be performed on a calibrated audiometer by a licensed 
audiologist.  The  following frequencies will be obtained:  Air: 250 Hz, 500 Hz, 1 kHz, 2 
kHz, 3 kHz, 4 kHz, 6 kHz, and 8 kHz; Bone: 500 Hz, 1 kHz, 2 kHz, 3kHz, and 4 kHz. 
11.2 Exploratory Efficacy Measurements Assessed 
11.2.1 Extended High Frequency Audiometry 
Extended high frequency audiometry will be performed to determine a subject’s threshold for 
hearing at frequencies beyond those in standard pure tone audiometry and will be performed 


 
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at the screening visit and Day 15, 60, 90, 150, and 210. This will be performed on a 
calibrated audiometer by a licensed audiologist. The following frequencies will be obtained: 
Air – 9 kHz, 10 kHz, 11.2 kHz, 12.4 kHz, 14 kHz, and 16 kHz. 
11.2.2 Tinnitus Functional Index (TFI) 
The Tinnitus Functional Index has eight subscales that address the intrusiveness of tinnitus, 
the sense of control the patient has, cognitive interference, sleep disturbance, auditory issues, 
relaxation issues, quality of life, and emotional distress.  The subject will report (either 
directly onto the questionnaire in person, via web, or over the phone) answers to each of the 
25 questions using a scale of 0-10.  The TFI will be given to the subject to complete at the 
Baseline, Day 60, Day 120, and Day 210 visits. 
11.2.3 Hearing Handicap Inventory for Adults (HHIA) 
The Hearing Handicap Inventory for Adults (HHIA), is a 25-item self-assessment scale 
composed of two subscales (emotional and social/situational).  The subject will report (either 
directly onto the questionnaire in person, via web, or over the phone) one of the following 
answers for each item on the scale: Yes, Sometimes, No.  The HHIA will be given to the 
subject to complete at the Baseline, Day 60, Day 120, and Day 210 visits. 
11.2.4 Hearing Screening Inventory (HSI) 
The Hearing Screening Inventory is a 12 item self report inventory to assess hearing 
impairment. The subject will self report one of the following answers, for each question from 
1 to 8: Never, Seldom, Occasionally, Frequently, Always, and for each question from 9 to 12: 
Good, Average, Slightly below average, Poor, Very Poor. The HSI is designed to assess 
subjective change during the study and will be given to the subject to complete at the 
Baseline and Day 210 visits.  
12 SAFETY ASSESSMENTS 
The planned schedule of assessments is in Section Error! Reference source not found.. 
12.1 Safety Measurements Assessed  
12.1.1 Concomitant Medication 
Subjects will be asked about concomitant medications at time points outlined in the Table of 
Assessments.  All concomitant medication information will be recorded in the eCRF. 
12.1.2 Clinical Laboratory Evaluation 
Blood samples will be collected for safety laboratory assessments for clinical chemistry and a 
complete blood count. 
Urine drug screen (cocaine, narcotics, benzodiazepines, tetrahydrocannabinol, barbiturates, 
and amphetamines) will be performed at Screening only. 
Screening for pregnancy will be performed (urine β-HCG) as outlined in Table 1. 


 
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12.1.3 Vital Signs 
Vital signs (temperature, blood pressure and heart rate) will be recorded at time points 
outlined in Table 1 and will be performed in a standardized manner, i.e., after the subject has 
rested in the sitting position for 5 minutes. 
 
12.1.4 Physical Exam (PE) 
A complete physical examination will be performed by a licensed provider at Screening. 
Complete physical examinations include: general appearance, head, ears, eyes, nose, throat, 
dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, 
musculoskeletal, and lymph nodes and any pertinent system based on any prior findings. 
Physical examinations may be performed at various unscheduled time points, if deemed 
necessary by the Investigator. 
 
12.1.5 Columbia Suicide and Severity Rating Scale (C-SSRS) 
This scale is used to determine if any suicide ideation or intention is present.  The 
questionnaire is read aloud to the subject and responses are recorded by the trained staff 
member. If any ideation or intention is present, the Investigator will interview the subject and 
have them follow up with their primary healthcare provider.  The C-SSRS will be completed 
at the Baseline, Day 60, Day 120, and Day 210 visits. 
12.1.6 Body Mass Index (BMI) 
BMI will be calculated by dividing the subject’s body weight in kilograms by the subject’s 
height in meters squared (BMI = kg/m2). Body height (centimeter) and body weight 
(kilograms) will be measured at the time points delineated in the Schedule of Assessments.  
 
12.1.7 Otoscopy 
Microscopic otoscopy will be included to specifically record any abnormalities of the 
external ear canal, tympanic membrane and middle ear and will be performed at Screening, 
prior to injection on Day 1, 8, 15, and 21 and at the Day 60, 90, 150, and 210 visits. 
 
12.1.8 Tympanometry 
Tympanometry (an objective test of tympanic membrane mobility) tests the integrity of the 
tympanic membrane by varying air pressure in the ear canal. Middle ear compliance, peak 
pressure, and tympanogram type will be recorded.  Tympanometry will be performed at the 
Screening, Day 15, and at the Day 60, 90, 150, and 210 Visits.  The assessment will be 
performed by a licensed audiologist on a calibrated tympanometer.  A print-out containing 
the tympanometry from the machine will be collected and stored in the source document.   
 


 
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13 ADVERSE EVENTS 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not it is related to the medicinal 
(investigational) product. This includes an exacerbation of pre-existing conditions or events, 
intercurrent illnesses, drug interaction or the significant worsening of the indication under 
investigation that is not recorded elsewhere in the eCRF under specific efficacy assessments. 
Anticipated fluctuations of pre-existing conditions, including the disease under study that do 
not represent a clinically significant exacerbation or worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. 
AEs will be elicited by asking the subject a nonleading question, for example, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?”.  AEs 
will be recorded from the time of the first treatment through the end of the follow up period.  
AEs should be reported on the appropriate page of the eCRF. 
 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction Definition 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort 
and does not interfere with everyday activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to 
the study drug. Causality should be assessed using the categories presented in the following 
table: 


 
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Not Related: 
Clinical event with an incompatible time relationship to study 
drug administration, and that could be explained by underlying 
disease or other drugs or chemicals or is incontrovertibly not 
related to the study drug. 
Unlikely: 
Clinical event whose time relationship to study drug 
administration makes a causal connection improbable, but that 
could plausibly be explained by underlying disease or other drugs 
or chemicals. 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent 
disease or other drugs or chemicals. 
Related: 
Clinical event with a reasonable time relationship to study drug 
administration and is unlikely to be attributed to concurrent 
disease or other drugs or chemicals. 
Adverse Events of Special Interest (Audiometric and Otoscopic) 
If any of the following criteria are met, the event will be recorded as an  adverse event of 
special interest (AESI) per ASHA guidelines (ASHA 1994): 
• Asymmetric loss of hearing greater than 20 dB at any one frequency in the treated ear 
compared to the Screening Visit. 
• Asymmetric loss of hearing greater than 10 dB at two adjacent frequencies in the 
treated ear compared to the Screening Visit. 
• Asymmetric loss of response at three consecutive test frequencies where responses 
were previously obtained in the treated ear compared to the Screening Visit. 
For word recognition testing, a follow up visit score in the treated ear that falls below the 
lower limit of the 95% confidence interval of the baseline word recognition score will be 
considered an AESI (Thorton and Raffin 1978). 
Additionally, if the subject experiences a perforation greater than 25% of the tympanic 
membrane in the treated ear this will be recorded as an AESI.  
If any subjects in the study experience the same AESI, the Medical Monitor will discuss these 
with the Principal Investigators and each subject’s condition will be discussed.  The Medical 
Monitor, in consultation with the sponsor, will determine whether to proceed with any future 
doses if the subjects have not completed all 4 doses. 
Action Taken with Study Treatment in Response to Adverse Event 
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
• Dose Increased,  
• Dose Not Changed,  
• Dose Reduced,  
• Drug Interrupted,  
• Drug Withdrawn,  


 
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• Not Applicable,  
• Unknown 
 
 Follow-up of Adverse Events 
All Investigators should follow up subjects with AEs until the event is resolved or until, in 
the opinion of the investigator, the event is stabilized or determined to be chronic. Details of 
AE resolution must be documented in the eCRF. 
Documentation and Reporting of Adverse Events 
AEs should be reported and documented in accordance with the procedures outlined below. 
All AEs occurring during the study (after study treatment has begun) must be documented on 
the relevant eCRF pages. The following data should be documented for each AE: 
• Description of the symptom event, or underlying diagnosis 
• Classification of ‘serious’ or ‘not serious’ 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken (see definitions above) 
• Causal relationship 
• Outcome of event (unknown, recovered, not yet recovered, recovering/resolving, 
recovered with sequelae, deaths[with date and cause reported]) 
13.1 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of 
death from the event as it occurred, i.e., it does not include a reaction that might have 
caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing 
non--worsening condition is not, however, considered an AE. The details of such 
hospitalizations must be recorded on the medical history or physical examination page 
of the eCRF). 
• Results in persistent or significant disability/incapacity. (An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject’s 
ability to carry out normal life functions). 
• Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification is 
required in situations other than those defined for SAEs above. This may include any event 
that the Investigator regards as serious that did not strictly meet the criteria above but may 
have jeopardized the subject or required intervention to prevent one of the outcomes listed 


 
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above, or that would suggest any significant hazard, contraindication, side effect, or 
precaution that may be associated with the use of the investigational product. 
Reporting of Serious Adverse Events 
Any SAE must be reported by the Investigator if it occurs during the clinical study, whether 
or not the SAE is considered to be related to the investigational product. The Serious Adverse 
Event eCRF must be completed, with as much information as is available, within 24 hours of 
when the investigative site becomes aware of the event. Once the eCRF is saved, this triggers 
an automatic email to 
 Additional contact details of the Medical Monitor 
can be found in the Site Operation Manual. 
The Investigator should not wait to receive additional information to document fully the 
event before notification of a SAE, though additional information may be requested. 
Information from relevant laboratory results, hospital case records, and autopsy reports 
should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study drug administration and linked by the investigator to this study, 
should be reported to the study monitor. 
The sponsor and/or CRO will promptly notify all relevant investigators and the regulatory 
authorities of findings that could adversely affect the safety of subjects, impact on the 
conduct of the study or alter the independent ethics committee (IEC)/institutional review 
board (IRB) approval/favorable opinion of the study. In addition, CRO on behalf of the 
sponsor, will expedite the reporting to all concerned investigators, to the IRBs, where 
required, and to the regulatory authorities of all adverse reactions that are both serious and 
unexpected. 
Details of the procedures to be followed if a pregnancy occurs are provided in Section 8.4.4. 
13.2 Expedited Safety Reporting  
All serious and unexpected suspected adverse reactions (SUSARs) will be the subject of 
expedited reporting. The sponsor and/CRO shall ensure that all relevant information about a 
SUSAR that is fatal or life-threatening is reported to the regulatory authorities and IRB 
within 7 days after knowledge by the sponsor of such a case and that relevant follow up 
information is communicated within an additional 8 days. All other SUSARs will be reported 
to the regulatory authorities and IRB within 15 days after knowledge by the sponsor of such a 
case. All Investigators should follow up SUSARs until the event is resolved or until, in the 
opinion of the Investigator, the event is stabilized or determined to be chronic. Post study 
SUSARs that occur after the subject has completed the clinical study must be reported by the 
investigator to the sponsor. 


 
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14 STATISTICAL METHODS 
14.1 Statistical and Analytical Plans 
14.1.1 Descriptive Statistics 
This is a Phase 2a, prospective, randomized, double-blind, placebo-controlled, single and 
repeat-dose, multicenter, exploratory efficacy study of FX-322, administered by 
intratympanic injection, in adults with stable sensorineural hearing loss (no changes in air 
conduction greater than 10 dB at a single frequency or greater than 5dB at two contiguous 
frequencies from the prior audiogram to the Screening audiogram ).  The primary objectives 
of the study are to explore the efficacy of FX-322 associated with various dosing schedules 
and to describe the local and systemic safety.   
Subjects will be randomized to one of four treatment groups using a 1:1:1:1 allocation ratio.   
Subjects will be stratified at randomization by baseline (last assessment before study drug 
administration Word Recognition (above and below 50% correct) and etiology of hearing loss 
(Sudden vs Noise).  For the analysis, baseline will be defined as the last measurement prior to 
the first exposure to study drug. 
 
The exploration of efficacy will be descriptive as well as analytical to describe dose response 
trends among the four treatment groups (three FX-322 dosing schedules and placebo).  
Additional analyses will include comparisons of each individual FX-322 to placebo and 
between the three FX-322 groups as well as the pooled FX-322 group to placebo.  These 
analyses will examine each timepoint and explore the longitudinal aspects of the study 
design.   
 
Safety will be analysed descriptively.   
 
Study data will also be provided in line listings. 
 
Details of the statistical analysis will be provided in the Statistical Analysis Plan (SAP) which 
will be finalized prior to database lock and study blind break. 
 
14.1.2 Sample Size 
The sample size of approximately 24 subjects per treatment group was considered adequate 
to explore the potential efficacy of FX-322 associated with various dosing schedules and was 
not based on formal statistical evaluation.  
 
14.1.3 Analysis Sets 
• Full Analysis Set (FAS) 
 
The Full Analysis Set is defined as all randomized subjects who receive at least one dose of 
study drug.  Subjects will be analysed according to their randomized treatment group.  The 
FAS will be used to explore efficacy.  Details will be provided in the SAP. 
 
• Per Protocol Analysis Set (PPAS) 
 


 
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The Per Protocol Analysis Set is defined as subjects receiving all four doses of study drug or 
placebo and without major protocol deviations that could interfere with interpretation of the 
results.  These major protocol deviations will be identified prior to breaking the study blind.  
If different from the FAS, the PPAS may be used in additional sensitivity analyses.  PPAS 
subjects will be analysed according to their randomized treatment group.  Details will be 
provided in the SAP.  
 
 
• Safety Analysis Set (SfAS) 
 
The Safety Analysis Set will include all subjects exposed to study drug or placebo and will be 
analyzed according to the actual treatment group regardless of their randomized treatment 
assignment.  The SfAS  will be used for the analysis of safety.  Both the treated and untreated 
ear will be included in the SfAS when the ear is the unit of the safety analysis.    
 
14.1.4 Subject Disposition, Demographics and Baseline Disease Status 
Descriptive statistics for subject disposition, demographics, and baseline disease status will 
be provided.  Tabulations will be summarized by randomized treatment group and a pooled 
FX-322 group.  Where applicable, summaries by the two stratification factors used at 
randomization will also be provided. 
14.1.5 Efficacy Exploration 
Efficacy endpoints will be summarized descriptively at each study timepoint including 
baseline.  Calculations will include the observed data at each timepoint, and if relevant, the 
change from baseline.  For continuous endpoints means, medians, standard deviations, 
minimums and maximum will be provided.  For categorical endpoints the number and 
percent of subjects within each category will be calculated.  Tabulations for selected 
endpoints will be presented by subgroups such as age, study site, duration of hearing loss, 
smoking status, and stratification factors used at randomization.  Details will be provided in 
the SAP.  For descriptive analyses, subjects with missing data will be excluded for a 
particular calculation. 
For questionnaires, the analysis will follow the instructions for scoring and handling of 
missing data appropriate for the particular instrument. 
Inferential statistical methods examining continuous endpoints will be examined via a Mixed 
Model for Repeated Measures (MMRM).  Analyses will include pairwise contrasts and dose 
response.  Inferential analyses for categorical endpoints will be analysed using univariate 
methods and/or Generalized Linear Mixed Models (GLMM).  When appropriate, models will 
include adjustments for baseline as well as the stratification factors used at randomization.  
Departures of these models from the statistical assumptions will be assessed and alternative 
approaches maybe employed.  Additionally, univariate models such as Analysis of 
Covariance and/or count models examining single timepoints of interest may also be 
examined. General methods for handling missing data for inferential analyses are described 
below (Section 14.2).  
The inferential analyses will not be adjusted for multiple endpoints; however, for a given 
endpoint, adjusted p-values for pairwise comparisons to a control will be provided where 


 
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relevant along with the unadjusted p-values.  Unadjusted 95% confidence intervals will also 
be provided.  In some circumstances, adjusted confidence intervals may be calculated. 
Efficacy endpoints will be analysed using the FAS.  Further details regarding the exploratory 
analysis of efficacy will be outlined in the SAP.  
 
14.1.6 Interim Analyses 
The blinded data will be continuously monitored for safety.  Interventional level aggregated 
data monitoring will be conducted once all enrolled subjects have completed the Day 90 visit 
(Visit 5) or were early discontinuations. An interim analysis of all Day 90 data may be 
performed in order to assist in data interpretation or to understand patterns of missingness in real-
time  or to monitor data integrity. The study will continue as planned to final analysis when all 
patients have completed their day 210 visit. 


 
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14.1.7 Safety Analyses 
Safety will be evaluated using the safety analysis set and will include the incidence of 
adverse events (AEs), serious adverse events (SAE)s, vital signs, clinical laboratory 
measurements, concomitant medications, otology, questionnaire responses, and 
tympanometry assessments.  Summary descriptive statistics will be provided by actual 
treatment group, pooled FX-322 group, and overall using the SfAS.  No safety data will be 
imputed except for partial dates if required to determine if an adverse event is treatment 
emergent or a medication concomitant with exposure to study drug.  Details of partial date 
imputation will be provided in the SAP. 
 
14.1.7.1  Adverse Events 
The number and percentage of subjects reporting adverse events (AEs) will be summarized 
via the MedDRA system by organ class and preferred term.  Data will be tabulated by 
severity, physician assessment of relationship to study drug, serious AEs, and AEs leading to 
death or study withdrawal.  Adverse events of the ear will also be summarized by treated vs. 
non-treated ear. 
 
14.1.7.2  Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be presented as summary statistics by treatment group for 
each timepoint as well as changes from baseline and/or shift tables.  Pregnancy results will 
not be summarized but will be provided in line listings.   
 
14.1.7.3  Vital Signs and Physical Examation 
Vital signs and physical exams will be summarized via descriptive statistics similar to 
laboratory evaluations described above. 
 
14.1.7.4  Prior and Concomitant Medications 
Prior and concomitant medications will be coded to identify the drug class and preferred drug 
name.  Concomitant medications will include all medications that started, or were continuing, 
during or after administration of study drug.  Prior medications will include all recorded 
medications that started and stopped prior to administration of study drug.  In the event that a 
subject begins a prior medication following first dose of study drug or placebo, the post-dose 
use will be considered concomitant while the prior use medication will still be reported.   
 
The number and percent of subjects using concomitant medications will be tabulated by drug 
class and preferred drug name.  Prior medications will be presented in line listings only.  
Concomitant medications will also be provided in line listings. 
 
14.1.7.5 Tympanometry and Otoscopy 
Tympanometry and otoscopic results will be presented by treatment group and ear (treated vs. 
untreated) at each visit with changes and/or shifts from baseline.   
 
 
14.2 Handling of Missing Data and Subject Withdrawals 


 
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Except for partial dates to assess AESIs and concomitant medications, safety data will not be 
imputed.  Imputation of efficacy data may be implemented based on the analysis of patterns 
of missingness in the visit assessments for subjects.  Details of how this will be conducted 
and the imputation methods planned will be provided in the SAP. 
 
15 QUALITY ASSURANCE AND QUALITY CONTROL 
15.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit during the 
course of the study by the sponsor or its nominated representative. In addition, inspections 
may be conducted by regulatory authorities at their discretion. 
15.2 Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed for 
each subject who signs an informed consent form (ICF) and is administered study drug. 
In accordance with GCP and ICH guidelines, the study monitor will carry out source 
document verification and request clarification at regular intervals to ensure that the data 
collected in the eCRF are accurate, complete and reliable. Study monitor has the 
responsibility of assessing the progress of the study, of checking that the informed consent 
forms have been signed by the patient, ensuring adhesion to and compliance with the study 
protocol and other study-related documents 
The investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs.   
15.3 Data Management and Coding 
The sponsor or CRO will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database and data transfer mechanisms, 
along with appropriate validation of data and resolution of queries. Data generated within this 
clinical study will be handled according to the relevant standard operating procedures (SOPs) 
of the data management and biostatistics departments of sponsor or CRO. 
Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study center. Data to be recorded directly on the 
eCRF will be identified and the eCRF will be considered the source document. Any changes 
to the data entered into the EDC system will be recorded in the audit trail and will be FDA 
CFR 21 Part 11 compliant. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and WHO Drug for medications. 
Missing or inconsistent data will be queried in EDC for clarification. Subsequent 
modifications to the database will be documented. 


 
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16 RECORDS AND SUPPLIES 
16.1 Drug Accountability 
On receipt of the study drug, the Investigator (or designee) will conduct an inventory of the 
supplies and verify that study drug supplies are received intact and in the correct amounts 
before completing a supplies receipt. The Investigator will retain the original of this receipt at 
the study center and return a copy to the study monitor. The monitor may check the study 
supplies at each study center at any time during the study. 
It is the responsibility of the study monitor to ensure that the Investigator (or designee) has 
correctly documented the amount of the study drug received, dispensed, and returned on the 
dispensing log that will be provided. A full drug accountability log will be maintained at the 
study center at all times. The study monitor will arrange collection of unused study drug 
returned by the subject. The study monitor will also perform an inventory of study drug at the 
close-out visit to the study center. All discrepancies must be accounted for and documented. 
16.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between CRO 
and the sponsor. 
17 ETHICS 
17.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the subjects, and any other relevant study documentation will be submitted 
to the appropriate IEC/IRB. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the study drug is released to the 
Investigator. Any necessary extensions or renewals of IEC/IRB approval must be obtained 
for changes to the study such as amendments to the protocol, the ICF or other study 
documentation. The written approval of the IEC/IRB together with the approved ICF must be 
filed in the study files. 
The Investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the study. The Investigator will 
submit written summaries of the study status to the IEC/IRB as required. On completion of 
the study, the IEC/IRB will be notified that the study has ended. 
17.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities will 
be notified that the study has ended. 
17.3 Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 


 
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17.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
The Investigator is responsible for ensuring that no subject undergoes any study related 
examination or activity before that subject has given written informed consent to participate 
in the study. 
The Investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits, potential risks, and inconveniences of the study. The subject should be 
given every opportunity to ask for clarification of any points s/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the subject will be given 
ample time to consider the study. Subjects will be required to sign and date the ICF. After 
signatures are obtained, the ICF will be kept and archived by the investigator in the 
investigator’s study file. A signed and dated copy of the subject ICF will be provided to the 
subject or their authorized representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw from 
the study at any time, without consequences for their further care or penalty or loss of 
benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained. 
17.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the United States FDA, as well as that of any 
other applicable agency(ies), will be granted direct access to the study subjects’ original 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subjects to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the subjects’ identity will remain 
confidential. 
All personal data collected and processed for the purposes of this study should be managed 
by the investigator and his/her staff with adequate precautions to ensure confidentiality of 
those data, and in accordance with the Health Insurance Portability and Accountability Act 
(1), applicable to national and/or local laws and regulations on personal data protection. 
 
 
Reporting and Publication, Including Archiving 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last visit of the last subject), all documents and data relating to the 


 
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study will be kept in an orderly manner by the investigator in a secure study file. This file 
will be available for inspection by the sponsor or its representatives. Essential documents 
should be retained for 2 years after the final marketing approval in an ICH region or for at 
least 2 years since the discontinuation of clinical development of the investigational product. 
It is the responsibility of the sponsor to inform the study center when these documents no 
longer need to be retained. The investigator must contact the sponsor before destroying any 
study related documentation. In addition, all subject medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives 
of the study. Data from individual study centers in multicenter studies must not be published 
separately. 


 
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18 REFERENCES 
1. 
US Department of Health and Human Services.  The Health Insurance Portability and 
Accountability 
Act 
(HIPAA) 
of 
1996 
(P.L.104-191) 
[HIPAA].  
http://aspe.hhs.gov/admnsimp/pl104191.htm. Effective August 21, 1996. 
2. 
Li, L., Chao, T., Brant, J., O'Malley Jr, B., Tsourkas, A., & Li, D. (2017). Advances in Nano-
based inner ear delivery systems for the treatment of sensorineural hearing loss. Adv Drug 
Delivery. Advanced Drug Delivery Reviews. 
3. 
Hong , O., Kerr, M., & Poling , G. (April, 2013). Understanding and preventing noise-induced 
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19 APPENDIX 1 
Word Recognition Scoring Chart 
 
 
 
 


 
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20 INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 2a, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Single and Repeat-Dose, Multicenter, Exploratory 
Efficacy Study of FX-322 Administered by Intratympanic 
Injection in Adults with Stable Sensorineural Hearing Loss 
 
Protocol Number: 
 
FX-322-202 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and 
I will conduct the study as described in compliance with this protocol (and amendments), 
GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Frequency Therapeutics and of the IRB. I will submit the protocol 
amendments and/or any ICF modifications to Frequency Therapeutics and IRB, and approval 
will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to the sponsor. Clinical information may be 
reviewed by the sponsor or its agents or regulatory agencies. Agreement must be obtained 
from the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Frequency Therapeutics, to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required.