A Phase II, Randomized, Double-blind, Active Comparator, Parallel Group Study to Evaluate the Efficacy and Safety of K-285 Compared With Menthol Gel for the Treatment of Delayed Onset Muscle Soreness (DOMS) in the Lower Extremity
Phase: PHASE2
Conditions: Acute Pain
Sponsor: Kowa Research Institute, Inc.

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
A P h ase II, R a n d o mize d, D o u ble- bli n d, Acti ve C o m p ar at or, P a r all el 
Gr o u p St u d y t o E v al u ate t he Effi c a c y a n d S afet y of K- 2 8 5 C o m p a re d 
wit h
Me nt h ol Gel f or t he Tre at me nt of Del a ye d O nset M uscle S o re ness 
( D O M S) i n t he L o wer E xtre mit y 
Cli ni c al St u d y P r ot oc ol 
Dr u g N a me:  
K- 2 8 5
St u d y N u m ber:
U. S. I N D N u m ber: 
Pr ot oc ol Versi o n D ate: 
Versi o n #:
N a me of S p o ns or:
A d dress:
M a n a gi n g C o ntr act Rese arc h 
Or g a niz ati o n ( C R O):
A d dress:
C o nt act N u m bers:
K- 2 8 5- 2 0 1
I N D 1 3 5 3 4 8 
1 0 A pril 2 0 2 0 
1. 0 
K o w a Rese arc h I nstit ute, I nc. 
 
 
 
 
 
P r o pert y of K o w a Rese a rc h I nstit ute, I nc. 
C o nfi de nti al 
M a y n ot be use d, di v ul g e d, p u blis he d, o r ot her wise discl ose d 
wit h o ut t he c o nse nt of K o w a Rese arc h I nstit ute, I nc. 
Cli nic al Tri als. g o v                            N C T 0 4 4 8 4 4 2 8
Cli nic al Tri als. g o v                            N C T 0 4 4 8 4 4 2 8
ClinicalTrials.gov                            NCT04484428

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
ii1 6
I N V E S TI G A T O R’ S S T A T E M E N T 
I, t he i n vesti gat or, u n dersta n d t hat all i nf or mati o n c o ncer ni n g t he pr o d uct s u p plie d t o me 
b y 
K o wa 
Researc h I nstit ute, I nc. ( K RI) a n d  
 i n 
c o n necti o n wit h t his st u d y a n d n ot pre vi o usl y p u blis he d is c o nfi de ntial i nf or mati o n. 
T his i nf or mati o n i ncl u des t h e I n vesti gat ors’ Br oc h ure, pr ot oc ol, case re p ort f or ms, assa y 
met h o ds, tec h nical met h o d ol o g y a n d basic scie ntific data. 
I u n dersta n d t hat a n y c ha n ges t o t he pr ot oc ol m ust be a p pr o ve d i n writi n g b y K RI,  
 
 a n d t he I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee 
(I R B/I E C) bef ore i m ple me ntati o n, e xce pt 
w h ere ne cessar y t o eli mi nate a p pare nt 
i m m e diate h azar ds t o t h e s u bjects. 
I c o nfir m t h at I will re p ort all a d verse e ve nts ( A Es) f oll o wi n g t he re g ulati o ns i n di cate d i n 
t he pr ot oc ol. 
I c o nfir m t hat I will c o n d uct t his st u d y i n c o nf or ma nce wit h t he pri n ci ples of t h e 
Decl arati o n of Helsi n ki, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), 
G o o d Cli nical Practi ce ( G C P), a n d t he la ws a n d r e g ulati o ns of t he c o u ntr y w here t he st u d y 
is t o be c o n d ucte d. 
I c o nfir m t h at I a m i nf or me d of t h e n ee d f or rec or d ret e nti o n a n d t hat n o data ca n b e 
destr o ye d. 
B y m y si g nat ure bel o w, I here b y attest t hat I h a ve rea d, u n d erst o o d a n d a gr ee t o a bi d e b y 
all c o n diti o ns, i nstr ucti o ns a n d restricti o ns c o ntai ne d i n t his versi o n of t he pr ot oc ol 
date d 
 A pril 2 0 2 0. 
I n v esti g at or’s Si g n at ure:
Date:
m m/ d d/yyyy
Pri nte d N a me:

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
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SI G N A T U R E P A G E

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
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P R O T O C O L S Y N O P SI S
N a me of S p o ns or C o m p a n y:
K o wa Researc h I nstit ut e, I nc. 
Dr u g U n der St u d y:
K- 2 8 5
Title of Pr ot o c ol: 
A P hase II, Ra n d o mize d, D o u ble- bli n d, Acti v e C o m parat or, Parallel Gr o u p St u d y t o E val uate 
t h e Efficac y a n d Safet y of K- 2 8 5 C o m pare d wit h M e nt h ol Gel f or t h e Treat m e nt of Dela ye d 
O nset M uscl e S ore ness ( D O M S) i n t he L o wer E xtre mit y
Pr ot oc ol N u m ber:
K- 2 8 5- 2 0 1
P h as e:
II
I n dic ati o n:
Ac ute pai n relief
St u d y Desi g n:
T his is a p hase II, ra n d o mize d, d o u ble- bli n d, acti ve c o m parat or, parallel gr o u p st u d y t o e val uat e 
t h e efficac y a n d safet y of K- 2 8 5 c o m pare d wit h me nt h ol gel f or t he treat me nt of dela ye d o nset 
m uscl e s ore ness ( D O M S) i n t he l o wer e xtre mit y. T he st u d y will c o nsist of scree ni n g, a n e xercise 
visit ( D O M S i n d ucti o n), i n- patie nt a n d o ut- pati e nt peri o ds u p t o 3 wee ks, a n d a f oll o w- u p 
tele p h o ne call. 
D uri n g t he Scree ni n g Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete scree ni n g 
assess m e nts i ncl u di n g me dical hist or y, i d e ntificati o n of t he d o mi na nt le g, p h ysical a n d s ki n 
e xa mi n ati o ns, bl o o d a n d uri ne t ests, vit al si g ns meas ure me nts, el ectr ocar di o gra m ( E C G), a n d 
ot h er scree ni n g pr oce d ures. S u bjects w h o are a ble t o partici pate i n t he st u d y ( Peri o d 1 a n d 2) 
a n d w h o meet t he pre-e xercis e i ncl usi o n a n d e xcl usi o n criteri a will be e nr oll e d i nt o t he st u d y 
a n d ret ur n t o t he cli nic o n Da y - 1. 
Eli gi bilit y will be c o nfir me d a n d e nr oll e d s u bjects will perf or m a sta n dar dize d re petiti ve 
q ua dri ce ps m uscle e xercise t o creat e D O M S t o b ot h le gs ( Da y - 1). T he e xercise re gi me n will 
c o nsist of a war m- u p, deter mi nati o n of ma xi m u m t olerat e d wei g ht, a n d ti me d a n d u n-ti m e d 
w or k o ut p hases. Wit hi n 2 4 t o 3 0 h o urs after t he e xercise sessi o n ( Da y 1), s u bjects will rate t he 
pai n of b ot h le gs usi n g a cate g orical s cale a n d rec or d pai n i nte nsit y of b ot h le gs at rest a n d w hil e 
st a n di n g usi n g a 0- 1 0 0 p oi nt electr o ni c vis ual a nal o g scale (e V A S) (a ca pt ure pr o gra m will 
li nearl y c o n vert t he pi x el t o uc he d t o a n i nt e ger bet wee n 0 a n d 1 0 0) t o deter mi ne eli gi bilit y f or 
ra n d o mizati o n. 
 
 
 
 If b ot h l e gs meet p ost-e xercise i ncl usi o n criteri a, t he st u d y le g will b e t h e 
d o mi na nt le g, base d o n ha n d d o mi n a nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will b e gi ve n 
a p pr o priate sta n dar d of care. 
A t otal of 2 4 0 s u bjects w h o meet p ost-e xercis e i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 
1: 1 rati o t o Treat me nt Ar m A ( K- 2 8 5 gel) or Treat me nt Ar m B ( Me nt h ol gel). 
 
 
 
 
.  

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
v 1 6
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n Peri o d 1 (
 st u d y gels will be a p plie d t o ra n d o mize d s u bjects o n a
 
 o n t he st u d y le g as f oll o ws:  
Treat me nt Ar m A: Eac h s u bject will a p pl y K- 2 8 5 t o t he st u d y le g.
Treat me nt Ar m B: Eac h s u bject will a p pl y me nt h ol gel t o t h e st u d y le g.
T he first st u d y gel a p pli cati o n t o t he st u d y le g will be a p plie d b y t he s u bj ect wit h i n vesti gat or 
( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n at t h e cli nic o n Da y 1 wit hi n 2 4 t o 3 0 h o urs 
after D O M S i n d ucti o n. S u bse q ue nt st u d y g el a p pli cati o ns at t he cli ni c will be a p plie d t o t he 
st u d y le g b y t he s u bject wit h i n vesti gat or ( or desi g nee) o versi g ht t o e ns ure pr o per a p pli cati o n. 
O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t h e a p plicati o n site will be perf or me d pri or t o 
eac h st u d y gel a p pli cati o n. S u bj ects will re mai n i n t he cli nic u ntil t he y are disc har ge d f oll o wi n g 
c o m pleti o n of st u d y assess me nts o n Da y 2.  
Pai n i nte nsit y assess m e nts will be perf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest a n d 
w hile sta n di n g usi n g a  0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli n e ( 0 h o urs ) a n d at 
 
 
after t he first st u d y gel a p plicati o n. Pai n assess m e nts sc he d ule d bet wee n mi d ni g ht a n d 6 a m m a y 
be s ki p pe d if s u bjects are aslee p b ut s u bj ects ma y n ot s ki p m ore t ha n t w o se q ue nti al assess me nts. 
A ti me wi n d o w of + 3 0 mi n ut es will be all o we d bet wee n q ualificati o n ( baseli ne assess m e nt) a n d 
first gel a p plicati o n ( 0 h o ur). T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h pai n 
assess m e nt ti me p oi nt: 
 
 
 
F oll o wi n g disc har ge fr o m t he cli nic o n Da y 2, s u bse q ue nt st u d y gel a p plicati o ns a n d pai n 
i nte nsit y assess me nts will be perf or me d b y t he s u bject o n a n o ut- pati e nt basis ( Da y 2 t hr o u g h 
Da y 8 ). S u bjects will be i nstr ucte d n ot t o s h o wer or bat he f or at least 3 0 mi n utes bef ore a n d at 
least 1 h o ur after gel a p plicati o n. All pai n i nte nsit y assess me nts will be rec or de d i n e- di aries 
t hr o u g h Da y 8 ( Peri o d 1), a n d all st u d y gel a p plicati o ns will be rec or de d i n e-diaries b y t he 
s u bj ect t hr o u g h Da y 2 2 ( Peri o d 1 a n d 2). A t ele p h o ne call will be c o n d ucte d b y st u d y staff o n 
Da y 5 ( ± 1 da y) t o assess safet y. S u bj ects will ret ur n t o t he cli nic f or assess me nts o n Da y 8 
( ± 1 da y). F or s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 wee k, Da y 8 e n d of st u d y 
( E O S) ( + 1 da y) will be a cli nic visit a n d a f oll o w-u p tele p h o ne call t o assess safet y will be 
c o n d uct e d b y st u d y staff o n Da y 1 5 ( ± 1 da y). S u bjects w h o are assi g ne d t o recei ve st u d y gel f or 
3 wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut- patie nt basis fr o m Da y 8 t o Da y 2 2 ( Peri o d 2) 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
vi 1 6
acc or di n g t o t h eir assi g ne d d osi n g re gi me n (
 ( Ta ble 1 
). F or s u bjects w h o are 
d osi n g i n P eri o d 2, tele p h o n e calls t o assess safet y will be c o n d ucte d b y st u d y staff o n Da y 1 1 
( ± 1 da y) a n d Da y 1 8 ( ± 1 da y), st u d y gel a p pli cati o ns a n d use of a n y resc ue m e dicati o ns will 
be rec or de d i n e- diaries b y t he s u bjects t hr o u g h Da y 2 2, a n d a n e n d of st u d y ( E O S) cli nic visit 
will occ ur o n Da y 2 2 ( + 1 da y). A f oll o w- u p t ele p h o ne call t o assess safet y will be c o n d ucte d 
b y st u d y st aff o n Da y 2 9 ( ± 1 da y). 
Use of a n y res c ue m e dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs ( Da y 8) after 
t h e first st u d y g el a p plicati o n, at w hic h ti me o ver-t he-c o u nter ( O T C) aceta mi n o p he n ( o ne 
5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue m e dicati o n f or 
D O M S is per mitte d if re q uire d. S u bjects e x perie nci n g se vere pai n or i na bilit y t o m o ve or wal k 
d ue t o pai n ma y be per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet 
t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y gel a p plicati o n. 
If s u bjects ta ke resc ue me dicati o n bef ore t he first 1 6 8 h o urs, it will be ca pt ure d as a c o nc o mita nt 
me dicati o n, a n d s u bjects will rec or d t heir pai n i nte nsit y i n t he e- di ar y bef ore ta ki n g t he resc ue 
me dicati o n. T he n u m ber of ta blets ta ke n a n d t h e date a n d ti me will be rec or de d i n t h e e- di ar y.  
 
 
. T he i nteri m a nal ysis 
will assess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5). If f utilit y is deter mi ne d, t h e st u d y will 
be ter mi nate d. If c o nti n uati o n of t he trial is deter mi ne d, s u bject e nr oll me nt will be res u me d. 
Pri m ar y O bjecti v e: 
T o e val uat e t he efficac y of K- 2 8 5 c o m pare d wit h m e nt h ol gel bet wee n 0 t o 2 4 h o urs aft er
t h e first gel a p plicati o n f or t he treat me nt of D O M S
Sec o n d ar y O bjecti ves: 
T o e val u at e t he efficac y of K- 2 8 5 c o m pare d wit h me nt h ol gel after t he first gel a p plicati o n
f or t he treat me nt of D O M S
T o e val uate t he s afet y a n d t olera bilit y of K- 2 8 5 c o m pare d wit h me nt h ol gel aft er t h e first
gel a p plicati o n f or t h e treat me nt of D O M S
S u bject P o p ul ati o n: 
T he st u d y p o p ulati o n will be a d ult m al e a n d fe male s u bjects a ge d 1 8 t o 3 5 years, i ncl usi ve, wit h 
a b o d y mass i n de x ( B MI) bet wee n 1 8 a n d 3 2 k g/ m 2, i ncl usi ve. 
N u m ber of S u bjects: 
T otal 2 4 0 s u bjects wit h 1 2 0 s u bjects i n eac h of t he 2 
treat m e nt ar ms (Ta ble 1 
).  
N u m ber of Ce nters:
1 sit e i n t he U nite d St at es 
D ose Le vels:
K- 2 8 5: 
Me nt h ol gel:
R o ute of A d mi nistr ati o n:
T o pical gel 
D ur ati o n of Tre at me nt: 
1 wee k d osi n g ( Peri o d 1): Eac h s u bject will a p pl y 
. 
 ( Peri o d 1 a n d 2): Eac h s u bject will a p pl y 
 
. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
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Criteri a f or E v al u ati o n: 
Effic ac y:
Pri mar y E n d p oi nt: 
 
T he s u m of p ai n i nte nsit y differe nce ( S PI D) bet wee n 
) 
f or t h e st u d y le g after t h e first st u d y gel a p plicati o n w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
Sec o n dar y E n d p oi nts:
F or b ot h t he st u d y le g a n d t he n o n-st u d y le g 
 
S PI D 0- 2 4 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 1 2 h o urs ( S PI D 0- 1 2) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 1 2 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 4 8 h o urs ( S PI D 0- 4 8) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 4 8 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 7 2 h o urs ( S PI D 0- 7 2) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 7 2 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
S afet y: 
Safet y assess me nts will i ncl u de a d verse e ve nts ( A Es), vital si g n m eas ure m e nts (s yst olic bl o o d 
press ure, diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y t e m perat ure), E C G, 
p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel a p plicati o n site reacti o ns, cli ni cal 
la b orat or y t est res ults, st u d y gel use, a n d c o nc o mit a nt m e dicati o n use. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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Criteri a f or I ncl usi o n: 
Pre-e xercise Criteri a f or I ncl usi o n:
1.
S u bject 
m ust pr o vi de i nf or me d c o nse nt bef ore a n y st u d y- s pecific e val uati o n is 
perf or me d. 
2.
S u bject is m al e a n d fe m al e a ge d 1 8 t o 3 5 years, i ncl usi ve. 
3.  S u bject has a b o d y mass i n d e x of 1 8 t o 3 2 k g/ m 2, i ncl usi ve  
 
 
 
 
6.
S u bject he mat ol o g y, ser u m c he mistr y, uri nal ysis, vit al si g n meas ure me nts (s yst olic 
bl o o d press ure, diast olic bl o o d press ure, p ulse rate, a n d oral b o d y te m perat ure) a n d 
1 2-lea d E C G res ults s h o w n o cli nicall y rele va nt a b n or malities, as j u d ge d b y t he 
i n vesti g at or at t h e Scree ni n g Visit. 
7.
All fe m ale s u bjects m ust ha ve a ne gati v e ser u m pre g na nc y test res ult at scree ni n g a n d 
ne gati v e uri ne pre g na nc y t est o n Da y - 1 pri or t o a d missi o n t o t he cli nic. Fe male s u bjects 
of c hil d beari n g p ote ntial m ust us e o ne of t he f oll o wi n g acce pta ble birt h c o ntr ol m et h o ds 
as s pecifie d bef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y: 
a. S ur gical sterilizati o n ( bilateral t u bal li g ati o n, 
h ysterect o m y, 
bil ateral 
o o p h orect o m y) at least 6 m o nt hs bef ore t he first d ose of st u d y gel; 
b.
I ntra uteri ne de vice i n place f or at least 3 m o nt hs bef ore t he first d ose of st u d y 
gel a n d t hr o u g h o ut t he st u d y; 
c. Barrier met h o d (c o n d o m or dia p hra g m) wit h s per mici d e f or at least 1 4 da ys 
bef ore t h e first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
d.
S ur gical sterilizati o n of t he male part ner ( vasect o m y at least 6 m o nt hs bef ore 
t h e first d ose of st u d y gel); 
e. H or m o nal c o ntrace pti ves f or at least 3 m o nt hs wit h a barrier met h o d 1 4 da ys 
bef ore t h e first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
f. A bsti n e nce. 
8.  S u bject is a bl e a n d willi n g t o c o m pl y wit h t h e pr ot o c ol a n d st u d y pr oce d ures. 
9.
S u bject has n e gati ve test res ults f or dr u gs a n d al c o h ol at scree ni n g a n d is a ble a n d 
willi n g t o a bstai n fr o m marij ua na a n d alc o h ol use f or 4 da ys b ef ore Da y 1 a n d 
t hr o u g h o ut t he st u d y. N ot e t hat a p ositi v e scree ni n g res ult f or marij ua na is acce pta ble 
pr o vi de d t he s u bject will a bst ai n f or t h e st u d y as descri be d a b o ve. 
1 0. S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at least 6 m o nt hs bef ore t he 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y. 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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Criteri a f or E xcl usi o n:
Pre-e xercise Criteri a f or E xcl usi o n:
 
 
 
 
 
3.
S u bject has recei ve d oral or t o pical a nal gesic me di cati o ns wit hi n 1 4 da ys bef ore t he 
Scree ni n g Visit.
4.
S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0 da ys bef ore t he Scree ni n g Visit. 
5.
S u bject has a me di cal hist or y t hat i n cl u des a c o ntrai n di cati o n f or t he use of me nt h ol or 
n o nster oi dal 
a nti- i nfl a m mat or y 
dr u gs ( N S AI Ds) (e. g., 
gastr oi ntesti n al 
ulcer, 
gastr oi ntesti n al blee di n g). 
6.
S u bject is ta ki n g me dicati o ns or ot her s u bst a nces c o ntrai n di cat e d beca use of t he nat ure 
of t he st u d y gel or t he p ote ntial f or dr u g i nteracti o ns. T his i ncl u des s u bjects wit h 
aller gies t o prescri pti o n or O T C pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.  S u bject is pre g na nt or n ursi n g. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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1 5. S u bject h as parti ci pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0 da ys bef ore 
Scree ni n g. 
1 6. S u bject is a me m ber or a fa mil y me m ber of t he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve d i n t h e st u d y. 
1 7. S u bject has partici pat e d i n ot her cli ni cal trials f or K- 2 8 5. 
1 8.  S u bject has a b n or mal fi n di n gs or assess m e nts t hat are cli nicall y n ot e w ort h y. 
1 9. S u bject w h o, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d n ot partici pate i n t he st u d y.
St atisti c al A n al ysis:
I n g e neral, assess m e nts wit h c o nti n u o us o utc o m es will be s u m mari ze d usi n g t he descri pti ve 
st atisti cs n, mea n, st a n dar d de viati o n ( S D), me dia n, mi ni m u m a n d m a xi m u m. F or assess m e nts 
wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nt a ge will be calc ulate d. Detaile d 
st atisti cal met h o d ol o g y will be prese nte d i n a se parate statistical a nal ysis pla n.  
St u d y P o p ul ati o ns: 
T hree a nal ysis p o p ulati o ns will be e val uate d:  
 
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mi ze d s u bjects w h o ha ve a b aseli ne pai n 
sc ore, a n d at least 1 st u d y gel a p pli e d  
 
T he p er- pr ot oc ol set ( P P S) will i ncl u de all ra n d o mize d s u bjects w h o ha ve a baseli ne pai n 
sc ore, at least 1 st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns. 
 
T he safet y set will i n cl u de all s u bjects w h o ha ve at least 1 st u d y gel a p plie d. 
Pri m ar y Effic ac y A n al ysis:   
T he pri m ar y a nal ysis p o p ulati o n is t he F A S. T he pri m ar y a nal ysis will be re pe ate d usi n g t he 
P P S. 
 
 
 
. If t here e xist missi n g V A S val u es t o be i m p ute d, a n y s uc h 
val ues will be i m p ute d bef ore cal c ulati n g t he S PI D. Aft er calc ulati n g t he S PI D, a n a nal ysis of 
c o varia nce ( A N C O V A) m o del will be a p plie d f or t he pri mar y e n d p oi nt wit h ge n der a n d 
treat me nt as mai n effects a n d baseli n e pai n as a c o variate.  
Sec o n d ar y Effic ac y A n al yses:  
A mi xe d effect m o del re peate d- meas ures ( M M R M) wit h t h e sa me m ai n effects a n d c o variate 
will be a p pli e d t o t he PI D w hile st a n di n g a n d PI D at rest t o i n vesti gate treat me nt differe nces. 
 
. T he ti me t o first d ose of resc ue me dicati o n, will be a nal yze d usi n g t he Ka pla n- Meier 
met h o d t o esti mate t he s ur vi val distri b uti o n f u ncti o n.  
S afet y: 
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. A d verse e ve nts will be c o de d 
usi n g t h e latest versi o n of t he M e dical Di cti o nar y f or Re g ul at or y Acti vities ( Me d D R A). A d vers e 
e ve nts a n d s eri o us A Es ( S A Es) will be s u m marize d b y treat me nt gr o u p f or o verall n u m b er of 
A Es, se verit y, a n d rel ati o ns hi p t o st u d y gel. T he i nci de nce of A Es will be s u m m ari ze d b y b o d y 
s yste m a n d treat me nt gr o u p. T he i nci de nce of treat me nt-e mer ge nt A Es ( T E A Es) will als o be 
s u m marize d b y s yst e m or ga n cl ass a n d preferre d ter m. Cli nical la b orat or y res ults will be 
s u m marize d b y treat me nt gr o u p al o n g wit h c ha n ge fr o m Bas eli ne. Vital si g n meas ure m e nts will 
be s u m marize d b y gr o u p a n d ti me p oi nt al o n g wit h c ha n ge fr o m Baseli ne. All A E, cli nical 
la b orat or y, vital si g n, p h ysical e xa mi nati o n, st u d y gel a p plicati o n site reacti o n, st u d y gel use 
a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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.
S a m ple Size C alc ul ati o n:
T he para meters are c o nser vati vel y esti mate d base d o n t he D O M S st u d y wit h   
 gel. T he 
bet wee n- gr o u p differe nce i n t he m ea n   
 is 1 1. 0 7 wit h a S D of 2 5. 6 2. T o ha ve statistical 
p o wer of 9 0 %, 
. Ta ki n g i nt o acc o u nt i nf or mati o n l oss ca use d 
b y missi n g data, it is esti m at e d t hat 1 2 0 s u bjects nee d t o be treate d wit h eac h st u d y gel.  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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T A B L E O F C O N T E N T S
1. 0  
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N ............................ 1
1. 1   
B A C K G R O U N D I N F O R M A TI O N ................................................................................... 1  
1. 2   
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N ................................................... 2  
2. 0   
S T U D Y O B J E C TI V E S ..................................................................................................... 4  
2. 1   
P RI M A R Y O BJ E C TI V E .................................................................................................... 4  
2. 2   
S E C O N D A R Y O BJ E C TI V E S............................................................................................ 4  
2. 3   
P RI M A R Y E F FI C A C Y E N D P OI N T ................................................................................. 4  
2. 4   
S E C O N D A R Y E F FI C A C Y E N D P OI N T S ......................................................................... 4  
2. 5   
S A F E T Y E N D P OI N T S ...................................................................................................... 5  
3. 0   
S T U D Y D E S C RI P TI O N .................................................................................................. 6  
3. 1   
S T U D Y D E SI G N ............................................................................................................... 6  
4. 0   
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A ................................. 1 4  
4. 1   
I N C L U SI O N C RI T E RI A ................................................................................................. 1 4 
4. 1. 1  
Pre-e xercise I ncl usi o n Criteria .......................................................................................... 1 4  
4. 1. 2  
P ost-e xercis e Ra n d o mizati o n I ncl usi o n Criteria: .............................................................. 1 5  
4. 2   
E X C L U SI O N C RI T E RI A ................................................................................................ 1 5  
4. 3   
DI S C O N TI N U A TI O N A N D WI T H D R A W A L C RI T E RI A ............................................ 1 6  
4. 3. 1  
Disc o nti n uati o n d ue t o a n A p plicati o n Site Reacti o n ....................................................... 1 7  
5. 0   
P R O C E D U R E S F O R E F FI C A C Y A N D S A F E T Y E V A L U A TI O N S ....................... 1 8  
5. 1   
E F FI C A C Y E V A L U A TI O N S .......................................................................................... 1 8  
5. 1. 1  
Pai n I nte nsit y .................................................................................................................... 1 8  
5. 1. 1. 1  Vis ual A nal o g Scale .......................................................................................................... 1 8  
5. 1. 1. 2  Cate g orical Scal e .............................................................................................................. 1 8  
5. 1. 2  
Use of Resc ue Me dicati o n ................................................................................................ 1 8  
5. 1. 3  
Ti me t o O nset of First Perce pti ble a n d Mea ni n gf ul Pai n Relief ....................................... 1 9  
5. 1. 3. 1  O nset of Perce pti ble Pai n Relief ....................................................................................... 1 9  
5. 1. 3. 2  O nset of Mea ni n gf ul Pai n Relief ...................................................................................... 1 9  
5. 2   
S A F E T Y E V A L U A TI O N S .............................................................................................. 1 9  
5. 2. 1  
A d verse E ve nts ................................................................................................................. 1 9  
5. 2. 2  
Cli ni cal La b orat or y Tests .................................................................................................. 2 0  
5. 2. 2. 1  Ele vat e d Le vels of Ser u m Creati n e Ki nase....................................................................... 2 0  
5. 2. 3  
Vital Si g ns......................................................................................................................... 2 1  
5. 2. 4  
Electr ocar di o gra m ............................................................................................................. 2 1  
5. 2. 5  
P h ysical E xa mi nati o n ....................................................................................................... 2 1  
5. 2. 6  
S ki n E xa mi nati o n ( A p plicati o n Site Reacti o n) ................................................................. 2 1  
5. 2. 7  
C o nc o mita nt Me dicati o ns ................................................................................................. 2 2  
5. 3   
O T H E R E V A L U A TI O N S ................................................................................................ 2 2  
5. 3. 1  
De m o gra p hics, Me di cal Hist or y a n d Ot her Baseli ne C haracteristics ............................... 2 2  
5. 3. 2  
Dr u g a n d Al c o h ol Scree ni n g ............................................................................................. 2 2  
5. 3. 3  
Pre g na nc y.......................................................................................................................... 2 3  
5. 3. 4  
Sta n dar di ze d E xercise Re gi me n ....................................................................................... 2 3  
5. 3. 5  
P h ot o gra p h a n d Resi d ue E val uati o n ................................................................................. 2 3  
5. 3. 5. 1  P h ot o gra p hic A nal ysis ...................................................................................................... 2 3  
5. 3. 5. 2  Resi d ue E val u ati o n ........................................................................................................... 2 4  
5. 4   
T O T A L B L O O D V O L U M E............................................................................................. 2 4  
6. 0   
C O N D U C T O F S T U D Y ................................................................................................. 2 4  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N ............................................................ 2 4
6. 2   
S U BJ E C T I N F O R M E D C O N S E N T ................................................................................ 2 5  
6. 3   
S T U D Y VI SI T S ................................................................................................................ 2 6  
6. 4   
C O M P LI A N C E WI T H T H E P R O T O C O L ...................................................................... 3 2  
6. 5   
T E R MI N A TI O N O F T H E S T U D Y.................................................................................. 3 2  
7. 0   
S T U D Y M E DI C A TI O N ................................................................................................. 3 2  
7. 1   
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N .................................................................. 3 2  
7. 2   
D R U G P A C K A GI N G ....................................................................................................... 3 3  
7. 3   
D R U G L A B E LI N G .......................................................................................................... 3 3  
7. 4   
D R U G S T O R A G E ............................................................................................................ 3 4  
7. 5   
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T ....................................... 3 4  
7. 5. 1  
Dis pe nsi n g of St u d y Gel ................................................................................................... 3 4  
7. 5. 2  
A p plicati o n Trai ni n g ......................................................................................................... 3 4  
7. 5. 3  
Dr u g A d mi nistrati o n ......................................................................................................... 3 4  
7. 5. 4  
e- Diar y .............................................................................................................................. 3 6  
7. 5. 5  
P h ysical E xercise .............................................................................................................. 3 6  
7. 6   
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L D O SI N G R E GI M E N .................. 3 6  
7. 7   
D R U G A C C O U N T A BI LI T Y ........................................................................................... 3 6  
7. 8   
P R O C E D U R E F O R U N B LI N DI N G ................................................................................ 3 6  
8. 0   
C O N C O MI T A N T M E DI C A TI O N ............................................................................... 3 8  
8. 1   
G E N E R A L C O N SI D E R A TI O N S .................................................................................... 3 8  
8. 2   
P R O HI BI T E D M E DI C A TI O N A N D T H E R A PI E S ........................................................ 3 8  
8. 3   
P E R MI T T E D M E DI C A TI O N .......................................................................................... 3 8  
9. 0   
A D V E R S E E V E N T S ...................................................................................................... 3 9  
9. 1   
A D V E R S E E V E N T D E FI NI TI O N .................................................................................. 3 9  
9. 2   
R E P O R TI N G A D V E R S E E V E N T S ................................................................................ 3 9  
9. 3   
F O L L O W- U P O F A D V E R S E E V E N T S .......................................................................... 4 1  
1 0. 0  
S E RI O U S A D V E R S E E V E N T S .................................................................................... 4 2  
1 0. 1  
LI F E- T H R E A T E NI N G A D V E R S E E V E N T ................................................................... 4 2  
1 0. 2  
H O S PI T A LI Z A TI O N ....................................................................................................... 4 2  
1 0. 3  
I M P O R T A N T M E DI C A L E V E N T .................................................................................. 4 2 
1 0. 4  
P R E G N A N C Y .................................................................................................................. 4 2  
1 0. 5  
S U BJ E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L ............................................. 4 3  
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S............................. 4 3  
1 0. 7  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G ................................................................. 4 4  
1 1. 0  
S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S ............................................... 4 5  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N ................................................................................... 4 5  
1 1. 2  
S T U D Y P O P U L A TI O N S ................................................................................................. 4 5  
1 1. 3  
DI S P O SI TI O N .................................................................................................................. 4 5  
1 1. 4  
D E M O G R A P HI C/ B A S E LI N E I N F O R M A TI O N ............................................................ 4 5  
1 1. 5  
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S ................................................................. 4 5  
1 1. 5. 1  Pri mar y Efficac y Para meters ............................................................................................ 4 5  
1 1. 5. 2  Sec o n dar y Effi cac y Para met ers ........................................................................................ 4 6  
1 1. 6  
A N A L Y SI S O F S A F E T Y D A T A .................................................................................... 4 6  
1 1. 7  
I N T E RI M A N A L Y SI S ..................................................................................................... 4 7 
1 2. 0  
S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N ............................................ 4 8  
1 2. 1  
E T HI C A L C O N D U C T O F T H E T RI A L ......................................................................... 4 8  
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E ........ 4 8 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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1 2. 3 
S U BJ E C T I N F O R M E D C O N S E N T ................................................................................ 4 8
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L ......................................................................... 4 9  
1 2. 5  
S T U D Y I NI TI A TI O N ...................................................................................................... 4 9  
1 2. 6  
S T U D Y M O NI T O RI N G .................................................................................................. 4 9  
1 2. 7  
C A S E R E P O R T F O R M .................................................................................................... 5 0  
1 2. 8  
V E RI FI C A TI O N P R O C E D U R E S.................................................................................... 5 0  
1 2. 9  
R E T E N TI O N O F R E C O R D S........................................................................................... 5 0  
1 2. 1 0  I N S U R A N C E A N D I N D E M NI T Y .................................................................................. 5 1 
1 2. 1 1  A U DI T .............................................................................................................................. 5 1  
1 3. 0  
U S E O F I N F O R M A TI O N ............................................................................................. 5 2  
1 3. 1  
G E N E R A L A S P E C T S ...................................................................................................... 5 2  
1 3. 2  
S U BJ E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N ..................................... 5 2  
1 3. 3  
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y .......................................................... 5 2  
1 4. 0  
R E F E R E N C E S ................................................................................................................ 5 4  
1 5. 0  
A P P E N DI C E S ................................................................................................................. 5 5  
1 5. 1  
A P P E N DI X 1 ................................................................................................................... 5 5  
VI S U A L A N A L O G S C A L E ( E X A M P L E O F P A P E R V A S) ...................................................... 5 5  
VI S U A L A N A L O G S C A L E ( E X A M P L E O F E L E C T R O NI C V A S) .......................................... 5 6  
1 5. 2  
A P P E N DI X 2 ................................................................................................................... 5 7  
C A T E G O RI C A L P AI N S C A L E A S S E S S M E N T ......................................................................... 5 7  
1 5. 3  
A P P E N DI X 3 ................................................................................................................... 5 8  
K- 2 8 5- 2 0 1 A P P LI C A TI O N I N S T R U C TI O N S ............................................................................. 5 8  
1 5. 4  
A P P E N DI X 4 ................................................................................................................... 6 0  
E X A M P L E I M A G E S O F A P P LI C A TI O N SI T E R E A C TI O N S .................................................. 6 0  
 
List of T a bles 
Ta ble 1: Treat me nt Assi g n m e nt ....................................................................................................... 7  
Ta ble 2: Cli nical E val u ati o n Sc he d ule ........................................................................................... 1 0  
Ta ble 3. Cli nical La b orat or y Test Para meters ............................................................................... 2 0  
 
List of Fi g ures
Fi g ure 1. St u d y Sc he m a ................................................................................................................... 9  
Fi g ure 2. St u d y Gel All ocati o n ...................................................................................................... 3 3  
Fi g ure 3: Meas uri n g St u d y Gel ...................................................................................................... 3 5  
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
x v
1 6
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S
A PI  
acti v e p har m ace utical i n gre di e nts 
A E  
a d v erse e ve nt
A L T  
ala ni ne a mi n otra nsferas e
A N C O V A
a nal ysis of c o varia nce
A S T  
as partate a mi n otra nsferas e
A U C  
area u n d er t h e c ur ve 
B MI  
b o d y mass i n de x
C F R  
C o de of Fe d eral Re g ulati o ns
C K  
creati ne ki n ase
C K- M B  
creati ne ki n ase- m y ocar di al ba n d 
C K- M M  
creati ne ki n ase i n s k eletal m uscle 
C ma x
ma xi m u m c o nce ntrati o n 
C O X(- 2)  
c ycl o o x y ge nase i n hi bit ors
C R F  
case re p ort/rec or d f or m 
C R O  
C o ntract R esearc h Or ga nizati o n
D O M S  
dela ye d o nset m uscle s ore ness
E C G  
electr ocar di o gra m
e C R F  
electr o nic Cas e Re p ort/ R ec or d F or m 
e- diar y  
electr o nic diar y de vic e 
e V A S  
electr o nic vis ual a nal o g s cale 
E T  
earl y ter mi nati o n 
F A S  
f ull a nal ysis set
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P   
G o o d Cli nical Practi ce 
GI  
gastr oi ntesti nal
I C F  
i nf or me d c o nse nt f or m
I C H  
I nter nati o nal C o u ncil f or Har m o nis ati o n 
I E C  
I n d e pe n de nt Et hics C o m mittee
I R B   
I nstit uti o nal Re vie w B o ar d

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
x vi
1 6   
 
K RI   
K o wa Researc h I nstit ute, I n c.
L D H  
lactate de h y dr o ge nase 
L O C F  
last o bser vati o n carrie d f or war d
M A R   
missi n g at ra n d o m
M D M A  
3, 4- met h yle ne di o x y- met ha m p heta mi ne ( E cstas y)
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities 
MI   
m ulti ple i m p utati o n
M T W   
Ma xi m u m t olerate d wei g ht
N S AI D  
n o n-ster oi dal a nti-i nfla m mat or y dr u g
O T C  
o ver-t he-c o u nter
P C P  
p he nc ycli di ne
PI D  
pai n i nte nsit y differe n ce
P K  
p har mac o ki n etics 
P P S   
per- pr ot oc ol s et 
S A E  
Seri o us A d verse E v e nt 
S D  
sta n dar d de viati o n 
S O P  
St a n dar d O perati n g Pr oce d ure/s
S PI D   
s u m of pai n i nte nsit y differe nce
S PI D 0- 1 2 
s u m of pai n i nte nsit y differe nce o v er 1 2 h o urs after t he first gel a p plicati o n  
S PI D 0- 2 4 
s u m of pai n i nte nsit y differe n ce o v er 2 4 h o urs after t he first gel a p plicati o n
S PI D 0- 4 8 
s u m of pai n i nte nsit y differe nce o ver 4 8 h o urs after first gel a p plicati o n
S PI D 0- 7 2 
s u m of p ai n i nte nsit y differe nce o ver 7 2 h o urs after first gel a p plicati o n
S T E  
s h ort ti me e x p os ure
S U S A R  
Seri o us U ne x pect e d S us pect e d A d v erse Re acti o n
T E A E  
Treat me nt-e mer ge nt A E 
T R P  
tra nsie nt rec e pt or p ote nti al
(e) V A S  
(electr o ni c) vis ual a nal o g scale
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 of 6 0 
 
1. 0
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N
1. 1  
B A C K G R O U N D I N F O R M A TI O N 
N o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds), i ncl u di n g n o n-selecti ve N S AI Ds a n d 
t he m ore selecti ve c ycl o o x y ge nase ( C O X- 2) i n hi bit ors, are e xte nsi vel y use d i n t he U nite d 
States a n d rest of w orl d f or t h e relief of pai n a n d t he re d u cti o n of i nfla m mati o n. T his class 
of me dicati o ns is t he m ost wi d el y use d w he n prescri pti o n a n d o ver-t h e-c o u nter ( O T C) 
pr o d ucts are c o nsi dere d. H o we v er, its oral us e is n ot wit h o ut ris k, w hi c h m ost n ota bl y 
i ncl u des t o xicit y ass ociate d wit h gastr oi ntesti nal ( GI) i nfla m mati o n a n d blee di n g. 
Half of patie nts ta ki n g N S AI Ds re g ularl y ha v e e n d osc o picall y c o nfir me d g astric er osi o ns, 
a n d 1 0 %- 3 0 % h a ve ulc ers. 1 T hese ris ks are a m plifie d i n hi g h ris k gr o u ps, i ncl u di n g t he 
el derl y, t h ose 
wit h pre-e xisti n g gastr o pat h y, c hr o nic a d mi nistrati o n, c o nc o mit a nt 
c ortic oster oi d use a n d Helic o bacter p yl ori i nfecti o n pri or t o N S AI D t hera p y. 2 T he use of 
selecti v e C O X- 2 i n hi bit ors, pr u de nt use of pr ot o n p u m p i n hi bit ors, a n d alter nati ve 
me dicati o ns ha ve i m pr o ve d t he i nci de nce of g astr o pat h y, b ut ha ve n ot eli mi n ate d it.
C O X- 2 i n hi bit ors still de m o nstrate a si g nifica nt ris k of GI c o m plicati o ns. 3  
T he wi d es prea d use of O T C N S AI Ds, w hic h i ncl u des all n o n-selecti ve C O X i n hi bit ors, 
p oses a great ris k of GI c o m plicati o ns. Rece nt acti vit y has als o s h o w n t he p ote ntial f or 
car di o vasc ular ris k fr o m t he s yste mic use of C O X- 2 i n hi bit ors, w hic h was hi g hli g hte d b y 
t he 2 0 0 4 wit h dra wal of r ofec o xi b ( Vi o x x® ). Wit h t his bac k gr o u n d, t here is a nee d f or safer 
alter nati ves t o orall y a d mi nistere d N S AI Ds, es peciall y f or t h ose i n hi g her ris k gr o u ps, or 
t h ose i nt olera nt of orall y a d mi nistere d N S AI Ds.  
T o pical a nal g esics offer a n alter n ati v e t o t he us e of s yste mic N S AI Ds f or relief of f ocal
pai n a n d i nfla m mati o n. T hese fall i nt o se veral cate g ories, i ncl u di n g a nest hetics, 
c o u nterirrita nts a n d a nal gesics. T he first t w o cate g ories are ill ustrate d b y t h e a p pr o v e d 
li d ocai n e 5 % p atc h ( Li d o der m® ), a n d ca psaici n, res pecti vel y. Fle ct or ®  ( dicl ofe nac 
e p ola mi ne t o pical p atc h 1. 3 %) is a n e x a m ple of a prescri pti o n N S AI D a nal gesic patc h. A 
meta-a n al ysis of 2 6 d o u ble- bli n d place b o-c o ntr olle d 
N S AI Ds trials t hat e nr olle d
2, 8 5 3 patie nts de m o nstrate d t hat i n 1 9/ 2 6 tri als t h e N S AI D was s u peri or t o place b o a n d 
was s h o w n t o be safe. 4
l- Me nt h ol is a nat urall y occ urri n g c yclic m o n oter pe ne alc o h ol of pla nt ori gi n. Its use 
e xte n ds fr o m c uli nar y ite ms t o c os metic pr o d ucts t o p har mace utic al i n gre die nts. 
Wit h 
re gar ds t o its 
me dici n al p ur p oses, b ot h pres cri b e d a n d 
O T C 
me nt h ol c o ntai ni n g 
me dicati o ns are c urre ntl y a vaila ble t hr o u g h o ut t he w orl d f or a h ost of c o n diti o ns, i ncl u di n g 
res pirat or y dise ases, GI dis or ders, c o m m o n c ol d, a n d m usc ul os keletal pai n. It is als o 
c o m m o nl y use d as part of a nal g esic, a ntis e pti c, t o pical a nti pr uritic, a n d c o u nterirrita nt 
pr o d ucts. Its a bilit y t o m o d ulate Tra nsie nt Rece pt or P ote ntial ( T R P) cati o n c ha n nels a n d 
n u mer o us 
ot her i o n 
c ha n nels 
m a y 
u n derlie its 
re p ute d 
a nal gesic 
effects. 5
Me nt h ol-c o ntai ni n g O T C 
m e dicati o ns are c urre ntl y 
mar kete d i n t h e U S as t o pical 
a nal gesics at c o n ce ntr ati o ns u p t o 1 6 % l- me nt h ol i n t he U S.  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 of 6 0 
 
1. 2   
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N
K o wa C o m pa n y Lt d. h as de vel o pe d K- 2 8 5, a pr o d uct c o ntai ni n g 
 
 f or relief of p ai n d ue t o m uscle 
s ore ness, s prai ns a n d strai ns. 
T he acti ve p h ar mace utical i n gre die nts ( A PI) i n K- 2 8 5 t o pical gel are 
 
 T he m e nt h ol gel c o ntai ns 
.  
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 of 6 0 
 
T he 
m ost c o m m o nl y re p orte d treat me nt-relate d, treat m e nt-e mer g e nt a d v erse e v e nts 
( T E A Es) (i. e., t h ose re p orte d b y m ore t h a n 2 s u bj ects o verall) were a p plicati o n sit e pai n, 
a p plicati o n site er yt h e ma, a p plicati o n site disc ol orati o n, a p plicati o n site e xf oli ati o n, 
a p plicati o n site pr urit us, a n d a p plicati o n site dr y n ess. All T E A Es re p ort e d were mil d i n 
se verit y. T here were n o m o derate or se v ere T E A Es, seri o us a d verse e ve nts ( S A Es), or 
deat hs re p orte d d uri n g t h e st u d y. O ne s u bject ( 6. 7 %) disc o nti n ue d fr o m t he st u d y d ue t o a 
treat me nt-relate d T E A E of a p plicati o n site disc har ge. All T E A Es were res ol ve d b y t he e n d 
of t he st u d y. Der mat ol o gical fi n di n gs relate d t o t he a p plicati o n site were re p orte d as 
T E A Es, b ut t hese e ve nts a n d cli nical l a b orat or y ass ess me nts, vital si g n meas ure me nts, 
electr ocar di o gra m ( E C G) assess me nts, a n d p h ysical e x a mi n ati o ns were n ot c o nsi dere d 
cli nicall y si g nifica nt. M ulti ple a p plicati o ns of K- 2 8 5 were s afe a n d g e nerall y well t olerate d 
b y healt h y s u bjects i n t his st u d y.  
Base d o n t he P h ase 1 st u d y res ults, t h e d os a ge of K- 2 8 5, 
 
s h o we d hi g her 
, a n d t h us was s electe d t o e val uate effic ac y a n d s afet y at 
1 wee k ( Peri o d 1). F or P eri o d 2, b ot h t he 
) 
d osi n g re gi me ns were selecte d t o e val uate t he a d diti o nal safet y pr ofile at 2 wee ks. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 of 6 0 
 
2. 0
S T U D Y O B J E C TI V E S
2. 1  
P RI M A R Y O B J E C TI V E
T he pri m ar y o bjecti v e is t o e val uate t he efficac y of K- 2 8 5 c o m pare d wit h me nt h ol gel 
bet wee n 0 t o 2 4 h o urs after t he first g el a p plicati o n f or t he treat me nt of dela ye d o ns et 
m uscle s ore ness ( D O M S). 
2. 2  
S E C O N D A R Y O B J E C TI V E S 
T he sec o n d ar y o bjecti v es are: 
 
T o e val uat e t he effi cac y of K- 2 8 5 c o m pare d wit h me nt h ol gel aft er t he first gel 
a p plicati o n f or t he treat m e nt of D O M S
T o e val u ate t he safet y a n d t olera bilit y of K- 2 8 5 c o m pare d wit h me nt h ol g el aft er first 
gel a p pli cati o n f or t he treat me nt of D O M S 
2. 3  
P RI M A R Y E F FI C A C Y E N D P OI N T 
Pri mar y E n d p oi nt: 
 
T he s u m of pai n i nte nsit y differe nce 
 
 f or t h e st u d y le g after t h e first st u d y gel a p plicati o n w hile sta n di n g usi n g a 
0- 1 0 0 p oi nt electr o nic vis ual a nal o g scale (e V A S) 
2. 4  
S E C O N D A R Y E F FI C A C Y E N D P OI N T S
Sec o n dar y E n d p oi nts: 
F or b ot h t he st u d y le g a n d t he n o n-st u d y le g 
 
S PI D 0- 2 4 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 1 2 h o urs ( S PI D 0- 1 2) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
S PI D 0- 1 2 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 4 8 h o urs ( S PI D 0- 4 8) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
 
S PI D 0- 4 8 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 7 2 h o urs ( S PI D 0- 7 2) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
 
S PI D 0- 7 2 after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 of 6 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
2. 5  
S A F E T Y E N D P OI N T S 
Safet y assess m e nts will i ncl u de a d v erse e ve nts ( A Es), vit al si g n meas ure me nts (s yst olic 
bl o o d press ure, diast oli c bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y 
te m perat ure), E C G, p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel a p plicati o n 
site reacti o ns (i ncl u di n g via a n irrit ati o n rati n g scal e), cli nical la b orat or y test res ults, st u d y 
gel use, a n d c o n c o mita nt me dicati o n use. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 6 of 6 0 
 
3. 0  
S T U D Y D E S C RI P TI O N
3. 1  
S T U D Y D E SI G N
T his is a p has e II, ra n d o mize d, d o u ble- bli n d, acti ve c o m parat or, p arall el gr o u p st u d y t o 
e val uate t he effi cac y a n d safet y of K- 2 8 5 c o m p are d wit h me nt h ol gel f or t h e treat m e nt of 
D O M S i n t h e l o wer e xtre mit y.
T he st u d y will c o nsist of scree ni n g, a n e xercise visit ( D O M S i n d ucti o n), i n- patie nt a n d 
o ut- patie nt peri o ds u p t o 3 wee ks, a n d a f oll o w- u p tele p h o ne call. D uri n g t h e S cree ni n g 
Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete s cree ni n g assess me nts 
i ncl u di n g m e dical hist or y, i de ntificati o n of t he d o mi na nt le g as deter mi n e d b y ha n d 
d o mi n a nce, p h ysical a n d s ki n e xa mi nati o ns, bl o o d a n d uri ne tests, vital si g ns 
meas ure me nts, E C G, a n d ot her scree ni n g pr oce d ures. S u bjects w h o are a ble t o parti ci pate 
i n t h e st u d y ( Peri o d 1 a n d 2) a n d w h o meet t he pre-e xercis e i ncl usi o n a n d e xcl usi o n crit eria 
will be e nr olle d i nt o t h e st u d y a n d ret ur n t o t h e cli nic o n Da y - 1. Eli gi bilit y will b e 
c o nfir me d a n d e nr olle d s u bjects will perf or m a sta n dar dize d re petiti ve q ua drice ps m uscl e 
e xercis e t o creat e D O M S t o b ot h le gs ( Da y - 1). T he e xercise re gi m e n will c o nsist of a 
war m- u p, d eter mi nati o n of ma xi m u m t olerate d wei g ht, a n d ti me d a n d u n-ti me d w or k o ut 
p hases. 
Wit hi n 2 4 t o 3 0 h o urs aft er t h e e x ercis e sessi o n ( Da y 1), s u bjects will rat e t he pai n of b ot h 
le gs usi n g a cate g orical scale a n d rec or d p ai n i nte nsit y of b ot h le gs at rest a n d w hile 
sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S (a ca pt ure pr o gra m will li nearl y c o n vert t he pi xel 
t o uc he d t o a n i nte ger b et wee n 0 a n d 1 0 0) t o d eter mi n e eli gi bilit y f or ra n d o mizati o n. T he 
s pecific p ost-e x ercise   
 i ncl usi o n crit eri o n will be mas ke d t o s u bjects.  
 
 
 
 If b ot h le gs meet p ost-e xercise i ncl usi o n criteria, t he st u d y le g will be t he 
d o mi n a nt l e g, base d o n h a n d d o mi na nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will be 
gi ve n a p pr o priate sta n d ar d of care. A t otal of 2 4 0 s u bjects w h o meet p ost-e xercise 
i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o Treat m e nt Ar m A ( K- 2 8 5 gel) 
or Treat me nt Ar m B ( Me nt h ol gel). 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 7 of 6 0 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 o n t he st u d y le g as f oll o ws:
 
Treat m e nt Ar m A: Eac h s u bject will a p pl y K- 2 8 5 t o t he st u d y le g.  
 
Treat m e nt Ar m B: Eac h s u bject will a p pl y me nt h ol gel t o t he st u d y le g. 
T he first st u d y gel a p plicati o n t o t he st u d y le g
will b e a p plie d b y t he s u bject wit h 
i n vesti gat or ( or d esi g nee) o versi g ht t o e ns ure pr o per a p pli cati o n at t he cli nic o n Da y 1 
wit hi n 2 4 t o 3 0 h o urs after D O M S i n d ucti o n. S u bse q ue nt st u d y gel a p plicati o ns at t h e cli nic 
will b e a p plie d t o t h e st u d y le g b y t he s u bject wit h i n vesti gat or ( or d esi g nee) o versi g ht t o 
e ns ure pr o p er a p plicati o n. O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t he 
a p plicati o n site will be p erf or me d pri or t o eac h st u d y gel a p plicati o n. S u bj ects will re mai n 
i n t h e cli nic u ntil t h e y are disc har ge d f oll o wi n g c o m pleti o n of st u d y assess me nts o n Da y 2. 
Pai n i nte nsit y assess me nts will be p erf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest a n d 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli ne ( 0 h o urs) a n d at   
 
 
after t h e first st u d y gel a p plicati o n. Pai n assess m e nts sc he d ule d bet wee n mi d ni g ht 
a n d 6 a m ma y be s ki p pe d if s u bjects are aslee p b ut s u bjects ma y n ot s ki p m ore t ha n t w o 
se q ue nti al assess me nts. A ti m e wi n d o w of + 3 0 mi n utes will be all o we d b et wee n q u alif yi n g 
pai n assess m e nts a n d first st u d y gel a p plicati o n ( 0 h o urs).  
T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h pai n assess m e nt ti m e p oi nt: 
± 1 5 mi n utes f or assess me nts fr o m 1 t o 1 2 h o urs ( Da y 1), ± 3 0 mi n utes f or assess me nts at 
1 8 t hr o u g h 2 4 h o urs ( Da y 2), a n d ± 1 h o ur f or ass ess me nts at 3 6 t o 1 6 8 h o urs ( Da y 2 t o 
Da y 8). F oll o wi n g disc h ar ge fr o m t he cli nic o n Da y 2, s u bse q ue nt st u d y gel a p plicati o ns 
a n d pai n i nte nsit y assess me nts will be perf or me d b y t he s u bject o n a n o ut- patie nt basis 
( Da y 2 t hr o u g h Da y 8). S u bjects will be i nstr ucte d n ot t o s h o wer or bat he f or at least 
3 0 mi n utes b ef ore a n d at least 1 h o ur after gel a p plicati o n.  
All pai n i nte nsit y assess me nts will b e rec or d e d i n e- diaries t hr o u g h Da y 8 ( Peri o d 1), a n d 
all st u d y gel a p plicati o ns will be rec or de d i n t he e- diar y b y t he s u bject t hr o u g h Da y 2 2 
( Peri o d 1 a n d 2). A tele p h o ne call will be c o n d ucte d b y st u d y staff o n Da y 5 ( ± 1 da y) t o 
assess safet y. S u bjects will ret ur n t o t he cli nic f or assess me nts o n Da y 8 ( ± 1 da y). F or 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 8 of 6 0 
 
s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 wee k, Da y 8 ( + 1 da y) will be a n e n d 
of st u d y ( E O S) cli nic visit a n d a f oll o w- u p t ele p h o ne call t o assess s afet y will be c o n d ucte d 
b y st u d y staff o n Da y 1 5 ( ± 1 da y). S u bjects w h o are assi g ne d t o recei v e st u d y gel f or 
3 wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut- patie nt basis fr o m Da y 8 t o Da y 2 2 
( Peri o d 2) acc or di n g t o t heir assi g ne d d osi n g re gi me n (  
) (Ta bl e 1 : Treat me nt 
Assi g n me nt). F or s u bjects w h o are d osi n g i n Peri o d 2, tele p h o ne calls t o ass ess safet y will 
be c o n d ucte d b y st u d y staff o n Da y 1 1 ( ± 1 da y) a n d Da y 1 8 ( ± 1 d a y), st u d y gel a p plicati o ns 
a n d use of a n y resc u e m e dicati o ns will be rec or d e d i n e- diaries b y t he s u bjects t hr o u g h 
Da y 2 2, a n d a n e n d of st u d y ( E O S) cli nic visit will occ ur o n Da y 2 2 ( + 1 d a y). A f oll o w- u p 
tele p h o ne call t o assess safet y will be c o n d u cte d b y st u d y staff o n Da y 2 9 ( ± 1 da y). 
Use of a n y resc ue me di cati o n f or D O M S is str o n gl y disc o ura ge d u ntil 
) 
after t he first st u d y gel a p plicati o n, at w hic h ti me o ver-t he-c o u nter ( O T C) aceta mi n o p he n 
( o ne 5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t h a n e ver y 6 h o urs) as resc ue 
me dicati o n f or D O M S is per mitte d if re q uire d. S u bjects e x perie nci n g se vere p ai n or 
i na bilit y t o m o ve or wal k d ue t o pai n m a y b e per mitte d t o use res c ue me dicati o n 
( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 
1 6 8 h o urs after t he first st u d y gel a p plicati o n. If s u bjects ta ke res c ue me dicati o n bef ore t he 
first 1 6 8 h o urs, it will be ca pt ure d as a c o n c o mita nt me dicati o n, a n d s u bjects will rec or d 
t heir pai n i nte nsit y i n t he e- diar y b ef ore ta ki n g t he resc u e me dicati o n. T he n u m ber of 
ta blets ta ke n a n d t he d ate a n d ti me will be rec or de d i n t h e e- diar y. 
W he n 
 
 
. T he 
i nteri m a nal ysis will ass ess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5). If f utilit y is 
deter mi n e d, t h e st u d y will be ter mi nate d. If c o nti n uati o n of t h e trial is deter mi n e d, s u bject 
e nr oll me nt will be res u m e d. 
A st u d y sc he matic is s h o w n i n Fi g ure 1 . T he s c he d ule of assess me nts is s h o w n i n Ta ble  2 .  
 

C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 9 of 6 0
 
 
 
 
 
 
 

C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 0 of 6 0
 
T a ble 2: Cli nic al E v al u ati o n Sc he d ule
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n
p atie nt 
O ut
p atie nt 
Safet y 
Visit 
O ut
p atie nt 
Safet y
Visit 
O ut
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
I nf or me d c o nse nt
X
De m o gra p h y 
X 
 
 
 
 
 
 
 
 
 
 
Me dical/ m e dicati o n 
hist or y 
X 
X 
 
 
 
 
 
 
 
 
 
Pre-e x ercise i n cl usi o n 
criteria, e x cl usi o n 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
A d missi o n t o cli nic a
X 
 
 
 
 
 
Disc h ar ge fr o m cli nic a 
 
 
 
X 
 
 
 
 
 
 
 
Visit t o cli nic ( o ne 
d a y) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
T ele p h o ne Call ( Da ys 
5, 1 1, 1 8, a n d Da y 1 5 
or 2 9) b
 
 
 
 
X 
 
X
 
 
X 
 
 
X 
Pre-e x ercise pai n 
assess me nt ( pa p er 
V A S) 
 
X 
 
 
 
 
 
 
 
 
 
D O M S i n d u cti o n 
e xercise 
 
X 
 
 
 
 
 
 
 
 
 
e- diar y, st u d y trai ni n g
X
Iss u e e- diar y
X
V A S Q u alif yi n g Pai n 
assess me nts c
 
 
X 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 1 of 6 0
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n  
p atie nt 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
Cate g orical 
Q u alif yi n g Pai n 
assess me nts c  
 
 
X 
 
 
 
 
 
 
 
 
P ost-e x ercise 
i ncl usi o n criteria 
 
 
X 
 
 
 
 
 
 
 
 
Ra n d o mizati o n
X
 
 
 
 
Hei g ht a n d wei g ht
X
Vital si g ns d
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Electr o car di o gra m
X
X
 
 
 
X  
 
P h ysical e x a mi n ati o n 
X 
X 
 
 
 
X
X
X
S ki n e xa mi n ati o n /
assess me nt at st u d y 
g el site
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Pre g na n c y test e 
X
X
X
Uri n e dr u g scree n a n d 
alc o h ol test 
X 
X 
 
 
 
 
 
 
 
 
 
Cli nical la b orat or y 
tests ( he mat ol o g y, 
ser u m c h e mistr y, a n d 
uri n al ysis)
X
X
V A S pai n i nte nsit y 
assess me nt c
 
 
X 
X 
X 
X 
 
 
 
( X) k
Perce pti ble a n d 
Mea ni n gf ul p ai n relief 
assess me nts c
 
 
X 
X 
X 
X 
 
 
 
( X) k
P h ot o gra p hic a n d 
resi d ue e v al u ati o nf
X

C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 2 of 6 0
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n  
p atie nt 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
P h ot o gra p hic
e val uati o n of 
a p plicati o n site 
reacti o nsg
 
 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
 
Dis p e nse st u d y g el 
 
 
 
X 
 
X 
 
X 
 
 
 
A p pl y st u d y g el h
X
X
X
X
X
X
X
( X)  
Rec or d a d verse e v e nts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rec or d c o nc o mita nt 
me dicati o ns i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rec or d resc u e 
me dicati o n use 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C ollect st u d y g el
X
C ollect s u bject e- diar y 
 
 
 
 
 
 
 
 
 
X 
 
; D O M S, d ela y e d o nset m uscle s ore ness; e- diar y, electr o nic diar y d e vice; E O S, e n d of st u d y; E T, earl y ter mi n ati o n; 
; V A S, vis u al a nal o g 
scale; ( X), p erf or me d as i n dicate d i n t h e f o ot n ote.  
a S u bjects will e nter t h e cli nic o n Da y 1 a n d will b e disc h ar g e d o n Da y 2 after st u d y assess me nts at 
 g el a p pli cati o n are c o m plete d.
b St u d y staff will c o ntact s u bjects b y tele p h o n e f or assess me nt of A Es, s ki n c o n diti o n a n d c o nc o mit a nt me dicati o ns, a n d use of resc ue me dicati o n. All s u bjects will b e c o ntacte d 
o n Da y 5 ( ± 1 da y). S u bjects p artici p ati n g i n P eri o d 1 will b e c o ntacte d o n Da y 1 5 ( ± 1 d a y). S u bjects p artici p ati n g i n Peri o d 2 will be c o ntacte d o n Da y 1 1 ( ± 1 d a y), Da y 1 8 
( ± 1 d a y), a n d Da y 2 9 ( ± 1 d a y). 
c V A S a n d cate g orical q u alif yi n g pai n assess me nts will b e p erf or me d o n b ot h le gs wit hi n 2 4- 3 0 h o urs of e x ercise t o i n d uce D O M S. Pai n i nte nsit y assess me nts will be p erf or me d 
f or t h e st u d y le g a n d n o n-st u d y le g at rest a n d w hil e sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli n e ( 0 h o urs) a n d at 
 
 after t h e first st u d y g el a p plicati o n. Baseli ne ( 0 h o urs) is t h e ti me p oi nt f or t h e first st u d y g el a p plicati o n; a ti me 
wi n d o w of + 3 0 mi n utes will b e all o we d b et wee n q u alif yi n g p ai n assess me nts ( q u alif yi n g p ost-e x ercise i n cl usi o n criteria) a n d first st u d y g el a p plicati o n ( 0 h o ur). T h e f oll o wi n g 
ti me wi n d o ws will b e all o we d f or eac h p ai n assess me nt ti me p oi nt: ± 1 5 mi n utes f or assess me nts fr o m 1 t o 1 2 h o urs ( Da y 1), ± 3 0 mi n utes f or assess me nts at 1 8 t hr o u g h 
2 4 h o urs ( Da y 2), a n d ± 1 h o ur f or assess me nts at 3 6 t o 1 6 8 h o urs ( Da y 2 t o 8). Ti me t o p erce pti bl e a n d mea ni n gf ul p ai n relief will be rec or de d b y s u bjects i n t h eir e- diar y. 
W h e n st u d y gel a p plicati o n a n d pai n assess me nt o cc ur at t h e sa me ti me p oi nt, pai n assess me nts will be p erf or me d b ef ore st u d y gel a p plicati o n. 
d Vital si g n meas ure me nts will i n cl u d e s yst olic bl o o d press ure, diast olic bl o o d press ure, p ulse rate, a n d oral b o d y te m p erat ure. Bl o o d press ure a n d p ulse rat e will b e meas ure d 
aft er t h e s u bject h as b ee n resti n g i n t h e s u pi n e p ositi o n f or at least 5 mi n utes. 
e Ser u m pre g n a n c y test at S cree ni n g a n d uri n e pre g n a n c y t est at E x ercise visit, E O S Visit ( Da y 8 or Da y 2 2) (fe males o nl y). 
f P h ot o gra p hic a n d resi d ue e v al u ati o ns of t h e a p plicati o n site will b e p erf or me d bef ore t h e 
 st u d y gel a p plicati o ns o n Da y 2.  

C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 3 of 6 0
g
Be gi n ni n g wit h t h e 
, w he n a n a p plicati o n site reacti o n is o bser ve d at t h e cli nical site, p h ot o gra p hs of t h e a p plicati o n site will be ta k e n 
b y site staff t o vis u all y d o c u me nt t h e s ki n c o n diti o n at t h e site of gel a p pli cati o n. If n ee d e d, t h e p h ot o gra p hs will b e p eri o dicall y ta k e n t o f oll o w- u p t h e a p plicati o n site 
reacti o n. If a n a p plicati o n site reacti o n is o bser v e d at h o me, p h ot o gra p hs of t h e a p plicati o n site will b e ta k e n b y site staff w h e n s u bject ret ur ns t o t he cli nical site. All 
p h ot o gra p hs s h o ul d be ta k e n pri or t o gel a p plicati o n. 
h
 
 
 
T h e f oll o wi n g ti me wi n d o ws will b e all o we d f or eac h st u d y g el a p plicati o n ti me p oi nt: + 3 0 mi n utes f or first st u d y g el a p plicati o n ( 0 h o ur) after q u alif yi n g p ai n assess me nts, 
± 1 5 mi n utes f or t h e 
 a p plicati o ns, ± 3 0 mi n utes f or t h e 
 a p plicati o ns, a n d ± 1 h o ur f or ot her a p plicati o n ti me p oi nts.  
At t h e site, st u d y g el is a p plie d t o t h e st u d y le g b y t h e s u bject wit h i n v esti gat or ( or d esi g n ee) o v ersi g ht t o e ns ure pr o p er a p plicati o n. F oll o wi n g disc h ar g e fr o m t h e cli nic o n 
Da y 2, s u bse q u e nt st u d y gel a p plicati o ns will be p erf or me d b y t h e s u bject. F or s u bjects p artici pati n g o nl y i n Peri o d 1, t h e last a p plicati o n of st u d y g el is a p plie d at 6 a m o n 
Da y 8. F or s u bjects partici pati n g i n Peri o d 2, t h e last a p plicati o n of st u d y g el is a p plie d at 6 a m o n Da y 2 2. 
i
All me dicati o ns a n d ot h er treat me nts ta k e n b y s u bjects wit hi n 3 0 d a ys b ef ore d osi n g a n d d uri n g t he st u d y will b e rec or d e d i n t h e C R F. A n y c h a n g es i n t h e c o nc o mit a nt 
me dicati o ns after disc h ar g e fr o m t h e cli nic o n Da y 2, eit h er prescri b e d or self-a d mi nistere d, will b e d o c u me nte d a n d re vie we d d uri n g tele p h o n e calls, Safet y visits a n d at t he 
E O S Visits. 
j F or s u bjects partici p ati n g o nl y i n Peri o d 1 E O S is o n Da y 8 ( + 1 d a y), f or s u bjects p artici pati n g i n Peri o d 2 E O S is o n Da y 2 2 ( + 1 d a y). N ote t h at E O S visits h a v e a wi n d o w 
of + 1 d a y w hereas Safet y visits ha ve a wi n d o w of ± 1 d a y. 
k F or Da y 8, Peri o d 1. 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 4 of 6 0 
4. 0
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A
S u bjects w h o d o n ot meet eli gi bilit y criteria will be classifie d as s cree n fail ures a n d t h e 
reas o n(s) will be rec or de d i n t he case re p ort f or m ( C R F)/electr o ni c C R F (e C R F).
4. 1 
I N C L U SI O N C RI T E RI A
4. 1. 1 
Pre-e xercise I ncl usi o n Criteri a
S u bjects are eli gi ble f or t he st u d y if all of t he f oll o wi n g crit eria are met:
1.  S u bject 
m ust pr o vi de i nf or m e d c o nse nt bef ore a n y st u d y-s pecific e val uati o n is 
perf or me d. 
2.  S u bject is male a n d fe male a ge d 1 8 t o 3 5 years, i n cl usi v e. 
3.  S u bject has a b o d y mass i n de x ( B MI) of 1 8 t o 3 2 k g/ m 2, i ncl usi ve 
 
 
 
 
 
 
6.  S u bject  h e mat ol o g y, ser u m c he mistr y, uri nal ysis, vital si g n meas ure me nts (s yst olic 
bl o o d press ure, di ast olic bl o o d press ure, p ulse r ate, a n d oral b o d y te m perat ure) a n d 
1 2-lea d E C G res ults s h o w n o cli nicall y rel e va nt a b n or malities, as j u d ge d b y t he 
i n vesti gat or at t he Scree ni n g Visit. 
7.  All fe male s u bjects m ust ha ve a ne g ati ve ser u m pre g n a nc y test res ult at Scree ni n g a n d 
ne gati v e uri n e pre g na nc y test o n Da y - 1 pri or t o a d missi o n t o t he cli ni c. Fe male 
s u bjects of c hil d beari n g p ote ntial m ust use o ne of t h e f oll o wi n g acce pta ble birt h c o ntr ol 
met h o ds as s pecifie d b ef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y: 
a. S ur gical 
sterilizati o n 
( bilateral 
t u bal 
li gati o n, 
h ysterect o m y, 
bilateral 
o o p h orect o m y) at le ast 6 m o nt hs bef ore t h e first d ose of st u d y gel; 
b.  I ntra uteri ne de vice i n place f or at least 3 m o nt hs b ef ore t he first d ose of st u d y gel 
a n d t hr o u g h o ut t he st u d y; 
c. Barrier met h o d (c o n d o m or dia p hra g m) wit h s per mici de f or at least 1 4 da ys bef ore 
t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
d.  S ur gical sterilizati o n of t he male p art n er ( v asect o m y at least 6 m o nt hs bef ore t h e 
first d ose of st u d y gel); 
e. H or m o nal c o ntrace pti ves f or at least 3 m o nt hs wit h a barrier met h o d 1 4 da ys b ef ore 
t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
f. A bsti ne nce. 
8.  S u bject is a ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol a n d st u d y pr oce d ures.
9.  S u bject h as ne g ati ve test res ults f or dr u gs a n d alc o h ol at scree ni n g a n d is a bl e a n d 
willi n g t o a bstai n fr o m marij u a na a n d alc o h ol use f or 4 da ys bef ore Da y 1 a n d 
t hr o u g h o ut t he st u d y. N ote t hat a p ositi ve scree ni n g res ult f or marij ua na is acce pta bl e 
pr o vi de d t he s u bject will a bstai n f or t h e st u d y as d escri b e d a b o ve. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 5 of 6 0 
1 0. S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at l east 6 m o nt hs bef ore t h e 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y. 
 
 
 
 
.
4. 2  
E X C L U SI O N C RI T E RI A
S u bjects are e x cl u de d fr o m t h e st u d y if a n y of t he f oll o wi n g criteria are m et: 
 
 
 
 
 
 
 
 
3.  
S u bject h as recei ve d oral or t o pical a nal gesic m e dicati o ns wit hi n 1 4 da ys bef ore t h e 
Scree ni n g Visit.
4.  
S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0 da ys bef ore t he Scree ni n g Visit.
5.  
S u bject has a me dical hist or y t hat i ncl u des a c o ntr ai n dicati o n t o t h e use of me nt h ol or 
N S AI Ds (e. g., g astr oi ntesti nal ulcer, gastr oi ntesti nal blee di n g).
6.  
S u bject is ta ki n g me dicati o ns or ot h er s u bsta nces c o ntrai n dicate d beca us e of t he nat ure 
of t he st u d y g el or t h e p ote ntial f or dr u g i nteracti o ns. T his i n cl u des s u bjects wit h 
aller gi es t o pres cri pti o n or O T C pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 6 of 6 0 
 
 
 
 
 
 
 
 bee n a de q uatel y treate d, a n d d o n ot i n v ol v e t h e i n vesti g ati v e 
sites are all o wa ble. 
1 4.
S u bject is pre g na nt or n ursi n g. 
1 5.
S u bject has partici pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0 da ys bef ore 
Scree ni n g.
1 6.
S u bject is a me m ber or a fa mil y me m ber of t h e pr ofessi o nal or a ncillar y pers o n nel 
i n v ol v e d i n t he st u d y.  
1 7.
S u bject has partici pate d i n ot her cli nical trials f or K- 2 8 5. 
1 8.
S u bject has a b n or mal fi n di n gs or assess me nts t hat are cli nicall y n ote w ort h y. 
1 9.
S u bject w h o, i n t he o pi ni o n of t h e i n vesti g at or, s h o ul d n ot partici pate i n t he st u d y. 
4. 3   
DI S C O N TI N U A TI O N A N D WI T H D R A W A L C RI T E RI A 
S u bjects m a y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o t heir f ut ure me di cal care b y t he i n vesti gat or or at t he st u d y site. T he 
i n vesti gat or ma y disc o nti n ue treat m e nt of a s u bject or wit h dra w a s u bject fr o m t he st u d y 
u n der s p ecific circ u msta nces, descri be d b el o w. T he pri mar y reas o n(s) f or disc o nti n uati o n 
or wit h dra wal ( b y t he s u bject or t h e i n vesti gat or) will be d oc u me nt e d a n d rec or d e d i n t he 
case re p ort f or m C R F/e C R F.  
T he s u bject will be dis c o nti n ue d fr o m st u d y gel if a n y of t h e f oll o wi n g occ ur: 
1.  
T here is a deteri orati o n i n t he s u bject’s si g ns/s y m pt o ms a n d/ or t he s u bject de vel o ps a 
disease or c o n diti o n t h at i n t he o pi ni o n of t h e i n vesti g at or, w o ul d c o m pr o mise t he 
s u bject’s safet y b y c o nti n ui n g i n t he st u d y. 
2.  
I n t he i n v esti gat or’s j u d g me nt, it is i n t he s u bject’s best i nterests. 
3.  
Vi olati o n of t he pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria. 
4.  
T he s u bject be gi ns t o ta k e a n y me dicati o n(s) t hat is e xcl u de d b y t he pr ot o c ol. 
5.  
It is deter mi ne d t hat t here is disc ol orati o n, e xf oli ati o n or er osi o n, e d e ma, disc har ge, 
blisteri n g, e x u date, 
2 p oi nt o n der mal res p o nses sc ore ( Secti o n 5. 2. 6 ), a n d/ or a n y 
ot her der m al c ha n g e t h at i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise t he
s u bject’s safet y b y c o nti n ui n g i n t he st u d y at t h e a p pli cati o n site. T he pr ocess f or 
disc o nti n uati o n d ue t o a n a p plicati o n site reacti o n is descri b e d i n Secti o n 4. 3. 1 bel o w. 
6.  
Occ urre n ce of seri o us a d verse e v e nt(s). 
7.  
Pre g na nc y. 
T he s u bject will be wit h dra w n fr o m t he st u d y if a n y of t he f oll o wi n g occ ur: 
1.  
T he s u bject wit h dra ws c o nse nt. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 7 of 6 0 
2.  
T he s u bject is l ost t o f oll o w- u p. 
3.  
A n y of t he c o n diti o ns are met i n Secti o n 6. 5 , Ter mi n ati o n of t h e St u d y. 
4.  
T he s u bject is u na ble or u n willi n g t o c o o perate wit h st u d y staff. 
5.  
Deat h. 
 
S u bjects w h o disc o nti n ue or wit h dra w fr o m t he trial d ue t o t he a b o ve criteria or a n y ot her 
reas o n, will be e nc o ura g e d t o c o m plete t he fi nal e val uati o ns as detaile d i n Ta ble  2 . If a 
s u bject decli nes t o c o m pl ete earl y ter mi nati o n pr oce d ures, t his decisi o n will be rec or de d i n 
t he case re p ort f or m C R F/e C R F.  
If a s u bject dis c o nti n ues or wit h dra ws fr o m t he st u d y d ue t o a n A E, t he s u bject will be 
as ke d t o ret ur n t o t he cli nic f or, at a mi ni m u m, t h e e val u ati o ns sc he d ule d f or t he E O S/ E T 
Visit ( Da y 8/ Da y 2 2). If t he A E has still n ot res ol ve d, a d diti o nal f oll o w- u p will be 
perf or me d, as a p pr o priate, a n d d oc u me nte d i n t he s u bject’s me dical rec or ds. As a mi ni m u m 
re q uire me nt, A Es m ust b e f oll o we d f or 3 0 d a ys after t he s u bje ct’s last d ose of st u d y gel or 
u ntil res ol uti o n or u ntil u nres ol ve d A Es are j u d ge d b y t he i n vesti gat or ( or d esi g nee) t o h a ve 
sta bilize d.  
If s u bjects are l ost t o f oll o w- u p, atte m pts t o c o ntact t h e m m ust be ma de a n d d oc u m e nte d 
i n t h e me dical rec or ds. S u bjects w h o fail t o ret ur n f or a st u d y visit will be c o ntacte d directl y 
b y t he st u d y staff. A mi ni m u m of 2 d oc u me nte d p h o ne calls will be m a de. If t h e st u d y staff 
recei v es n o res p o nse, t h e y will se n d a certifie d l ett er re q u esti n g t hat t h e s u bject c o ntact t h e 
st u d y sit e re gar di n g his or her stat us i n t h e st u d y.  
Disc o nti n ue d or wit h dra w n s u bjects will n ot be re place d. 
4. 3. 1  Disc o nti n u ati o n d ue t o a n A p plic ati o n Site Re acti o n 
1.  D uri n g a cli nical site visit, t h e a p plicati o n site reacti o n will be assesse d b y st u d y 
staff. If t here are a n y si g nifica nt fi n di n gs, t he y will b e n ote d i n eac h s u bject’s 
s o urce d oc u m e nts.  
 
If t he a p plicati o n site reacti o n is j u d ge d t o meet t h e dis c o nti n uati o n crit eria 
(Secti o n 4. 3 ), t he s u bject will be dis c o nti n ue d fr o m t he st u d y. 
 
2.  D uri n g t he o ut- patie nt peri o d at h o me, a p pli cati o n site reacti o ns will be assesse d 
b y t he s u bject. If a n y a p plicati o n site reacti o n is n otice d, t h e s u bject will c o ntact 
t he site bef ore d osi n g.  
 
T he s u bject will n ot a p pl y st u d y gel u ntil recei vi n g c o nfir mati o n fr o m t he site 
t o pr ocee d. 
If t h e s u bject c o ntacts t he sit e a n d t he n t he a p pli cati o n site reacti o n is j u d ge d
t o 
meet t h e disc o nti n uati o n criteria (Secti o n 4. 3 ), t he s u bject will be 
disc o nti n ue d fr o m t he st u d y. At t hat ti me, t he s u bject will be as ke d t o gat her 
safet y refere nce i nf or mati o n as f oll o ws: 
o  
Rec or d t h e s c ore of d er mal res p o nse ( Secti o n 5. 2. 6 ) i n t he e- diar y. 
Refere n ce i m a ges of a p plicati o n site reacti o ns are s h o w n i n A p pe n di x 4 .
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 8 of 6 0 
5. 0
P R O C E D U R E S F O R E F FI C A C Y A N D S A F E T Y 
E V A L U A TI O N S 
5. 1  
E F FI C A C Y E V A L U A TI O N S
5. 1. 1
P ai n I nte nsit y  
Pri or t o e xercis e t o i n d uce D O M S, p ai n will be assesse d f or b ot h le gs at rest a n d w hile 
sta n di n g usi n g a 0- 1 0 0 p oi nt pa per V A S t o e xcl u d e s u bjects wit h ot her pai n. 
F oll o wi n g e xercise t o i n d uce D O M S, pai n at rest a n d w hile st a n di n g will be assesse d f or 
b ot h le gs usi n g a 0- 1 0 0 p oi nt e V A S a n d a cate g orical scale t o deter mi ne q ualificati o n f or 
ra n d o mizati o n a n d t o i de ntif y t he st u d y le g ( baseli ne assess me nt). All pai n assess me nts 
will b e rec or d e d i n t he e- diar y. 
After ra n d o mizati o n, pai n at rest a n d w hile sta n di n g will be assesse d f or t he st u d y le g a n d 
t he n o n-st u d y le g usi n g a 0- 1 0 0 p oi nt e V A S at all p ost-st u d y gel a p plicati o n ti me p oi nts i n 
Peri o d 1 ( T a ble 2 ). W he n st u d y gel a p plicati o n a n d p ai n assess me nt occ ur at t h e sa me ti me 
p oi nt, p ai n assess me nts will be perf or me d b ef ore st u d y gel a p pli cati o n. 
T he s u bject will rest q uietl y f or at least 5 mi n utes bef ore assessi n g pai n at rest f or t he st u d y 
le g a n d n o n-st u d y le g (t h e st u d y le g will be ass esse d first). T he s u bject will sit f or at least 
5 mi n utes, t he n sta n d u p a n d rate t h e w orst p ai n ca us e d b y sta n di n g (t he act of m o vi n g 
fr o m a sitti n g t o sta n di n g p ositi o n) f or t he st u d y le g a n d n o n-st u d y le g (t h e st u d y le g will 
be assesse d first). 
5. 1. 1. 1  
T he pai n V A S, a u ni di m e nsi o nal meas ure of p ai n i nte nsit y, is a c o nti n u o us scale fr o m 0 t o 
1 0 0 c o m prise d of a h oriz o ntal li ne a nc h ore d b y 2 descri pt ors, o ne f or eac h s y m pt o m 
e xtre me: “ n o pai n” (sc ore of 0) a n d “ w orst p ossi ble pai n” (sc ore of 1 0 0). A pa per versi o n
of t he pai n V A S will be use d f or pre-e x ercis e p ai n assess me nts ( A p pe n di x 1 ). 
T he pai n e V A S is el ectr o nicall y dis pla ye d a n d is c o m plete d b y t he s u bject f or baseli ne a n d 
eac h p ost-ra n d o mizati o n pai n i nte nsit y assess me nt b y t o uc hi n g t he p oi nt o n t h e e V A S t hat 
re pres e nts t heir pai n i nte nsit y. ( A ca pt ure pr o gra m will li nearl y c o n vert t he pi x el t o uc he d 
t o a n i nte ger b et wee n 0 a n d 1 0 0). T he i nte g ers of t h e e V A S will b e referre d t o as p oi nts. 
T he assess me nt d ate a n d ti me f or t h e st u d y le g a n d f or t he n o n-st u d y le g is rec or de d i n t he 
e- diar y ( A p pe n di x 1 ).  
5. 1. 1. 2
A 4- p oi nt cate g orical scale ( n o ne, mil d, m o derate, se vere) at rest will b e use d t o assess pai n 
i nte nsit y f oll o wi n g t he e xercise sessi o n. A cate g orical scal e is pr o vi de d i n A p pe n di x 2 . 
5. 1. 2  Use of Res c ue Me dic ati o n 
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs after t he 
first st u d y gel a p plicati o n, at w hic h ti me O T C aceta mi n o p he n ( o ne 5 0 0 m g aceta mi n o p he n 
ta blet t wice d ail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue me dicati o n is per mitte d if 
re q uire d.
S u bjects e x perie nci n g s e vere p ai n, or i na bilit y t o m o ve or wal k d ue t o pai n,
ma y be 
per mitte d t o use res c ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet t wice dail y, 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 9 of 6 0 
n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y gel a p plicati o n. If 
s u bjects ta ke resc ue me dicati o n wit hi n t he first 1 6 8 h o urs after t h e first st u d y gel 
a p plicati o n, it 
will be rec or de d i n t he e- diar y as resc ue 
me dicati o n a n d 
will be 
pr o gra m maticall y c ate g orize d as a c o nc o mita nt me dicati o n. S u bjects will rec or d t heir p ai n 
i nte nsit y i n t h e e- diar y bef ore ta ki n g t he res c ue me dicati o n. T he n u m b er of ta blets ta ke n 
a n d t he d ate a n d ti me will be rec or de d i n t he e- diar y. 
5. 1. 3  Ti m e t o O ns et of First Perce pti bl e a n d Me a ni n gf ul P ai n Relief  
Pai n assess me nts of ti me t o first perce pti ble p ai n relief a n d ti m e t o mea ni n gf ul pai n relief 
f or b ot h le gs at rest a n d w hile st a n di n g will be rec or de d b y s u bjects usi n g t heir e- diar y. At 
t he ti me of first perce pti ble p ai n relief a n d at t he ti me of mea ni n gf ul pai n relief, s u bjects 
will use t h eir e- diar y t o rec or d t h e ti me t he e ve nts are e x perie nce d. Si nce t hese assess me nts 
will be ca pt ure d i n t he e- diar y, t he electr o nic d ata base will be t he direct p oi nt of data 
ca pt ure a n d will ser v e as s o urce f or t his varia ble.  
5. 1. 3. 1
O nset of p erce pti ble pai n relief will be ass esse d f or t he st u d y le g a n d n o n-st u d y le g b y 
res p o n di n g “n o ” or “yes” t o a q uesti o n s uc h as t h e f oll o wi n g e xa m ple: 
“ H ave y o u ex perie n ce d a n y p ai n relief i n t he st u dy le g ( n o n-st u dy le g) si n ce st arti n g t o 
use t he st u dy g el ? ”.  
5. 1. 3. 2  
O nset of mea ni n gf ul pai n relief is assesse d f or t h e st u d y le g a n d n o n-st u d y le g o nl y after 
o nset of perce pti ble pai n reli ef has bee n ac hie ve d. T he s u bject res p o n ds “ n o ” or “yes” t o a 
q uesti o n s uc h as t he f oll o wi n g e xa m ple:
“ H ave y o u ex peri e nce d me a ni n gf ul p ai n r elief i n t he st u dy l e g ( n o n-st u dy le g) si nce 
st arti n g t o use t he st u dy gel ?”.
T he s u bject will be t ol d t h at “ mea ni n gf ul p ai n r elief” is “ W he n t h e relief fr o m p ai n is 
me a ni n gf ul or si g nific a nt t o y o u. T his d oes n ot necess arily me a n t h at y o u f eel c o m plet ely 
better, alt h o u g h y o u mi g ht. ”
5. 2  
S A F E T Y E V A L U A TI O N S 
5. 2. 1  A d verse E ve nts  
A d vers e e ve nts will be rec or de d acc or di n g t o t he s c he d ule i n Ta bl e 2 . All A Es, w het her 
ascri b e d t o st u d y pr oce d ures or n ot, will be d oc u me nte d o n t he e C R F a n d will i ncl u de t he 
date a n d ti me of o nset, a descri pti o n of t he A E, se verit y, d urati o n, acti o ns ta ke n, o utc o me, 
a n d t he relati o ns hi p bet wee n t h e st u d y gel
a n d t he e ve nt. 
A n y s u bject 
w h o 
disc o nti n ues/ wit h dra ws fr o m t he st u d y d ue t o a n A E will be f oll o we d u p u ntil t h e o utc o me 
is d eter mi ne d a n d writt e n r e p orts are pr o vi de d b y t he i n v esti gat or. A d verse e ve nt 
defi niti o ns, a n d re p orti n g a n d f oll o w- u p re q uire me nts are descri b e d i n Secti o n 9. 1 , 9. 2, a n d 
9. 3 , res pecti vel y. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 0 of 6 0 
5. 2. 2
Cli ni c al L a b or at or y Tests
Cli nical la b orat or y tests will be perf or me d b y t he sit e’s l ocal la b orat or y. Bl o o d sa m ples 
will be c ollecte d acc or di n g t o t he sc he d ule i n Ta ble 2 a n d pr ocesse d as detaile d i n t he 
La b orat or y M a n ual.  
Uri nal ysis will be perf or me d b y t he site’s l ocal la b orat or y acc or di n g t o t he sc he d ule i n 
Ta ble 2 . Uri ne s a m ples will be c ollecte d a n d pr ocesse d as detaile d i n t he La b orat or y
Ma n ual. If micr os c o p y is re q uire d, a uri ne s a m ple will be se nt t o t he l ocal la b orat or y. 
T he para meters b ei n g meas ure d are s h o w n i n T a ble 3 . 
T a bl e 3. Cli nic al L a b o r at or y Test P a r a m eters
He m at ol o g y
Cli nic al C he mistr y
Uri n al ysis
Bas o p hils 
E osi n o p hils 
He mat o crit 
( Pac ke d cell 
v ol u me) 
He m o gl o bi n 
L y m p h oc ytes 
Mea n cell 
h e m o gl o bi n 
Mea n cell 
h e m o gl o bi n 
c o n ce ntrati o n 
Mea n cell v ol u me  
M o n oc ytes 
Ne utr o p hils 
Platelet c o u nt 
Re d bl o o d cell 
 
c o u nt 
W hite bl o o d cell 
c o u nt 
 
Ala ni n e a mi n otra nsferase  
Al b u mi n 
Al k ali ne p h os p hatase 
As partate a mi n otra nsferase 
Bicar b o n ate 
Bilir u bi n (t otal) 
Bilir u bi n ( direct; o nl y if t otal is ele v ate d) 
Calci u m 
C hl ori d e 
Creati n e ki n ase 1 
Creati ni n e 
F ollicle-sti m ulati n g h or m o n e ( p ost- m e n o pa usal fe male 
p atie nts o nl y) 
Ga m m a gl uta m yl tra nsferase 
Tri gl y ceri des 
Gl u c ose (fasti n g) 
H u ma n c h ori o nic g o n a d otr o pi n (all fe male p atie nts) 
L actate d e h y dr o g e n ase 
Ma g nesi u m 
P otassi u m 
P h os p h ate (i n or g a nic) 
Pr otei n (t otal) 
S o di u m 
Bl o o d urea nitr o g e n ( B U N) 
Uric aci d
Bilir u bi n
Bl o o d 
Gl u c ose 
Ket o n es 
L e u k o c ytes 
Nitrites 
p H 
Pr otei n 
S p ecific gra vit y 
Ur o bili n o g e n 
At t he discreti o n of 
t he i n v esti g at o r b ase d 
o n uri n al ysis res ults 
Micr o bi ol o g y 
Uri ne Micr osc o p y 
1 Ele vate d le vels of creati ne ki n ase are e x p ecte d as a res ult of t h e e x ercise p erf or me d o n Da y - 1 a n d will be h a n dle d as 
d escri b e d i n Secti o n  5. 2. 2. 1.
 
5. 2. 2. 1
Ele vati o ns of ser u m creati ne ki nase ( C K) are e x p ecte d t o o cc ur as a c o ns e q u e nce of t h e 
e xercis e perf or me d o n Da y - 1 a n d will n ot be re p orte d as A Es. A d diti o nal s afet y ste ps will 
be ta ke n t o m o nit or t he s u bjects f or si g ns of r ha b d o m y ol ysis. If a s u bject has a ser u m C K
a b o ve 1 0, 0 0 0 U/ L (a n d ass ociate d el e vati o ns of lactate de h y dr o ge nas e
L D H], as partate 
a mi n otra nsfer ase  
, or al a ni n e a mi n otr a nsferase  
]), b ut n o si g nifica nt si g ns or 
s y m pt o ms of r ha b d o m y ol ysis ot her t h a n m uscle pai n a n d s welli n g at t he e x ercise d m uscles, 
t he f oll o wi n g acti o ns will be ta ke n wit h t he s u bject u ntil t he E O S Visit ( Da y 8 f or s u bjects 
d osi n g d uri n g Peri o d 1 a n d Da y 2 2 f or s u bje cts d osi n g d uri n g Peri o d 2): 
 
S u bjects will be i nstr ucte d t o m o nit or t he uri ne f or c ha n ges i n c ol or caref ull y. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 1 of 6 0 
 
S u bjects will be i nstr ucte d t o re p ort a n y uri ne disc ol orati o n, s uc h as dar k yell o w,
br o w n, c ola or t ea c ol ore d uri ne, t o st u d y pers o n n el.
S u bjects will be i nstr ucte d t o mai ntai n a de q uate h y drati o n at h o me (a p pr o xi matel y 1 5. 5 
c u ps 3. 7 lit ers] of fl ui ds f or males a n d 1 1. 5 c u ps 2. 7 lit ers] of fl ui ds a d a y f or fe mal es) 
  
I n a d diti o n, t he f oll o wi n g acti o ns ma y be ta ke n wit h t he s u bject at t he discreti o n of t he 
i n vesti gat or: 
S u bjects will be as ke d t o sta y o ver ni g ht at t he st u d y site w here vi g or o us h y drati o n will 
be a d mi nistere d a n d m o nit ori n g f or a n y cli nical si g ns or s y m pt o ms of r ha b d o m y ol ysis 
will b e u n derta ke n. T he s u bject will be releas e d w h e n, per t he i n vesti gat or’s discreti o n, 
it is a p pr o priate t o d o s o. Pri or t o releas e, t h e s p o ns or’s Me dical M o nit or will be 
n otifie d.
S u bjects will ha ve a ser u m C K cli nical la b orat or y re peate d as cli nic all y i n dicate d.
 
S u bjects will ha ve a uri n al ysis re peat e d as cli nicall y i n dicate d. 
 
If t here is a n ele vati o n i n C K a n d r h a b d o m y ol ysis is s us pecte d, t he w or k- u p s h o ul d als o 
i ncl u de e val uati o n of C K, C K- m y ocar dial b a n d ( C K- M B), C K i n s keletal 
m uscle 
( C K- M M), tr o p o ni n, creati ni ne, 
m y o gl o bi n (ser u m a n d uri ne), tra nsa mi nases, t otal 
bilir u bi n le vels, a n d uri nal ysis i ncl u di n g uri ne se di me nt. A p h ysical e xa mi n ati o n s h o ul d be 
perf or me d t o d oc u me nt fi n di n gs s uc h as m uscle te n der ness, wea k n ess, or ras h. A n E C G 
s h o ul d als o be perf or me d. A b n or malities s h o ul d be f oll o we d u ntil t h e y ha ve ret ur n e d t o 
baseli n e, or u ntil t he i n vesti gat or c o nsi ders t he m cli nicall y sta ble. 
5. 2. 3  Vit al Si g ns 
Vital si g n meas ure me nts will i n cl u de s yst oli c bl o o d press ure, diast olic bl o o d press ure, 
p ulse rate, res pirat or y rat e a n d oral b o d y te m perat ure. Bl o o d press ure a n d p ulse rate will 
be meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at least 5 mi n utes.
Meas ure me nts will be p erf or me d acc or di n g t o t h e sc he d ule i n Ta ble 2 .
5. 2. 4
Electr oc a r di o gr a m
T he E C Gs will be perf or m e d acc or di n g t o t h e sc h e d ule i n Ta ble 2 . 
5. 2. 5
P h ysic al E x a mi n ati o n
Ge neral p h ysical e xa mi n ati o ns will be perf or me d acc or di n g t o t h e sc he d ul e i n Ta ble 2 . T he 
e xa mi n ati o n will i n cl u de t he f oll o wi n g: ge neral c o n diti o n, der mat ol o gic, e yes, ears, n os e, 
t hr oat, nec k, t h yr oi d, heart, res pirat or y s yste m, a b d o me n, ki d ne ys, s k eletal s yste m, 
e xtre mities, l y m p hatic s yste m, ner v o us s yste m.  
5. 2. 6   S ki n E x a mi n ati o n ( A p plic ati o n Site Re acti o n)
S ki n e xa mi nati o n will be perf or me d acc or di n g t o t he sc he d ul e i n T a ble 2 . T he i n vesti gat or
or desi g nee will assess t he tar g et a p plicati o n site t o e ns ure t hat t he s ki n is n ot br o ke n or 
irritate d bef ore eac h st u d y gel a p pli cati o n a n d d oc u m e nt t he s ki n c o n diti o n i n t he e C R F 
usi n g f oll o wi n g rati n g scales.  
Der m al Res p o nses
0 = n o e vi de nce of irritati o n 
1 = mi ni mal er yt h e ma, b arel y perce pti ble

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 2 of 6 0 
2 = defi nite er yt he ma, rea dil y visi ble; mi ni m al e de ma or mi ni mal pa p ular res p o nse 
3 = er yt h e ma a n d pa p ules 
4 = defi nite e de ma
5 = er yt h e ma, e de ma a n d pa p ules
6 = vesic ular er u pti o n 
7 = str o n g reacti o n s prea di n g be y o n d a p pli cati o n site
N otes: Pa p ules are d efi n e d as s oli d, circ u mscri b e d s ki n ele vati o ns u p t o t h e size of a s plit p ea ( 5 m m). 
Vesicles are d efi n e d as s mall blisters. 
 
Ot her Effects ( Wit h C o rres p o n di n g N u meric Sc ore) 
N o ne ( 0) = n o c ha n g e i n a p peara nce 
A ( 0) = sli g htl y glaze d a p peara n ce
B ( 1) = mar ke d glaze d a p peara n ce
C ( 2) = glazi n g wit h peeli n g a n d crac ki n g 
F ( 3) = glazi n g wit h fiss ures
G ( 4) = fil m of drie d ser o us e x u dates c o v eri n g all or part of t h e a p plicati o n site
H ( 5) = s m all p etec hial er osi o ns a n d/ or sca bs 
 
S u bjects will be i nstr ucte d t o n otif y st u d y staff if t he y e x perie nce a n y dr y ness, it c hi n g, 
b ur ni n g, pai n, s ore ness, or ot her s y m pt o m at t he a p plicati o n site e ve n d uri n g t h e o ut- patie nt 
peri o d. If t here are u nsc he d ule d visits d ue t o A Es, t he i n vesti gat or will assess t he tar get 
a p plicati o n site a n d all a p plicati o n site reacti o ns will be rec or d e d i n t he e C R F. 
T hese si g ns of s ki n irritati o n will be i ncl u de d i n t he A E s ecti o n of t he e C R Fs. If a s u bject 
is dis c o nti n ue d fr o m t h e st u d y d ue t o a n a p pli cati o n site reacti o n, t he A E will be f oll o we d 
t o res ol uti o n or u p t o 3 0 da ys after t h e last d ose, w hic he ver c o mes first. 
S u bjects w h o disc o nti n ue d d ue t o a p pli cati o n site reacti o n ma y u n der g o a patc h test, at t he 
discreti o n of t h e i n vesti g at or. 
5. 2. 7  C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt me dicati o ns will be rec or d e d acc or di n g t o t he sc he d ule i n Ta ble 2 .  
5. 3  
O T H E R E V A L U A TI O N S 
5. 3. 1  De m o gr a p hics, Me dic al Hist or y a n d Ot her B aseli n e C h a r acteristics 
De m o gra p hics a n d ot her baseli ne c haracteristics (a g e, se x, race, et h nicit y, hei g ht, a n d 
wei g ht) as well as me dical hist or y i nf or mati o n i ncl u di n g i de ntificati o n of d o mi na nt le g, 
s ki n c o n diti o n ( hist or y of ras h, aller g y, ecze ma, etc.) a n d a n y aller g y hist or y (i ncl u di n g 
fra gra nce, j e welr y, d ust, cl ot hi n g, h o use d ust, a ni mal, metal, r u b ber, n yl o n, f o o d, p olle n 
aller g y, etc.) will be c ollecte d o n all s u bjects at t h e Scree ni n g Visit. 
5. 3. 2  Dr u g a n d Alc o h ol Scree ni n g 
A uri ne dr u g scree n a n d alc o h ol breat h test will b e c o n d ucte d acc or di n g t o t he sc he d ule i n 
Ta ble 2 . Uri ne dr u g s cree n will i ncl u de uri ne s cree n f or c ocai ne, m arij ua na, o piates, 
a m p heta mi nes, met ha m p heta mi nes, p he nc ycli di ne ( P C P), be nz o di aze pi n es, bar bit urat es, 
met ha d o ne, o x yc o d o n e, 3, 4- met h yle ne di o x y- met h a m p heta mi ne ( M D M A or ecstas y), a n d 
tric yclic a nti de pressa nts. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 3 of 6 0 
5. 3. 3
Pre g n a nc y
All fe male s u bjects will ha ve a ser u m pre g n a nc y test at t he Scree ni n g Visit. S u bjects wit h 
a p ositi v e pre g na nc y test res ult will n ot be ra n d o mize d. A uri ne pre g na nc y test will be 
perf or me d at t he E xercis e visit a n d at t h e E O S/ E T Visits ( Da y 8 or Da y 2 2). 
5. 3. 4  St a n d ar dize d E x ercise Re gi m e n 
All e nr olle d s u bjects will p erf or m a sta n d ar diz e d re petiti ve q u a drice ps m uscle e x ercise 
c o nsisti n g of war m- u p, deter mi nati o n of ma xi m u m t olerate d wei g ht ( M T W), a n d ti me d 
a n d u nti me d w or k- o ut p hases, des cri b e d b el o w. S u bjects will be i nstr ucte d t o sta y well 
h y drate d b y i ncreasi n g t h eir water i nta ke, mi ni mizi n g caffei nate d be v era g es, a n d a v oi di n g 
alc o h ol d uri n g t h e e xercis e re gi me n. 
1. War m- u p a n d deter mi nati o n of M T W 
S u bjects will c o m plete a war m- u p of 4 sets of 1 0 re g ular b o d y wei g ht s q uat e xercis es fr o m 
sta n di n g p ositi o n ( 2 sets wit h o ut wei g hts a n d 2 sets wit h a p pr o xi matel y 1 0- 2 0 p o u n ds of 
wei g ht). T he M T W o n t h e le g c url m ac hi n e is t he n deter mi ne d f or eac h le g b y ha vi n g t he 
s u bject d o a f ull e xte nsi o n a n d fle xi o n wit h resista nce starti n g wit h a l o w b ut reas o na bl e 
wei g ht selecte d b y t he st u d y staff a n d i ncreasi n g it wit h e ver y re petiti o n u ntil s u bjects reac h 
t heir M T W. T h e M T W is defi n e d as t he hi g h est wei g ht u n der w hic h a s u bject c o ul d 
perf or m a f ull e xte nsi o n a n d fle xi o n. 
2. W or k o ut: ti me d p hase 
Starti n g wit h t he d o mi na nt le g, s u bjects will perf or m 6 sets of 1 0 le g e xte nsi o n a n d fle xi o n 
e xercis es wit h eac h l e g o n t he c url m ac hi n e u n d er 8 0 % of t h e M T W f or t hat le g. Eac h 
re petiti o n is perf or me d t hr o u g h t he f ull pai n-free ra n ge of m oti o n i n a sl o w, c o ntr olle d 
ma n ner. S u bjects perf or m t he c o nce ntric p orti o n of t he re p etiti o n f or 2 sec o n ds, pa use at 
f ull c o ntracti o n f or 1 sec o n d, a n d t h e n c o m plete t he e cce ntric p orti o n o ver a 4 sec o n d 
peri o d (f or a t otal of 7 sec o n ds per re petiti o n). S u bjects perf or m eac h set as t olerate d a n d 
are gi v e n a 1- 2 mi n ute rest peri o d i n bet wee n s ets. Re petiti o ns are p erf or me d u ntil s u bjects 
are u na bl e t o m o ve t h e wei g ht l oa d t hr o u g h t he f ull ra n ge of m oti o n. If s u bjects are u n a ble 
t o c o m plete t he f ull 6 s ets u n der 8 0 % M T W, t he wei g ht is decreas e d i n 5 p o u n d i ncre me nts 
u ntil s u bjects ca n n o l o n ger c o m plete 6 0 % M T W, or 6 sets are c o m plete d. 
3. W or k o ut: u nti me d p hase 
S u bjects c o m plete u nti me d fle xi o n-a n d-e xte nsi o n e xercises ( 1 5- 2 0 re petiti o ns) be gi n ni n g 
wit h t h e last wei g ht use d i n t he ti me d p hase. T he wei g hts are gra d u all y decrease d i n 
i ncre me nts of 5 p o u n ds u ntil n o wei g ht is use d.  
T he sa me pr ot oc ol is perf or me d o n t he s u bject’s o p p osite le g. 
5. 3. 5  P h ot o gr a p h a n d Resi d ue E v al u ati o n 
5. 3. 5. 1  
T o vis ualize t he s ki n c o n diti o n at t he site of st u d y gel a p plicati o n, p h ot o gra p hs of t h e 
a p plicati o n site will be ta ke n bef ore t h e 
 st u d y gel a p plicati o ns o n   
  
Als o, w he n a n a p plicati o n sit e reacti o n is o bser ve d at t h e cli nical sit e, p h ot o gra p hs of t he 
a p plicati o n site will be t a ke n b y site staff t o vis uall y d oc u me nt t he s ki n c o n diti o n at t he site 
of gel a p plicati o n. P h ot o gra p hs ma y be t a ke n peri o dicall y as nee d e d t o f oll o w- u p o n t he 
c o n diti o n of t he a p plicati o n sit e reacti o n. If a n a p plicati o n site reacti o n is o bser ve d at h o me, 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 4 of 6 0 
p h ot o gra p hs of t he a p pli cati o n site will be ta ke n b y site staff w he n s u bject ret ur ns t o t he 
cli nical site. 
P h ot o gra p hs s h o ul d be ta ke n at a n a n gle of less t h a n 4 5 de grees relati ve t o t h e s ki n pla ne 
wit h t h e area of g el a p plicati o n cl osest t o t he di git al ca mera. Eac h p h ot o gra p h will i n cl u de 
a pa per la b el i n t he p h ot o gra p h i de ntif yi n g t he s u bj ect n u m ber, date, assess m e nt ti me p oi nt, 
a n d i nitials of t he p h ot o gra p her. T he la b el will b e place d o n t he s ki n a djace nt t o t he gel 
a p plicati o n. 
5. 3. 5. 2  
T o e val uate t he s u bject’s i m pressi o n of t he drie d w hite gel resi d ue, t h e f oll o wi n g rati n g 
scale will be assesse d b ef ore t h e fift h a n d si xt h st u d y gel a p plicati o ns o n Da y 2 a n d will be 
rec or d e d o n t he a p pr o priate f or m. S u bjects m ust n ot s h o wer, bat he, or was h t he treate d area
u ntil after disc har g e o n Da y 2. 
T he f oll o wi n g rati n g scal e will be use d:
0 = N o drie d w hite resi d ue was o bser ve d
1 = Drie d w hite resi d ue was o bser v e d b ut n o disc o mf ort. 
2 = Drie d w hite resi d ue was o bser v e d a n d sli g ht dis c o mf ort ( bet wee n 1 a n d 3) 
3 = Drie d w hite resi d ue was o bser v e d a n d u nc o mf orta ble 
 
5. 4  
T O T A L B L O O D V O L U M E
T he t otal bl o o d v ol u me pla n n e d f or c ollecti o n d uri n g t he st u d y will be d escri be d i n t h e 
i nf or me d c o nse nt f or m (I C F).
 
6. 0  
C O N D U C T O F S T U D Y 
6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N  
T he st u d y will be d o u ble- bli n d. T he i n vesti g at or, s u bjects, a n d s p o ns or pers o n nel i n v ol v e d 
i n t h e m o nit ori n g or c o n d uct of t he st u d y will be bli n de d t o t he i de ntit y of t he treat m e nt 
fr o m t he ti me of ra n d o mizati o n u ntil t he ti m e of u n bli n di n g. U n bli n di n g will o nl y occ ur i n 
t he case of s u bject e mer g e ncies (Secti o n 7. 8 ) a n d at t he c o ncl usi o n of t he st u d y. St u d y staff 
will i nstr uct s u bjects n ot t o tal k a b o ut t h eir st u d y me dicati o n, t h eir pai n i nte nsit y, st u d y 
desi g n etc., a m o n g s u bje cts. 
 will pre pare t he ra n d o mi zati o n s c he d ule bef ore 
t he st u d y. E nr olle d, eli gi ble s u bjects will recei ve a kit c o ntai ni n g st u d y gels acc or di n g t o 
a n all o cati o n ta ble t h at ra n d o ml y assi g ns s u bjects b y or der of e nr oll me nt t o recei v e st u d y 
gel f or 
 i n 1 of 2 treat m e nt ar ms ( A or B) 
(Secti o n 7. 2 ). Se parate all o cati o n ta bles will be pre pare d f or 1 2 0 mal e a n d 1 2 0 fe mal e 
s u bjects. Male or fe mal e e nr oll me nt ma y e xcee d t he tar g et sa m ple size ( n = 1 2 0 eac h 
ge n der) b y ± 1 0 %. If t he t ar get s a m ple size is e x cee de d i n o ne ge n der, t he ne xt a vaila ble kit 
n u m ber i n t he ot her ge n d er will be assi g ne d. 
T he i de ntit y of t he st u d y gels i n t h e treat m e nt ar ms will be m as ke d b y h a vi n g i de ntical 
a p peara nce, pac k a gi n g, la beli n g a n d sc he d ul e of a d mi nistrati o n. Ra n d o mizati o n data are 
ke pt strictl y c o nfi de nti al, accessi ble o nl y t o a ut h orize d pers o ns, u ntil t h e ti me of u n bli n di n g.  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 5 of 6 0 
6. 2  
S U B J E C T I N F O R M E D C O N S E N T 
Writte n c o nse nt will be o btai ne d fr o m t he s u bject pri or t o a n y st u d y s p ecifi c pr oc e d ure or 
i n vesti gati o n. 
I nf or mati o n a b o ut t h e st u d y will b e gi v e n t o t h e s u bject b ot h ver b all y a n d i n writi n g. T he 
writte n s u bject i nf or mati o n will e x plai n t he o bjecti v es of t h e st u d y, its p ote ntial ris ks a n d 
be nefits. T he s u bject m ust ha ve a de q uate ti me t o rea d t h e i nf or mati o n a n d t o as k t he 
i n vesti gat or a n y q u esti o ns. T he i n vesti g at or
m ust be satisfie d t hat t h e s u bject h as 
u n derst o o d t he i nf or mati o n pr o vi de d b ef ore writt e n c o nse nt is o btai ne d. If t h ere is a n y 
d o u bt as t o w het her t he s u bject has u n derst o o d t he writte n a n d v er b al i nf or mati o n, t h e 
s u bject s h o ul d n ot e nter t he st u d y. 
Partici pati n g s u bjects will be as ke d t o si g n a n d date a n I C F, t he ori gi n al c o p y of w hic h will 
be ke pt b y t he i n vesti gat or. A c o p y of t he si g ne d I C F will be gi ve n t o t he s u bject. A rec or d 
will b e ma de i n t he n otes t hat t h e s u bject v ol u ntaril y a gree d t o parti ci p ate i n t he st u d y. T he 
ori gi nal si g ne d I C F m ust be ma de a vaila ble t o t he st u d y m o nit or f or i ns pecti o n.  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 6 of 6 0 
6. 3  
S T U D Y VI SI T S 
N ote: Ti mi n g of pr oce d ures a n d assess me nts are pr o vi d e d as e xa m ples. Act ual ti mi n g ma y 
var y f or eac h s u bject. Ti me p oi nts a n d ti me wi n d o ws f or st u d y gel a p pli cati o n a n d p ai n 
assess me nts are d escri b e d i n Ta ble 2 . 
 Da y - 3 0 t o Da y - 2:  
o  Scree ni n g Visit: T he Scree ni n g Visit at t he cli nic t o deter mi ne s u bject 
eli gi bilit y ca n t a ke place a n yti me wit hi n t his ti me peri o d.
Assess me nts 
i ncl u de t he f oll o wi n g: 
I nf or me d c o ns e nt
 De m o gra p hics
 Me dical/ m e dicati o n hist or y 
 Pre-e x ercis e i n cl usi o n criteria, e xcl usi o n criteria 
 Hei g ht a n d wei g ht 
 Vital si g ns 
 E C G 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 Pre g na nc y test (ser u m) (fe males o nl y) 
Uri ne dr u g scree n a n d al c o h ol test 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)
 Rec or d A Es
Rec or d c o n c o mita nt me dicati o ns 
 Da y - 1:  
o  E xercis e Visit: O n Da y - 1 pr oce d ures a n d assess me nts are as f oll o ws:
U p date Me dic al/ m e dicati o n hist or y
Pre-e x ercis e i n cl usi o n a n d e xcl usi o n criteria
 Pai n assess me nt ( pre-e x ercise t o e xcl u de s u bjects wit h ot her pai n 
usi n g a pa per V A S) 
 D O M S i n d ucti o n e xercis e  
 Vital si g ns 
 E C G 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 e- diar y, st u d y trai ni n g 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 7 of 6 0 
Uri ne dr u g scree n a n d al c o h ol test 
Pre g na nc y test ( uri ne) (fe males o nl y) 
 Rec or d A Es
Rec or d c o n c o mita nt me dicati o ns 
 S u bjects ret ur n h o me after c o m pleti n g pr oce d ures a n d assess me nts
 Da y 1 t o Da y 2
o  A d missi o n Visit: O n Da y 1, s u bjects will b e a d mitte d t o t he cli nic. Da y 1 
pr oce d ures a n d ass ess me nts are as f oll o ws: 
V A S Q ualif yi n g Pai n assess me nts. N ote: Ti me 0 h o urs is t h e 
baseli n e ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs 
wit hi n 3 0 mi n utes of q ualif yi n g pai n assess me nts ( p ost-e xercise 
i ncl usi o n criteria). 
Cate g orical Q u alif yi n g Pai n ass ess me nts. N ote: Ti me 0 h o urs is t he 
baseli n e ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs 
wit hi n 3 0 mi n utes of q ualif yi n g pai n assess me nts ( p ost-e xercise 
i ncl usi o n criteria). 
 P ost-e xercise i ncl usi o n criteria 
 Ra n d o mizati o n (f or s u bjects w h o meet p ost-e xercise eli gi bilit y 
criteria) 
 Iss u e e- diar y 
 Vital si g ns 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule  
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt). 
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt).  
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p plicati o n, be gi n ni n g wit h t he s ec o n d st u d y gel 
a p plicati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 8 of 6 0 
o  Da y 2 pr oce d ures a n d ass ess me nts are as f oll o ws: 
 Vital si g ns 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt) 
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt) 
 P h ot o gra p hic a n d resi d ue e val uati o n ( bef ore t he fift h a n d si xt h st u d y 
gel a p pli cati o ns) 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n 
 Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Disc har ge fr o m t he cli nic (aft er st u d y assess me nts at 2 4 h o urs a n d 
t he si xt h st u d y gel a p plicati o n are c o m plet e d) 
 Da y 3 t o Da y 8 
o
O ut- patie nt p orti o n Peri o d 1: S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat m e nt a n d rec or d assess m e nts as f oll o ws: 
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt)  
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt)  
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule  
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 5 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 1 t o assess safet y a n d s ki n c o n diti o n. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 9 of 6 0 
Rec or d A Es
Rec or d s ki n c o n diti o n if a p plica bl e.
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 8:  
o  E O S Visit Peri o d 1 ( + 1 da y). Pr oce d ures a n d assess me nts are as f oll o ws: 
 Vital si g ns 
 E C G 
 Pre g na nc y test ( uri ne) (fe males o nl y) 
 Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis) 
 P h ysi cal e xa mi n ati o n 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 
  
 
 
 
 A p pl y st u d y gel at 6 a m o n Da y 8 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 C oll ect st u d y gel 
 C oll ect e- diar y 
o  Safet y Visit Peri o d 2 ( ± 1 da y). Pr oce d ures a n d ass ess me nts are as f oll o ws: 
 Vital si g ns 
 P h ysi cal e xa mi n ati o n 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 
  
 
 
 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 0 of 6 0 
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 A p pl y st u d y g el (
 acc or di n g t o treat m e nt assi g n me nt. 
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit.
Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Da y 9 t o Da y 2 2: 
o  O ut- patie nt p orti o n Peri o d 2: S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat m e nt a n d rec or d assess m e nts as f oll o ws: 
 A p pl y st u d y gel (
 acc or di n g t o treat m e nt assi g n me nt. 
P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 1 1 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 1 5 ( ± 1 da y): 
o  F oll o w- u p Tele p h o n e Call Peri o d 1 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e 
 Rec or d c o n c o mita nt me dicati o ns 
o  Safet y Visit Peri o d 2 
 Vital si g ns 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 1 of 6 0 
A p pl y st u d y g el (
 acc or di n g t o treat m e nt assi g n me nt.
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit.
Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Da y 1 8 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
Rec or d A Es
Rec or d s ki n c o n diti o n if a p plica bl e.
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 2 2 ( + 1 d a y): 
o  E O S Visit Peri o d 2: T he visit pr oce d ures i ncl u de safet y assess me nts, a n d 
c ollecti o n of st u d y gel a n d e- diaries.
Vital si g ns
E C G 
Pre g na nc y test ( uri ne) (fe males o nl y) 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 A p pl y st u d y gel at 6 a m o n Da y 2 2 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 C oll ect st u d y gel 
 C oll ect e- diar y 
 Da y 2 9 ( ± 1 da y): 
o  F oll o w- u p Tele p h o n e Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e. 
 Rec or d c o n c o mita nt me dicati o ns 
T he pr oce d ures a n d assess me nts t o be perf or me d at eac h visit are i n dicate d i n Ta ble  2 .  

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 2 of 6 0 
6. 4   
C O M P LI A N C E WI T H T H E P R O T O C O L
T he i n vesti gat or m ust a gree t o i m ple me nt t he st u d y pr ot oc ol as writte n a n d a d here t o t he 
g ui deli nes gi ve n i n t he “I n v esti gat or’s State me nt ”, w hic h will be si g ne d pri or t o t he start 
of t he st u d y. T he st u d y will be perf or me d i n acc or da nce wit h Healt h I ns ura nce P orta bilit y 
a n d 
Acc o u nta bilit y 
Act, 
Declarati o n 
of 
Helsi n ki, I nter nati o nal 
C o nfere nce 
o n 
Har m o nisati o n (I C H) G o o d Cli nical Practice ( G C P) g ui deli nes, l o cal la ws, F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) G C P re g ulati o ns 
5 0, 5 4, 5 6, a n d 3 1 2), a n d ot her a p pli ca ble g ui d a nce d oc u me nts.
If t h e i n v esti gat or c o nsi d ers e nr olli n g a s u bject t hat d oes n ot meet all i ncl usi o n or e x cl usi o n 
criteria, a n e xe m pti o n m ust be re q u este d fr o m t h e K o wa R esearc h I nstit ute, I nc. ( K RI) 
Me dical M o nit or pri or t o s u bject e nr oll m e nt. T he j ustificati o n f or t he e xe m pti o n m ust be 
d oc u me nt b y t he i n vesti gat or. T he a p pr o val or rejecti o n of t he e xe m pti o n m ust be 
d oc u me nte d b y t he K RI Me dical M o nit or pri or t o t he s u bject’s e nr oll me nt or scree n fail ure.  
Pr ot oc ol n o nc o m plia nce m ust be re p orte d t o t h e 
C R O] 
Me dical M o nit or a n d K RI. Eac h de viati o n a n d t he reas o n f or its o cc urre nce m ust b e 
d oc u me nte d a n d e ntere d o n t h e C R F/e C R F. K RI retai ns t h e ri g ht t o re q uire t he wit h dra wal 
of a n y s u bject w h o vi olat es t he pr ot o c ol. 
6. 5  
T E R MI N A TI O N O F T H E S T U D Y 
If, i n t he o pi ni o n of t he i n vesti gat or, t h e cli nical o bser vati o ns i n t he st u d y s u g gest t hat it 
ma y be u n wise t o c o nti n ue, or if t here is a n u n e x p ecte d, u nacce pta ble or si g nifica nt safet y 
ris k p ose d t o war d st u d y s u bjects, t he st u d y ma y b e ter mi nate d after c o ns ultati o n wit h t h e 
a n d K RI. A writte n state m e nt f ull y d oc u m e nti n g t he reas o n(s) f or 
t he ter mi nati o n will b e pr o vi de d t o K RI. I n a d diti o n, K RI ma y ter mi nate t he st u d y at a n y 
ti m e.  
If it bec o mes a p p are nt t hat s u bject e nr oll me nt is u nsatisfact or y wit h res p ect t o q ualit y or 
q ua ntit y, or data rec or di n g is i nacc urate or i nc o m plete o n a c hr o nic b asis, or pr ot o c ol 
re q uire me nts are n ot bei n g met, K RI has t he ri g ht t o ter mi n ate t he st u d y a n d re m o ve all 
st u d y m aterials fr o m t he i n vesti gati o nal sit e. A writte n state me nt will be pr o vi de d t o t he 
i n vesti gat or, t he I nstit uti o nal Re vie w B oar d/I n d e p e n de nt Et hics C o m mittee (I R B/I E C), 
a n d re g ul at or y a ut h orities, if re q uire d. I n t h e e ve nt of a n y seri o us or n o n-seri o us A Es 
ha vi n g occ urre d at a site, all d oc u me ntati o n rel ati n g t o t he e ve nt(s) m ust b e o btai ne d. 
 
7. 0  
S T U D Y M E DI C A TI O N 
7. 1   
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N
T he st u d y gels i ncl u de K- 2 8 5 a n d me nt h ol gel. 
 
K- 2 8 5 is a t o pical g el w hic h c o ntai ns 
 
 
Me nt h ol gel c o ntai ns 
. 
 
Eac h of t h e st u d y gels c o ntai ns t he f oll o wi n g e xci pie nts: 
 
, 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 3 of 6 0 
 
7. 2 
D R U G P A C K A GI N G  
T he st u d y gels are fille d i n al u mi n u m-la mi nate d t u bes at a wei g ht of   
of st u d y gel 
per t u be. 
F or eac h tr eat m e nt ar m, 2 t y pes of kits c o ntai ni n g st u d y gel, d osi n g s p o o ns, a n d a p plicati o n 
te m plate materi als will be pre pare d (
) (Fi g ure 2 ). 
 
   
 
 
 
 
T he bl ue c ol or b o x i n Fi g ure 2 re prese nts kits f or s u bjects assi g ne d t o 
 
( Peri o d 1) (act ual cart o n will be w hite). Eac h s u bject will a p pl y   
of assi g ne d st u d y 
 T h e a m o u nt of st u d y gel nee de d per s u bject is 
). Eac h s u bject will be assi g ne d a kit c o ntai ni n g 
 of assi g ne d 
st u d y gel (f or a t otal of   
 eac h st u d y gel). 
T he pi n k c ol or b o x i n Fi g ure 2 re pres e nts kits f or s u bjects assi g ne d t o 
 
( Peri o d 1 a n d Peri o d 2) (act u al cart o n will be w hit e). Eac h s u bject will a p pl y 
 
 
 a n d eit her 
 f or a n ot her 2 wee ks. T he 
ma xi m u m a m o u nt of st u d y gel nee de d per s u bject is 
 
 
 
 Eac h s u bject will be assi g ne d a kit c o ntai ni n g 
 t u bes of 
st u d y gel (f or a t otal of 
st u d y gel).  
Dis pe nsi n g of st u d y gel is descri be d i n Secti o n  7. 5. 1 . 
Re place m e nt kits will be pr o vi de d o nl y if p ac ka gi n g is da ma ge d pri or t o recei pt of deli ver y. 
7. 3  
D R U G L A B E LI N G 
St u d y gel will be la bele d wit h t he f oll o wi n g i nf or mati o n: 
1)  St u d y n u m ber 
2)  C o nte nts a n d a m o u nt 
3)  L ot n u m ber 
4)  Kit N u m ber 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 4 of 6 0 
5)
T he st ora ge c o n diti o ns 
6)
Na me a n d a d dress of S p o ns or (e. g., K RI)  
7)  Ca uti o n - Ne w Dr u g Li mite d b y Fe deral La w t o I n vesti g ati o nal Use 
8)  Ca uti o n - Kee p o ut of reac h of c hil dre n 
9)  Ca uti o n – A v oi d o pe n fire or s m o ki n g u ntil t h e gel has drie d 
1 0)  I nstr u cti o n – A p pl y t h e g el usi n g t he pr o vi de d d osi n g s p o o ns acc or di n g t o t he 
detail e d i nstr ucti o ns o n t he kit pac ka g e la bel 
7. 4  
D R U G S T O R A G E 
St u d y gels m ust be st ore d at c o ntr olle d r o o m t e m p erat ure of 
 wit h 
e xc ursi o ns p er mitte d bet wee n 
 as i n dicate d o n t h e dr u g la bel. 
7. 5  
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T 
7. 5. 1  Dis pe nsi n g of St u d y Gel 
St u d y gel will be dis pe nse d o n Da y 2, Da y 8 a n d Da y 1 5. A s ufficie nt n u m ber of t u bes t o 
s u p pl y e n o u g h st u d y gel f or 1 wee k at a ti me will be pr o vi d e d. 
7. 5. 2  A p plic ati o n Tr ai ni n g 
O n Da y - 1, s u bjects will rec ei ve trai ni n g o n t h e a p plicati o n of st u d y gel i ncl u di n g vi de o 
trai ni n g. F urt her a p plicati o n i nstr ucti o ns are pr o vi de d i n A p pe n di x 3 . 
7. 5. 3  Dr u g A d mi nistr ati o n  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 5 of 6 0 
3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 6 of 6 0 
 
 
7. 5. 4  e- Di ar y 
A n e- diar y will be iss ue d t o eac h s u bject b y st u d y staff o n Da y 1. S u bjects will rec or d
i nf or mati o n as d etaile d i n t he e- diar y trai ni n g a n d d oc u me ntati o n f or t he st u d y l e g a n d 
n o n-st u d y le g (if re q uir e d) at t h e ti m e p oi nts s pecifie d i n Ta ble 2 .  
T he act u al ti me a n d date t hat eac h set of pai n assess m e nts is starte d at eac h ti m e p oi nt m ust 
be rec or de d i n t he e- diar y. 
T he e- diar y will be c ollecte d fr o m t he s u bj ect o n Da y 8 (s u bjects d osi n g d uri n g Peri o d 1) 
or Da y 2 2 (s u bjects d osi n g d uri n g Peri o d 2) after t he E O S/ E T assess me nt a n d data will be 
tra nscri b e d i nt o t he e C R F b y a me m ber of t h e st u d y staff. 
7. 5. 5  P h ysic al E xercise 
T he sta n dar dize d re petiti v e q ua drice ps m uscle e xercise is descri be d i n Secti o n 5. 3. 4 . 
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d. 
7. 6  
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L D O SI N G R E GI M E N 
T he st u d y gel will be a p plie d at t he cli nic o n Da ys 1 a n d 2. St u d y gel f or a p pli cati o n b y 
s u bjects fr o m t he ni g ht d ose o n Da y 2 t hr o u g h t he m or ni n g d ose o n Da y 8 will b e dis pe nse d 
t o s u bjects o n Da y 2. F or s u bjects assi g ne d t o Peri o d 2, st u d y gel f or a p plicati o n b y s u bjects 
will b e dis pe nse d at t he Da y 8 a n d Da y 1 5 Safet y visits. St u d y gel t u bes will be wei g he d, 
i n gra ms, a n d t he t otal wei g ht f or all t u bes rec or d e d pri or t o dis pe nsi n g t o s u bjects. St u d y 
gel will be c ollecte d o n Da y 8 (f or Peri o d 1 s u bjects) a n d Da y 2 2 (f or Peri o d 2 s u bjects), 
wei g he d a n d t h e fi nal wei g ht rec or de d. C o m plia nce will be d eter mi ne d fr o m t he fi nal 
wei g ht of t he t u bes c o m pare d t o t he e x p ecte d decreas e fr o m t h e starti n g wei g ht, base d o n 
t he assi g ne d d osi n g sc he d ule (  
per d ose × t he n u m ber of d os es). 
7. 7  
D R U G A C C O U N T A BI LI T Y 
T he i n vesti gat or or desi g nee will si g n a recei pt f or t he st u d y gel w he n recei v e d. T he st u d y 
gel m ust b e st ore d as d es cri be d ( Secti o n 7. 4 ), ke pt i n a s ec ure d l ocati o n t o w hic h o nl y t he 
i n vesti gat or a n d desi g nate d staff ha ve access, a n d dis pe nse d o nl y t o t h ose s u bjects f or mall y 
e nr oll e d i n t he st u d y.  
T he i n vesti gat or or desi g nee m ust mai ntai n a n acc urate rec or d of t h e s hi p me nt a n d 
dis pe nsi n g of st u d y g el i n a dr u g acc o u nt a bilit y le d ger. Dr u g acc o u nt a bilit y will be 
m o nit ore d b y t h e st u d y m o nit or d uri n g m o nit ori n g visits a n d at t h e c o m pleti o n of t he st u d y.
All dr u g will b e i n ve nt orie d b y   
 at t he c o ncl usi o n of t he st u d y. Sec ure dis p osal at t he 
e n d of t h e st u d y will be arra n ge d after t he cli nical st u d y re p ort has bee n fi n alize d.  
7. 8  
P R O C E D U R E F O R U N B LI N DI N G 
As nee de d, t he ra n d o miz ati o n c o d e ma y be br o ke n b y t he i n vesti gat or t o m a na ge a n ur ge nt 
me dical e ve nt. W h e n p ossi ble, u n bli n di n g will be reser v e d f or sit uati o ns w here treat me nt 
all ocati o n is re q uire d t o be k n o w n f or safet y reas o ns. If p ossi ble, t he Me dical M o nit or is 
c o ntacte d t o disc uss t he case bef ore t he c o de is br o ke n. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 7 of 6 0 
If it bec o mes n ecess ar y t o u n bli n d treat me nt i nf or mati o n d uri n g t h e st u d y, t he reas o n f or 
u n bli n di n g is d oc u me nte d i n t he C R F/e C R F. T he i n vesti gat or m ust c o ntact t he Me di cal 
M o nit or pr o m ptl y a n d e x plai n t he reas o n f or t he pre m at ure u n bli n di n g. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 8 of 6 0 
8. 0
C O N C O MI T A N T M E DI C A TI O N
T he i n vesti gat or m ust rec or d t he use of all c o nc o mita nt me dicati o ns, b ot h prescri be d a n d 
o ver-t h e-c o u nter, i n t he C R F/e C R F. T his i ncl u des dr u gs use d o n a c hr o nic a n d as- n ee de d 
basis. S u bjects m ust be disc o ura ge d fr o m starti n g a n y ne w m e dicati o n, b ot h prescri be d a n d 
o ver-t h e-c o u nter, wit h o ut c o ns ulti n g t he i n vesti gat or, u nless t he ne w me dicati o n is 
re q uire d f or e mer ge nc y use.
8. 1   
G E N E R A L C O N SI D E R A TI O N S 
All me dicati o ns a n d ot her treat m e nts ta ke n b y s u bjects wit hi n 3 0 da ys bef ore d osi n g a n d 
d uri n g t he st u d y will be rec or de d i n t h e C R F. A n y c ha n ges i n t he c o nc o mit a nt me dicati o ns 
after disc h ar g e fr o m t he cli nic o n Da y 2, eit her prescri be d or self-a d mi nistere d, will be 
d oc u me nte d a n d re vie we d acc or di n g t o t he s c he d ule i n Ta ble  2.   
8. 2  
P R O HI BI T E D M E DI C A TI O N A N D T H E R A PI E S 
T he f oll o wi n g me di cati o ns a n d t hera pies are pr o hi bite d d uri n g t he st u d y: 
 
Oral or t o pical a nal gesi c me dicati o ns wit hi n 1 4 da ys bef ore t h e S cree ni n g Visit.
 
S yst e mic c ortic oster oi d wit hi n 3 0 d a ys bef ore t h e Scree ni n g Visit.
 
Prescri pti o n or o ver-t he-c o u nter pr o d u cts c o ntai ni n g me nt h ol or N S AI Ds. 
 
Slee p 
me dicati o n, 
m us cle rela xa nt, a ntic o n v ulsa nt, or a nti de press a nt i n t he last 
6 m o nt hs t o treat a c hr o nic pai n c o n diti o n. 
 
A ntic o n v ulsa nt or a nti de pressa nt f or a n o n- p ai nf ul c o n diti o n at a d ose t hat h as n ot bee n 
sta ble f or at least 3 m o nt hs bef ore t h e Scree ni n g Visit.
 
T he a p pli cati o n or us e of ice, heat, mass a ge, a n d wra p pi n g o n t he l e gs 
 
Me dicati o ns or treat m e nts t hat w o ul d si g nifica ntl y i nfl ue nce or e xa g gerat e res p o nses 
t o t h e gel, or t h at w o ul d alter i nfla m mat or y or i m m u ne res p o nses t o t h e g el, wit hi n 3 0 
da ys bef ore t he first d ose of st u d y g el (e. g., c ycl os p ori ne, tacr oli m us, c yt ot o xic dr u gs, 
i m m u ne gl o b uli n, Bacill us Cal mette- G ueri n vacci n e, m o n ocl o nal a nti b o dies, ra di ati o n 
t hera p y). 
 
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d. 
8. 3  
P E R MI T T E D M E DI C A TI O N 
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs after t he 
first st u d y gel a p plicati o n, at w hic h ti me o ver-t h e-c o u nter ( O T C) acet a mi n o p he n ( o ne 
5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue 
me dicati o n is per mitte d, if re q uire d. S u bjects e x p erie nci n g se vere pai n or i na bilit y t o m o ve 
or wal k d ue t o pai n m a y be per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C 
aceta mi n o p he n ta blet t wi ce dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs aft er t h e 
first st u d y gel a p plicati o n. If s u bjects ta k e resc u e me dicati o n bef ore t he first 1 6 8 h o urs, it 
will b e ca pt ure d as a c o n c o mit a nt me dicati o n. 
N o ot her m e dicati o ns (i n cl u di n g s u p ple me nts) are per mitte d d uri n g t h e st u d y, e xce pt as 
necessar y t o treat a n A E, at t he i n vesti gat or’s dis creti o n. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 9 of 6 0 
9. 0
A D V E R S E E V E N T S
9. 1   
A D V E R S E E V E N T D E FI NI TI O N 
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har m ace uti cal 
pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t h e p har mace utical 
pr o d uct. A n A E ca n, t h eref ore, be a n y u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m, or 
disease te m p orall y ass o ciate d wit h t he use of a m e dici nal pr o d uct, w h et her or n ot relate d 
t o t h e me dici n al pr o d uct. A n y w orse ni n g of t he s u bject’s disease u n der st u d y or ot h er 
me dical c o n diti o ns will als o be c o nsi dere d t o be a n A E, u nless it is wit hi n t he n or mal ra n g e 
of disease fl u ct uati o n f or t hat s u bject. 
Cli nicall y mea ni n gf ul (f or a gi ve n s u bject) c h a n g es i n p h ysical e xa mi nati o n fi n di n gs a n d 
a b n or mal o bjecti v e test fi n di n gs (e. g. cli nical la b orat or y tests e xce pt f or ele vate d test
res ults f or ser u m C K, Secti o n 5. 2. 2. 1 ], E C Gs) are als o rec or d e d as A Es. T he criteria f or 
deter mi ni n g w het her a n a b n or mal o bjecti v e test fi n di n g s h o ul d be re p orte d as a n A E are as 
f oll o ws:
1. test res ult is ass ociate d wit h acc o m pa n yi n g s y m pt o ms, a n d/ or; 
2.  test res ult re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n, 
a n d/ or; 
3.  test res ult lea ds t o a c ha n ge i n st u d y d osi n g or dis c o nti n uati o n fr o m t he st u d y, 
si g nifica nt a d diti o nal c o nc o mita nt dr u g treat m e nt or ot h er t h era p y, a n d/ or;
4. test res ult lea ds t o a n y of t he o utc o mes i ncl u de d i n t he defi niti o n of a seri o us A E
( S A E). 
Merel y re p eati n g a test, i n t h e a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot m eet 
c o n diti o n n u m b er 2 a b o v e f or re p orti n g as a n A E.
A n y a b n or mal test res ult t hat is deter mi ne d t o b e a n err or d o es n ot re q uire re p orti n g as a n 
A E. 
A T E A E is defi n e d as a n A E t h at be gi ns after t h e start of st u d y gel or a n e ve nt t hat be gi ns 
bef ore t h e start of t he st u d y gel a n d w orse ns i n i nt e nsit y after starti n g treat m e nt.
9. 2   
R E P O R TI N G A D V E R S E E V E N T S 
At eac h e val uati o n, t h e i n vesti gat or will d eter mi ne w het her a n y A Es h a ve occ urre d. T h e 
s u bject will be q uesti o ne d i n a ge n eral wa y a n d n o s pecific s y m pt o ms will b e s u g geste d. If 
a n y A Es h a ve o cc urre d, t he y will be rec or de d o n t he A E pa ges of t he C R F or e C R F a n d i n 
t he s u bject’s me dical rec or d. If k n o w n, t h e dia g n osis will b e rec or d e d, i n prefere nce t o t he 
listi n g of i n di vi d ual si g ns a n d s y m pt o ms. 
A d vers e e ve nt re p orti n g be gi ns w he n i nf or m e d c o nse nt is o btai ne d a n d e n ds at t he 
c o ncl usi o n of t h e st u d y, u nless a n u nres ol ve d A E is still bei n g f oll o we d.
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 0 of 6 0 
T he se verit y of t h e A E will b e gra de d as f oll o ws: 
 
Mil d 
T he A E is easil y t olerat e d a n d d oes n ot i nterfere wit h n or mal dail y 
acti vities. 
 
M o derat e   
T he A E ca uses s o me i nterfere nce wit h dail y acti vities. 
 
Se vere 
T he A E ca uses all n or mal dail y acti vities t o be c o m pletel y halte d.
 
T he i n vesti gat or will ma ke a j u d g me nt re gar di n g w het her or n ot t he A E was relat e d t o t he 
st u d y gel. ( Please refer t o t he defi niti o ns bel o w.) T he i n vesti gat or will e val uate a n y c ha n g es 
i n la b orat or y val ues, ma ke a deter mi n ati o n as t o w het her or n ot t he c ha n ge is cli nicall y 
i m p orta nt, a n d w het her or n ot t h e c h a n ges were relate d t o t he st u d y gel. H o we ver, e ve n if 
t he i n vesti gat or feels t here is n o relati o ns hi p t o t he st u d y g el, t he A E or l a b orat or y 
a b n or malit y M U S T  be rec or de d i n t he C R F/e C R F. T he f oll o wi n g g ui da n ce will be use d 
b y i n vesti gat ors w he n assessi n g relati o ns hi p: 
Rel ate d 
 
Occ urs wit hi n a reas o n a ble te m p oral se q ue n ce t o a d mi nistrati o n of st u d y gel or,
 
Ca n n ot be e x plai n e d b y c o nc urre nt disease or ot h er dr u gs or c h e micals or,  
 
I m pr o v es or disa p p ears o n st o p pi n g or re d uci n g st u d y gel ( de-c halle n ge) 
 
Rea p pears o n re p eate d e x p os ure t o st u d y gel (re-c halle n ge) 
 
Is a n u n us u al e v e nt t hat is k n o w n t o b e ass ociate d wit h t he dr u g or t his class of 
c o m p o u n d, a n d ca n n ot be e x plai ne d b y ot her t hera p y or t he p artici pa nt’s p h ysical 
c o n diti o n 
 
U nli kel y t o be attri b ute d t o c o nc urre nt disease or ot her dr u gs or a cli nicall y reas o na bl e 
res p o nse o n wit h dra wal ( de-c h alle n ge) 
U nrel ate d 
 
Occ urs wit h a te m p oral relati o ns hi p t o a d mi nistrati o n of st u d y gel w hic h m a kes a ca us al 
relati o ns hi p i m pr o ba ble or,  
Ot her dr u gs, c he micals or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns of 
ca usalit y or, 
 
Is k n o w n t o b e ass ociate d wit h t he partici pa nt’s cli nical c o n diti o n, or wit h ot her 
me dicati o n ta ke n b y t he partici pa nt
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 1 of 6 0 
T he i n vesti gat or will rec or d t h e acti o n ta ke n a n d o utc o me f or eac h A E acc or di n g t o t he 
f oll o wi n g:
Acti o n t a ke n
 
N o ne
 
Treat m e nt re q uire d 
 
H os pitalizati o n
S u bject wit h dra w n
Ot her (s pecif y)
Acti o n T a ke n Wit h St u d y Tre at me nt 
 
D ose n ot c ha n g e d
 
Dr u g i nterr u pte d 
Dr u g wit h dra w n
N ot a p plica ble
O utc o m e 
 
Res ol ve d: T he e ve nt h as rec o v ere d
 
N ote: A n S A E/ A E st o p date s h o ul d be pr o vi d e d.
 
Rec o vere d/ Res ol ve d wit h se q uelae: T he st u d y s u bject h as rec o vere d as m uc h as ma y 
be e x pecte d b ut is left wit h se q uela e of t he e ve nt t h at are n ot e x p ecte d t o rec o ver f urt her
 
N ote: If t h e se q uelae are se vere e n o u g h t o re prese nt a si g nifica nt disa bilit y or 
i nca pacit y t he n t he e ve nt s h o ul d be re p orte d as a n S A E. 
 
Rec o veri n g/ Res ol vi n g: C a n be use d i n cases w here st u d y s u bject is k n o w n t o be clearl y 
rec o v eri n g fr o m t he e ve nt at t he e n d of a st u d y, alt h o u g h t he e ve nt is n ot yet res ol ve d, 
a n d t he i n vesti gat or a n d Me dical M o nit or a gree t hat f urt her f oll o w- u p is n ot necess ar y.
 
Fatal: T he st u d y s u bject die d as a res ult of t h e A E 
 
N ote: Deat h is c o nsi dere d a n o utc o me of a n A E rat her t ha n a n A E i n its o w n 
ri g ht, a n d t he ca us e of deat h s h o ul d be rec or de d as t he A E. T here ma y be rare 
circ u msta nc es w here t h e ca use of d eat h is u n k n o w n a n d t he deat h ma y h a ve t o 
be rec or de d as t he e ve nt (e. g., “s u d de n car diac deat h ”). A d vers e e ve nts 
res ulti n g i n deat h are S A Es.
 
N ot rec o v ere d/ N ot res ol ve d: T he s u bject has a n A E t hat has n ot i m pr o ve d or 
rec u p erate d at t h e ti me of t he re p ort 
9. 3  
F O L L O W- U P O F A D V E R S E E V E N T S
If a n y A Es are prese nt w he n a s u bj ect c o m pletes t he st u d y, or w he n a s u bje ct dis c o nti n ues 
or is wit h dra w n fr o m t h e st u d y, t he s u bject will be re-e v al uate d. At t h e i n vesti gat or’s 
discreti o n, mi n or A Es ca n be re-e val uate d via tele p h o ne a n d d oc u me nte d. If t he A E is still
n ot res ol ve d, a d diti o nal f oll o w- u p will be perf or m e d as a p pr o priate. E v er y eff ort will be 
ma de b y t he i n v esti gat or or dele gate t o c o ntact t he s u bject u ntil t h e A E is res ol ve d or 
sta bilize d, or t h e M e dical M o nit or a n d i n vesti gat or a gree t hat f urt her f oll o w- u p is n ot 
necessar y. T he f oll o w- u p of A Es will be d oc u me nte d i n t he s u bject’s me dical rec or ds.

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 2 of 6 0 
1 0. 0
S E RI O U S A D V E R S E E V E N T S
A n S A E is a n y u nt o war d me di cal o cc urre nce t hat at a n y d ose:
 
Res ults i n deat h 
Is lif e-t hreate ni n g
Re q uires s u bject h os pit alizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
 
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 
Is a c o n ge nital a n o mal y/ birt h defect
 
I m p ort a nt me dical e v e nt 
Me dical a n d scie ntific j u d g me nt will be e x ercis e d i n deci di n g w het h er e x pe dite d re p orti n g 
is a p pr o priate i n ot h er sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot b e 
i m m e diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par diz e t he 
s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o n e of t he ot h er o utc o mes liste d i n t he 
defi niti o n a b o ve. E v e nts t h at re q uire e x p e dite d re p orti n g will als o be c o nsi dere d t o be 
S A Es. 
1 0. 1  
LI F E- T H R E A T E NI N G A D V E R S E E V E N T 
T he ter m “life-t hreate ni n g” i n t he defi niti o n of “s eri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t h e e v e nt. It d o es n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h, if it were m ore se vere.
1 0. 2  
H O S PI T A LI Z A TI O N 
H os pitalizati o n is d efi n e d as t he s u bject bei n g h os pitalize d o ver ni g ht, or t he s u bject’s 
h os pital sta y bei n g pr ol o n ge d f or at least a n a d diti o nal o ver ni g ht sta y. Pre- pla n ne d h os pit al 
sta ys or h os pital sta ys f or n o n- me dical s oci al reas o ns are n ot a p plica ble. T we nt y-t hree h o ur 
h os pitalizati o ns f or o bser v ati o n will be disc usse d wit h t he Me dic al M o nit or t o deter mi ne 
w het h er t h e y are a p pr o priate f or S A E re p orti n g. 
1 0. 3  
I M P O R T A N T M E DI C A L E V E N T 
Me dical a n d sci e ntific j u d g me nt will be e xercis e d i n deci di n g w het her e x p e dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pit alizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uir e i nter v e nti o n t o pre ve nt o ne of t h e ot h er o ut c o mes liste d i n t he 
defi niti o n a b o ve. 
1 0. 4  
P R E G N A N C Y 
A n y s u bject 
w h o 
bec o mes 
pre g na nt 
d uri n g t he st u d y 
m ust i m me diatel y 
be
disc o nti n ue d/ wit h dra w n. T he i n vesti g at or is re q uire d t o n otif y t he K RI M e dical M o nit or 
i m m e diatel y if a n y s u bj ect bec o mes pre g na nt d uri n g t h e st u d y. Pre g n a nt s u bjects will 
re q uire peri o dic f oll o w- u p wit h d oc u me ntati o n of t he o utc o me of t he pre g na nc y i n t he 
st u d y rec or ds.

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 3 of 6 0 
1 0. 5
S U B J E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L
If a s u bject e x perie n ces a n A E t hat lea ds t o disc o nti n uati o n of st u d y gel treat m e nt a n d 
wit h dra wal fr o m t he st u d y, t he C R F/e C R F
will i de ntif y t he A E as t he reas o n f or 
wit h dra wal. S u bjects t hat disc o nti n ue st u d y gel treat me nt will be as ke d t o c o nti n ue 
sc he d ule d st u d y visits t hr o u g h t he F oll o w- u p p h o n e call. 
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S
Acc or di n g t o F D A C F R 3 1 2. 3 2(a) a n d F D A G ui da nce “ Safet y Re p orti n g Re q uire me nts f or 
I N Ds a n d B A/ B E St u dies” fi nalize d Dece m ber 2 0 1 2, s us pecte d a d vers e r e acti o n mea ns 
a n y A E f or w hic h t h ere is a reas o na bl e p ossi bilit y t hat t h e m e dici nal pr o d uct ca us e d t he 
A E. T he p hrase “reas o n a ble p ossi bilit y” mea ns t here is e vi d e nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t h e A E a n d t he m e dici nal pr o d uct. 
 
T he f oll o wi n g are e x a m ples of t y pes of e vi d e nce t hat w o ul d s u g gest a ca us al relati o ns hi p 
bet wee n t h e dr u g a n d t he A E (i.e., re as o n a ble p ossi bilit y): 
 
A si n gle occ urre nce of a n e ve nt t hat is u n c o m m o n a n d k n o w n t o b e str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi o e de ma, h e patic i nj ur y, Ste ve ns-J o h ns o n S y n dr o me)  
 
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociat e d wit h dr u g 
e x p os ure, b ut is ot her wise u nc o m m o n i n t h e p o p ulati o n e x p ose d t o t he dr u g 
(e. g., te n d o n r u pt ure)  
 
S us pecte d a dverse re acti o ns are t he s u bset of all A Es f or w hic h t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he e v e nt. 
 
A s us pecte d a d v ers e reacti o n is c o nsi d ere d “ u ne x pecte d ” if it is n ot liste d i n t he 
I n v esti gat or’s Br oc h ure or ot h er a p plica ble pr o d uct i nf or mati o n or is n ot liste d at t h e 
s pecificit y or se v erit y t hat has bee n o bser ve d.
 
A n A E or s us pecte d a d v erse reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her t he 
i n vesti gat or or s p o ns or, it res ults i n a n y of t h e f oll o wi n g o utc o m es: 
Deat h, a 
life-t hreat e ni n g A E, i n- p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, a 
persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t h e a bilit y t o c o n d uct n or m al 
life f u ncti o ns, or a c o n ge nital a n o mal y/ birt h defe ct. I m p ort a nt me dical e ve nts t hat ma y n ot 
res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y j e o par dize t he patie nt or s u bject 
a n d ma y re q uire me dical or s ur gic al i nter ve nti o n t o pre ve nt o n e of t h e o ut c o mes liste d i n 
t his defi niti o n. 
 
A n y A E meeti n g t he defi niti o ns of s us pecte d a d verse reacti o n, u ne x pecte d, a n d seri o us is 
c o nsi dere d a seri o us u ne x pecte d s us p ecte d a d v ers e reacti o n ( S U S A R). I n acc or da n ce wit h 
t he F D A G ui da n ce “ Safet y Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies”, 
fi nalize d D ece m ber 2 0 1 2, K RI will u n bli n d t he st u d y data f or s u bjects e x peri e nci n g 
S U S A Rs a n d o nl y re p ort t h ose f or s u bjects w h o are o n st u d y gel. All s uc h re p orts will be 
s u b mitte d t o t he i n vesti gat or(s), F D A, a n d I R B/I E C i n a n e x pe dite d ma n ner. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 4 of 6 0 
1 0. 7
S E RI O U S A D V E R S E E V E N T R E P O R TI N G
 
S E RI O U S A D V E R S E E V E N T S A N D S A E S, W H E T H E R O R N O T R E L A T E D T O 
T H E S T U D Y G E L, M U S T B E R E P O R T E D I M M E DI A T E L Y T O T H E S T U D Y 
M E DI C A L M O NI T O R: 
 
 
 
Sit es nee di n g t o c o ntact t he Me dical M o nit or s h o ul d use t he a b o ve 2 4/ 7 S A E h otli ne 
n u m ber a n d 
e mail bef ore c o ntacti n g a n
i n di vi d ual M e dical M o nit or. T he h otli ne n u m b er will e m pl o y a call tree t o c o ntact 
i n di vi d uals i n or der of a call list. 
 
 
 
 
 
 
K o wa Researc h I nstit ute, I n c. will c o n d uct a me di cal re vie w of S A E re p orts. 
 
K o w a Rese arc h I nstit ute, I nc. 
 
 
 
 
 
 
K o wa Researc h I nstit ute, I nc. will o btai n details fr o m t he i n vesti g at or of all seri o us, 
u ne x pecte d a n d rel ate d A Es ( or ot her e ve nts de p e n di n g o n t he s pecific re q uire me nts) t h at 
s h o ul d be re p orte d t o I R Bs/I E Cs, as a p pr o priate. Writte n c o nfir m ati o n t h at t h ese seri o us, 
u ne x pecte d a n d r elate d A Es ha ve bee n s u b mitte d t o t h e I R B/I E C m ust be f or war de d t o 
K RI a n d ke pt i n t he i n vesti gat or files. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 5 of 6 0 
1 1. 0
S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S
I n ge n eral, ass ess me nts 
wit h c o nti n u o us o utc o mes 
will b e s u m m arize d usi n g t he 
descri pti ve statistics n, mea n, sta n d ar d de vi ati o n ( S D), me dia n, mi ni m u m a n d ma xi m u m. 
F or assess m e nts wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nta ge will be 
calc ulate d. Detaile d statistical met h o d ol o g y will be prese nte d i n a se parate statisti cal 
a nal ysis pla n.  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N 
T he para meters are c o ns er vati v el y esti mate d base d o n t he D O M S st u d y wit h   
 g el.
T he bet wee n- gr o u p differe nce i n t h e me a n   
 is 1 1. 0 7 wit h a S D of 2 5. 6 2. T o ha ve 
statisti cal p o wer of 9 0 %, 
. T a ki n g i nt o acc o u nt 
i nf or mati o n l oss ca us e d b y missi n g data, it is esti mate d t hat   
 nee d t o be treat e d 
wit h eac h st u d y gel. 
1 1. 2  
S T U D Y P O P U L A TI O N S
T hree a nal ysis p o p ulati o ns will be e val uate d: 
 
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mize d s u bjects w h o h a ve a b aseli ne 
pai n sc ore a n d at least 1 st u d y gel a p plie d. 
 
T he per- pr ot o c ol set ( P P S) will i ncl u de all ra n d o mi ze d s u bjects w h o h a ve a baseli ne 
pai n sc ore, at least 1 st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns. 
 
T he safet y set will i ncl u de all s u bjects w h o ha ve at least 1 st u d y gel a p plie d. 
1 1. 3 
DI S P O SI TI O N
T he n u m ber of s u bjects scree n e d, ra n d o mize d, a n d treate d will be s u m marize d. T he 
n u m ber of s u bjects disc o nti n ui n g treat me nt/ wit h dra wi n g fr o m t he st u d y 
will be 
s u m marize d al o n g wit h t he reas o ns f or dis c o nti n uati o n/ wit h dra wal. S u bjects w h o are 
scree n fail ures al o n g wit h t he m ai n reas o ns f or fail ure will als o be s u m mari ze d. 
1 1. 4 
D E M O G R A P HI C/ B A S E LI N E I N F O R M A TI O N 
De m o gra p hics a n d ot her baseli ne c haract eristics will be s u m marize d wit h descri pti ve 
statisti cs. F or q u a ntitati v e data, mea ns, me dia ns, sta n d ar d d e viati o ns, mi ni m u m a n d 
ma xi m u m val ues will be deter mi ne d. F or q ualit ati ve data, perce nt a ges will be calc ul ate d.  
1 1. 5 
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S
1 1. 5. 1 Pri m ar y Effic ac y P ar a meters 
 
T he pri mar y a n al ysis p o p ulati o n is t he F A S. T he pri mar y a nal ysis will be re peate d usi n g 
t he P P S. 
 
 
 
. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 6 of 6 0 
If t here e xist missi n g V A S val ues t o be i m p ute d, a n y s uc h v al u es will be i m p ute d bef ore 
calc ulati n g t h e   
. I nt er m e diate missi n g V A S val ues d ue t o a n o missi o n of rec or di n g 
pai n i nte nsit y or s u bject’s slee p will n ot be i m p ute d, t heref ore, t he o bs er ve d val ues bef ore 
a n d after t h e missi n g meas ure me nt will be directl y c o n necte d i n or der t o calc ulate t h e 
. If s u bj ects nee d t o t a ke t he resc ue me di cati o n, t he y will rec or d t h eir pai n i nte nsit y 
i n t h e e diar y b ef ore ta ki n g t he resc ue m e dicati o n. If t he resc ue me dicati o n is ta ke n wit hi n 
6 h o urs of a n o mi nal pai n i nte nsit y assess me nt ti me p oi nt, t h e pai n i nte nsit y sc ore t h at was 
rec or d e d bef ore t a ki n g t he res c ue me dicati o n will be carrie d f or war d t o t he ne xt pai n 
i nte nsit y assess me nt ti me p oi nt. Missi n g val ues ca use d b y wit h dra wal fr o m t he st u d y d ue 
t o e ve nts w hic h are n ot prefera ble t o s u bjects s uc h as a n a d verse e ve nt a n d/ or lac k of 
effic ac y will be i m p ute d b y last o bs er vati o n carri e d f or war d ( L O C F) w hil e t h ose v al ues 
d ue t o l ost t o f oll o w- u p will be i m p ute d u n der t h e missi n g at ra n d o m ( M A R) ass u m pti o n 
wit h t h e m ulti ple i m p utati o n ( MI) t ec h ni q ue. B y usi n g t h e MI t ec h ni q ue, 1 0 0 datasets will 
be ge nerate d. After calc ul ati n g t he   
, a n a nal ysis of c o varia n ce ( A N C O V A) m o del will 
be a p pli e d f or t h e pri mar y e n d p oi nt wit h ge n d er a n d treat m e nt as m ai n effects a n d b aseli ne 
pai n as a c o v ariate i n eac h dataset. M ulti ple res ults will be c o m bi ne d usi n g R u bi n’s r ule. 
As f or a se nsiti vit y a nal ysis, t he L O C F val ues will be re place d b y t h e w orst val ue o bser ve d 
i n t his st u d y, a n d t he n t he sa me pr o ce d ure will be a p pli e d. 
1 1. 5. 2  Sec o n d ar y Effic ac y P ar a meters  
A mi xe d effect m o del re peate d- meas ures ( M M R M) will be a p plie d t o t h e PI D w hile 
sta n di n g a n d PI D at rest t o i n vesti gate treat m e nt differe nces. 
 
. T he ti me t o first 
d ose of resc ue me di cati o n, will be a nal yze d usi n g t he Ka pla n- Meier met h o d t o esti mate 
t he s ur vi val distri b uti o n f u ncti o n.  
1 1. 6 
A N A L Y SI S O F S A F E T Y D A T A
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. 
T he A Es
will be c o de d usi n g t he latest versi o n of Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A). A ge neral s u m mar y of t h e A Es a n d S A Es will be s u m marize d b y 
o verall n u m ber of A Es, se verit y a n d relati o ns hi p t o st u d y gel, per treat m e nt gr o u p. T he 
n u m ber of A Es lea di n g t o disc o nti n uati o n/ wit h dra wal a n d S A Es lea di n g t o deat h will als o 
be s u m marize d. T he i nci de nce of A Es will b e s u m m arize d b y b o d y s yste m a n d treat m e nt 
gr o u p. T he i n ci de nce of T E A Es will als o be s u m marize d b y s yste m or ga n class a n d 
preferre d t er m. 
T he cli nical l a b orat or y d ata will be s u m marize d b y treat m e nt gr o u p, al o n g wit h c ha n g es 
fr o m t he b aseli ne. T he v al ues t hat are b el o w t he l o wer li mit or a b o ve t he u p per li mit of t h e 
refere nce ra n g e will be fl a g ge d. T h ose val u es or c ha n ges i n val ues, w hic h are i de ntifie d as 
bei n g cli nicall y si g nifica nt, will be fla g ge d. 
Vital si g ns will als o be s u m marize d b y treat m e nt gr o u p a n d ti m e p oi nt, al o n g wit h t h e 
c ha n ges fr o m baseli n e.  
All A E, cli nical la b orat or y, vit al si g n, p h ysical e xa mi nati o n, st u d y g el a p pli cati o n site 
reacti o n, st u d y gel use a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 7 of 6 0 
 
 
 
 
  
 
 
 
 
 
 
 
. 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 8 of 6 0 
1 2. 0
S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N
1 2. 1 
E T HI C A L C O N D U C T O F T H E T RI A L
T his st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol, F D A G C P, as descri be d i n 2 1 C F R
Parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2; t he W orl d Me dical Ass ociati o n Decl arati o n of Helsi n ki; t he
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A); a n d I C H G C P ( E 6/ R 1). 
Eac h i n vesti gat or will c o n d uct t he trial als o acc or di n g t o a p plica ble l ocal or re gi o nal 
re g ulat or y re q uire me nts. 
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S 
C O M MI T T E E 
T he I R B/I E C m ust b e c o nstit ute d acc or di n g t o t he a p plica ble state, fe deral a n d l ocal 
re q uire me nts of eac h partici pati n g l ocati o n, a n d t h ose of t he I C H G C P g ui da nce a n d F D A 
G C P re g ulati o ns. 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal site t o s u b mit t he pr ot o c ol, I n v esti gat or’s 
Br oc h ure, s u bject i nf or me d c o nse nt, s u bject recr uit me nt materials (if a p plica ble), a n d ot her 
re q uire d d oc u m e ntati o n t o t he I R B/I E C f or re vi e w a n d a p pr o v al. C o pies of t he writte n 
a p pr o v als m ust be pr o vi d e d t o 
. T h e d oc u me ntati o n s h o ul d clearl y 
me nti o n t h e a p pr o val/fa v ora ble o pi ni o n of t he pr ot oc ol, t he s u bject I C F, a n d s u bject 
recr uit m e nt m aterials (if a p plica ble). T he res p ecti ve versi o n dates are t o b e i ncl u de d. T he 
writte n a p pr o vals a n d a list of t h e v oti n g me m bers, t heir titles or o cc u pati o ns, a n d t heir 
i nstit uti o nal affiliati o ns m ust be o btai ne d fr o m t he I R B/I E C a n d pr o vi de d t o 
 
pri or t o t he release of cli nical st u d y s u p plies t o t h e i n vesti gati o nal sit e a n d 
c o m me nce m e nt of t h e st u d y. If a n y me m ber of t h e I R B/I E C has direct partici pati o n i n t he 
st u d y, writt e n n otificati o n re gar di n g his or her a bsti ne nce fr o m v oti n g m ust als o be 
o btai ne d. 
Sit es m ust a d here t o all re q uire me nts sti p ulate d b y t he I R B/I E C. T his i n cl u des n otificati o n 
t o t h e I R B/I E C re g ar di n g pr ot o c ol a me n d me nts; u p dates t o t he s u bject i nf or me d c o ns e nt 
a n d recr uit me nt materi als i nte n de d f or vie wi n g b y s u bjects; I n vesti gati o nal Ne w Dr u g 
safet y re p orts; seri o us a n d u ne x pecte d A Es; u p dat es re gar di n g t he o n g oi n g re vie w of t h e 
st u d y at i nter vals s pecifie d b y t h e I R B/I E C; a n d fi nal st u d y re p orts or s u m maries. 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal sit e t o s u b mit i nf or mati o n t o t he a p pr o priate 
I R B/I E C f or a n n ual re vi e w a n d a n n ual re-a p pr o val. 
1 2. 3  
S U B J E C T I N F O R M E D C O N S E N T 
Pri or t he i m ple me ntati o n of st u d y pr oce d ures, s u bj ects a n d pers o ns c o n d ucti n g t h e c o nse nt 
disc ussi o n will be re q uire d t o si g n a n d date t he I R B/I E C-a p pr o v e d I C F a n d eac h s u bject 
will b e gi v e n a c o p y. I n a d diti o n, t his i nf or mati o n will be rec or de d i n t he s u bject’s me dical 
rec or d (i.e., s o urce d oc u me nt). 
T he writte n c o nse nt d oc u me nt will e m b o d y t h e ele me nts of i nf or me d c o nse nt as descri be d 
i n t h e HI P A A, W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki, F D A 2 1 C F R Part 
5 0. 2 5, I C H G C P, a n d i n acc or da n ce wit h a n y l ocal re g ulati o ns. T he i n vesti gat or is 
res p o nsi ble f or t he pre parati o n, c o nte nt, a n d I R B/I E C a p pr o val of t h e I C F. T he I C F m ust 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 9 of 6 0 
be a p pr o ve d b y t h e site- d esi g nate d I R B/I E C a n d b e acce pt a ble t o K RI a n d  
 
. 
T he I C F m ust b e writte n i n a la n g ua ge f ull y c o m pre he nsi ble t o t he pr os pecti v e s u bject. T he 
i n vesti gat or or desi g nee will gi v e t h e s u bj ect a de q uate o p p ort u nit y t o rea d it bef ore it is 
si g ne d a n d date d. I nf or mati o n pr o vi de d will b e gi ve n i n b ot h oral a n d writte n f or m 
w he ne ver p ossi ble a n d i n t he ma n ner d ee me d a p pr o priate b y t he I R B/I E C. S u bjects m ust 
be gi ve n a m ple o p p ort u nit y t o i n q uire a b o ut st u d y details. 
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L 
A n a me n d m e nt m ust be a gree d t o i n writi n g b y K RI a n d 
, s u b mitt e d 
as a n I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n a me n d me nt, a n d s u b mitte d t o a n d 
a p pr o v e d b y t h e res pecti v e I R B/I E C f or eac h i n v esti gati o nal sit e bef ore it is i m ple me nt e d. 
Writte n a p pr o val of a pr ot oc ol a me n d me nt is n ot re q uire d pri or t o i m ple me ntati o n f or 
c ha n ges t o t h e pr ot o c ol, w hic h eli mi nate i m me diate hazar d t o t he s u bject; h o we ver, 
a p pr o v al m ust be o btai n e d as s o o n as p ossi ble t h ereafter. A p pr o v e d a me n d me nts m ust als o 
be si g ne d b y t he i n vesti gat or. 
1 2. 5  
S T U D Y I NI TI A TI O N 
T he i n vesti gat or m ust n ot e nr oll a n y s u bjects pri or t o t h e c o m pleti o n of a f or mal meeti n g 
c o n d ucte d b y a re prese ntati ve of 
( or K RI). T his meeti n g will 
i ncl u de a d etaile d re vie w of t h e st u d y pr ot oc ol a n d C R F/e C R Fs. St u d y gel will n ot be 
s u p plie d t o a n i n vesti gat or u ntil all t he n ecessar y pre-st u d y re q uire m e nts ha ve bee n 
c o m plete d a n d esse ntial si g ne d d oc u me nts are re cei v e d b y 
, as 
a p plica ble, a n d K RI. 
1 2. 6
S T U D Y M O NI T O RI N G 
It is t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat t h e st u d y is c o n d ucte d i n acc or da nce 
wit h t h e pr ot oc ol, I C H/ F D A G C Ps, a p plica ble re g ulat or y re q uire me nts, HI P A A, a n d t he 
c urre nt Declarati o n of Helsi n ki. Vali d data are t o be e ntere d i nt o t he C R Fs/e C R Fs. 
M o nit ori n g acti vities will b e c o n d ucte d as d escri be d i n a n a p pr o ve d M o nit ori n g Pl a n. 
O versi g ht visits ma y be c o n d ucte d b y K RI Cli nical O perati o ns t o assess m o nit ori n g
perf or ma n ce. 
T o ac hi e ve t his o bj ecti ve, t he m o nit or’s d uties are t o ai d t h e i n vesti gat or a n d, at t he s a me 
ti m e, K RI i n t he mai nte na nce of acc urat e, c o m plete, le gi ble, well- or ga nize d a n d easil y 
retrie va bl e data. T he m o nit or will re vie w t h e pr ot oc ol wit h t h e i n vesti gat or. I n a d diti o n, 
t he m o nit or will e x plai n t he i n vesti gat or’s re p orti n g res p o nsi bilities a n d all a p plica ble 
re g ulati o ns c o n cer ni n g t he cli nical e val u ati o n of t he st u d y gel. 
T he i n vesti gat or will per mit t he re prese nt ati ves of K RI a n d
 t o 
m o nit or a n d o versee t he st u d y as fre q ue ntl y as 
 ( or K RI) dee ms is 
necessar y t o deter mi n e t h at data rec or di n g a n d pr ot oc ol a d here nce are acce pta ble. T he 
C R Fs/e C R Fs a n d rel ate d s o urce d oc u me nts will be re vi e we d i n detail b y t h e m o nit or at 
eac h visit, i n acc or da n ce wit h rel e va nt Sta n dar d O perati n g Pr oce d ures ( S O Ps), I C H G C P
g ui da nce, a n d F D A G C P re g ulati o ns. T his i ncl u des res ults of tests perf or me d as a 
re q uire me nt f or parti ci p ati o n i n t his st u d y a n d a n y ot h er m e dic al rec or ds re q uire d t o 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 0 of 6 0 
c o nfir m i nf or mati o n c o ntai n e d i n t he C R Fs, s uc h as past me dical hist or y a n d sec o n d ar y 
dia g n oses. T he i n vesti gat or a n d staff will be e x pecte d t o c o o perate wit h t he m o nit or/ K RI
a n d pr o vi de a n y missi n g i nf or mati o n, w he ne ver p ossi ble. 
All m o nit ori n g a n d K RI o versi g ht acti vities will b e re p orte d a n d arc hi ve d. A n y iss ues 
i de ntifie d will be re p orte d a n d f oll o we d- u p u ntil res ol ve d. I n a d diti o n, eac h m o nit ori n g 
visit will be i d e ntifie d at t he i n vesti gati o nal site b y t h e m o nit or’s / K RI’s si g nat ure a n d dat e 
o n t he st u d y-s pecific m o nit ori n g l o g. 
1 2. 7 
C A S E R E P O R T F O R M
All s u bject data ge nerate d d uri n g t h e st u d y will be rec or de d o n t he C R F/ e C R F. 
T he i n vesti gat or will e ns ure t hat all d ata are e ntere d pr o m ptl y, le gi bl y, c o m pletel y, 
acc uratel y a n d c o nf or m t o s o urce d oc u me nts, i n acc or da nce wit h s pecifi c i nstr ucti o ns 
acc o m p a n yi n g t he C R Fs/e C R Fs, d esi g ne d s p ecificall y f or t his st u d y a n d s u p plie d b y   
 
 f or eac h s u bject.  
 will o nl y c o nsi der t h e C R Fs/e C R Fs t o be c o m plete after t he y are 
re vie we d a n d si g ne d b y t he i n vesti gat or, i n dicati n g his/ her ass ura nce of t h e acc urac y of all 
rec or d e d dat a. It is e x p ecte d t hat t he i n vesti gat or a n d staff will c o o p erate wit h t he 
m o nit ori n g tea m a n d pr o vi de missi n g data i n a ti mel y ma n ner. 
1 2. 8 
V E RI FI C A TI O N P R O C E D U R E S 
I n f ulfill m e nt of t h eir o bli g ati o ns t o K RI a n d t o v erif y c o m plia nce wit h t his pr ot oc ol, I C H 
G C P g ui d a nce, a n d F D A G C P re g ul ati o ns, t he i n vesti gat or will per mit 
 
, t h e I R Bs/I E Cs, t h e m o nit or, a n d re g ulat or y a ut h oriti es t o ha ve direct access t o 
t he s u bj ect’s me dical rec or ds. 
It is t he i n vesti gat or’s o bli gati o n t o e ns ure d oc u me ntati o n of all rele v a nt data i n t he 
s u bject’s me dical rec or d, C R Fs/e C R Fs, a n d o n st u d y f or ms, w he n a p plica bl e, acc or di n g t o 
pr oce d ures pr o vi de d i n t he pr ot o c ol. 
T he i n vesti gat or will mai ntai n a S u bject I d e ntifi cati o n C o de List t o e na ble u na m bi g u o us 
i de ntificati o n of t h e s u bjects (s u bject na mes a n d c orres p o n di n g s u bject n u m bers). T he 
S u bject I d e ntificati o n C o de List is a n esse ntial d oc u me nt a n d as s uc h m ust be mai ntai ne d 
acc or di n g t o t he I C H G C P g ui deli n es. 
1 2. 9 
R E T E N TI O N O F R E C O R D S 
All d oc u me ntati o n pertai ni n g t o t h e st u d y will be retai ne d b y K RI a n d 
 
i n acc or da nce wit h U. S. F D A re g ulati o ns a n d t he I C H G C P g ui d a nce d oc u me nt. 
will pr o vi de eac h i n vesti gat or wit h a st u d y bi n der, w hic h will be 
use d t o file t he I n v esti gat or’s 
Br oc h ure; pr ot oc ol; dr u g acc o u nta bilit y rec or ds; 
c orres p o n d e nce 
wit h t he I R B/I E C, 
K RI, a n d 
; a n d ot her 
st u d y-relate d d oc u m e nts. 
T he i n vesti gat or a grees t o kee p rec or ds a n d t h ose d oc u me nts t h at i ncl u de ( b ut are n ot 
li mite d t o) t he i de ntificati o n of all partici pati n g s u bjects, me dical rec or ds, st u d y-s pecific 
s o urce d oc u me nts, s o urce w or ks heets, all ori gi n al si g ne d a n d date d I C Fs, c o pi es of all 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 1 of 6 0 
C R Fs/e C R Fs, q uer y res p o nses, a n d detaile d rec or ds of dr u g dis p ositi o n, t o e na ble 
e val uati o ns or a u dits fr o m re g ulat or y a ut h orities a n d K RI or its desi g nees. 
T he i n vesti gat or a n d 
will retai n rec or ds re q uire d t o be mai nt ai ne d 
u n der fe d eral re g ul ati o ns f or a peri o d of 2 years f oll o wi n g t he date a mar keti n g a p plicati o n 
is a p pr o ve d f or t h e dr u g f or t h e i n dicati o n f or w hic h it is bei n g i n v esti gate d; or, if n o 
a p plicati o n is t o b e file d or if t he a p plicati o n is n ot a p pr o ve d f or s uc h i n dicati o n, u ntil 
2 years after t he i n vesti gati o n is dis c o nti n ue d a n d F D A is n otifie d. H o we ver, t hese 
d oc u me nts
will be retai n e d f or a l o n ger peri o d if re q uire d b y t he a p plica ble re g ulat or y 
re q uire me nt(s) or if nee de d b y K RI. I n a d diti o n, t he i n vesti g at or m ust ma ke pr o visi o n f or 
t he s u bject’s me dical rec or ds t o be k e pt f or t h e s a m e peri o d of ti me. 
S u bjects’ me dical rec or ds a n d ot her ori gi nal data will be arc hi v e d i n acc or da n ce wit h 
a p plica ble re g ulati o ns a n d re q uire me nts est a blis he d b y t he i n vesti gati o nal sites.
1 2. 1 0
I N S U R A N C E A N D I N D E M NI T Y 
K RI’s o bli gati o ns re g ar di n g i ns ura nce a n d i n de m nificati o n are d escri be d i n ot h er 
d oc u me nts or a gree me nts. 
1 2. 1 1
A U DI T 
It is t he res p o nsi bilit y of 
a n d K RI t o perf or m a u dits (if a p plica ble), 
as part of i m ple me nti n g q ualit y ass ura nce. T h e p ur p ose of a n a u dit, w hic h is i n de pe n d e nt 
of a n d se parate fr o m r o uti ne m o nit ori n g or q ualit y c o ntr ol f u ncti o ns, is t o e val uate trial 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, S O Ps, I C H/ F D A G C Ps, HI P A A, a n d ot her 
a p plica ble re g ul at or y re q uire me nts. T he a u dit or a n d re g ulat or y a ut h oriti es will re q uire 
direct access t o t he s u bject’s me dical rec or ds a n d all st u d y rec or ds. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 2 of 6 0 
1 3. 0
U S E O F I N F O R M A TI O N
1 3. 1 
G E N E R A L A S P E C T S 
All i nf or mati o n c o ncer ni n g 
a n d K RI, s u c h as pate nt a p plicati o ns, 
f or m ula, 
ma n ufact uri n g pr ocesses, basic scie ntific data or f or m ulati o n i nf or mati o n 
s u p plie d b y K RI a n d n ot pre vi o usl y p u blis he d, are c o nsi dere d c o nfi de ntial a n d will re mai n 
t he s ole pr o pert y of K RI. T h e i n vesti gat or a grees t o us e t his i nf or m ati o n o nl y i n 
acc o m plis hi n g t his st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut t h e writte n c o nse nt 
of K RI, e xce pt f or official re prese nt ati v es, s uc h as re g ulat or y a ut h orities.
It is u n derst o o d b y t he i n vesti g at or t hat t he i nf or m ati o n de vel o pe d i n t his cli nical st u d y, i n 
c o n necti o n wit h t he d e vel o p me nt of K- 2 8 5 will be use d b y K RI a n d, t h eref ore, ma y b e 
discl ose d b y K RI as re q uire d t o ot her cli nical i n vesti gat ors, ot her p har mace uti cal 
c o m pa nies a n d t o ot her g o ver n m e nt a ge n cies. I n or d er t o all o w f or t he use of t he 
i nf or mati o n deri v e d fr o m cli nical st u dies, it is u n derst o o d t hat t here is a n o bli gati o n t o 
pr o vi de t o K RI c o m plete test res ults a n d all data c o m pile d i n t his st u d y. 
1 3. 2
S U B J E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N 
K o wa Researc h I nstit ute, I n c. a n d its desi g nees affir m a n d u p h ol d t he pri nci ple of t he 
s u bject’s ri g ht t o pr otecti o n a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his st u d y, all d ata will 
be li n ke d t o t he C R F/ e C R F via a u ni q ue i de ntificati o n n u m ber a n d t h e s u bject's i nitials. 
T he d at a will be bli n de d c orr es p o n di n gly i n all d at a a n alyses . 
H o we ver, i n c o m pli a nce wit h t h e g ui d eli n es a n d re g ulati o ns of t he U S F D A c o ncer ni n g 
t he acce pta n ce of cli nical st u dies i n s u p p ort of I N D a p plicati o ns a n d t he I C H G C P ( w het h er 
perf or me d i n t h e U nite d States or else w here), a n d i n f ulfill me nt of its o bli g ati o ns t o K RI
t o verif y c o m plia nce wit h t his pr ot o c ol, K RI’s desi g nee re q uir es t h at t h e i n vesti gat or t o 
per mit its m o nit or, re prese ntati ves fr o m t h e F D A, K RI’s d esi g nate d a u dit ors, I R Bs/I E Cs, 
a n d ot her g o ver n me ntal re g ulat or y a ut h oriti es t o re vie w t he s u bject’s pri m ar y m e dical 
rec or ds (s o urce data or d oc u m e nts) i n cl u di n g, b ut n ot li mite d t o la b orat or y test res ult 
re p orts, E C G re p orts, a d missi o n a n d disc har g e s u m m aries f or h os pital a d missi o ns 
occ urri n g d uri n g a s u bj ect’s st u d y partici pati o n, a n d a ut o ps y re p orts rel ate d t o deat hs 
occ urri n g d uri n g t he st u d y. 
S h o ul d access t o s uc h m e dical rec or ds re q uir e a wai ver or a ut h orizati o n se parate fr o m t he 
state me nt of i nf or me d c o nse nt, t he i n vesti g at or will o btai n s uc h per missi o n i n writi n g fr o m 
t he s u bject b ef ore t he s u bject is e ntere d i nt o t he st u d y. 
1 3. 3
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y 
All i nf or mati o n re g ar di n g t his st u d y will be ke pt strictl y c o nfi de ntial. All d ata deri v e d fr o m 
t he st u d y will be t h e pr o pert y of K RI. T he i n vesti gat or m ust u n derta ke n ot t o s u b mit a n y 
part of t h e data fr o m t his st u d y f or p u blicati o n wit h o ut pri or c o nse nt of K RI. K RI ma y 
discl ose data deri v e d fr o m t h e st u d y t o ot her i n vesti gat ors a n d dr u g re g ulat or y a ut h orities. 
After c o m pleti o n of t he st u d y, a n d as a gree d b y t h e i n vesti gat or a n d K RI, t he i n vesti gat or 
ma y se n d a draft m a n us cri pt t o K RI t o be re vie we d i n or der t o reac h a n a gree me nt re gar di n g 
p u blicati o n. T he i n vesti gat or m ust recei ve writt e n a p pr o v al fr o m K RI bef ore t h e fi n al 
versi o n of t h e m a n uscri pt is s u b mitte d f or p u blicati o n. 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 3 of 6 0 
At t he c o ncl usi o n of t h e st u d y, aft er t h e d ata are a nal yze d, K RI or its desi g n ee will pre pare 
a fi nal cli nical re p ort. 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 4 of 6 0 
1 4. 0
R E F E R E N C E S
1.
Lai ne L. N o nster oi d al a nti-i nfla m mat or y dr u g gastr o pat h y. Gastr oi ntest E n d osc Cli n
N A m 1 9 9 6, 6: 4 8 9- 5 0 4.
2.
Bec ker J C, D o msc h k e W, P o hle T. C urre nt a p pr oac hes t o pre ve nt N S AI D-i n d uce d
gastr o pat h y – C O X selecti vit y a n d be y o n d. Br J Cli n P h ar mac ol. 2 0 0 4 Dece m ber;
5 8( 6): 5 8 7 – 6 0 0.
3.
J ü ni P. Are selecti ve C O X 2 i n hi bit ors s u peri or t o tra diti o nal n o nster oi d al
a ntii nfla m mat or y dr u gs? B MJ. 2 0 0 2 J u ne 1; 3 2 4( 7 3 4 9): 1 2 8 7 – 1 2 8 8.
4.
Mas o n L, M o ore R A, E d war ds J E, Derr y S, Mc Q ua y HJ. T o pical N S AI Ds f or ac ut e
pai n: a meta-a n al ysis. B M C Fa m Pract. 2 0 0 4 M a y 1 7; 5: 1 0.
5.
Oz M., El Ne brisi E. G., Ya n g, K- H. S., H o wart h F. C, a n d Al K ur y L T. C ell ular a n d
M olec ular T ar gets of Me nt h ol Acti o ns. Fr o nt. P h ar mac ol. 2 0 1 7; 8: 4 7 2.
6.
Ki m D H, Li m Y Y, Ki m H M, Ki m S Y, Ki m BJ. T he Safet y E val u ati o n of a P ote nt
A n gi o ge nic Acti v at or, S y nt hetic Pe pti de S F K L R Y- N H 2, f or t he S ki n A p plicati o n.
T o xic ol o gical Researc h. 2 0 1 2; 2 8: 5 1- 5 6.
7.
Gri mes D, L yssi kat os J. H u ma n Der m al Safet y T esti n g f or T o pical Dr u g Pr o d ucts.
F D A W or ks h o p. 2 0 1 8.

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 5 of 6 0 
1 5. 0
A P P E N DI C E S
 
1 5. 1 
A P P E N DI X 1
VI S U A L A N A L O G S C A L E ( E X A M P L E O F P A P E R V A S) 
 
 
Assess me nt of t he pai n i nte nsit y of D O M S at rest a n d w hile sta n di n g usi n g a 0 t o 1 0 0 p oi nt 
pai n V A S  
 
 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 6 of 6 0 
VI S U A L A N A L O G S C A L E ( E X A M P L E O F E L E C T R O NI C V A S) 
 
 
Assess me nt of t he pai n i nte nsit y of D O M S at rest a n d w hile sta n di n g usi n g a 0 t o 1 0 0 p oi nt 
pai n V A S  
 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 7 of 6 0 
1 5. 2 
A P P E N DI X 2
 
 
  
 
  
  
 
 
 
  
   
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 8 of 6 0 
1 5. 3 
A P P E N DI X 3
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 9 of 6 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 6 0 of 6 0 
1 5. 4 
A P P E N DI X 4