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 dy Pr ot oc 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 ar allel 
Gr o u p St u d y t o E v al u ate t he Effic ac y a n d S afet y of K -2 8 5  C o m p are d 
w it h Me nt h ol Gel  f or t he Tre at me nt of Del a ye d O nset M uscle S ore ness 
( D O M S) i n t he L o wer E xtre mit y  
  
 
Cli nic al St u d y Pr ot oc ol  
 
 
Dr u g N a me:   
K -2 8 5  
St u d y N u m ber:  
K -2 8 5 -2 0 1  
U. S. I N D N u m ber:  
I N D 1 3 5 3 4 8 
Pr ot oc ol Ori gi n al Versi o n D ate : 1 0  A pril  2 0 2 0  
Ori gi n al Versi o n #:  
1. 0  
Pr ot oc ol A me n d me nt 1. 0  
2 8  Ma y 2 0 2 0  
Versi o n #:   
2. 0  
N a me of S p o ns or:  
K o w a Rese arc h I nstit ute, I nc.  
A d dress:  
 
 
 
M a n a gi n g C o ntr act Res e arc h 
Or g a niz ati o n ( C R O):  
 
A d dress:  
C o nt act N u m bers:  
 
 
 
 
Pr o pert y of K o w a Rese arc h I nstit ute, I nc.  
C o nfi de nti al  
M a y n ot  be use d, di v ul ge d, p u blis he d, or 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
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.  
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Versi o n 2. 0 2 8 M ay  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 in vesti gat or , u n d ersta 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 v i 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 he I n vesti gat ors’ Br oc h ure, pr ot o c ol, cas e 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 s cie 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 here necessar y t o eli mi nate a p pare nt 
i m me diate hazar ds t o t he s u bjects. 
I c o nfir m t hat 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 dicate 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 co nf or ma nce wit h t he pri nci ples of t h e 
Declarati 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 Practice ( G C P), a n d t he la ws a n d re 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 hat I a m i nf or me d of t he nee 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 gree t o a bi de 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 dat e d 
1 0  A pril 2 0 2 0 . 
 
I n vesti g at or’s S i 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  
 
 
 
 
 
 
 
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iii1 6 
 
SI G N A T U R E P A G E  
 
 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m/ d d/yyyy  
 
        
 
 
 
 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m / d d/yyyy 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m / d d/yyyy 
s  
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
   
m m/ d d/yyyy  
 
 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
iv1 6 
 
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 ute, I nc.  
Dr u g U n der St u d y:  
K -2 8 5  
Title of Pr ot oc ol:  
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 uate 
t he Efficac y a n d Safet y of K-2 8 5 C o m pare d w it h Me nt h ol Gel f or t he Treat me nt of Dela ye d 
O nset M uscle 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 ase:  
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 uate 
t he 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 uscle 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 -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 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 me nts i ncl u di n g me dical hist or y, i de 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 nati o ns, bl o o d a n d uri ne tests, vital si g ns meas ure me nts, electr ocar di o gra m ( 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 partici p ate 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 xercise i ncl usi o n a n d e xcl usi o n criteria will be e nr olle 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 enr olle d s u bjects will perf or m a sta n dar dize d re petiti ve  
q ua drice ps m uscle e xercise t o create 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 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 . W it 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 pai n scale a n d rec or d pai 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 electr o nic  vis ual a nal o g scale (eV 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 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. T he s pecific p ost -e xercise  
 i ncl usi o n criteri 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 na nt le g, base d o n ha 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 dar 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 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.  
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Versi o n 2. 0 2 8 M ay  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 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 be a p plie d 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 plicati 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 he cli nic  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 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 perf or me d pri or t o 
t he 
 st u d y gel a p plicati o n. S u bjects 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 .  
 
P ai n i nte nsit y assess me 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 ne ( 0 h o ur s) a n d at 
 
 
after t he first  st u d y gel a p plicati o n. P ai n assess me 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 bject s 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 ntial assess me nts. 
A  ti me wi n d o w of  + 3 0  mi n utes will  be all o we d bet wee n q ualificati o n ( baseli ne assess me 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 me nt  (e V A S, Perce pti ble Pai n 
Relief, a n d 
Mea ni n gf ul Pai n 
Relief)  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 -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 bef ore a n d at 
least 1 h o ur after gel a p plicati o n.  A ll pai n i nte nsit y assess me nts i ncl u di n g e V A S, Perce pti ble 
Pai n Relief , a n d Mea ni n gf ul Pai n Relief will be rec or de 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 a n d resc ue me dicati o ns will  be rec or de d i n  t he e-diar y  b y t he 
s u bject thr o u g h Da y  2 2  ( Peri o d 1 a n d 2). Perce pti ble Pai n Relief a n d Mea ni n gf ul Pai n Relief 
will be rec or de d i n t he e -diar y u ntil ac hie ve d  i n Peri o d 1. 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 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 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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vi 1 6 
 
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 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 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) acc or di n g t o t heir assi g ne d d osi n g re gi me n (
 (Ta ble 1  a b o ve). 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 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 plicati o ns a n d use of a n y resc ue 
me 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 an 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  tele p h o ne call t o assess safet y 
will be c o n d ucte 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 dicati o n f or D O M S is str o n gl y disc o ura ge d u ntil 1 6 8 h o urs ( Da y 8) 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 ha 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 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 mit te 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 onc 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 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 he date a n d ti me will be rec or de d i n t he e -diar y.   
W he n t he 
 
 
. 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 he 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 ve:  
•  
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 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 uate 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 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 gel after t he first 
gel a p plicati o n f or t he 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 male 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 me nt 
arm s (Ta ble  1  a b o ve).  
N u m ber of Ce nters:  
1 site i n t he U nite d States 
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:  
( Peri o d 1):  Eac h s u bject will a p pl y 
of st u d y gel 
 
 ( Peri o d 1  a n d 2):  Eac h s u bject will a p pl y 
of st u d y gel 
 
a n d t he n will a p pl y st u d y gel 
 
 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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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 pai n i nte nsit y differe nce ( S PI D) bet wee n 
 
f or t he st u d y le g after t he 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 nt s: 
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 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 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 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 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 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 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 meas ure me 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 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, cli nical 
la b orat or y test res ults, st u d y gel use , a n d c o nc 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.  
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viii 1 6 
 
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 male a n d fe male 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 de 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,  vital si g n meas ure me nts (s yst olic 
bl o o d press ure, diast olic bl o o d pre ss ure, p ulse rate, res pirat or y 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 gat or at t he Scree ni n g V isit. 
7.  All fe male s u bjects m ust ha ve a ne gati ve ser u m pre g na nc y test res ult at scree ni n g a n d 
ne gati ve uri ne 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 nic. Fe male s u bjects 
of c hil d beari n g p ote ntial m ust use o ne of t he f oll o wi n g acce pta ble birt h c o ntr ol met 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 gati o n, 
h ysterect o m y, 
bilateral 
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. Ba rrier 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 part ner ( vasect o m y at least 6  m o nt hs bef ore 
t he first d ose of st u d y gel); 
e. H or m o nal c o ntr ace 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 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 has ne gati 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 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 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 ble 
pr o vi de d t he s u bject will a bstai n f or t he s t 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
i x1 6 
 
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 dicati o ns wit hi n 1 4  da ys bef ore t he 
S cree ni n g V isit. 
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 V isit. 
5.  S u bject has a me dical hist or y t hat i ncl u des a c o ntrai n dicati o n f or t he use of me nt h ol or 
n o nster oi dal 
a nti -i nfla m mat or y 
dr u gs ( N S AI Ds) (e. g., 
gastr 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 her s u bsta nces c o ntrai n dicate 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
x 1 6 
 
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 he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve 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 he i n vesti gat or, s h o ul d n ot partici pate i n t he st u d y.  
St atistic al A n al ysis:  
I n ge neral, assess me nts wit h c o nti n u o us o utc o mes will be s u m marize d usi n g t he descri pti ve 
statistics n, mea n, sta n dar d de viati o n (S D ), me dia n, mi ni m u m a n d ma xi m u m. F or assess me 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 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 mize d s u bjects w h o ha ve a baseli 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 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 ncl 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 mar y a nal 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 .
 
 
 
. 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 
val ue s will be i m p ute d bef ore calc ulati n g t he S PI D. After calc ulati n g t he S PI D , an 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 ne 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 he sa me mai n effects a n d c o variate 
will be a p plie d t o t he PI D w hile sta 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 he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). A d verse 
e ve nts a n d seri 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 ber of 
A Es, se verit y, a n d relati 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 marize 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 yste m or ga n class 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 Baseli ne. Vital si g n meas ure me 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xi 1 6 
 
 
 
 
 
 
 
 
 r
 
 
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 mea 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 %, 1 1 3 s u bjects per gr o u p are re q uire d. T a 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 mated 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xii 1 6 
 
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R’ S S T A T E M E N T ............................................................................................. ii 
SI G N A T U R E P A G E  ..................................................................................................................... iii 
P R O T O C O L S Y N O P SI S  ............................................................................................................. i v 
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  ............................................. x v  
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 TE RI A  ................................................................................................. 1 4  
4. 1. 1  
Pre -e xercise I ncl usi o n Criteria  .......................................................................................... 1 4  
4. 1. 2  
P ost -e xercise 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 Pai n Scale  ...................................................................................................... 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 nical La b orat or y Tests  .................................................................................................. 2 0  
5. 2. 2. 1  Ele vate d Le vels of Ser u m Creati ne 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 dical Hist or y a n d Ot her Baseli ne C haracteristics  ............................... 2 2  
5. 3. 2  
Dr u g a n d Alc o h ol Scree ni n g  ............................................................................................. 2 3  
5. 3. 3  
Pre g na nc y .......................................................................................................................... 2 3  
5. 3. 4  
Sta n dar dize d E xercise Re gi me n  ....................................................................................... 2 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xiii 1 6 
 
5. 3. 5  
P h ot o gra p h a n d Resi d ue E val uati o n  ................................................................................. 2 4  
5. 3. 5. 1  P h ot o gra p hic A nal ysis  ...................................................................................................... 2 4  
5. 3. 5. 2  Resi d ue E val uati 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  
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 3  
6. 5  
T E R MI N A TI O N O F T H E S T U D Y .................................................................................. 3 3  
7. 0  
S T U D Y M E DI C A TI O N  ................................................................................................. 3 3  
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 3  
7. 2  
D R U G P A C K A GI N G  ....................................................................................................... 3 4  
7. 3  
D R U G L A B E LI N G  .......................................................................................................... 3 4  
7. 4  
D R U G S T O R A G E  ............................................................................................................ 3 5  
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 5  
7. 5. 1  
Dis pe nsi n g of St u d y Gel  ................................................................................................... 3 5  
7. 5. 2  
A p plicati o n Trai ni n g  ......................................................................................................... 3 5  
7. 5. 3  
Dr u g A d mi nistrati o n  ......................................................................................................... 3 5  
7. 5. 4  
e-Diar y  .............................................................................................................................. 3 7  
7. 5. 5  
P h ysical E xercise  .............................................................................................................. 3 7  
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 7  
7. 7  
D R U G A C C O U N T A BI LI T Y  ........................................................................................... 3 7  
7. 8  
P R O C E D U R E F O R U N B LI N DI N G  ................................................................................ 3 8  
8. 0  
C O N C O MI T A N T M E DI C A TI O N  ............................................................................... 3 9  
8. 1  
G E N E R A L C O N SI D E R A TI O N S  .................................................................................... 3 9  
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 9  
8. 3  
P E R MI T T E D M E DI C A TI O N  .......................................................................................... 3 9  
9. 0  
A D V E R S E E V E N T S  ...................................................................................................... 4 0  
9. 1  
A D V E R S E E V E N T D E FI NI TI O N  .................................................................................. 4 0  
9. 2  
R E P O R TI N G A D V E R S E E V E N T S  ................................................................................ 4 0  
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 2  
1 0. 0  
S E RI O U S A D V E R S E E V E N T S  .................................................................................... 4 3  
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 3  
1 0. 2  
H O S PI T A LI Z A TI O N  ....................................................................................................... 4 3  
1 0. 3  
I M P O R T AN T M E DI C A L E V E N T  .................................................................................. 4 3  
1 0. 4  
P R E G N A N C Y  .................................................................................................................. 4 3  
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 4  
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 4  
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 5  
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 6  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N  ................................................................................... 4 6  
1 1. 2  
S T U D Y P O P U L A TI O N S  ................................................................................................. 4 6  
1 1. 3  
DI S P O SI TI O N  .................................................................................................................. 4 6  
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 6  
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 6  
1 1. 5. 1  Pri mar y Efficac y Para meters  ............................................................................................ 4 6  
1 1. 5. 2  Sec o n dar y Efficac y Para meters  ........................................................................................ 4 7  

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 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xiv 1 6 
 
1 1. 6  
A N A L Y SI S O F S A F E T Y D A T A  .................................................................................... 4 7  
1 1. 7  
I N T E RI M A N A L Y SI S ..................................................................................................... 4 8  
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 9  
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 9  
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 9  
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 9  
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  ......................................................................... 5 0  
1 2. 5  
S T U D Y I NI TI A TI O N  ...................................................................................................... 5 0  
1 2. 6  
S T U D Y M O NI T O RI N G  .................................................................................................. 5 0  
1 2. 7  
C A S E R E P O R T F O R M  .................................................................................................... 5 1  
1 2. 8  
V E RI FI C A TI O N P R O C E D U R E S .................................................................................... 5 1  
1 2. 9  
R E T E N TI O N O F R E C O R D S ........................................................................................... 5 1  
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 2  
1 2. 1 1  A U DI T  .............................................................................................................................. 5 2  
1 3. 0  
U S E O F I N F O R M A TI O N  ............................................................................................. 5 3  
1 3. 1  
G E N E R A L A S P E C T S  ...................................................................................................... 5 3  
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 3  
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 3  
1 4. 0  
R E F E R E N C E S  ................................................................................................................ 5 5  
1 5. 0  
A p pe n dices  ....................................................................................................................... 5 6  
1 5. 1  
A P P E N DI X 1  .................................................................................................................... 5 6  
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 6  
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 7  
1 5. 2  
A P P E N DI X 2  .................................................................................................................... 5 8  
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 8  
1 5. 3  
A P P E N DI X 3  .................................................................................................................... 5 9  
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 9  
1 5. 4  
A P P E N DI X 4  .................................................................................................................... 6 2  
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 2  
 
 
List of T a bles  
T a ble 1: Tre at me nt Assi g n me nt  ................................................................................................... 7  
T a ble 2: Cli nic al E v al u ati o n Sc he d ule  ....................................................................................... 1 0  
T a ble 3. Cli nic al L a b or at or y Test P ar a 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 oc ati o n  .................................................................................................... 3 4  
Fi g ure 3: Me as uri n g St u d y Gel  .................................................................................................. 3 6  
 
 
 

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 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xv 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 ve p har m ace utical i n gre die nts  
A E  
ad verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e 
A N C O V A  
anal 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 he 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 keletal m uscle 
C ma x  
m a xi m u m c o nce ntrati o n  
C O X (-2 ) 
c ycl o o x y ge nas e i n hi bit ors  
C R F  
case re p ort/rec or d for m  
C R O  
C o ntract Researc h Or g a nizati o n  
D O M S  
d ela 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/ Rec or d F or m 
e-diar y  
electr o nic d iar y d e vice  
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  
full 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 Practice  
GI  
gastr oi ntesti nal  
I C F 
inf or me d c o nse nt f or m  
I C H 
I nter nati o nal C ou ncil f or Har m o nisati 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 oar d 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xvi 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 nas e  
L O C F  
last o bser vati o n carrie d f or war d 
M A R  
m issi 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 im 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  
p ai n i nte nsit y differe n ce  
P K  
p har mac o ki netics  
P P S  
p er-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  
Sta n dar d O perati n g Pr oce d ure/s  
S PI D  
su m of pai n i nte nsit y differe nce  
S PI D 0 -1 2  
su 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  
su m of pai n i nte nsit y differe nce o v er 2 4 h o urs after t he first gel a p plicati o n  
S PI D 0 -4 8  
su m of pai n i nte nsit y differe nce o ver 4 8 h o urs after fi rst gel a p plicati o n 
S PI D 0 -7 2  
su m of pai 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 pecte d A d v erse Reacti o n  
T E A E  
Treat me nt -e mer ge nt A E  
T R P  
tra nsie nt rece pt or p ote nti al  
V A S  
V is ual A nal o g S cale  
 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 1  of 6 2  
 
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 
Sta tes a n d rest of w orl d f or t he 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 del y use d w he n prescri pti o n a n d o ver -t he-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 o ta 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 ve e n d osc o picall y c o nfir me d gastric er osi o ns, 
a n d 1 0 %-3 0 % h a ve ulc ers. 1 T hese ris ks are a m plifi e 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 mita nt 
c ortic oster oi d use a n d H elic 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 ve 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 nate 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 des 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 vas c 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 of fer a n alter nati ve 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 n al gesics. T he first t w o cat e g ories are ill ustrate d b y t he a p pr o ve d 
li d ocai ne 5 % p atc h ( Li d o der m® ), a n d ca psaici n, res pecti vel y. Flect or®  ( dicl ofe nac 
e p ola mi ne t o pical patc 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 nal 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 nst rate d t hat i n 1 9/ 2 6 tri als t he 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 y clic 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 utical 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 be 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 nd 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 ntise ptic, 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 
ma y 
u n derlie i ts 
re p ute d 
a nal gesic 
effects.5 
Me nt h ol -c o ntai ni n g O T C 
me dicati o ns are c urre ntl y 
mar kete d i n t he U S as t o pical 
a nal gesics at c o nce 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2  of 6 2  
 
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 a s de vel o pe d K-2 8 5, a pr o d uct c o ntai ni n g 
 
f or relief of pai 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 me nt h ol gel c o ntai ns 
.  
 
 
 
 
 
  
  
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3  of 6 2  
 
T he 
m ost c o m m o nl y re p orte d treat me nt -relate d, treat me nt-e mer g e nt a d verse e v e nt s 
(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 site pai n, 
a p plicati o n site er yt he m a, a p plicati o n site disc ol orati o n, a p plicati o n site e xf oliati o n, 
a p plicati o n site pr urit us, a n d a p plicati o n site dr y ness.  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 ort e d as 
T E A Es, b ut t hese e ve nts a n d cli nical l a b orat or y assess 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 nati 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 ge n erall y well t olerate d 
b y h ealt h y s u bjects i n t his st u d y.   
Base d o n t he P hase  1 st u d y res ults, t he d os a ge of K -2 8 5, 
), 
s h o we d hi g her 
, a n d t h us  was selecte d t o e val uate efficac y a n d safet 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 sel ecte 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4  of 6 2  
 
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 mar y o bjecti ve 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 ves 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 uat e 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 after first 
gel a p plicati o n f or t he tr eat 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 he st u d y le g after t he 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 scal e (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 stu 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 he 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 ur s 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 he 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 he 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 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  
 
 
 
 
 
 
 
 
 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
2. 5  
S A F E T Y E N D P OI N T S  
Safet y assess me nts will i ncl u de ad verse e ve nts ( A Es), vital si g n meas ure me nts (s yst olic 
bl o o d press ure, diast oli c bl o o d press ur e, p ulse rate, res pirat or y rate, a n d oral b o d y 
te m perat ur e), 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 irritati o n rati n g scale), 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6  of 6 2  
 
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 arallel 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 he treat me nt of 
D O M S i n t he l o wer e xtr e 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 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 me nts 
i ncl u di n g me dical hist or y, i de ntificati o n of t he d o mi na nt le g as deter mi ne d b y ha n d 
d o mi na 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 p artici 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 criteria 
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 be 
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 pe titi 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 me 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 he 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 oric al pai n 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 ur e 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 bet wee n 0 a n d 1 0 0) t o d eter mi ne 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 na nt le g, base d o n h a 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 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 me nt Ar m A ( K-2 8 5 gel) 
or Treat me nt Ar m B ( Me nt h o l 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 7  of 6 2  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n Peri o d 1 (
 
 
 
 o n t he st u d y le g as f oll o ws:  
•  
Treat me nt Ar m A: E ac 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 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 be a p plie d 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 plicati 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 u e nt st u d y gel a p plicati o ns at t he cli nic 
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 d esi g nee) o versi g ht t o 
e ns ure pr o per 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  t he 
 st u d y gel a p plicatio n. S u bjects 
will re mai n i n t he cli nic u ntil t he y are disc h ar ge d f oll o wi n g c o m pleti o n of st u d y 
assess me nts o n D a y  2 . P ai n i nte nsit y assess me nts will be p erf or m e 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 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 he first st u d y gel a p plicati o n. Pai n assess me nts 
sc he d ule d bet w ee 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 asle e p b ut s u bjects 
ma y n ot s ki p m or e t ha n t w o se q ue ntial assess me nts. A  ti me wi n d o w of  + 3 0  mi n utes will 
be all o we d bet w ee n q u alif yi n g pai n assess me 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 p ai n assess m e nt  (e V A S, Perce pti ble 
Pai n Relief , a n d Mea ni n gf ul Pai n Relief)  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), -2 0  mi n utes t o + 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 -2 0  mi n utes t o + 1  h o ur f or assess me nts at 3 6 t o 
 (
 
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 h e s u bject o n a n o ut -p atie nt basis ( Da y 2  
t hr o u g h Da y 8 ). S u bjects will be i nstr uct e d n ot t o s h o wer or bat h e 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 i ncl u di n g e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul 
pai n relief will be rec or de d i n e -diari es 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 a n d resc ue me dicati 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 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 8  of 6 2  
 
Da y  2 2  (Peri o d 1  a n d 2 ). Perce pti ble Pai n Relief a n d Mea ni n gf ul Pai n Relief will be 
rec or de d i n t he e-diar y u ntil ac hie ve d i n Peri o d 1. 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 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 tele p h o ne 
call t o assess s afet y will be c o n d uct e d b y st u d y st aff 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 ble 1 : Treat me nt Assi g n me nt ). F or s u bjects w h o are dosi n g i n Peri o d 2, tele p h o n e 
calls t o assess safet y will be c o n d u cte d b y st u d y st aff 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 plicati o ns a n d use of a n y resc ue me 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 D a y 2 2 , a n d an 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 ass ess safet y will be c o n d ucte 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 dicati 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 ha 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 p erie nci n g se vere p ai n or 
i na bilit y t o m o ve or w al 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 bef 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 he e -diar 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 he st u d y will be ter m i 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 m e d.  
A st u d y sc he matic is s h o w n i n Fi g ur e 1 . T he s c he d ule of assess me nt s 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 9  of 6 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 0  of 6 2 
 
 
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 xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p h y  
X  
 
 
 
 
 
 
 
 
 
 
Me dical/ me dicati o n 
hist or y  
X  
X  
 
 
 
 
 
 
 
 
 
Pre -e x ercise i ncl 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  
 
 
 
 
 
 
 
V isit t o cli nic ( o ne 
da y)  
X  
X  
 
 
 
X  
 
X  
 
X  
 
Tele 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 p ai n 
assess me nt ( pa p er 
V A S)  
 
X  
 
 
 
 
 
 
 
 
 
D O M S i n d ucti o n 
e x ercise  
 
X  
 
 
 
 
 
 
 
 
 
e-diar y, st u d y trai ni n g  
 
X  
 
 
 
 
 
 
 
 
 
Iss ue e-diar y  
 
 
X  
 
 
 
 
 
 
 
 
eV A S q ualif yi n g p ai n 
assess me nts c (e-diar y)   
 
 
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 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 1  of 6 2 
 
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 xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
Cate g orical q ualif yi n g 
p ai n assess me nts c (e-
diar y)  
 
 
X  
 
 
 
 
 
 
 
 
P ost -e x ercise incl 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 ocar di o gra m  
X  
X  
 
 
 
 
 
 
 
X  
 
P h ysical e xa mi nati o n  
X  
X  
 
 
 
X  
 
X  
 
X  
 
S ki n e x a mi nati o n / 
assess me nt at st u d y gel  
site  
X  
X  
X  
X  
 
X  
 
X  
 
X  
 
Pre g na n c y test e 
X  
X  
 
 
 
 
 
 
 
X  
 
Uri ne 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 nal ysis)  
X  
 
 
 
 
 
 
 
 
X  
 
eV A S pai n i nte nsit y 
assess me nt sc (e-diar y)  
 
 
X  
X  
X  
X  
 
 
 
( X)l 
 
Perce pti ble a n d 
Mea ni n gf ul pai n relief  
assess me nts c (e-diar y)  
 
 
X  
 
 
 
( X) l 
 
P h ot o gra p hic a n d 
resi d ue e v al uati 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 2  of 6 2 
 
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 xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
P h ot o gra p hic  
e v al uati o n of 
a p plicati o n site 
reacti o nsg 
 
 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
 
Dis pe nse st u d y gel  
 
 
 
X  
 
X  
 
X  
 
 
 
A p pl y st u d y gel h 
 
 
X  
X  
X  
X  
X  
X  
X  
(X )  
 
Rec or d a d verse e ve 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 ue 
me dicati o n use j (e-
diar y)  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
C ollect st u d y gel  
 
 
 
 
 
 
 
 
 
X  
 
C ollect s u bject e -diar y  
 
 
 
 
 
 
 
 
 
X  
 
 
; D O M S, del a y e d o nset m uscle s ore ness; e -diar y, electr o nic diar y de vice; E O S, e n d of st u d y; E T, earl y ter mi nati o n; 
 a 
; 
V A S, vis ual  a n al o g scale ; ( X), perf or me d as i n dicate d i n t he f o ot n ote.  
a S u bjects will e nter t he cli nic o n Da y 1 a n d will be disc har ge d o n  Da y  2 after st u d y assess m e nt s at 
 st u d y gel a p plicati 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 ne f or assess me nt of A E s, s ki n c o n diti o n a n d c o nc o mita nt me dicati o ns, a n d use of resc ue me dicati o n. All s u bjects 
will be c o ntacte d o n Da y 5 ( ± 1 da y). S u bjects partici pati n g i n Peri o d 1 will be c o ntacte d o n Da y 1 5  ( ± 1 da y). S u bjects partici pati n g i n Peri o d 2 will be 
c o ntacte d o n Da y 1 1 ( ± 1 da y), Da y 1 8 ( ± 1 da y), a n d Da y 2 9 ( ± 1 da y). 
c V A S a n d cate g orical q ualif yi n g pai n assess me nts will be perf or me d o n b ot h le gs wit hi n 2 4 -3 0 h o urs of e xercise t o i n d uce D O M S. Pai n i nte nsit y assess m e nts  
(e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul Pai n Relief)  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 ne ( 0 h o urs) a n d at 
 
 after t he first st u d y gel a p plicati o n. Baseli ne ( 0 h o urs) is t he ti me p oi nt f or t he  first st u d y gel a p plicati o n; a ti me wi n d o w of + 3 0 mi n utes will be all o we d 
bet wee n q ualif yi n g pai n assess me nts  (q ualif yi n g p ost -e xercise i ncl usi o n criteria)  a n d first st u d y 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 me nt (e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul Pai n Relief) 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), -2 0  mi n utes t o + 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 -2 0  mi n utes t o + 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 perce pti ble a n d mea ni n gf ul pai n relief will be rec or de d b y s u bjects i n t heir e -diar y  u ntil ac hie ve d  i n Peri o d 1. W he n st u d y gel a p plicati o n a n d 
pai n assess me nt o cc ur at t he sa me ti me p oi nt, pai n assess me nts will be perf or me d bef ore st u d y gel a p plicati 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 3  of 6 2 
 
d  Vital si g n meas ure me nts will i ncl u de 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 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.  
e Ser u m pre g na n c y test at Scree ni n g a n d uri ne pre g na nc y test at E xercise visit , E O S  V isit (D a 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 uati o ns of t he a p plicati o n site will be perf or me d bef ore t he 
 st u d y gel a p plicati o ns o n Da y 2.  
g  Be gi n ni n g wit h t he 
 w he n a n a p plicati o n site reacti o n is o bser ve d at t he cli nical site, p h ot o gra p hs of t he a p plicati o n 
site will be ta ke n b y site staff t o vis ually 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.  If nee de d, t he p h ot o gra p hs will be peri o dicall y ta ke n t o 
f oll o w-u p t he a p plicati o n site reacti o n.  If a n a p plicati o n site reacti o n is o bser ve d at h o me, p h ot o gra p hs of t he a p plicati 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. All p h ot o gra p hs s h o ul d be ta ke n pri or t o gel a 
  
h 
 
 
 
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 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 gel a p plicati o n  ( 0 h o ur) after q ualif yi n g 
pai n assess me nts , ± 1 5 mi n utes f or t he 
 a p plicati o ns, -2 0  mi n utes t o + 3 0 mi n utes  f or t he 
 a p plicati o ns , a n d -2 0  mi n utes 
t o +1 h o ur f or ot her a p plicati o n  ti me p oi nts.  
At t he site,  st u d y gel is 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 plicati o n. 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 will be perf or me d b y t he s u bject.  F or s u bjects partici pati n g o nl y i n Peri o d 1, t he last a p plicati o n 
of st u d y gel 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 he last a p plicati o n of st u d y gel 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 her treat me 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 he eC R F. A n y c h a n ges i n t he 
c o nc o mita nt me dicati o ns after disc h ar ge 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 d uri n g tele p h o ne 
calls, Safet y visits a n d at t he E O S  Visits.  
j S u bjects will rec or d all resc ue me dicati o n use i n t he e -diar y a n d it will be e ntere d i nt o t he e C R F as a c o nc o mita nt me dicati o n.  
k F or s u bjects partici pati n g o nl y i n Peri o d 1 E O S is o n Da y 8 (+ 1 da y),  f or s u bjects partici pati n g i n Peri o d 2 E O S is o n Da y 2 2 (+ 1 da y).  N ote t hat E O S visits 
ha v e a wi n d o w of + 1 da y w hereas Safet y visits ha ve a wi n d o w of ± 1 da y.  
l 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 dy Pr ot oc ol 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 4  of 6 2  
 
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 he 
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 criteria are met:  
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 male a n d fe male a ge d 1 8 t o 3 5  years, i n cl usi ve.  
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 he 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, 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 ur e) 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 gat or at t he Scree ni n g  V isit. 
7.  All fe male s u bjects m ust ha ve a ne g ati ve ser u m pre g na nc y test res ult at Scree ni n g a n d 
ne gati ve 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 he 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 least 6  m o nt hs bef ore t he first d ose of st u d y gel; 
b.  I ntr a uteri ne de vic e 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 part ner ( vasect o m y at least 6  m o nt hs bef ore t he 
first d ose of st u d y gel); 
e. H or m o nal c o ntr ace 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 he first d ose of st u d y gel an 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 has 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 ble a n d 
willi n g t o a bstai n fr o m marij ua na a n d al c 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 he st u d y as d escri be 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 5  of 6 2  
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.  
 
 
 
 
 
 
 
 
 
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 he st u d y if a n y of t he f oll o wi n g criteria are met:  
 
 
 
 
 
 
  
  
  
  
  
  
 
  
 
 
 
 
3.  
S u bject has 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 
S cree ni n g V isit. 
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 V isit. 
5.  
S u b ject 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 he 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 her 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 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 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  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 6  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
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 he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve d i n t he st u d y.  
1 7.  S u bject has part ici 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 he i n vesti gat 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 bject s ma 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 dical care b y t he i n vesti gat or or at t he st u d y site. T he 
in vesti gat or ma y disc o nti n ue treat me 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 pecific circ u msta nces, des cri 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 w al ( b y t he s u bject or t he in vesti gat or) will be  d oc u me nt e d  a n d rec or de 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 disc o nti n ue d fr o m st u d y gel  if a n y of t he f oll o wi n g occ ur : 
1.  
T here is a deteri or ati 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 hat i n t he o pi ni o n of t he in 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. 
2.  
I n t he in 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 hat 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 plicati o n site.  T he pr ocess f or 
disc o nti n uat i o n d ue t o a n a p plicati o n site reacti o n is descri be d i n Secti o n  4. 3. 1  bel o w.  
6.  
Occ urre nce 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  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 7  of 6 2  
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 nati o n of t he 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 bject s w h o di sc 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 di sc 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 he e val uati o ns sc h e 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 pri ate , 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 be f oll o we d f or 3 0 d a ys after t he s u bject’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 
stabilize 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 he m m ust be ma de a n d d oc u me nte d 
i n t he 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 ma de. If t he st u d y staff 
recei v es n o res p o nse, t he y will se n d a certifie d lett er re q u esti n g t hat t he s u bject c o ntact t he 
st u d y site re gar di n g his or her stat us i n t he st u d y.  
Disc o nti n ue d  or w it h dra w n s u bjects will n ot  be re place d.  
4. 3. 1  D isc o nti n u ati o n d ue t o a n A p plic ati o n S ite R e acti o n  
1.  D uri n g a cli nical site visit, t he 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 hey w ill be 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 he 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. 
 
2.  D uri n g t he o ut -patie nt peri o d at h o me, a p plicati 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 he 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 he s u bject c o ntacts t he site a n d t he n t he a p plicati o n site reacti o n is j u d ge d 
t o meet t he 
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 h at ti me, t he s u bject will be as ked t o gat her 
safet y refere nce i nf or mati o n as f oll o ws:  
o  
R ec or d t he s c ore of d er mal res p o nse (S ecti o n 5. 2. 6 ) in t he e -diar y. 
R efere n ce  i ma 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  1 5. 4 .  
 

C O N FI D E N TI A L  
 
 
 
 
 
 
 
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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
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Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 8  of 6 2  
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 xercise  t o i n d uce D O M S, pai 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, p ai n at rest a n d w hile sta 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 pai n scale t o det er 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 p ai n assess me nts 
will be rec or de d i n t he e-diar y.  
After ra n d o mizati o n, pai n at r est 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 eV A S  at all p ost -st u d y gel a p plicati o n ti me p oi nt s 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 pai n assess me nt occ ur at t he sa me ti me 
p oi nt, pai n assess me nts will be perf or me d b ef ore st u d y gel a p plicati o n.  
T he s u bject will rest q uietl y f or at least 5 mi n u tes 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 he 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 he w orst p ai n ca use 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 ng 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 he st u d y le g will 
be assesse d  first). 
5. 1. 1. 1  
Vis u al A n al o g Sc ale  
T he pai n V A S , a u ni di me nsi o nal meas ure of pai 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 ercise p ai n assess me nts ( A p pe n di x 1 ). 
T he pai n eV 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 he 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 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 he i nte g ers of t he e V A S will be referre d t o as p oi nts.  
T he assess me nt d ate a n d ti me f or t he 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  
C ate g ori c al P ai n Sc ale  
A 4 -p oi nt cate g orical pai n scale ( n o ne, mil d, m o derate, se vere) at rest will be 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 pai n scale is pr o vi de d i n 
A p pe n di x 2 . 
5. 1. 2  Use of R es c ue M e 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 disc 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 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 mitted if 
re q uire d.  

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K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 9  of 6 2  
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 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 g el a p plicati o n. If 
s u bjects ta ke res c ue me dicati o n wit hi n  t he first 1 6 8  h o urs  after t he 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 e ntere d i nt o t he 
e C R F as a c o n c o mita nt me dicati o n , a n d will be pr o gra m maticall y cate g orize d  as a 
c o nc o mita nt me dicati o n . S u bjects  will rec or d t heir pai n i nte nsit y i n t he e -diar 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 he date a n d ti me will be 
rec or de d i n t he e-di ar y.  
5. 1. 3  Ti m e t o O nset of First Perce pti ble a n d Me a ni n gf ul P ai n Relief  
Pai n assess me nts of t i me t o first perce pti ble pai n relief a n d ti me t o mea ni n gf ul pai n relief 
f or b ot h le gs at rest a n d w hile sta n di n g will be rec or de d b y s u bjects usi n g t heir e -diar y  u ntil 
ac hie ve d  i n Peri o d 1. At t he ti me of first perce pti ble pai 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 heir e -diar y t o rec or d t he ti me  t he e ve nts are 
e x perie n ce d . Si nce t h es e assess me nts will be  ca pt ure d i n t he e -diar y, t he electr o ni c 
data base will be t he di rect p oi nt of data ca pt ur e a n d will ser ve as s o ur ce f or t his varia ble.  
5. 1. 3. 1  
O nset of Perce pti ble P ai n Relief  
O nset of perce 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 at rest 
a n d w hile sta n di n 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 he f oll o wi n g 
e xa m ple: 
Please c o nfir m t hat y o u w o ul d li ke t o re p ort t hat y o u ha ve e x p erie nce d perce pti ble pai n 
relief at R E S T / w hile S T A N DI N G  i n y o ur S T U D Y / N O N-S T U D Y  le g. Please n ote t hat 
“p erce pti ble p ai n relief” mea ns a n y pai n r elief at a ll. If y o u feel t he pai n is getti n g e ve n a 
little bit better, t he n please a ns wer “ Y E S.”  
5. 1. 3. 2  
O nset of Me a ni n gf ul P ai n Relief  
O nset of mea ni n gf ul pai n relief is ass esse 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 hile sta n di n g  o nl y after o nset of perce pti ble pai n relief 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: 
Please c o nfir m t hat y o u w o ul d li ke t o re p ort t hat y o u ha ve e x p erie nce d mea ni n gf ul pai n 
relief at R E S T/ w hile S T A N DI N G i n y o ur S T U D Y/ N O N -S T U D Y le g. P lease n ote t hat 
“ mea ni n gf ul pai n r elief” is “ W he n t he relief fr o m pai n is mea ni n gf ul or si g nifica nt t o 
y o u. ” T his d oes n ot necessaril y mea n t hat y o u feel c o m pletel y better, alt h o u g h y o u mi g ht. 
Re me m ber t o tell t he Diar y w he n y o u first  e x p erie nce mea ni n gf ul p ai n relief.  
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 verse e ve nts will be rec or de d  acc or di n g t o t he sc he d ule i n Ta bl e 2 . All A Es, w het her 
ascri be 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 he 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 he o utc o me 
is deter mi ne d a n d writte n re p orts are pr o vi de d b y t he i n v esti gat or. A d verse e ve 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 0  of 6 2  
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 be d i n Secti o n  9. 1 , 9. 2 , a n d 
9. 3 , res pecti vel y. 
5. 2. 2  Cli nic 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 a ce ntral 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 a ce ntral la b orat or y acc or di n g t o t he s c he d ule i n Ta bl e 2 . 
Uri ne sa 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 osc o p y is re q uire d, a uri ne sa 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  me as ure d  are s h o w n i n  T a ble 3 . 
T a ble 3 . Cli nic al L a b or at or y Test P ar a meters  
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 m at ocrit 
( Pac k e d cell 
v ol u me)  
He m o gl o bi n  
L y m p h oc ytes  
Mea n cell 
he m o gl o bi n  
Mea n cell 
he m o gl o bi n 
c o nce 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 ne a mi n otra nsferase  
Al b u mi n  
Al kali ne p h os p hatase  
As partate a mi n otra nsferase  
Bicar b o nate  
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 de  
Creati ne ki nase 1 
Creati ni ne  
F ollicle -sti m ulati n g h or m o ne ( p ost-me n o pa usal fe male 
patie nts o nl y)  
Ga m ma gl uta m yl tra nsferase  
Tri gl yceri des  
Gl uc ose (fasti n g)  
H u ma n c h ori o nic g o na d otr o pi n (all fe male patie nts)  
Lactate de h y dr o ge nase  
Ma g nesi u m  
P otassi u m  
P h os p hate (i n or ga nic)  
Pr o tei n (t otal) 
S o di u m  
Bl o o d urea nitr o ge n ( B U N)  
Uric aci d  
Bilir u bi n  
Bl o o d  
Gl uc ose  
Ket o nes  
Le u k oc ytes  
Nitrites  
p H  
Pr otei n  
S pecific gra vit y  
Ur o bili n o ge n  
At t he discreti o n of 
t he i n vesti g at or 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 pecte d as a res ult of t h e e xercise perf or me d o n Da y -1  a n d will be ha n dle d as 
descri b e d i n Secti o n  5. 2. 2. 1 . 
 
5. 2. 2. 1  
Ele v ate d Le vels of Ser u m Cre ati ne Ki n ase  
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 ue nce of t h e 
e xercis e perf or me d o n D a 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 bjec ts 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 nsferase  [ A S T], or al a ni ne a mi n otr a nsferase [ A L T]), 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 ha n m uscle pai n a n d s welli n g at t he e x ercise d m uscles, 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 1  of 6 2  
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 bjects 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.  
•  
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 , 
b ro w n,  c ola or t ea c ol or e d  uri ne,  t o st u d y pers o n nel. 
•  
S u bjects wil l 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 liters ] of fl ui ds f or m ales a n d 1 1. 5 c u ps [2. 7 liters ] of fl ui ds a d a y f or fe males) 
  
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 be u n derta ke n. T he s u bject will be release d w he n, per t he i n vesti gat or’s discr eti o n, 
it is a p pr o priate t o d o s o. Pri or t o releas e, t he s p o ns or’s M e 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 peat e d as cli nicall y i n dicate d.  
•  
S u bjects will ha ve a uri n al ysis re peate d as cli nicall y i n dicate d.  
 
If there is a n ele vati o n i n C K a n d r ha b d om 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  Pa nels (t otal C K , C K -m y ocar dial ba n d [C K -M B ], C K i n s keletal 
m uscle [C K -M M ] a n d C K i n brai n [ C K-B B]) , tr o p o ni n, creati ni ne, m y o gl o bi n (ser u m a n d 
ur i 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 nati 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 ness, 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 he y ha ve ret ur n e d t o baseli ne, or u ntil t he i n v esti 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 ncl u de s yst olic 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 he 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 me d acc or di n g t o t he 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  
G e neral p h ysical e xa mi n ati o n s will be perf or me d  acc or di n g t o t he sc he d ul e i n Ta ble 2 . T he 
exa mi nati o n will i ncl 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 S ite R e 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 plicati o n a n d d oc u me 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.  

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 2  of 6 2  
Der m al Res p o nses  
0 = n o e vi de nce of irritati o n  
1 = mi ni mal er yt he ma, b arel y perce pti ble  
2 = defi nite er yt he ma, rea dil y visi ble; mi ni mal e de ma or mi ni mal pa p ular res p o nse  
3 = er yt he ma a n d pa p ules  
4 = defi nite e d e ma  
5 = er yt he 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 plicati o n site  
N otes: Pa p ules are defi ne d as s oli d, circ u mscri be d s ki n ele v ati o ns u p t o t he size of a s plit pea ( 5 m m). 
Vesicles are defi ne d as s ma ll blisters. 
 
Ot her Effects ( Wit h C o rres p o n di n g N u m eric 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 k e 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 he a p plicati o n site 
H ( 5 ) = s mall pete c 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, itc 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 he o ut -patie nt 
peri o d. If t here are u nsc he d ule d visit s d ue t o A E s, 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 de d i n t he e C R F.  
T hese si g ns of s ki n irritati o n will b e 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 disc o nti n ue d fr o m t h e st u d y d ue t o a n a p plicati 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 plicati 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 he i n vesti g at or.  
S u bjects w h o c h o ose t o disc o nti n ue fr o m partici p ati n g i n t he st u d y will rate t heir der mal 
res p o nse i n t he e-diar y. Der mal Res p o nses sc ore d b y s u bjects will n ot be re c or de d i n t he 
e C R F.   
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 de 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 ne C h ar acteristics  
De m o gra p hics a n d ot her baseli ne c haracteristics  (a ge, se x, race,  et h nicit y , hei g ht, a n d 
wei g ht ) as well as m e 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 
allerg y, etc. ) will be c ollecte d o n all s u bjects  at t he Scree ni n g  V isit. 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 3  of 6 2  
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, or alc o h ol sali va test , will be 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 scree n will i ncl u de uri ne scree n f or 
c ocai ne, marij ua na, o piates, a m p heta mi nes, m et ha m p heta mi nes, p he nc y cli di ne ( P C P), 
be nz o diaze pi nes,  
b ar bit urates,  
met ha d o n e,  
o x yc o d o ne, 
3, 4 -met h yle ne di o x y -
met ha m p heta mi ne  (M D M A  or ecstas y), b u pre n or p hi ne ( B U P 9), m or p hi ne, pr o p o x y p he ne, 
a n d tric yclic a nti de pressa nts. 
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 V isit. S u bjects wit h 
a p ositi ve pre g na n c 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 he E O S / E T V isits ( Da y 8 or  Da y  2 2) . 
5. 3. 4  St a n d ar dize d E xercise Re gi m e n  
A ll e nr olle d s u bjects will perf or m a sta n d ar dize 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 be d b el o w . S u bjects will be i nstr uct e 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 he e xercise 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 xercises 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 he le g c url mac hi ne 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 ne 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 fl e 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 mac hi ne u n d er 8 0 % of t he 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 he n c o m plete t he ecce 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 r e 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 w ee 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 he 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 he 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.  

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 4  of 6 2  
5. 3. 5  P h ot o gr a p h a n d R esi d ue E v al u ati o n  
5. 3. 5. 1  
P h ot o gr a p hic A n al ysis  
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 he 
a p plicati o n site will be ta ke n bef ore  t he 
st u d y gel a p plicati o ns o n 
  
Als o , w he n  a n a p plicati o n site reacti o n is o bser ve d at t he cli nical site, p h ot o gra p hs of t he 
a p plicati o n site will be ta 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 site reacti o n. If a n a p plicati o n site reacti o n is o bser ve d at h o me, 
p h ot o gra p hs of t he a p plicati 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 h s 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 he s ki n pla ne 
wit h t he area of g el a p plicati o n cl osest t o t he di gital ca mera. Eac h p h ot o gra p h will i ncl u de 
a pa p er 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 m e p oi nt, 
a n d i nitials of t he p h ot o gra p her.  T he la bel 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  
Resi d ue E v al u ati o n   
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 he f oll o wi n g rati n g 
scale will be assesse d b ef ore t he 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 de 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 ge o n D a 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 disc 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 ne d f or c ol lecti 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 gat or, s u bjects, a n d s p o ns or pers o n nel i n v ol ve d 
i n t he 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 me nt 
fr o m t he ti me of ra n d o mizati o n u ntil t he ti me 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 heir 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 mizati 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 ocati o n ta ble t hat 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 me nt ar ms ( A or B ) 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 5  of 6 2  
(Secti o n  7. 2 ). Se parate  all ocati o n ta ble s 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 get 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 he treat me nt ar ms will be mas 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 ntial, accessi ble o nl y t o a ut h orize d pers o ns, u ntil t he ti me of u n bli n di n g.   
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 oce 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 be gi ve n t o t h e s u bject b ot h ver ball 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 ves of t he st u d y, its p ote n tial 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 he 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 gat 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 here 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 bal i nf or mati o n, t he 
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 w ill be as ke d t o si g n a n d date a n I C F, t he ori gi nal c o p y of w hic h will 
be ke pt b y t he in vesti g at 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 be ma de i n t he n otes t hat t he s u bject v ol u ntaril y a gree d t o partici 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 v aila 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 6  of 6 2  
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 de 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 plicati o n a n d pai 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 S cree ni n g V isit at t he cli nic t o deter mi ne s u bject 
eli gi bilit y  ca n ta ke place a n yti m e 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 orme d c o ns e nt  
▪ De m o gra p hics  
▪ Me dical/ me dicati o n hist or y  
▪ Pre -e xercise i ncl usi o n  criteria, excl usi o n criteria  
▪ Hei g ht a n d wei g ht  
▪ Vital si g ns  
▪ E C G  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  of b ot h le gs  
▪ 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 xercise Visit : O n Da y -1  p r oce d ures a n d assess me nts  are as f oll o ws:  
▪ U p date Me dical/ me dicati o n hist or y  
▪ Pre -e xercise i ncl 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 ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt  at st u d y gel site  of b ot h le gs  
▪ 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 7  of 6 2  
▪ 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 be a d mitte d t o  t he cli nic. Da y 1 
pr oce d ures a n d a ss ess me nts are as f oll o ws:  
▪ Iss u e e-di ar y (s u bjects will rec or d e V A S a n d Cate g orical Q ualif yi n g 
Pai n Assess me nts i n e -diar y pri or t o r a n d o mizati o n)  
▪ V A S Q ualif yi n g Pai n assess me nt . N ote : Ti me 0 h o urs is t he baseli ne 
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 nt s ( p ost-e xercis e i ncl usi o n 
criteria). 
▪ Cate g orical Q ualif yi n g P ai n assess me nt . N ote: Ti me 0 h o urs is t he 
baseli ne 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 nt s ( p ost-e xercise 
i ncl usi o n criteria). 
▪ P ost -e xercise incl 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)  
▪ Vital si g ns  
▪ S ki n e xa mi nati o n / assess 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 me nt occ ur at t he sa me ti me 
p oi nt ). 
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief 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). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u ntil ac hie ve d i n Peri o d 1.  
▪ 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 d e d  
( bef ore st u d y gel a p plicati o n, be gi n ni n g wit h t he sec 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 8  of 6 2  
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 nati o n / assess 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 me nt occ ur at t he sa me ti me 
p oi nt ) 
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief 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). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u nti l ac hie ve d i n Peri o d 1. 
▪ 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 plicati o n s) 
▪ 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 d e d 
( bef ore st u d y gel a p plicati 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 -pa tie 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 me nt a n d rec or d assess me nts as f oll o ws:  

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 9  of 6 2  
▪ 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 me nt occ ur at t he sa me ti me 
p oi nt )  
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief 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). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u ntil ac hie ve d i n Peri o d 1.   
▪ 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 d e d 
( bef ore st u d y gel a p plicati 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 as sess 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 ble.  
▪ 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:  

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 0  of 6 2  
▪ 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 ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess 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 d e d 
( bef ore 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 use  
▪ C ollect st u d y gel  
▪ C ollect 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 ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess 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 d e d 
( bef ore st u d y gel a p plicati 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 1  of 6 2  
▪ 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 gel  (
 acc or di n g t o treat me 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 me nt a n d rec or d assess me nts as f oll o ws:  
▪ A p pl y st u d y gel  (
 acc or di n g t o treat me 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 d e d 
( bef ore 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 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 ble  
▪ 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 ne 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 ble  
▪ 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 ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess 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 d e d 
( bef ore 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 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 2  of 6 2  
▪ A p pl y st u d y gel  (
 acc or di n g t o treat me 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 ble. 
▪ 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 v isit pr oce d ures i ncl u de safet y assess me nts, a n d 
c ollect i 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 ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess 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 d e d 
( bef ore 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 use  
▪ C ollect st u d y gel  
▪ C ollect e-diar y  
•  Da y 2 9  (± 1  da y) : 
o  F oll o w -u p 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 ble.  
▪ 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 3  of 6 2  
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 in 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 
A ct, 
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 ocal 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 ( 2 1 C o de of Fe deral Re g ulati o ns [ C F R] Parts 1 1, 
5 0, 5 4, 5 6, a n d 3 1 2), a n d ot her a p plica ble g ui d a nce d oc u me nts .  
If t he 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 ueste d fr o m t h e  K o wa Res earc h I nstit ute, I nc.  (K RI ) 
Me dic al M o nit or pri or t o s u bject e nr oll me 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 e d b y t he in 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 he C o ntract Researc h Or ga nizati o n [ 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 he C R F /e C R F. K RI retai ns t he 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 oc 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 in vesti gat or, t he 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 w ar d st u d y s u bjects, t he st u d y ma y b e ter mi nated after c o ns ultati o n wit h  t he 
a n d K RI. A writte n state m e nt f ull y d oc u me nti n g t he reas o n (s) f or 
t he ter mi nati o n will be 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 me.  
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 oc ol 
re q uire me nts are n ot bei n g met, K RI  h as t he ri g ht t o ter mi nate t he st u d y a n d re m o ve all 
st u d y materials fr o m t he i n vesti gati o nal site. A writte n state me nt will be pr o vi de d t o t he 
in vesti gat or, t he I nstit uti o nal Re vie w B oar d/I n d e pe n de nt Et hics C o m mittee (I R B/I E C), 
a n d re g ul at or y aut h orities, i f re q uir e d. I n t h e e v e 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 relati 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 p ical g el w hic h c o ntai ns 
 
 
•  
Me nt h ol gel c o ntai ns 
 
 
Eac h of t he 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 4  of 6 2  
7. 2  
D R U G P A C K A GI N G   
T he st u d y gel s 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 treat me 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 materials will b e pre p are d  (f or 1 wee k of d osi n g a n d 3 wee ks of d osi n g)  (Fi g ur e  
2 ). 
 
 
 
 
 
 
 
 
T he b l ue 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 ) (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 
gel 
. 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 t w o
 
). 
T he p i n k 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  a n d Peri o d  2 ) (act ual cart o n will be w hit e). Eac h s u bject will a p pl y 
 
. 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  
 
l).  
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 me nt kit s will be pr o vi de d o nl y if p ac k a 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  
5)  T he st ora ge c o n diti o 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 5  of 6 2  
6)  Na me a n d a d dress of S p o ns or (e. g., KRI )  
7)  Ca uti o n - Ne w Dr u g Li mite d b y Fe deral La w t o In vesti gati o nal U se 
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 he gel has dri e d  
1 0)  I nstr u cti o n –  A p pl y t he gel 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 
detaile 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 or e d at c o ntr olle d r o o m t e m perat ur e of 
) wit h 
e xc ursi o ns per 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 de d . 
7. 5. 2  A p plic ati o n Tr ai ni n g  
O n Da y -1, s u bjects will recei ve tr ai ni n g o n t he 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  ap plica ti o n instr ucti o ns are pr o vi de d i n A p pe n di x  1 5. 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 6  of 6 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 7  of 6 2  
 
 
7. 5. 4  e-Di ar y  
A n  e-d iar 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  pri or t o ra n d o mizati o n . 
S u bjects will  rec or d pai n i nte nsit y assess me nts (e V A S, Cate g orical Q ualif yi n g Pai n Scale, 
Perce pti ble Pai n Relief , a n d 
Mea ni n gf ul Pai n Relief), i ncl u di n g der mal res p o nse  (if 
a p plica ble), resc u e me dicati o ns  (if a p plica ble) a n d st u d y gel a p plicati o ns  as detaile d i n t he 
e-diar y trai ni n g . D o c u me ntati o n f or t h e st u d y le g a n d n o n-st u d y l e g (if re q uire d) will b e 
perf or me d at t he ti me  p oi nts s pecifie d i n Ta ble 2 .  
T he act ual ti me a n d date t hat eac h set of pai n assess me nts is starte d at eac h ti me 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. 
7. 5. 5  P h ysic al E xercise  
T he sta n dar dize d re petiti ve 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 y s 1  a n d 2. T he st u d y gel f or a p plicati o n 
o n Da y 1 will be dis pe ns e d b y t he site p har mac y, a n d f or Da ys 2 -8 will be dis pe nse d t o t he 
s u bjects pri or t o disc har ge 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 be dis pe nse d at t he Da y  8 a n d Da y 1 5  Safet y visits . S t 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 de 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 he fi nal wei g ht rec or de d. C o m plia nce will be 
deter mi ne d fr o m t he fi nal wei g ht of t he t u be s c o m pare d t o t he e x pecte d decrease fr o m t he 
starti n g wei g ht, base d o n t he assi g ne d d osi n g sc h e d ule (
 ×  t he n u m b er 
of d oses).  
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 ve d . T he st u d y 
gel  m ust be st ore d as d es cri be d  (Secti o n 7. 4 ), ke pt i n a sec 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 olle 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 urat e rec or d of t he 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 he st u d y m o nit or d uri n g m o nit ori n g visits a n d at t he c o m pleti o n of t he st u d y.  
All dr u g will be i n ve nt ori e 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 he 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.   

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 8  of 6 2  
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 mizati o n c o de ma y be br o ke n b y t he in vesti gat or t o ma 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 ve d  f or sit uati o ns w he re 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 ons.  If p ossi ble, K RI  a n d t he  
 
is c o nta cte d t o disc uss t he cas e b ef ore t h e c o de is br o k e n.  
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 he 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 h e in vesti gat or  m ust c o ntact K RI a n d t h e 
 pr o m ptl y a n d e x plai n t he reas o n f or t he pre mat 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 9  of 6 2  
8. 0  
C O N C O MI T A N T M E DI C A TI O N  
T he in vesti gat or m ust rec or d t he us e of all c o n c o mita nt me dicati o ns i ncl u di n g resc ue 
me dicati o ns , b ot h pres cri be d a n d o v er -t h e-c o u nt er, 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 -nee 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 
me dicati o n, b ot h prescri be d a n d o ver -t he-c o u nter, wit h o ut c o ns ulti n g t he in vesti gat or , 
u nless t he ne w me dic ati o n is re q uire d f or e mer g e n c 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 me 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 he C R F. A n y c ha n ges i n t he c o nc o mita nt me dicati o ns 
after disc h ar ge 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 dicati 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 gesic me dicati o ns wit hi n 1 4  da ys bef ore t he S cree ni n g V isit. 
•  
S yste mic c ortic oster oi d wit hi n 3 0  da ys bef ore t he Scree ni n g V isit. 
•  
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 uscle rela xa nt, a ntic o n v uls a 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 he S cree ni n g V isit. 
•  
T he a p plicati o n or use of ice, heat, mass a ge, a n d wra p pi n g  o n t he le gs  
•  
Me dicati o ns or treat me 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 he gel, or t hat w o ul d alter i nfla m mat or y or i m m u ne res p o nses t o t he 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 glo b uli n, Bacill us Cal mette -G ueri n vacci ne, m o n ocl o nal a nti b o dies, ra diati 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 disc 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 he-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 u e 
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 or e t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs aft er t he 
first st u d y gel a p plicati o n. If s u bjects ta ke resc u e 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.  
N o ot her me dicati o ns (i ncl u di n g s u p ple me nts) are per mitte d d uri n g t he 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 discreti 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 0  of 6 2  
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 mace utical 
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 he p har mace utical 
pr o d uct. A n A E  ca n, t heref ore, be a n y u nfa v ora ble a n d u ni nte n de d si g n, 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 het her or n ot relate d 
t o t he me dici nal 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 her 
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 ve 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 de 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 ve 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 disc 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 me nt or ot her t hera 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 he a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot meet 
co n diti o n n u m ber 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 m al 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 ne d as a n A E t hat 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 me 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 he in vesti gat or will deter mi ne w het her a n y A Es  ha v e 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  ha 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  be rec or de 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 verse 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 he 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 1  of 6 2  
T he se verit y of t h e A E  will be 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 derate  
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 in 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 in vesti gat or will e val uat e a n y c ha n g es 
i n la b orator y val ues,  ma ke a deter mi nati 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 he 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 in 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 nce 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 ne d b y c o nc urre nt diseas e or ot her 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 ual e v e nt t hat is k n o w n t o be 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 halle n g e)  
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 ma 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 dise ase 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 be ass ociat e 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 2  of 6 2  
T he in vesti gat or will rec or d t he 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 me nt r e 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 me  
•  
Res ol ve d: T he e ve nt has rec o vere d  
− 
N ote: A n S A E/ A E st o p date s h o ul d be pr o vi de d.  
•  
Rec o vere d/ Res ol ve d wit h se q uelae: T he st u d y s u bject has rec o vere d as m uc h as ma y 
be e x pecte d b ut is left wit h se q uelae of t he e ve nt t hat are n ot e x p ecte d t o rec o ver f urt her  
− 
N ote: If t he se q uela e 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: Ca n be use d i n cas es w here st u d y s u bject is k n o w n t o be clearl y 
rec o veri 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 M e dical M o nit or a gree t hat f urt her f oll o w -u p is n ot necessar y.  
•  
Fatal: T he st u d y s u bject die d as a res ult of t he 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 nces w here t he 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 d e d as t he e ve nt (e. g., “s u d de n car diac deat h”). A d verse 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 perate d at t he 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 pres e nt  w he n a s u bj ect c o m plet es t he st u d y , or w he n  a s u bject  disc 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 in vesti gat or’s 
discreti o n, mi n or A Es ca n be re -e val uate d via tel e 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 me d as a p pr o priate. E v er y eff ort will be 
ma de b y t he in v esti gat or or del e gate t o c o ntact t he s u bject u ntil t he A E  is res ol ve d or 
sta bilize d, or t he M e dical M o nit or a n d in vesti gat or a gree t hat f urt her f oll o w-u p is n ot 
necessar y.  T h e 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 3  of 6 2  
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 dical occ urre n ce t hat at a n y d ose: 
•  
Res ults i n deat h  
•  
Is life-t hreate ni n g 
•  
Re q uires s u bject  h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  
Is a c o n ge nital a n o mal y/ birt h defect 
•  
I m p ort a nt m e dical ev 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 d ite d re p orti n g 
is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot b e 
i m me 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 dize t he 
s u bject or ma y re q uire i nter ve nti o n t o pre v e nt o ne of t he ot h er o u tc o mes liste d i n t he 
defi niti o n a b o ve.  E v e nts t hat re q uir e 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 hr eate 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 he 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 defi ne 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 b ei 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 pital 
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 vati o n will be disc usse d wit h t he M e dical M o nit or t o deter mi ne 
w het her t he 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 pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uir e i nter ve nti o n t o pre v e nt o ne of t he ot her 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 gat or  is re q uire d t o n otif y t he K RI M e dical M o nit or 
a n d 
 if a n y s u bject bec o mes pre g n a nt d uri n g t he st u d y. 
Pre g na 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 n c 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 4  of 6 2  
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 me 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 verse 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 he 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 me 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 de nce t hat w o ul d s u g gest a ca us al relati o ns hi p 
bet wee n t he dr u g a n d t he A E (i.e., re as o n a ble p ossi bility): 
•  
A si n gle occ urre n ce 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 oe de ma, he 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 ociate d wit h dr u g 
e x p os ure, b u t is ot her wise u nc o m m o n i n t he 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 ur e)  
 
S us pecte d a dverse re a cti 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 erse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he 
In v esti gat or ’s B r oc h ure or ot her a p plica ble pr o d uct i nf or mati o n or is n ot liste d at t he 
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 
in vesti gat or or s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
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 n ca pacit y or s u bsta ntial disr u pti o n of t he 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 defect. 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 je o par dize t he patie nt or s u bject 
a n d ma y re q uire me dical or s ur gical 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 verse 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 uir e 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 in 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 5  of 6 2  
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 , W H E T H E R O R N O T R E LA 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 : 
 
 
 
 
 
Sites 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 Me dical M o nit or. T he h otli ne n u m ber 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. 
 
 
L ot us Cli nic al Rese arc h, L L C  
 
 
 
 
 
 
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  d etails fr o m t he in vesti gat or  or C R O  of all 
seri o us, u ne x pecte d a n d relate d A Es  ( or ot her e ve nts de pe n di n g o n t he s pecific 
re q uire me nts) t hat 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 mati o n 
t hat t hese s eri o us, u n e x p ecte d a n d relate 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 w ar de d t o K RI a n d ke pt i n t he in 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 6  of 6 2  
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 be s u m marize d usi n g t he 
descri pti ve statistics n, mea n, sta n dar 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 me 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. Det aile d statistical met h o d ol o g y will be prese nte d i n a se parate statistical 
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 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 mea 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 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 ha v e a b aseli ne 
pai n sc or e 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 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 s et will i ncl u de all s u bjects w h o ha v e 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 disc o nti n uati o n/ wit hdra wal . S u bjects w h o are 
scree n fail ures al o n g wit h t he  mai 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 h ics a n d ot her baseli ne c haract eristics will be s u m marize d wit h descri pti ve 
statistics. F or  q u a ntitati ve data , mea ns, me dia ns, sta n dar d de viati o ns, mi ni m u m a n d 
ma xi m u m val ues w ill be deter mi ne d. F or q ualitati 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 ma r y a nal ysis will be re peate d usi n g 
t he P PS . 
 
 
 
  

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 7  of 6 2  
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 val u es will be i m p ute d bef ore 
calc ulati n g t he  
. I nt er me diate missi n g V A S val ues d ue t o a n o mis si 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 he missi n g meas ure m e nt will be directl y c o n necte d i n or der t o calc ulate t he 
 If s u bj ects nee d t o ta 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 he e diar y bef ore ta ki n g t he resc ue me 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 he pai n i nte nsit y sc ore t h at was 
rec or de d bef ore t a ki n g t he res c ue medicati 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 v e 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 for war d ( L O C F) w hile 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 m issi n g at ra n d o m ( M A R) ass u m pti o n 
wit h t he m ulti ple im p utati o n  ( MI) t ec h ni q ue. B y usi n g t he MI t ec h ni q ue, 1 0 0 datasets will 
be ge n erat e d. After ca lc 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 plie 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 me nt as mai 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 he 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 plie 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 he PI D w hile 
sta 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 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 he 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 me 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 be s u m marize 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 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 me 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 he 
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.  
V ital si g ns will als o be s u m marize d b y treat me nt gr o u p a n d ti me p oi nt , al o n g wit h t he 
c ha n ges 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 8  of 6 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 9  of 6 2  
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 Declarati 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 in 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 IR B/I E C m us t be c o nstit ute d acc or di n g t o t he a p plica ble state, fe d eral 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 oc ol, I n v esti gat or’s 
Br oc h ure, s u bject i nf or m e 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 val. C o pies of t he writte n 
a p pr o val s 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 he 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 me 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 val s a n d a list of t he v oti n g me m ber s, t heir titles or occ 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 he i n vesti gati o nal site a n d 
c o m me nce me nt of t he 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 h e 
st u d y, writte n n otificati o n re g ar 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.  
Sites 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 he I R B/I E C re g ar di n g pr ot oc ol a m e 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 materials 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 he 
st u d y at i nter vals s pecifie d b y t he 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 site 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 he c o nse nt 
disc ussi o n will be re q uir e d t o si g n a n d date t he I R B /I E C-a p pr o ve d I C F a n d eac h s u bject 
will be gi ve 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 he ele me nts of i nf or me d c o nse nt as descri be d 
i n t he 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 in vesti gat or is 
res p o nsi ble f or t he pre p arati 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 0  of 6 2  
be a p pr o ve d b y t he 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 be 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 ve s u bject. T he 
in vesti gat or or desi g nee will gi ve t he s u bject 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 dat e d. Inf 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 me nt m ust be a gree d t o i n writi n g b y K RI  a n d 
, s u b mitte 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 ve d b y t he res pecti ve I R B /I E C f or eac h i n v esti gati o nal site bef ore it is i m ple me nte 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 he pr ot oc 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 val m ust be o btai ne d as s o o n as p ossi ble t hereafter . 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 in vesti gat or.  
1 2. 5  
S T U D Y I NI TI A TI O N  
T he in vesti gat or m ust n ot e nr oll a n y s u bjects pri or t o t he 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 detaile d re vie w of t he 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 
su p plie d t o a n i n vesti gat or u ntil all t he necessar 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 recei ve 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 in vesti gat or t o e ns ure t hat t he st u d y is c o n d ucte d i n acc or da nce 
wit h t he pr ot oc ol, I C H / F D A G C P s, 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 be 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 Pla 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 or i n g 
perf or m an 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 in ves ti gat or a n d, at t he sa me 
ti me, 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 he pr ot oc ol wit h t he in vesti gat or.  I n a d diti o n, 
t he m o nit or will e x plai n t he in 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 ncer ni n g t he cli nical e val u ati o n of t he st u d y gel. 
T he in 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 an 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 ne t hat 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 RF s a n d relate d s o urce d oc u me nts will be re vi e we d i n detail b y t he m o nit or at 
eac h visit, i n acc or da n ce wit h rele 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 partici p ati o n i n t his st u d y a n d a n y ot her me dical 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 1  of 6 2  
c o nfir m i nf or mati o n c o ntai ne 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 in 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 v er p ossi ble.  
All m o nit ori n g a n d K RI o versi g ht acti vities will be 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 de ntifie d at t he i n vesti gati o nal site b y t he 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 he st u d y will be rec or de d o n t he C R F / e C R F.  
T he in vesti gat or will e ns ure t hat all data 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 n ce wit h s pecifi c i nstr ucti o ns 
acc o m pa n yi n g  t he C R Fs /e C R Fs, desi g ne d s pecificall 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 he 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 in vesti gat or, i n dicati n g his/ her ass ura nce of t he acc urac y of all 
rec or de d dat a. It is e x p ecte d t hat t he in 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 me nt of t heir o bli gati 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 da 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 he m o nit or, a n d re g ulat or y a ut h orities t o ha ve direct access t o 
t he s u bject’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 va 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 oc ol . 
T he in vesti gat or will m ai ntai n a S u bject I de 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 he 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 nes. 
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 he st u d y will be retai n e d b y  K RI a n d 
 
 in  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 in 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 in v esti 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 ur ce w or ks heets, all ori gi nal si g ne d a n d date d I C Fs, c o pies 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 2  of 6 2  
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 uir e d t o be mai ntai ne d 
u n de r 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 he 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 be 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 d icati o n, u ntil 
2  years after t he i n vesti gati o n is disc 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 d e d b y K RI . I n a d diti o n, t he in vesti gat 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 ke pt f or t he s a me 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 ve 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 her 
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 p arate fr o m r o uti ne m o nit ori n g o r 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 nt s. 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 3  of 6 2  
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 uc 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 an 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 nvesti 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 he writte n c o nse nt 
of K RI, e xce pt f or official re prese nt ati ves, 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 in vesti gat 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 v el 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 in vesti gat ors, ot her p har mace utical 
c o m pa nies a n d t o ot her g o ver n me nt a ge n cies . I n or der t o all o w f or t he use of t he 
i nf or mati o n deri ve 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 data 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 b er a n d t he s u bject's i nitials.  
T he d at a will be bli n de d c orres p o n di n gly i n all d at a a n alyses . 
H o we ver, i n c o m plia nce wit h t he g ui deli nes 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 ap plicati o n s a n d t he I C H G C P ( w het her 
perf or me d i n t he U nite d States or else w h ere) , a n d i n f ulfill me nt of its o bli gati o ns t o K RI  
t o verif y c o m plia nce wit h t his pr ot oc ol, K RI’s desi g nee re q uir es t hat t he i nvesti gat or t o 
per mit its m o nit or, re prese ntati ves fr o m t he F D A, K RI’s  d esi g n ate 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 orities t o re vie w t he s u bject’s pri mar y me dical 
rec or ds (s o urce data or d oc u me nts) i ncl 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 ge s u m maries 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 me dical rec or ds re q uir e a wai ver or a ut h ori zati o n se parat e fr o m t he 
state me nt of i nf or me d c o nse nt, t he in vesti gat 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 bef 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 data deri ve d fr o m 
the st u d y will be t he pr o pert y of K RI. T he in vesti gat or m ust u n derta ke n ot t o s u b mit a n y 
part of t he 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 ve d fr o m t he st u d y t o ot her in vesti gat ors a n d dr u g re g ulat or y a ut h orities.  
A fter 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 in vesti gat or a n d K RI, t he i n vesti gat or 
ma y se n d a draft ma 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 writte n a p pr o val fr o m K RI bef ore t he fi n al 
versi o n of t he ma 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 4  of 6 2  
At t he c o ncl usi o n of t he st u d y, after t he d ata are a n al yze d, K RI or its desi g n ee will pre pare 
a fi nal cli nical r e 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 5  of 6 2  
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 v e nt N S AI D -i n d uce d 
gastr o pat h y –  C O X sele cti vit y a n d be y o n d. Br J Cli n P har 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 dal 
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 Ma 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 Tar gets of Me nt h ol Acti o ns. Fr o nt. P har 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 vat 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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 6  of 6 2  
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 at rest a n d w hile sta n di n g  usi n g a  pa per  p ai n V A S .  
Please rec or d t he pai n i nt e nsit y w hile at rest/ w hil e st a n di n g  i n t he d o mi n a nt/ n o n -
d o mi n a nt le g  t hat y o u are e x peri e nci n g ri g ht n o w: 
 
 
 
Sc he matic is a re prese nt ati o n of t he pa per V A S i ma ge t hat will be pres e nte d t o s u bjects.  
 
 
 
 
 
 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 7  of 6 2  
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 pai n eV A S .  
Please rec or d t he pai n i nt e nsit y w hile at rest/ w hil e st a n di n g  i n t he st u d y le g/n o n -st u d y 
le g t hat y o u are e x peri e n ci n g ri g ht n o w d ue t o D O M S  ( dela ye d o nset m us cle s ore ness): 
 
 
 
 
Sc he matic is a re prese nt ati o n of t he eV A S i ma ge t hat will be prese nte d t o s u bjects.  
 
 
 
 
 
 

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 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 8  of 6 2  
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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 9  of 6 2  
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 dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 0  of 6 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 1  of 6 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 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 2  of 6 2  
 
1 5. 4  
A P P E N DI X 4