Clinical trial NCT03660943
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis Knee Pain
Sponsor: Centrexion Therapeutics
Start date: 2018-09-09; Completion date: 2020-06-11
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, 2-injection, 52-week study to evaluate the efficacy and safety of intra-articular injections of CNTX-4975-05 in subjects with chronic, moderate-to-severe osteoarthritis knee pain.

Detailed description:

Arms: arm 1: Matching placebo of 2.0 mL for IA injection arm 2: Pre-filled glass syringes administered as a single 2.0 mL IA injection
Interventions: intervention 1: Placebo intervention 2: CNTX-4975-05
Intervention descriptions: intervention 1: Receiving Placebo Injection intervention 2: Receiving CNTX-4975-05 Injection

Protocol documents:
Prot_SAP_000.pdf: 




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
2.  S Y N O P SI S  
P R O D U C T 
N A M E/ N U M B E R  
C N T X -4 9 7 5 -0 5  
P R O T O C O L 
N U M B E R  
C N T X -4 9 7 5i -O A -3 0 4  
D E V E L O P M E N T 
P H A S E  
P hase 3  
P R O T O C O L TI T L E  
A Ra n d o mize d, 
D o u ble -bli n d, Place b o -c o ntr olle d, 2 -I njecti o n, 5 2-Wee k St u d y t o 
E val uate t he Efficac y a n d Safet y of I ntra -artic ular I njecti o ns of C N T X -4 9 7 5 -0 5 i n 
S u bjects wit h C hr o nic, M o derate -t o-se vere Oste oart hritis K nee Pai n. 
I N DI C A TI O N 
K nee pai n d ue t o oste oart hritis ( O A)  
O BJ E C TI V E S  
T he o bjecti ves of t his st u d y i n s u bjects wit h m o derate -t o-se vere pai n d ue t o 
oste oart hritis of t he k nee are as f oll o ws:  
Pri m ary Effic acy O bjective:  
•  
T o de m o nstrate t he efficac y of C N T X -4 9 7 5 -0 5  
 o n O A pai n i n t he 
i n de x k nee f oll o wi n g a n i ntra-artic ular (I A) i njecti o n at Baseli ne, a n d als o t o 
assess t he i m pact of a  re peat I A i njecti o n of C N T X-4 9 7 5 -0 5 at Wee k 2 6 o n 
O A pai n i n t he k nee.  
Sec o n d ary E ffic acy O bjectives:  
•  
T o assess t he i m pact of a re peat I A i njecti o n of C N T X -4 9 7 5 -0 5 at Wee k 2 6 o n 
O A pai n i n t he k nee at Wee k 3 8.  
•  
T o e val uate t he o verall i m pr o ve me nt i n O A  of  t he i n de x k nee t hr o u g h Wee k 
2 6.  
Ex pl or at ory Effic acy O bjectives:  
•  
T o e x pl ore t he a nal gesic efficac y of C N T X -4 9 7 5 -0 5 o n O A pai n of t he i n de x 
k nee t hr o u g h 5 2 wee ks.  
•  
T o e x pl ore t he o verall be nefit o n O A of t he i n de x k nee t hr o u g h 5 2 wee ks.  
•  
T o e x pl ore t he p ote ntial t o dela y t he nee d f or a t ot al k nee re place me nt s ur ger y, 
base d o n t he s u bjects’ res p o nses a n d t he c o ntr ol of pai n a n d i m pr o ve me nt i n 
f u ncti o n, q ualit y of life, a n d o n slee p. 
•  
T o e x pl ore t he nee d f or resc ue a n d bac k gr o u n d a nal gesic me dicati o ns f or O A 
pa i n i n t he i n de x k nee.  
S u p p ortive  Effic acy O bjective:  
•  
T o e x pl ore t he a nal gesic efficac y a n d o verall be nefit o n O A of t he i n de x k nee 
t hr o u g h Wee ks 3 8 a n d 5 2, f oll o wi n g a re peat I A i njecti o n of C N T X-4 9 7 5 -0 5 at 
Wee k 2 6 .  
S afety O bjective:  
•  
T o e val uate t he saf et y of a n i nitial I A i njecti o n (at Baseli ne) a n d a re peat I A 
i njecti o n (at Wee k 2 6) of C N T X-4 9 7 5 -0 5 , c o m pare d t o place b o, i n t he i n de x 
k nee.  
S T U D Y D E SI G N  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 2 -injecti o n , 5 2-wee k st u d y t o 
e val uate t he efficac y a n d safet y of a n i nitial i ntra-artic ular i njecti o n (at Baseli ne) a n d a 
sec o n d i ntra-artic ular  i njecti o n (at Wee k 2 6) of  
 of C N T X-4 9 7 5 -0 5 , c o m pare d t o 
place b o , i n s u bjects wit h c hr o nic, m o derate-t o-se vere i n de x k nee pai n  fr o m O A . 
At ra n d o mizati o n, s u bjects will be stratifie d t o bala nce acr oss treat me nt gr o u ps f or:  
Pa ge 3 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
P L A N N E D 
N U M B E R O F 
S U BJ E C T S  
A p pr o xi matel y 3 2 5  s u bjects will be e nr olle d wit h a 2: 3 all ocati o n ( place b o t o acti ve) 
(a p pr o xi matel y 1 2 5  s u bjects assi g ne d t o place b o a n d 2 0 0  s u bjects assi g ne d t o  
 
C N T X -4 9 7 5 -0 5).   
S T U D Y E N T R Y 
C RI T E RI A  
I ncl usi o n Criteria: 
1.  Male or fe ma le s u bjects bet wee n 4 0 a n d 9 5 years of a ge (i ncl usi ve) at t he 
ti me of t he Scree ni n g Visit wit h t he a bilit y t o c o m pl y wit h a ns weri n g t he 
electr o nic diar y  usi n g t he st u d y -pr o vi de d ta blet  c o m p uter s. 
2.  C o nfir mati o n of O A of t he k nee: ra di o gra p h y of b ot h k nees wi t h a 
p osteri or -a nteri or, fi xe d -fle xi o n vie w ta ke n d uri n g t he Pre -scree ni n g 
Peri o d . T he i n de x k nee m ust s h o w e vi de nce of c hr o nic O A wit h a K -L 
g ra de of 2, 3 a n d 4.  T he I R T s yste m will li mit t he n u m ber of K-L gra de 4 
s u bjects t o a p pr o xi matel y 5 5 s u bjects (a ppr o xi matel y 2 0 % of e nr oll me nt) . 
3.  C o nfir mati o n of O A of t he i n de x k nee: A merica n C olle ge of 
R he u mat ol o g y ( A C R) dia g n ostic criteria.  
4.  M o derate t o se vere pai n i n t he i n de x k nee ass ociate d wit h O A m ust be 
sta ble f or a mi ni m u m of 6 m o nt hs pri or t o Scree ni n g, as assesse d b y t he 
i n vesti gat or. 
5.  F or q ualif yi n g Baseli ne k nee pai n  wit h wal ki n g , t he Baseli ne  sc ore will be 
deri ve d fr o m t he  1 4 da ys of pre -d ose pai n sc ores c ollecte d  i m me diatel y 
prece di n g s u bject ra n d o mizati o n o n Da y 1 . The Baseli ne pai n  sc ore will be 
calc ulate d b y t he ra n d o mizati o n al g orit h m as  t he mea n of t he sc ores fr o m 
t he 1 4 da ys ( or at a mi ni m u m, 8 da ys ) i m me diatel y prece di n g Da y 1. 
S u bjects m ust use  a n u meric pai n rati n g scale ( N P R S) ( 0 -1 0; 0 = n o pai n, 
1 0 = w orst pai n e ver) t o rate t heir i n de x k nee pain wit h wal ki n g, re p orte d 
usi n g t he e P R O s yste m.  Pai n i n t he i n de x k nee m ust be rate d dail y at 
be dti me ( 9: 0 0 P M ± 3 h o urs) t o deter mi ne t he a vera ge k ne e pai n wit h 
wal ki n g d uri n g t he pre vi o us 2 4  h o urs.  T he site a n d s u bject trai ni n g will 
tar get at least a n 8 5% c o m plia nce rate, usi n g o n g oi n g assess me nt of 
c o m plia nce data, a n d site c o m m u nicati o n wit h t he s u bject if c o m plia nce 
dr o ps bel o w 8 5 %.  
6.  At Baseli ne  o nl y,  pai n wit h wal ki n g will als o be c ollecte d a n d assesse d f or 
t he n o n-i n de x k nee, as n ote d i n t he assess me n t a b o ve ( 5). 
7.  C o m plia nce wit h diar y e ntr y t o meet mi ni mal acce pta ble criteria d uri n g 
Scree ni n g . 
8.  U n dersta n di n g of t he o utc o me meas ures , a n d t he relati o n s hi p a m o n g t he m, 
after s u bject trai ni n g a n d testi n g.  
9.  B MI ≤4 5 k g/ m 2. 
1 0.  S u bjects m ust ha ve faile d 2 or m ore pr i or t hera pies. Fail ure is dee me d t o 
be i na de q uate relief i n t he o pi ni o n of t he i n vesti gat or. A t hera p y ma y be 
dee me d t o ha ve bee n i na de q uate beca use o f o ne or m ore of t he f oll o wi n g: 
a) u nacce pta ble a d verse e ve nts ( A Es) ;  
b)  i na de q uate res p o nse, or l oss of res p o nse f or c hr o nic O A k nee pai n or 
o  
pai n i n t he i n de x k nee was mi ni mall y i m pr o ve d, n ot i m pr o ve d, or 
was w orse a n d/ or  
o  
i m pr o ve me nt f u ncti o n, a n d/ or stiff ness i n t he i n de x k nee was 
mi ni mall y i m pr o ve d, n ot i m pr o ve d, or was w orse  
c) me dical c o n diti o n res ulti n g i n c o ntr ai n dicati o n t o t he sta n dar d of care 
a p pr o priate t o t he se verit y of t he i n de x k nee O A  pai n.   
“ T hera pies” i ncl u de, b ut are n ot li mite d t o, eac h  of t he f oll o wi n g:  
o  
n o nster oi dal a nti -i nfla m mat or y dr u gs (N S AI D s) (i ncl u di n g 
t o pical), o pi oi ds, d ul o xeti ne, ot her syste mic t hera p y, I A 
c ortic oster oi ds, I A visc os u p ple me nts  
o  
p h ysical t hera p y, braci n g , a n d ort h otics.   
1 1.  Fe males n ot of c hil d beari n g p ote ntial, defi ne d as p ost -me n o pa usal f or at 
least 1 year, or s ur gicall y steri le ( bilateral t u bal li gati o n, bilateral 
Pa ge 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
o o p h orect o m y, or h ysterect o m y), or practici n g o ne of t he f oll o wi n g 
me dicall y acce pta ble met h o ds of birt h c o ntr ol t hr o u g h o ut t he st u d y peri o d:  
•  
H or m o nal met h o ds s uc h as oral, i m pla nta ble, i njecta ble, or 
tra ns der mal c ontrace pti ves f or a mi ni m u m of 1 f ull c ycle ( base d o n 
t he s u bject’s us ual me nstr ual c ycle peri o d) bef ore I P a d mi nistrati o n  
•  
T otal a bsti ne nce fr o m se x ual i nterc o urse si nce t he last me nses bef ore 
I P a d mi nistrati o n  
•  
I ntra uteri ne de vice 
•  
D o u ble barrier met h o d (c o n d o ms, s p o n ge, dia p hra g m, wit h 
s per mici dal jellies or crea m)  
1 2.  A ble t o s pea k, rea d, a n d u n dersta n d t he la n g ua ge of t he st u d y use d f or t he 
i nf or me d c o nse nt a n d e P R O. 
1 3.  Willi n g a n d a ble t o:  
a) u n dersta n d t he st u d y re q uire me nts,  
b)  a bi de b y t he st u d y restricti o ns a n d re q uire me nts,  
c) c o m plete t he st u d y pr oce d ures,  
d)  be c o m plia nt a n d i n de pe n de ntl y (ie, wit h o ut assista nce) rec or d 
res p o nses o n t he pai n scales a n d ma ke dail y  e ntries usi n g e P R O (e g, 
ha ve t he a bilit y t o c o m pl y wit h a ns weri n g t he electr o nic diar y usi n g 
t he st u d y pr o vi de d ta blet c o m p uter s),  
e) i n de pe n de ntl y c o m m u nicate mea ni n gf ull y wit h t he st u d y pers o n nel. 
1 4.  Si g ne d i nf or me d c o nse nt f or m a p pr o ve d b y t he i nstit uti o nal re vie w b oar d 
(I R B). 
1 5.  S u bject a grees t o sta y o n t heir c urre nt pai n me dicati o n (i ncl u di n g o ver t he 
c o u nter ( O T C) me dicati o ns) fr o m t he ti me of Pre -scree ni ng t hr o u g h 
Wee k  1 2. T he c urre nt pai n me dicati o n m ust be ta ke n o nl y f or pai n i n t he 
i n de x k nee, a n d n ot f or a n ot her pai n i n dicati o n. T heir c urre nt pai n 
me dicati o n m ust be o ne of t he all o we d resc ue me dicati o ns a n d d osa ges, or 
h y dr oc o d o ne at a d ose u p t o 1 5 m g  dail y ( or a n ot her o pi oi d e q ui vale nt). 
T he resc ue me dicati o n is n ot all o we d t o be i n t he sa me dr u g class as t he 
o n g oi n g me di cati o n. F or e xa m ple, s u bjects will n ot be all o we d t o ta ke 
tra ma d ol as a resc ue me dicati o n if t he y are ta ki n g a n o pi oi d as 
c o nc o mita n t me dicati o n, or a n N S AI D as resc ue if t he y are usi n g a n 
N S AI D as c o nc o mita nt me dicati o n. Fr o m Wee k 1 2 t o c o m pleti o n of t he 
st u d y, s u bjects ma y sta y o n c urre nt pai n me dicati o n as prescri be d or O T C 
me dicati o n, b ut t his is n ot re q uire d. If re d uci n g or st o p pi n g bac k gr o u n d 
me dicati o ns f or t he i n de x k nee O A pai n, t hat i nf or mati o n m ust be rec or de d 
b y t he site/s u bject.   
1 6.  S u bject a grees  t o ta ke o nl y t he all o we d resc ue me dicati o ns f or O A k nee 
pai n of t he i n de x k nee fr o m t he ti me of t he first T reat me nt Visit t hr o u g h 
st u d y c o m pleti o n a n d a grees t o use n o t o pical me dicati o ns f or O A k nee 
pai n d uri n g t he trial.  
E xcl usi o n criteria:   
1.  J oi nt re place me nt s ur ger y of t he i n de x k nee at a n y ti me  (f ull or partial), or 
o pe n s ur ger y of t he i n de x k nee i n t he past 2 4  m o nt hs.   
2.  Pri or art h r osc o pic s ur ger y of t he i n de x k nee wit hi n 6 m o nt hs of Scree ni n g. 
3.  A n y pai nf ul c o n diti o ns of t he i n de x k nee d ue t o j oi nt disea se ot her t ha n 
O A.  F or e xa m ple, ra dic ular or referre d pai n i n v ol vi n g t he i n de x k nee or 
fr o m j oi nt disease ot her t ha n O A i n v ol vi n g t he i n de x k nee, s uc h as, b ut n ot 
restricte d t o, i nfla m mat or y diseases, e g, r he u mat oi d art hritis, ps oriatic 
art hritis, c h o n dr o malacia patella, meta b olic diseases, g o ut/ pse u d o g o ut, 
he m oc hr o mat osis, acr o me gal y , etc.  
4.  Periartic ular pai n fr o m a n y ca use, i ncl u di n g referre d pai n, b ursitis, 
te n d o nitis, s oft tiss ue te n der ness, or s u bac u te/ac ute pai n f r om  i nj ur y.  
5.  Pai n i n t he n o n -i n de x k nee t hat is > 3 ( N P R S 0-1 0) w he n wal ki n g or at rest.  
Pa ge 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
6.  Ot her c hr o nic pai n a n y w here i n t he b o d y t hat re q uires t he use of a nal gesic 
me dicati o ns, i ncl u di n g, b ut n ot li mite d t o, l ocal pai nf ul areas, m y ofascial 
pa i n s y n dr o mes, fi br o m yal gia, ge netic, meta b olic a b n or malities, 
he mat ol o gic or ne ur o pat hic pai n , a n d a n y ac ute or c hr o nic pai n t hat ma y 
i nterfere wit h t he st u d y pai n assess me nts b y t he s u bject. 
7.  I nsta bilit y of t he i n de x k nee (e g, cr uciate li ga me nt tear or r u pt ure, 
si g nifica nt pr otr u di n g me nisc us, s u bsta ntial li ga me nt o us la xit y).  
8.  Misali g n me nt ( > 1 0  de grees var us or val g us) of t he i n de x k nee  o n sta n di n g . 
9.  D oc u me nte d hist or y of ne ur o pat hic art hr o pat h y or fi n di n g of b o n y 
fra g me ntati o n i n t he i n de x k nee wit h i ma gi n g (ra di o gra p hic, c o m p ute d 
t o m o gra p h y, or ma g netic res o na nce i ma gi n g). 
1 0.  P h ysical / occ u pati o nal/c hir o practic t hera p y f or t he l o wer e xtre mities or 
ac u p u nct ure f or t he l o wer e xtre mities wit hi n 3 0 da ys of Scree ni n g , or nee d 
f or s uc h t hera p y d uri n g t he st u d y. 
1 1.  Pla ns t o ha ve s ur ger y , ot her i n vasi ve pr oce d ures, or I A i njecti o ns ( ot her 
t ha n t he I P) w hile partici pati n g i n t he st u d y. 
1 2.  Has use d t o pical ca psaici n o n t he i n de x k nee wit hi n 9 0  da ys of Scree ni n g.  
1 3.  C urre nt use of o pi oi ds f or a n y c o n diti o n ot her t ha n f or O A of t he i n de x 
k nee ( ma xi m u m d ose of 1 5 m g of h y dr oc o d o ne [ or e q ui vale nt] per da y).  
1 4.  C ortic oster oi d i njecti o n i nt o t he i n de x k nee wit hi n 9 0  da ys of Scree ni n g.  
1 5.  Recei ve d I A visc os u p ple me ntati o n (e g,  S y n visc ® , H yal ga n® ) wit hi n 9 0 
da ys of Scree ni n g.  
1 6.  Hist or y of  aller gic reacti o n t o t he pla n ne d l ocal a nest hesia/ a nal gesic 
re gi me ns, et h yle ne dia mi netetraacetic aci d ( E D T A), K olli p h or H S 1 5, 
b ut ylate d h y dr o x yt ol ue ne ( B H T), or ca psaici n.  
1 7.  Prese nce of a n y me dica l c o n diti o n or u nsta ble healt h stat us t hat, i n t he 
j u d g me nt of t he i n vesti gat or, mi g ht a d versel y i m pact t he safet y of t he 
s u bject, or t he c o n d uct of t he st u d y, or ne gati vel y affect t he res ulti n g data, 
i ncl u di n g c hr o nic c o n diti o ns t hat are li kel y t o alter the rate of heali n g or 
are li kel y t o res ult i n safet y c o m plic ati o ns u nrelate d t o t he st u d y 
me dicati o n, or si g nifica ntl y c o m pr o mise ke y or ga n s yste ms. F or a n y 
q uesti o n re gar di n g eli gi bilit y, it is str o n gl y rec o m me n de d t hat t he 
i n vesti gat or disc uss t he s u bject wit h t he me dical m o nit or. 
1 8.  Is pre g na nt or is breast fee di n g. 
1 9.  Has a mali g na nc y, a hist or y of mali g na nc y, or has recei ve d treat me nt f or 
mali g na nc y at a n y ti me, wit h e xce pti o n of resecte d a n d c ure d basal cell 
carci n o ma a n d s q ua m o us cell carci n o ma of t he s ki n .  
2 0.  Re g ular use of a ntic oa g ula nt bl o o d t hi n ners (e xce pt l o w -d ose as piri n, 
Da bi gatra n 1 5 0  m g o nce dail y [ q d], E n o xa pari n 4 0  m g q d, Ri var o xa ba n 
1 0  m g q d, A pi xa ba n 2. 5  m g t wice dail y [ bi d],  or cl o pi d o grel  7 5 m g q d,  
w hic h are all o we d).   
2 1.  Acti ve c uta ne o us disease  at t he a ntici pate d site of I P i njecti o n t hat w o ul d 
pre ve nt t he safe a d mi nistrati o n of I P. 
2 2.  Ulcer or o pe n w o u n d a n y w here o n t he i n de x k nee . 
2 3.  S pecific la b orat or y a b n or malities:  
•  
He m o gl o bi n < 1 1 . 0 g/ d L  
•  
W hite bl o o d cells ( W B C) < 2. 5 X 1 0
9/ L 
•  
Ne utr o p hils < 1. 5 X 1 0 9/L  
•  
Platelets < 1 0 0 X 1 0 9/ L 
•  
As partate tra nsa mi nase ( A S T) or ala ni ne tra nsa mi nase ( A L T) > 2  X 
u p per li mit of n or mal  
•  
Creati ni ne > 1. 6 m g/ d L  
•  
Gl uc ose (fasti n g) > 2 5 0 m g/ d L  
•  
H g b A 1c > 9  
Pa ge 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
2 4.  Cli nicall y si g nifica nt a b n or mal la b orat or y res ult at t he Scree ni n g Visit (i n 
t he o pini o n of t he i n vesti gat or), or si g nifica nt or ga n disease t hat w o ul d p ut 
t he s u bject at u n d ue ris k or affect t he a bilit y of t he s u bject t o partici pate i n 
t he trial. F or a n y q uesti o n re gar di n g eli gi bilit y, it is str o n gl y rec o m me n de d 
t hat t he i n vesti gat or discusses t he s u bject wit h t he me dical m o nit or.  
2 5.  Use of a n i n vesti gati o nal me dicati o n wit hi n 3 0 da ys of Scree ni n g or 
5  p har mac o ki netic or p har mac o d y na mic half -li ves ( w hic he ver is l o n ger), 
or sc he d ule d t o recei ve s uc h a n a ge nt w hile partici pati n g i n t he c urre nt 
st u d y. 
2 6.  Pri or partici pati o n i n a n A L G R X 4 9 7 5 or C N T X -4 9 7 5 st u d y . 
2 7.  Has a n y of t he f oll o wi n g c haracteristics:  
•  
D oes n ot ha ve a q ualif yi n g Baseli ne mea n k nee pai n sc ore of ≥5 a n d 
≤9 o ut of 1 0 o n t he N P R S scale i n t he i n de x k nee  
•  
A cti ve or hist oric s u bsta nce use dis or der wit hi n t he pre vi o us year as 
defi ne d b y t he Dia g n ostic a n d Statistical Ma n ual f or Me ntal Healt h 
Dis or ders, fift h e diti o n  
•  
T est is p ositi ve u p o n uri ne dr u g scree n f or a s u bsta nce of a b use  
( prescri be d o pi oi ds acce pta ble) 
•  
H as a hist or y, at a n y ti me, or c urre ntl y, of s uici dal i deati o n, s uici de 
atte m pt, or i ncrease d ris k of s uici de 
•  
Has u nacce pta ble le vel of d e pressi o n or a n xiet y  as meas ure d b y t he 
H os pital A n xiet y a n d De pressi o n Scale ( H A D S ) sc ore of ≥1 1  
•  
Has u nacce pta ble c hr o nic pai n as meas ure d b y t he Fi br o m yal gia 
S y m pt o m  Scale  Sc ore ( F S S)  of ≥1 3  
•  
Has a  p ositi ve pre g na nc y test at t he Scree ni n g or Treat me nt Visit  
•  
Has o n g oi n g liti gati o n f or w or kers’ c o m pe nsati o n  
 
Has a n y c o n diti o n, or is ta ki n g a n y me dica ti o n, t hat w o ul d be 
c o ntrai n dicate d f or st u d y partici pati o n 
I N V E S TI G A TI O N A L 
P R O D U C T  
Na me:  C N T X -4 9 7 5 -0 5 ( tra ns-ca psaici n i njecti o n), pr o vi de d as a 
 
 
R E F E R E N C E 
P R O D U C T ( S) 
Na me:  Matc hi n g p lace b o, c o nsisti n g of  
 sali ne f or i njecti o n. 
T R E A T M E N T 
R E GI M E N S  
All s u bjects will recei ve a si n gle cli nical or ultras o u n d -g ui de d  i ntra-artic ular  i njecti o n of 
2 % li d ocai ne , f oll o we d b y C N T X -4 9 7 5 -0 5  
 or matc hi n g place b o , o n St u d y Da y 
1 ( Treat me n t Da y 1) a n d at Wee k 2 6 ( Treat me nt Da y 2) , al o n g wit h c o ntr olle d c o oli n g. 
P L A N N E D S T U D Y 
SI T E S  
A p pr o xi matel y  3 0  c o nc urre nt st u d y sites i n t he U S  
C RI T E RI A F O R 
E V A L U A TI O N  
Pri m ar y E ffic ac y E n d p oi nt s:  
T he pri mar y efficac y e n d p oi nt of t his st u d y, c o m pari n g r es ults i n s u bjects treate d wit h 
 of C N T X-4 9 7 5 -0 5  or place b o, is as f oll o ws:  
• 
C ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n t he a vera ge pai n i n t he i n de x k nee, 
usi n g t he Wester n O ntari o a n d Mc Master U ni versities Oste oart hritis I n de x 
( W O M A C) A ( pai n) s u bscale.  
Ke y Sec o n d ar y E ffic ac y E n d p oi nts:  
T he ke y sec o n dar y efficac y e n d p oi nts of t his st u d y, c o m pari n g res ults i n s u bjects treate d 
wit h  
 of C N T X -4 9 7 5 -0 5 or place b o, are as f oll o ws:  
• 
First Key Sec o n d ary:  C ha n ge fr o m st u d y baseli ne t o Wee k 3 8 i n t he a vera ge 
pai n i n t he i n de x k nee, usi n g t he W O M A C A ( pai n) s u bscale.  
Pa ge 8 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
• 
Sec o n d Key Sec o n d ary : C ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n t he a vera ge 
f u ncti o n i n t he i n de x k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale. 
 
Sec o n d ar y E ffic ac y E n d p oi nts:  
T he sec o n dar y effic ac y e n d p oi nts of t his st u d y, c o m pari n g res ults i n s u bjects treate d 
wit h  
 of C N T X -4 9 7 5 -0 5 or  place b o, i ncl u de t he f oll o wi n g:  
• 
P GI C res p o n ders (sc ores of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) f or t he 
i nde x k nee at Wee k 1 2.  
• 
Area u n der t he c ur ve ( A U C) ca lc ulate d base d o n t he c ha n ge fr o m st u d y 
baseli ne t hr o u g h Wee k 1 2 ( Da y 8 4) (i.e., Sta n dar dize d A U C Dail y -W k 1 2 ) i n t he 
a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g 
t he N P R S ( 0-1 0)  
• 
C ha n ge fr o m st u d y baseli ne ( mea n of m ost rece n t n o n-missi n g 8 o ut of 1 4 
da ys, fr o m Da y -1 4 t hr o u g h Da y -1) t o Wee k 1 2 ( mea n of Da y 7 8 t hr o u g h Da y 
8 4) i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 
h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
A U C calc ulate d o n c ha n ge fr o m st u d y baseli ne t hr o u g h Wee k 2 6 ( Da y 1 8 2) 
(i.e., Sta n dar dize d A U CDail y -W k 2 6 ) i n t he a vera ge pai n wit h wal ki n g i n t he i n de x 
k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a v era ge pai n i n t he i n de x k nee, 
usi n g t he W O M A C A ( pa i n) s u bscale. 
• 
C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a vera ge f u ncti o n i n t he i n de x 
k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale.  
• 
C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a vera ge pai n i n t he i n de x  k nee 
wit h wal ki n g o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
P GI C res p o n ders (sc ores of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) f or t he 
i n de x k nee at Wee k 2 6.  
E x pl or at or y Effic ac y E n d p oi nts:  
E x pl orat or y  efficac y e n d p oi nts of t his st u d y, c o m pari n g res ults i n s u bjects treate d wit h 
 of C N T X-4 9 7 5 -0 5 or  place b o, i ncl u de t he f oll o wi n g:  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k  5 2 i n t he a vera ge 
pai n i n t he i n de x k nee, usi n g t he W O M A C A  ( pai n) s u bscale. 
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge 
stiff ness i n t he i n de x k nee, usi n g t he W O M A C B (stiff ness) s u bscale. 
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge 
f u ncti o n i n the i n de x k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale.  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y we e k t hr o u g h Wee k 5 2 i n t he 
a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g 
t he N P R S ( 0-1 0).  
• 
A U C calc ulate d o n c ha n ge fr o m st u d y ba seli ne t hr o u g h Wee k 3 8 ( Da y 2 6 6) 
(i.e., Sta n dar dize d A U CDail y -W k 3 8 ) a n d Wee k 5 2 ( Da y 3 6 4) (i.e., Sta n dar dize d 
A U C Dail y -W k 5 2 ) i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he 
pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
T otal dail y, sta n dar dize d wee kl y, t otal wee kl y, resc ue -a dj uste d t otal dail y, a n d 
resc ue-a dj uste d t otal dail y A U C calc ulate d o n  c ha n ge fr o m st u d y baseli ne 
Pa ge 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
t hr o u g h Wee ks 1 2, 2 6, 3 8, a n d 5 2 i n t he a vera ge pai n wit h wal ki n g i n t he i n de x 
k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
P GI C f or t he i n de x k nee f or eac h st u d y visit t hr o u g h Wee k 5 2.  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he q ualit y 
of life ( Q O L), as meas ure d b y t he S F -3 6 Healt h S ur ve y.  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h W ee k 5 2 i n Q O L, as 
meas ure d b y t he fi ve -le vel versi o n of t he E Q-5 D -5 L.  
• 
D ura bilit y of efficac y of a  first ( u p t o Wee k 2 6) a n d a re peat I A i njecti o n ( u p t o 
Wee k  5 2), as meas ure d b y t he ti me fr o m Da y 1 (st u d y baseli ne) t o t he ret ur n of 
st u d y baseli ne ( N P R S pain wit h wal ki n g) pai n.  
• 
C u m ulati ve res p o n der a nal ysis f or all s u bjects at eac h st u d y visit, base d o n 
W O M A C A ( pai n), W O M A C B (stiff ness), a n d W O M A C C (f u ncti o n) sc ores. 
Res p o n ders at eac h st u d y visit ( W O M A C) / st u d y wee k ( N P R S) will be 
defi ne d usi n g 1) perce nt c ha n ge fr o m st u d y baseli ne, 2) t he a bs ol ute c ha n ge 
fr o m st u d y baseli ne, a n d 3) t he o bser ve d v al ue. 
• 
Fre q ue nc y of use of resc ue a n d bac k gr o u n d a nal gesic me dicati o n f or t he i n de x 
k nee pai n t hr o u g h o ut t he st u d y peri o d.  
• 
O M E R A C T -O A R SI criteria res p o n ders at eac h st u d y visit t hr o u g h Wee k 5 2 
( base d o n st u d y baseli ne). 
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n q ualit y of 
sleep, as meas ure d b y t he M O S slee p scale.  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n K O O S.  
• 
C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n wei g ht a n d 
b o d y mass i n de x ( B MI).  
• 
C ha n ge fr o m st u d y baseli ne t o Wee k 5 2 i n a b d o mi nal girt h a n d H b A 1c.  
• 
Li keli h o o d of s u bject nee d f or j oi nt re place me nt s ur ger y, base d o n pai n, 
f u ncti o n, a n d ot her patie nt-re p orte d o utc o mes, fr o m st u d y baseli ne t o eac h 
st u d y visit t hr o u g h Wee k 5 2.  
• 
C ha n ge fr o m  st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n W P AI: O A 
res ults. 
• 
T o e x pl ore t he effect of K -L gra de, se x, B MI, a n d a ge o n t he a nal gesic efficac y 
of C N T X -4 9 7 5 -0 5, meas ure d b y W O M A C A ( pai n) scale, W O M A C C 
(f u ncti o n) scale, a n d a vera ge wee kl y pai n with wal ki n g N P R S ( 0 -1 0) sc ore, 
t hr o u g h Wee k 5 2. A d diti o nall y, s u bjects wit h ra di o gra p hic e vi de nce of O A i n 
t he n o n-i n de x ( o p p osite) k nee ( K-L = 2, 3, or 4) vs s u bjects wit h n o ra di o gra p hic 
e vi de nce of O A i n t he n o n -i n de x k nee ( K-L = 0 or 1) will be a nal yze d.  
• 
S u b ject’s g uess as t o w hic h treat me nt t he y t hi nk t he y recei ve d.  
• 
S hift fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n w orst case 
assisti ve de vice usa ge.  
• 
S u bject satisfacti o n wit h treat me nt pr oce d ure.  
 
S u p p orti ve Effic ac y E n d p oi nts : 
S u p p orti ve effic ac y e n d p oi nts f or t he re peat i njecti o n, c o m pari n g res ults i n s u bjects 
treate d wit h  
 of C N T X-4 9 7 5 -0 5 or  place b o, i ncl u de t he f oll o wi n g:  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he 
a vera ge pai n i n t he i n de x k nee, usi n g t he W O M A C A ( pai n) s u bscale.  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he 
a vera ge stiff ness i n t he i n de x k nee, usi n g t he W O M A C B (stiff ness) s u bscale.  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he 
Pa ge 1 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
a vera ge f uncti o n  i n t he i n de x k nee, usin g t he W O M A C C (f u ncti o n) s u bscale.  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y wee k t hr o u g h Wee k 5 2 i n t he 
a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g 
t he N P R S ( 0-1 0).  
• 
A U C calc ulate d base d o n t he c ha n ge fr o m Wee k 2 6 baseli ne t hr o u g h Wee k 3 8 
a n d t hr o u g h Wee k 5 2 (i.e., Sta n dar dize d A U C Dail y -W k 2 6 W k 3 8  a n d Sta n dar dize d 
A U C Dail y -W k 2 6 W k 5 2 ) i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he 
pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
• 
T otal dail y,  sta n dar dize d wee kl y, t otal wee kl y, resc ue-a dj uste d t otal dail y, a n d 
resc ue-a dj uste d t otal dail y A U C calc ulate d o n c ha n ge fr o m Wee k 2 6 baseli ne 
t hr o u g h Wee ks 3 8 a n d 5 2 i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee 
o ver t he pre vi o us 2 4 h o urs, usi n g t he  N P R S ( 0 -1 0).  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he 
Q O L, as meas ure d b y t he S F -3 6 Healt h S ur ve y.  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n Q O L, 
as meas ure d b y E Q -5 D -5 L.  
• 
O M E R A C T -O A R SI criteria res p o n ders at eac h st u d y visit  t hr o u g h Wee k 5 2 
( base d o n Wee k 2 6 baseli ne). 
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n q ualit y 
of slee p, as meas ure d b y t he M O S slee p scale.  
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n K O O S.  
• 
C ha n ge fr o m We e k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n wei g ht 
a n d B MI. 
• 
C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 o n t he 
W P AI: O A.  
S afet y E n d p oi nts:  
Safet y e n d p oi nts i n s u bjects treate d wit h 
 of C N T X -4 9 7 5 -0 5  or  place b o , i ncl u de 
t he f oll o wi n g: 
•  
A Es  
•  
Vital si g ns  
•  
Cli nical la b orat or y e val uati o ns ( he mat o l o g y, c he mistr y, a n d uri nal ysis) 
•  
1 2 -lea d electr ocar di o gra ms ( E C G) 
•  
P h ysical e xa mi nati o n (i ncl u di n g t he prese nce or a bse nce of a n eff usi o n i n t he 
i n de x k nee, periartic ular pai n/te nder ness)  
•  
Se ns or y testi n g usi n g a 5 -p oi nt Li kert scale  
•  
C o nc o mita nt me dicati o ns a n d t hera pies  (i ncl u di n g bac k gr o u n d me dicati o ns) 
•  
De gree of pr oce d ure pai n  i n t he i n de x k nee o n Da y 1 a n d Wee k 2 6 ( n ot 
rec or de d as A Es) 
•  
L ocal p h ysical fi n di n gs aft er i njecti o n of t he i n de x k nee  
•  
I njecti o n site assess me nt of er yt he ma a n d e de ma. 
•  
Sta bilit y of k nee ra di o gra p hs fr o m pre -scree ni n g t o Wee k 5 2, e val uate d usi n g 
Oste oart hritis Researc h S ociet y I nter nati o nal ( O A R SI) sc ori n g criteria  
S T A TI S TI C A L 
M E T H O D S  
T he statistical a nal ysis was de vel o pe d t o meet t he re q uire me nts of t he U nite d States 
F o o d a n d Dr u g A d mi nistrati o n ( F D A) a n d t he E ur o pea n Me dici nes A ge nc y ( E M A).  
T he pri mar y a n d first ke y sec o n dar y efficac y e n d p oi nts are t he c ha n ge fr o m st u d y 
baseli ne t o Wee k 1 2 a n d Wee k 3 8, res pecti vel y, i n W O M A C A ( pai n) sc ores. A n 
M M R M a nal ysis will be perf or me d t hat i ncl u des c ha n ge fr o m st u d y baseli ne i n 
Pa ge 1 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
W O M A C A ( pai n) sc ores as t he de pe n de nt varia ble a n d ter ms f or treat me nt, p o ole d site, 
baseli ne K -L gra de cate g or y, st u d y b aseli ne B MI cate g or y, st u d y baseli ne O A t y pe, se x, 
st u d y wee k, treat me nt b y visit st u d y wee k i nteracti o n, a n d st u d y baseli ne W O M A C A 
( pai n) sc ore as a c o variate, usi n g a n u nstr uct ure d c o varia nce str uct ure. M ore details will 
be pr o vi de d i n t he statistical a na l ysis pla n ( S A P) o n h o w t o ha n dle p ote ntial 
c o n ver ge nce iss ues.  
T he sec o n d ke y sec o n dar y efficac y e n d p oi nt is t he c ha n ge fr o m st u d y baseli ne t o Wee k 
1 2 i n W O M A C C (f u ncti o n) sc ores ; it will be a nal yze d i n a ma n ner si milar t o W O M A C 
A ( pai n) sc ores .  
T hese  anal yses will be perf or me d usi n g t he I T T p o p ulati o n  a n d will be re peate d o n 
a d diti o nal p o p ulati o ns f or se nsiti vit y, as s pecifie d i n t he S A P.  
T he P GI C will be s u m marize d descri pti vel y usi n g fre q ue ncies a n d perce nta ges b y st u d y 
wee k a n d treat me nt gr o u p. A r esp o n der a nal ysis will be perf or me d f or eac h visit f or t he 
P GI C i n w hic h res p o n ders ( P GI C of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) will be 
c o m pare d t o n o n -res p o n ders.  
A nal ysis of t he c ha n ge fr o m st u d y baseli ne t o eac h st u d y wee k i n t he a vera ge pai n wit h 
wal k i n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs (a vera ge wee kl y pai n wit h 
wal ki n g N P R S [ 0 -1 0]), will c o me fr o m t he M M R M use d f or t he pri mar y a nal ysis a n d 
will be deri ve d usi n g c o ntrast state me nts wit hi n t hat m o del. T he M M R M a nal ysis will 
be prese nte d s h o w i n g all st u d y wee ks. T his a nal ysis will be base d o n a w orst 
o bser vati o n carrie d f or war d ( W O C F) a p pr oac h t hat will re place sc ores occ urri n g o n a 
da y w here resc ue me dicati o n was ta ke n wit h t he w orst o bser vati o n starti n g at Da y 2 . 
Details will be s pe cifie d i n t he S A P.  
C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n W O M A C A ( pai n) a n d C (f u ncti o n) sc ores 
will be a nal yze d usi n g a n M M R M wit h t he sa me ter ms as t hat descri be d f or t he pri mar y 
a nal ysis. 
All sec o n dar y efficac y a nal yses will be perf or me d usi n g t he I T T p o p ula ti o n, u nless 
ot her wise s pecifie d.  Se nsiti vit y a nal yses of sec o n dar y efficac y e n d p oi nts will be 
s pecifie d i n t he S A P. 
All s u p p orti ve a n d e x pl orat or y efficac y a nal yses will be perf or me d usi n g t he I T T 
p o p ulati o n. A n y P  val ues pr o vi de d i n a nal yses i n t his sect i o n will be i nf or mati o nal o nl y 
a n d n ot use d i n t he fi xe d -se q ue nce testi n g. 
T he t y pe I err or rate of α = 0. 0 5 will be mai ntai ne d f or t he st u d y b y usi n g a 
fi xe d-se q ue nce testi n g strate g y f or pri mar y, ke y sec o n dar y, a n d sec o n dar y e n d p oi nts. If 
t he pri mar y e n d p oi nt has P  ≤ 0. 0 5, t he n t he f ull α = 0. 0 5 will be passe d t o t he  ke y  
sec o n dar y e n d p oi nt s t he n sec o n dar y e n d p oi nts f or c o nti n ue d fi xe d-se q ue nce testi n g i n 
t he or der liste d; testi n g will st o p at t he first P  val ue > 0. 0 5 . T he fi xe d-se q ue nce testi n g 
will be  base d o n t he or der liste d  i n t he pri mar y, ke y sec o n dar y, a n d sec o n dar y 
e n d p oints, i n or der t o meet re g ulat or y re q ui re me nts. 
All ot her c o nti n u o us sec o n dar y a n d e x pl orat or y efficac y e n d p oi nt s will be s u m marize d 
usi n g descri pti ve statistics b y treat me nt gr o u p a n d wee k/ visit, as a p pr o priate, a n d 
a nal yze d usi n g a n M M R M a nal ysis or b y a n al ysis of c o varia nce, as a p pr o priate.  
Cate g orical e n d p oi nts will be c o m pare d bet wee n  treat me nts usi n g Pears o n’s c hi-s q uare 
or Fis her’s e xact test, as a p pr o priate.  
Safet y a nal yses will be c o n d ucte d usi n g da ta fr o m t he safet y p o p ulati o n. N o f or mal 
i nfere ntial a nal yses will be c o n d ucte d f or safe t y varia bles u nless ot her wise n ote d. 
A n y data a nal yses i ncl u de d i n t he u n bli n de d deli ver y will be c o nsi dere d fi nal, a n d n o 
c ha n ges t o t he a nal ysis res ults will be per mitte d f oll o wi n g u n bli n di n g. T he e ntire pr oject 
st u dy tea m (i ncl u di n g t he pr oject statisti cia n) will re mai n bli n de d u ntil t he fi nal data base 
l oc k.  
Pa ge 1 2 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
S A M P L E SI Z E 
D E T E R MI N A TI O N  
A p pr o xi matel y 3 2 5  s u bjects will be ra n d o mize d t o place b o (a p pr o xi matel y 
1 2 5  s u bjects) a n d t o C N T X -4 9 7 5 -0 5 (a p pr o xi matel y 2 0 0  s u bjects). 
I n t he pre vi o us versi o n s of t he  pr ot oc ol ( Versi o n s 1. 0 & 2. 0), t he pri mar y e n d p oi nt was 
a vera ge wee kl y pai n wit h wal ki n g N P R S ( 0 -1 0) t o Wee k 1 2. T he sa m ple size a n d p o wer 
calc ulati o ns were base d o n t hat e n d p oi nt.  
Res ults fr o m st u d y C N T X -4 9 7 5 -O A -5 0 2 pr o v i de d a sta n dar d de viati o n (S D)  of 2. 5 5 
a n d mea n c ha n ges fr o m baseli ne  of -3. 0 2 a n d -4. 4 2 f or place b o a n d 
 of C N T X -
4 9 7 5, res pecti vel y. Ass u mi n g a n effect size of 0. 5 , a sa m ple size of 2 9 3 e val ua ble 
s u bjects at Wee k 1 2 wit h a 2: 3 all ocati o n ( place b o t o  acti ve) will ac hie ve 9 8 % s tatistical 
p o wer f or ha vi n g a si g nifica nt C N T X -4 9 7 5 -0 5 a n d place b o c o m paris o n , usi n g a t w o -
si de d test at t he 5 % si g nifica nce le vel. A p o wer of 9 8 % was use d f or t he pri mar y 
a nal ysis at Wee k 1 2 i n or der t o mai ntai n a de q uate p o wer f or c o m paris o ns at later ti me 
p oi nts  o n t he pri mar y o utc o me a n d ke y sec o n dar y o utc o me meas ures .  
Pre vi o us k e y sec o n dar y o utc o mes, W O M A C B  (stiff ness) a n d W O M A C C (f u ncti o n), 
are p o were d at 7 5 % a n d 7 1 %, res pecti vel y, at Wee k 1 2 (t he pri mar y e n d p oi nt) usi n g a n 
N of 2 9 3  f or t he trial. T o acc o u nt f or dr o p o uts a n d s u bjects f or safet y e val uati o n, t he 
i nitial pla n ne d e nr oll me nt is a p pr o xi matel y 3 2 5 s u bjects (a p pr o xi matel y 1 2 5 s u bjects i n 
place b o a n d 2 0 0 s u bjects i n C N T X -4 9 7 5 -0 5).  
I n t his versi o n of t he pr ot oc ol ( Versi o n 3. 0), t he pri mar y e n d p oi nt is t he c ha n ge fr o m 
st u d y baseli ne t o Wee k 1 2 i n W O M A C A ( pai n). I n or der t o deter mi ne t he a p pr o xi mate 
p o wer f or t his pri mar y e n d p oi nt, a p ost h oc a nal ysis f or c ha n ge fr o m baseli ne t o 
Wee k  1 2 i n W O M A C A ( pai n) fr o m Ce ntre xi o n’s P hase 3 st u d y i n k nee O A, 
C N T X -4 9 7 5i -O A -3 0 1, was perf or me d. T he mea n c ha n ges fr o m baseli ne t o Wee k 1 2 
were -1 3. 4 3 a n d -1 6. 4 4 f or place b o a n d  
 C N T X -4 9 7 5 -0 5, res pecti vel y, wit h a 
p o ole d S D of t he p o p ulati o n of 1 1. 7 7 9 4. Wit h a calc ulate d effect size  of 0. 2 5 6, a 
statistical p o wer of 5 6 % is pre dicte d t o detect a si g nifica nt C N T X-4 9 7 5 -0 5 a n d place b o 
c o m paris o n, usi n g a 2 -si de d test at t he 5 % si g nifica nce le vel. 
S T U D Y A N D 
T R E A T M E N T 
D U R A TI O N  
T he o verall ma xi m u m st u d y d urati o n is e x pecte d t o be a p pr o xi mat el y 5 8  wee ks.  T he 
se q ue nce a n d ma xi m u m d urati o n of t he st u d y peri o ds will be as f oll o ws: 
•  
Pre -Scree ni n g  (s u bjects s h o ul d ret ur n f or Scree ni n g  as s o o n as feasi ble)  
•  
Scree ni n g Peri o d: u p t o 3 0 da ys  + 3 -da y wi n d o w  
•  
Treat me nt Peri o d ( d o u ble -bli n d, place b o -c o ntr olle d): first d ose at Da y 1 (1 da y ); 
sec o n d d ose at Wee k 2 6  (1  da y ) 
•  
P ost -Treat me nt D o u ble -Bli n d p eri o d: 5 2 wee ks 
T he ma xi m u m I P treat me nt peri o d f or eac h s u bject is 2 da ys. 
T he ma xi m u m st u d y d urati o n f or eac h s u bject is a p pr o xi matel y 5 8  wee ks.  
Pa ge 1 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
3.  T A B L E O F C O N T E N T S  
1.  A P P R O V A L SI G N A T U R E S  ...................................................................................................2  
2.  S Y N O P SI S  ...............................................................................................................................3  
3.  T A B L E O F C O N T E N T S  .......................................................................................................1 4  
3. 1.  LI S T O F  T A B L E S  ........................................................................................................1 9  
R E A S O N S F O R A M E N D M E N T ( 3. 0)  .........................................................................................2 0  
S U M M A R Y O F A M E N D E D S E C TI O N S ( 3. 0)  ...........................................................................2 1  
A M E N D E D P R O T O C O L  .............................................................................................................2 3  
4.  LI S T O F A B B R E VI A TI O N S  .................................................................................................2 4  
5.  I N T R O D U C TI O N ..................................................................................................................2 7  
5. 1.  Bac k gr o u n d a n d Rati o nale  ............................................................................................2 7  
5. 1. 1  Ca psaici n f or I njecti o n ( C N T X -4 9 7 5 -0 5)  .........................................................2 7  
5. 2.  Cli nical E x perie nce  .......................................................................................................2 7  
5. 3.  S u m mar y of P ote ntial Ris ks a n d Be nefits  .....................................................................2 9  
6.  O BJ E C TI V E S  .........................................................................................................................3 1  
6. 1.  Pri mar y Efficac y O bjecti ve  ...........................................................................................3 1  
6. 2.  Sec o n dar y Efficac y O bjecti ves  .....................................................................................3 1  
6. 3.  E x pl orat or y Efficac y O bjecti ve s ...................................................................................3 1  
6. 4.  S u p p orti ve Efficac y O bjecti ve  ......................................................................................3 1  
6. 5.  Safet y O bjecti ve:  ...........................................................................................................3 1  
7.  S T U D Y D E SI G N  ...................................................................................................................3 2  
7. 1.  O verall St u d y Desi g n a n d Pla n  .....................................................................................3 2  
7. 2.  Disc ussi o n of St u d y Desi g n  ..........................................................................................3 3  
7. 3.  St u d y Site(s)  ..................................................................................................................3 3  
7. 4.  St u d y M o dificati o ns f or t he C O VI D -1 9 Pa n de mic  .......................................................3 3  
8.  S U BJ E C T P O P U L A TI O N  .....................................................................................................3 4  
8. 1.  Selecti o n of St u d y P o p ulati o n a n d Dia g n osis  ...............................................................3 4  
8. 2.  St u d y E ntr y Criteria  ......................................................................................................3 4  
8. 2. 1  I nclusi o n Criteria  ...............................................................................................3 4  
8. 2. 2  E xcl usi o n Criteria  ..............................................................................................3 6  
8. 3.  Pre mat ure S u bject Wit h dra wal  .....................................................................................3 8  
8. 4.  S u bject Re place me nt Criteria  ........................................................................................3 8  
9.  T R E A T M E N T S  ......................................................................................................................3 9  
9. 1.  I de ntificati o n of I n vesti gati o nal Pr o d uct(s) ..................................................................3 9  
9. 2.  La beli n g a n d Pac ka gi n g  ................................................................................................3 9  
9. 3.  Treat me nts A d mi nistere d  ..............................................................................................3 9  
9. 4.  Dis pe nsi n g a n d St ora ge  .................................................................................................4 0  
9. 5.  Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps  ....................................................4 0  
Pa ge 1 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
9. 6.  Bli n di n g a n d U n bli n di n g Treat me nt Assi g n me nt  .........................................................4 1  
9. 7.  Selecti o n of D ose i n t he St u d y  ......................................................................................4 2  
9. 8.  D os e A dj ust me nt Criteria  ..............................................................................................4 2  
9. 9.  Selecti o n of Ti m i n g of D ose f or Eac h S u bject..............................................................4 2  
9. 1 0.  Dr u g Acc o u nta bilit y  ......................................................................................................4 2  
9. 1 1.  Treat me nt C o m plia nce  ..................................................................................................4 2  
9. 1 2.  Per mitte d a n d Pr o hi bite d T hera pies  ..............................................................................4 3  
9. 1 2. 1  Resc ue Me dicati o n f or O A K nee Pai n  ..............................................................4 3  
9. 1 2. 2  Pr o hi bite d T hera pies  ..........................................................................................4 4  
9. 1 3.  Treat me nt After E n d of  St u d y  .......................................................................................4 4  
1 0.  S T U D Y P R O C E D U R E S  ........................................................................................................4 5  
1 0. 1.  S t u d y Peri o ds a n d Visits ...............................................................................................4 5  
1 0 . 1. 1 Pre -Scree ni n g a n d Scree ni n g, Da y -3 0 t o Da y 1  ...............................................4 5  
1 0. 1. 1. 1  Pre -Scree ni n g Visit  ...............................................................................4 5  
1 0. 1. 1. 2  Scree ni n g Visit, Visit 1  .........................................................................4 5  
1 0. 1. 2  Treat me nt 1, Da y 1, Visit 2  ...............................................................................4 6  
1 0. 1. 3  D o u ble -bli n d P ost -treat me nt 1 Assess me nt a n d O bser vati o n Peri o d, Da y 3 t o 
Wee k  1 8, Visit 3 t o Visit 7  ................................................................................4 7  
1 0. 1. 3. 1  Da y 3, Te le p h o ne Visit 3 ......................................................................4 7  
1 0 . 1. 3. 2 Wee k 4, Visit 4  ......................................................................................4 7  
1 0. 1. 3. 3  Wee k 8, Visit 5  ......................................................................................4 8  
1 0. 1. 3. 4  Wee k 1 2, Visit 6  ....................................................................................4 8  
1 0. 1. 3. 5  Wee k 1 8, Visit 7  ....................................................................................4 9  
1 0. 1. 4  T reat me nt 2, Wee k 2 6, Visit 8 ..........................................................................4 9  
1 0. 1. 5  D o u ble -bli n d P ost -treat me nt 2 Assess me nt a n d O bser vati o n Peri o d, Da y 3 t o 
Wee k 4 6, Visit 9 t o  Visit 1 2  ..............................................................................5 0  
1 0. 1. 5. 1  Da y 3, Tele p h o ne Visit 9  ......................................................................5 0  
1 0. 1. 5. 2  Wee k 3 0, Visit 1 0  ..................................................................................5 1  
1 0. 1. 5 . 3 Wee k 3 8, Visit 1 1  ..................................................................................5 1  
1 0. 1. 5. 4  Wee k 4 6, Visit 1 2  ..................................................................................5 2  
1 0. 1. 6  Fi nal/ Earl y Ter mi nati o n ( E T) Visit, Wee k 5 2, Visit 1 3  ....................................5 2  
1 0. 2.  St u d y D urati o n  ..............................................................................................................5 3  
1 0. 2. 1  O verall St u d y Sc he d ule  .....................................................................................5 3  
1 0. 3.  Assess me nts  ..................................................................................................................5 3  
1 0. 3. 1  Efficac y  .............................................................................................................5 3  
1 0. 3. 1. 1  K nee Pai n, Stiff ness a n d F u ncti o n: Wester n O ntari o a n d Mc Ma ster 
U ni versities Art hritis I n de x ( W O M A C)  ................................................................5 3  
1 0. 3. 1. 2  Patie nt Gl o bal I m pressi o n of C ha n ge i n K nee Pai n  ..............................5 4  
1 0. 3. 1. 3  A vera ge Wal ki n g O A K nee Pai n ( N P R S)  ............................................5 4  
Pa ge 1 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0. 3. 1. 4  K nee I nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S)  ......................5 4  
1 0. 3. 1. 5  Me dical O utc o mes St u d y ( M O S) Slee p Scale  ......................................5 4  
1 0. 3. 1. 6  Q ualit y of Life ( E Q -5 D -5 L)  ..................................................................5 5  
1 0. 3. 1. 7  S h ort F or m -3 6 Healt h Stat us Q uesti o n naire  .........................................5 5  
1 0. 3. 1. 8  W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Scale ( W P AI)  .................5 5  
1 0. 3. 1. 9  Assisti ve De vice Usa ge  .........................................................................5 6  
1 0. 3. 1. 1 0  Resc ue Me dicati o n Use  .........................................................................5 6  
1 0. 3. 2  Cli nical P har mac ol o g y  ......................................................................................5 6  
1 0. 3. 3  Safet y  .................................................................................................................5 6  
1 0. 3. 3. 1  La b orat or y Safet y Assess me nts  ............................................................5 6  
1 0. 3. 3. 2  Cli nical E xa mi nati o ns  ...........................................................................5 8  
1 0. 3. 3. 3  Assess me nt of Pr oce d ure Pai n  ..............................................................5 9  
1 0. 3. 3. 4  Assess me nt of Satisfacti o n wit h t he Treat me nt Pr oce d ure  ...................5 9  
1 0. 3. 3. 5  Assess me nt of Sta bilit y of K nee Ra di o gra p hs (i n de x a n d n o n -i n de x 
k nees)  
5 9  
1 0. 3. 3. 6  A d verse E ve nts  .....................................................................................6 0  
1 1.  A D V E R S E E V E N T S  ..............................................................................................................6 1  
1 1. 1.  Defi niti o ns  .....................................................................................................................6 1  
1 1. 1. 1  A d verse E ve nts  ..................................................................................................6 1  
1 1. 1. 2  A d verse Dr u g Reacti o n  .....................................................................................6 1  
1 1. 1 . 3 U ne x pecte d A d verse E ve nt/ A d verse Dr u g Reacti o n  ........................................6 1  
1 1. 1. 4  Seri o us A d verse E ve nts/ Dr u g Reacti o n  ............................................................6 2  
1 1. 1. 5  Si g nifica nt A d verse E ve nts  ...............................................................................6 2  
1 1. 1. 6  Treat me nt -E mer ge nt A d verse E ve nts  ...............................................................6 2  
1 1. 2.  Ma na ge me nt of A d verse E ve nts  ...................................................................................6 2  
1 1. 2. 1  A d verse E ve nt of S pecial I nterest: Se vere Aller gic Reacti o n –  A na p h yla xis/ 
A na p h ylact oi d Reacti o n  ....................................................................................6 3  
1 1. 2. 2  C ollecti o n  ..........................................................................................................6 4  
1 1. 2. 3  E val uati o n  ..........................................................................................................6 4  
1 1. 2. 3. 1  Se verit y of A d verse E ve nts  ...................................................................6 4  
1 1. 2. 3. 2  Seri o us ness  ............................................................................................6 5  
1 1. 2. 3. 3  Act i o n(s) Ta ke n .....................................................................................6 5  
1 1. 2. 3. 4  O utc o me at t he Ti me of Last O bser vati o n  ............................................6 5  
1 1. 2. 3. 5  A d verse E ve nt Relati o ns hi p t o I n vesti ga ti o nal Pr o d uct........................6 6  
1 1. 2. 4  D oc u me ntati o n  ..................................................................................................6 6  
1 1. 2. 5  Treat me nt of A d verse E ve nts  ............................................................................6 6  
1 1. 2. 6  F oll o w -u p  ..........................................................................................................6 7  
1 1. 2. 7  N otificati o n  ........................................................................................................6 7  
1 1. 2. 7. 1  Seri o us A d verse E ve nts .........................................................................6 7  
Pa ge 1 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 1. 2. 7. 2  A d verse Dr u g Reacti o ns  .......................................................................6 8  
1 1. 2. 7. 3  N o n -Seri o us A d verse E ve nts  ................................................................6 8  
1 1. 3.  S pecial C o nsi derati o ns  ..................................................................................................6 8  
1 1. 3. 1  Pre g na nc y  ..........................................................................................................6 8  
1 1. 3. 2  O ver d ose  ............................................................................................................6 9  
1 2.  D A T A S A F E T Y M O NI T O RI N G B O A R D  ...........................................................................6 9  
1 3.  S T A TI S TI C S  ..........................................................................................................................7 0  
1 3. 1.  St u d y E n d p oi nts  ............................................................................................................7 0  
1 3. 1. 1  Pri mar y Efficac y E n d p oi nts  ..............................................................................7 0  
1 3. 1. 2  Ke y Sec o n dar y Efficac y E n d p oi nts:  ..................................................................7 0  
1 3. 1. 3  Sec o n dar y Efficac y E n d p oi nts  ..........................................................................7 0  
1 3. 1. 4  E x pl orat or y Efficac y E n d p oi nts  ........................................................................7 1  
1 3. 1. 5  S u p p orti ve Efficac y E n d p oi nts  ..........................................................................7 2  
1 3. 1. 6  Safet y E n d p oi nts  ................................................................................................7 3  
1 3. 2.  Sa m ple Size Deter mi nati o n  ...........................................................................................7 3  
1 3. 3.  A nal ysis P o p ulati o ns  .....................................................................................................7 4  
1 3. 4.  Statistical A nal yses  .......................................................................................................7 5  
1 3. 4. 1  St u d y S u bjects a n d De m o gra p hics  ....................................................................7 5  
1 3. 4. 1. 1  Dis p ositi o n a n d Wit h dra wals  ................................................................7 5  
1 3. 4. 1. 2  Pr ot oc ol De viati o ns  ...............................................................................7 5  
1 3. 4. 1. 3  De m o gra p hics a n d Ot her Baseli ne C haracteristics  ...............................7 5  
1 3. 4. 2  E x p os ure a n d C o m plia nce  .................................................................................7 6  
1 3. 4. 3  Efficac y A nal yses  ..............................................................................................7 6  
1 3. 4. 3. 1  Pri mar y Efficac y E n d p oi nt A nal ysis  .....................................................7 6  
1 3. 4. 3. 2  Ke y Sec o n dar y Efficac y E n d p oi nts A nal yses  .......................................7 7  
1 3. 4. 3. 3  Sec o n dar y Efficac y E n d p oi nts A nal yses  ..............................................7 7  
1 3. 4. 3. 4  E x pl orat or y Efficac y A nal yses  .............................................................7 8  
1 3. 4. 3. 5  S u p p orti ve Efficac y A nal yses  ...............................................................7 8  
1 3. 4. 4  Safet y a n d T olera bilit y A nal yses  ......................................................................7 8  
1 3. 4. 4. 1  A d verse E ve nts  .....................................................................................7 8  
1 3. 4. 4. 2  Cli nical La b orat or y E val uati o ns  ...........................................................7 8  
1 3. 4. 4. 3  Vital Si g ns  .............................................................................................7 9  
1 3. 4. 4. 4  Electr ocar di o gra ms  ...............................................................................7 9  
1 3. 4. 4. 5  P h ysical E xa mi nati o n Fi n di n gs  .............................................................7 9  
1 3. 4. 4. 6  I njecti o n Site Assess me nt .....................................................................7 9  
1 3. 4. 4. 7  Se ns or y Testi n g  .....................................................................................7 9  
1 3. 4. 4. 8  Pr oce d ure Pai n  ......................................................................................8 0  
1 3. 4. 4. 9  Satisfacti o n wit h t he Treat me nt Pr oce d ure  ...........................................8 0  
Pa ge 1 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 3. 4. 4. 1 0  K nee Ra di o gra p hs  .................................................................................8 0  
1 3. 4. 5  I nteri m A nal ysis ................................................................................................8 0  
1 4.  S T U D Y C O N D U C T  ...............................................................................................................8 1  
1 4. 1.  S p o ns or a n d I n vesti gat or Res p o nsi bilities  ....................................................................8 1  
1 4. 1. 1  S p o ns or Res p o nsi bilities  ...................................................................................8 1  
1 4. 1. 2  I n vesti gat or Res p o nsi bilities .............................................................................8 1  
1 4. 2.  Site I nitiati o n  .................................................................................................................8 1  
1 4. 3.  Scree n  Fail ures  ..............................................................................................................8 2  
1 4. 4.  St u d y D oc u me nts  ..........................................................................................................8 2  
1 4. 4. 1  G o o d Cli nical Practice D oc u me nts  ...................................................................8 2  
1 4. 4. 2  Case Re p ort F or ms  ............................................................................................8 2  
1 4. 4. 3  S o urce D oc u me nts  .............................................................................................8 3  
1 4. 5.  Data Q ualit y C o ntr ol  .....................................................................................................8 3  
1 4. 5. 1  M o nit ori n g Pr oce d ures  ......................................................................................8 3  
1 4. 5. 2  Data Ma na ge me nt  ..............................................................................................8 4  
1 4. 5. 3  Q ualit y Ass ura nce/ A u dit  ...................................................................................8 4  
1 4. 6.  St u d y Ter mi nati o n  .........................................................................................................8 4  
1 4. 7.  St u d y Site Cl os ure  .........................................................................................................8 4  
1 4. 7. 1  Rec or d Rete n ti o n ...............................................................................................8 5  
1 4. 8.  C ha n ges t o t he Pr ot oc ol  ................................................................................................8 5  
1 4. 9.  Use of I nf or mati o n a n d P u blicati o n  ..............................................................................8 5  
1 5.  E T HI C A L A N D L E G A L C O N SI D E R A TI O N S  ....................................................................8 7  
1 5. 1.  Declarati o n of Helsi n ki a n d G o o d Cli nical Practice  .....................................................8 7  
1 5. 2.  S u bject I nf or mat i o n a n d I nf or me d C o nse nt ..................................................................8 7  
1 5. 3.  A p pr o val b y I nstit uti o nal Re vie w B oar d  ......................................................................8 7  
1 5. 4.  Fi na nce a n d I ns ura nce  ...................................................................................................8 7  
1 6.  R E F E R E N C E S  .......................................................................................................................8 8  
1 7.  A T T A C H M E N T S  ...................................................................................................................8 9  
1 7. 1.  Sc he d ule of E ve nts  ........................................................................................................8 9  
1 7. 2.  I n vesti gat or’s A gree me nt ..............................................................................................9 5  
A P P E N DI C E S  ...............................................................................................................................9 6  
A.  
St u d y S pecific Re q uire me nts  ........................................................................................9 7  
B.  
Re g ulati o ns a n d G o o d Cli nical Practice G ui deli nes  .....................................................9 8  
1.  
Re g ulati o ns  ........................................................................................................9 8  
1.  
G o o d Cli nical Practice  G ui deli nes  ....................................................................9 8  
C.  
Se vere Aller gic Reacti o n –  A na p h yla xis/ A na p h ylact oi d Reacti o n  .............................9 9  
D.  
C O VI D -1 9 Me m o t o St u d y Site s ................................................................................1 0 0  
 
Pa ge 1 8 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
3. 1.  L I S T O F T A B L E S 
Ta ble 9 -1: Resc ue Me dicati o n La d der f or Pai n Relief  ..................................................................4 3  
Ta ble 1 7 -1: Sc he d ule of E ve nts  .....................................................................................................8 9  
 
 
 
 
Pa ge 1 9 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pa ge 2 1 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
A M E N D E D P R O T O C O L  
T he f oll o wi n g are t he a me n de d pr ot oc ol a n d a p pe n dices, i ncl u di n g all re visi o ns s pecifie d a b o ve.  
 
Pa ge 2 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
4.  LI S T O F A B B R E VI A TI O N S  
A C L S  
A d va nce d Car di ac Life S u p p ort   
A C R  
A merica n C olle ge of R he u mat ol o g y  
A D L  
acti vities of dail y li vi n g  
A D R  
a d ver se dr u g reacti o n 
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nts of s pecial i nterest  
A L T  
ala ni ne tra nsa mi nase  
A S T  
as partate tra nsa mi nase 
A T C  
A nat o mical T hera pe utic C he mical class 
A U C  
area u n der t he c ur ve  
B H T  
b ut ylate d h y dr o x yt ol ue ne  
bi d  
t wice dail y 
B MI  
b o d y  mass i n de x  
C N S  
ce ntral ner v o us s yste m 
C R A  
cli nical researc h ass ociate  
C R F  
case re p ort f or m  
C S R  
cli nical st u d y re p ort  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure  
E D T A  
et h yle ne dia mi netetraacetic aci d  
E M A  
E ur o p ea n Me dici nes A ge nc y  
e P R O 
electr o nic patie nt -re p orte d o utc o mes 
E Q -5 D -5 L  
fi ve-le vel versi o n of t he E ur o Q ol fi ve-di me nsi o nal q uesti o n naire  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S S  
Fi br o m yal gia S y m pt o m Scale s Sc ore  
G C P  
G o o d Cli nical Practice  
h  
h o ur  
H A D S  
H os pital  A n xiet y a n d / or De pressi o n Scale  
H g b A 1c  
h e m o gl o bi n A 1c  
H R  
heart rate  
Pa ge 2 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
I A 
i ntra-artic ular 
I B 
I n vesti gat or’s br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P h ar mace uticals f or H u ma n U se 
I P 
i n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve we b res p o nse s yste m 
I T T 
i nte nt-t o-treat 
K -L  
Kell gre n -La wre nce  
K O O S  
K nee I nj ur y a n d Oste oart hritis O utc o me Sc ore  
L O C  
le vel of c o nsci o us ness 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
mi xe d -m o del re peate d meas ures   
M O S  
Me dical O utc o mes St u d y slee p scale  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
N P R S  
n u meric p ai n rati n g scale  
N S AI D  
n o nster oi dal a nti-i nfla m mat or y dr ug  
O A  
oste oart hritis  
O A R SI  
Oste oart hritis Researc h S ociet y I nter nati o nal  
O M E R A C T  
O utc o me Meas ures i n R he u mat ol o g y  
O T C  
o ver t he c o u nter  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P K  
p har mac o ki netics  
P O  
per os  ( b y m o ut h; oral) 
P P  
Per pr ot oc ol  
P R N  
pr o r e nata  (as nee de d) 
q d  
o nce dail y  
QI D  
f o ur ti mes dail y 
Q O L  
q ualit y of life  
R B C  
re d bl o o d cells 
R R  
res pirat or y rate 
S A E  
seri o us a d verse e ve nt 
Pa ge 2 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S O C  
s yste m or ga n class  
S p ort/ Rec  
S p ort a n d Recreati o n  
T R P V 1  
tra nsie nt rece pt or p ote ntial va nill oi d s u bfa mil y me m ber 1 
U A D R  
u ne x pecte d a d verse dr u g reacti o n   
U A E  
u ne x pecte d a d verse e ve nt  
W B C  
w hite bl o o d cells  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O M A C  
Wester n O ntari o a n d Mc Master U ni versit ies Oste oart hritis I n de x 
W P AI  
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Scale  
Pa ge 2 6 of 1 3 3






Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
t he pr oce d ure pai n was s h ort-li ve d (t y picall y u n der 1 ho ur [ h] ) a n d was u n der satisfact or y c o ntr ol 
at t he ti me t he patie nt was disc har ge d fr o m t he cli nic.  
St u d y 4 9 7 5 -O A -5 0 1 i ncl u de d 3 0 s u bjects wit h O A of t he k nee w h ose i n de x k nee was treate d 
wit h 
 C N T X-4 9 7 5 I A.  T he f oc us of t his st u d y was t o f urt her ma na ge pr oce d ural pai n.  
T he res ults s u g geste d t he  best a p pr oac h i ncl u de d a c o m bi nati o n of o pi oi d pre -me dicati o n, 
1 5  m L  of li d ocai ne ( 2 %, wit h o ut e pi ne p hri ne) I A 1 5 -3 0 mi n utes bef ore I P i njecti on, c o m bi ne d 
wit h j oi nt c o oli n g . 
I n St u d y 4 9 7 5 -O A -5 0 2, t he safet y pr ofile of C N T X -4 9 7 5 -0 4 (re gar dless of d ose) wa s si milar t o 
t hat of place b o fr o m Da y 2 t hr o u g h Wee k 2 4. O n Da y 1 (t he da y of I P i njecti o n) at 2 h p ost-
i njecti o n, l ocal, mil d, or m o derate e de ma was o bser ve d i n 1 1. 4 %, 1 7. 6 %, a n d 1 6. 9 % of t he 
s u bjects i n t he place b o,  
 C N T X-4 9 7 5 -0 4, a n d  
 C N T X -4 9 7 5 -0 4 gr o u ps, 
res pecti vel y. At t he sa me ti me p oi nt, l ocal, mil d, or m o derate er yt he ma was o bser ve d i n 5. 7 %, 
5. 9 %, a n d 1. 4 % of t he s u bjects i n t he place b o,  
 C N T X -4 9 7 5 -0 4, a n d  
 
C N T X -4 9 7 5 -0 4 gr o u ps, res pecti vel y . T here were n o safet y si g nals or ad verse tre n ds relate d t o 
C N T X -4 9 7 5 -0 4 o bser ve d i n a n y of t he safet y para meter assess me nts. O verall, b ot h 
C N T X -4 9 7 5 -0 4 a n d t he i njecti o n pr oce d ur e were well t olerate d b y s u bjects 4 5 t o 8 0 years of a ge 
wit h O A i n t he k nee.  
T he prese nt st u d y, C N T X -4 9 7 5 i-O A -3 0 4 , is 1 of 2 pla n ne d p hase 3  pi v otal  st u dies a n d will be 
c o n d ucte d i n t he U S i n a p pr o xi matel y 3 2 5 s u bjects wit h m o derate-t o-se vere O A k nee pai n. T he 
st u d y desi g n is a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 2 -i njecti o n, 5 2-wee k st u d y t o 
e val uate t he efficac y a n d safet y of a n i nitial i njecti o n (at Baseli ne) a n d a sec o n d i njecti o n (at 
Wee k 2 6) of 
 of C N T X-4 9 7 5 -0 5, c o m pare d t o place b o , de li vere d i ntra-artic ularl y, t o t he 
i n de x k nee i n s u bjects wit h c hr o nic m o derate-t o-se vere O A k nee pai n. T he ot her 5 2 wee k 
p hase  3  pi v otal st u d y, C N T X-4 9 7 5 i-O A -3 0 1, will als o be c o n d ucte d i n t he U nite d St ates usi n g a 
si milar desi g n t o C N T X -4 9 7 5 i-O A -3 0 4 , e xcept t here will be o nl y a si n gle i njecti o n (at Baseli ne) 
of 
 of C N T X-4 9 7 5 -0 5, c o m pare d t o place b o .  
5. 3.  S u m m ar y of P ote nti al Ris ks a n d Be nefits  
T he p ote ntial be nefits of st u d y partici pati o n are t hat s u bjects wit h pai nf ul O A of t he k nee 1)  ma y 
e x perie nce a re d ucti o n i n ac ute a n d c hr o nic , m o derate -t o-se vere pai n as a res ult of treat me nt wit h 
C N T X -4 9 7 5 -0 5,  i n a d diti o n t o f u ncti o nal i m pr o ve me nts, i m pr o ve d q ualit y of life , a n d a decrease 
i n k nee stiff ness, a n d 2) will u n dersta n d t hat t he y are c o ntri b uti n g t o t he  scie ntific k n o wle d ge 
t hat ma y lea d t o e x pa nsi o n of t he treat me nt o pti o ns f or s u bjects wit h O A. N o ot her be nefits of 
partici pati o n are a ntici pate d.  
T he p ote ntial ris ks of st u d y partici pati o n i ncl u de t h ose ass ociate d wit h e x p os ure t o 
C N T X -4 9 7 5 -0 5  a n d t he risks of me dical e val uati o n, i ncl u di n g ve ni p u nct ure  a n d I A i njecti o n. 
S u bjects will be i njecte d wit h 2 %  li d ocai ne ( wit h o ut e pi ne p hri ne) t o pr o vi de diste nsi o n of t he 
j oi nt ca ps ule f or access t o t he w h ole j oi nt f or C N T X-4 9 7 5 -0 5 a n d sec o n daril y f or se ns or y 
bl oc k a de. I n pri nci ple, s u bjects wit h s u bsta ntial re d ucti o n of pai n a n d i m pr o ve me nt i n f u ncti o n 
after i njecti o n c o ul d o ver use t he j oi nt a n d s u bject t he i n de x j oi nt t o o ver use a n d a n accelerati o n 
of t he k nee O A.  
Pa ge 2 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
A s u m mar y of t he p har mace utical pr o perties a n d k n o w n p ote ntial ris ks of C N T X -4 9 7 5 -0 5  is 
pr o vi de d i n t he c urre nt versi o n of t he i n vesti gat or’s br oc h ure (I B).3 T he i n vesti gat or m ust 
bec o me fa miliar wit h all secti o ns of t he C N T X-4 9 7 5 I B bef ore t he start of t he s t u d y. 
Pa ge 3 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
6.  O B J E C TI V E S  
T he o bjecti ves of t his st u d y i n s u bjects wit h m o derate -t o-se vere pai n d ue t o O A  of t he k nee are 
as f oll o ws:  
6. 1.  Pri m ar y Effic ac y O bjecti ve  
•  T o de m o nstrate t he efficac y of C N T X -4 9 7 5 -0 5 ( 1. 0 m g) o n O A pai n i n t he i n de x k nee 
f oll o wi n g a n I A i njecti o n at Baseli ne, a n d als o t o assess t he i m pact of a re peat I A 
i njecti o n of C N T X-4 9 7 5 -0 5  at Wee k 2 6 o n O A pai n i n t he k nee . 
6. 2.  Sec o n d ar y Effic ac y O bjecti ves  
•  T o assess t he i m pact of a re peat I A i njecti o n of C N T X -4 9 7 5 -0 5 at Wee k 2 6 o n O A pai n 
i n t he k nee at Week 3 8.  
•  T o e val uate t he o verall i m pr o ve me nt i n O A  of t he i n de x k nee t hr o u g h Wee k  2 6.  
6. 3.  E x pl or at or y  Effic ac y O bjecti ves  
•  T o e x pl ore t he a nal gesic efficac y of C N T X -4 9 7 5 -0 5 o n O A pai n of t he i n de x k nee 
t hr o u g h 5 2  wee ks.  
•  T o e x pl ore  t he o verall be nefit o n O A of t he i n de x k nee t hr o u g h 5 2 wee ks. 
•  T o e x pl ore t he p ote ntial t o dela y t he nee d f or a t otal k nee re place me nt s ur ger y, base d o n 
t he s u bjects’ res p o nses a n d t he c o ntr ol of pai n a n d i m pr o ve me nt i n f u ncti o n, q ualit y of 
life, a n d o n slee p. 
•  T o e x pl ore  t he nee d f or resc ue a n d bac k gr o u n d a nal gesic me dicati o ns f or O A pai n i n t he 
i n de x k nee  
6. 4.  S u p p orti ve Effic ac y  O bjecti ve  
•  T o e x pl ore t he a nal gesic efficac y a n d o verall be nefit o n O A of t he i n de x k nee t hr o u g h 
Wee ks 3 8 a n d 5 2, f oll o wi n g a re peat I A i njecti o n of C N T X -4 9 7 5 -0 5 at We e k 2 6.  
6. 5.  S afet y O bjecti ve:  
•  T o  e val uate t he safet y of a n i nitial I A i njecti o n (at Baseli ne) a n d a re peat I A i njecti o n (at 
Wee k 2 6) of C N T X -4 9 7 5 -0 5 , c o m pare d t o place b o, i n t he i n de x k nee. 
 
Pa ge 3 1 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
Efficac y will be assesse d b y O A i n de x k ne e pai n wit h wal ki n g , i ncl u di n g d ura bilit y of treat me nt 
res p o nse a n d c u m ulati ve res p o n der a nal yses (c u m ulati ve a n d O utc o me Meas ures i n 
R he u mat ol o g y [ O M E R A C T] -Oste oart hri tis Researc h S ociet y I nter nati o nal [ O A R SI]; Wester n 
O ntari o a n d Mc Master U ni versities Oste oart hritis I n de x  [W O M A C ] k nee pai n , stiff ness, a n d 
f u ncti o n [W O M A C A, B a n d C, res pecti vel y ]; P atie nt Gl o bal I m pressi o n of C ha n ge [P GI C ] f or 
O A i n de x k nee pai n ; K nee I nj ur y a n d Oste oart hritis O utc o me Sc ore [K O O S ]; Me dical O utc o mes 
St u d y [M O S ] slee p scale; S F -3 6  healt h q uesti o n naire ; E Q -5 D -5 L q ualit y of life ; W or k 
Pr o d ucti vit y a n d Acti vit y I m pair me nt Scale [W P AI ]; assisti ve de vice usa ge; a n d resc ue 
me dicati o n use ).  
Saf et y will be assesse d b y i njecti o n site assess me nt (er yt he ma a n d e de ma), assess me nt of 
treat me nt pr oce d ure pai n, a d verse e ve nts ( A Es), p h ysical e xa mi nati o n fi n di n gs , se ns or y testi n g, 
vit al si g n meas ure me nts, 1 2 -lea d electr ocar di o gra ms ( E C G), cli nical la b orat or y test res ults, a n d 
t he sta bilit y of k nee ra di o gra p hs fr o m B aseli ne t o Wee k 5 2.  
All A E s o bser ve d b y t he st u d y pers o n nel or re p orte d b y t he s u bject d uri n g t he st u d y (fr o m t he 
ti me of t he si g ni n g of t he i nf or me d c o nse nt t hr o u g h t he p ost -treat me nt visit) will be d oc u me nte d. 
7. 2.  Disc ussi o n of St u d y Desi g n  
T his p hase 3 st u d y, C N T X -4 9 7 5i -O A -3 0 4 , is a ra n d o mize d, d o u ble -b li n d, p lace b o-co ntr olle d, 
2 -i njecti o n, 5 2 -w ee k st u d y t o eval uate t he efficac y a n d safet y of 1 a n d 2 I A i njecti o n s of 
C N T X -4 9 7 5 -0 5  i n su bjects wit h  chr o nic, m o derate -t o-se vere O A k nee pai n. Pr oce d ural pai n 
ass ociate d wit h I A i njecti o n of I P will be c o ntr olle d t hr o u g h pre -me dicati o n wit h I A li d ocai ne 
a n d a dj u nct c o ntr olle d  j oi nt c o oli n g. T he pla n ne d safet y a n d efficac y assess me nts are sta n dar d 
a n d a p p r o priate. 
7. 3.  St u d y Site(s)  
T he st u d y will ta ke place at a p pr o xi matel y 3 0  c o nc urre nt sites i n t he U S . Eac h site is a ntici pate d 
t o scree n a s ufficie nt n u m ber of s u bjects to be a ble t o ra n d o mize a p pr o xi matel y 3 2 5  s u bjects. A 
st u d y site wit h a n acce pta ble  recr uitme nt rate a n d acce pta ble q ualit y metrics ma y  be a ll o we d t o 
recr uit m ore s u bjects if ot her sites ha ve u n der  e nr oll me nt . 
7. 4.  St u d y M o dific ati o ns f or t he C O VI D -1 9 P a n de mic  
O n 2 4 -A pril  2 0 2 0, a me m o was se nt t o all Pri nci pal I n vesti gat ors a n d St u d y Staff detaili n g  
a dj ust me nts t hat were bei n g ma de t o all o w f or t he safet y of b ot h st u d y s u bjects a n d st u d y staff 
f oll o wi n g t he o nset of t he C O VI D-1 9 pa n de mic  (see A p pe n di x D). At t he ti me t hat t his me m o 
was se nt t o t he st u d y sites, all s u bjects ha d alrea d y bee n e nr olle d.  
T hese a dj ust me nts i ncl u de d  a wi de ni n g of t he wi n d o w f or t he Wee k 5 2 fi nal vi sit as well as t he 
We e k 5 2 ra di o gra p h. T he ori gi nal wi n d o w of +/ - 7 b usi ness da ys was i ncrease d t o -1 4/ + 1 2 0 
b usi ness da ys.  
 
Pa ge 3 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
8.  S U B J E C T P O P U L A TI O N   
8. 1.  Selecti o n of St u d y P o p ul ati o n  a n d Di a g n osis  
Base d o n  t he mec ha nis m of acti o n a n d use of tra ns -ca psaici n f or t he treat me nt of pai n, t here are 
n o ge n der -s pecific a d verse effects k n o w n or t o be e x pecte d. T h us, male a n d fe male s u bjects will 
be i ncl u de d i n t he st u d y.  A scree ni n g l o g of p ote ntial s t u d y ca n di dates a n d/ or a n e nr oll me nt l o g 
of e nr olle d s u bjects m ust be mai ntai ne d at eac h st u d y site.  
8. 2.  St u d y E ntr y  Criteri a   
8. 2. 1  I ncl usi o n Criteri a 
A s u bject will be eli gi ble f or st u d y partici pati o n if t he s u bject meets all of t he f oll o wi n g criteria:  
1.  Male or fe m ale s u bjects bet wee n 4 0 a n d 9 5 years of a ge (i ncl usi ve) at t he ti me of t he 
Scree ni n g Visit wit h t he a bilit y t o c o m pl y wit h a ns weri n g t he elect r o nic diar y usi n g t he 
st u d y-pr o vi de d ta blet  c o m p uter s. 
2.  C o nfir mati o n of O A of t he k nee: r a di o gra p h y of b ot h k nees w it h a p osteri or-a nteri or, 
fi xe d-fle xi o n vie w ta ke n d uri n g t he Pre -scree ni n g Peri o d . T he i n de x k nee m ust s h o w 
e vi de nce of c hr o nic O A wit h a K -L  g ra de of 2, 3 a n d 4.  T he I R T s yste m will li mit t he 
n u m ber of K -L gra de 4 s u bjects t o a p pr o xi matel y 5 5 s u bjects (a p pr o xi matel y 2 0 % of 
e nr oll me nt).  
3.  C o nfir mati o n of O A of t he i n de x k nee: A merica n C olle ge of R he u mat ol o g y ( A C R) 
dia g n ostic criteria.  
4.  M o derate t o se vere pai n i n t he i n de x k nee ass ociate d wit h O A m ust be sta ble f or a mi ni m u m 
of 6 m o nt hs pri or t o Scree ni n g, as assesse d b y t he in vesti gat or.  
5.  F or q ualif yi n g Baseli ne k nee pai n wit h wal ki n g, t he Baseli ne sc ore will be deri ve d fr o m t he 
1 4 da ys o f pre-d ose pai n sc ores c ollecte d i m me diatel y prece di n g s u bject ra n d o mizati o n o n 
Da y 1. T he Baseli ne pai n sc ore will be calc ul ate d b y t he ra n d o mizati o n al g orit h m as t he 
mea n of t he sc ores fr o m t he 1 4 da ys ( or at a mi ni m u m, 8 da ys) i m me diatel y prece di n g Da y 1. 
S u bjects m ust use a n u meric pai n rati n g scale ( N P R S) ( 0 -1 0; 0 = n o pai n, 1 0 = w orst pai n 
e ver) t o rate t heir i n de x k nee pa i n wit h wal ki n g, re p orte d usi n g t he e P R O s yste m. Pai n i n t he 
i n de x k nee m ust be rate d dail y at be dti me ( 9: 0 0 P M ± 3 h o urs) t o determi ne t he a vera ge k nee 
pai n wit h wal ki n g d uri n g t he pre vi o us 2 4  h o urs.  T he site a n d s u bject trai ni n g will tar get at 
least a n 85 % c o m plia nce rate, usi n g o n g oi n g assess me nt of c o m plia nce data, a n d site 
c o m m u nicati o n wit h t he s u bject if c o m plia nce dr o ps bel o w 8 5 %.  
6.  At Baseli ne  o nl y,  pai n wit h wal ki n g will als o be c ollecte d a n d assesse d f or t he n o n -i n de x 
k nee , as n ote d i n t he assess me nt a b o ve ( 5).  
7.  C o m plia nce wit h diar y e ntr y t o meet mi ni mal acce pta ble criteria d uri n g Scree ni n g . 
8.  U n dersta n di n g of t he o utc o me meas ur es, a n d t he relati o ns hi p a m o n g t he m, after s u bject 
trai ni n g a n d testi n g. 
9.  B MI ≤4 5 k g/ m 2. 
Pa ge 3 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0.  S u bjects m ust ha ve faile d 2 or m ore pri or t hera pies. Fail ure is dee me d t o be i na de q uate relief 
i n t he o pi ni o n of t he i n vesti gat or. A t hera p y ma y be dee me d t o ha ve bee n i na de q uate beca use 
of o ne or m ore of t he f oll o wi n g:   
a) u nacce pta ble a d verse e ve nts ( A Es ); 
b)  i na de q uate res p o nse, or l oss of res p o nse f or c hr o nic O A k nee pai n or 
o  pai n i n t he i n de x k nee was mi ni mall y i m pr o ve d, n ot i m pr o ve d, or was w orse a n d/ or  
o  i m pr o ve me nt f u ncti o n, a n d/ or stiff ness i n t he i n de x k nee was mi ni mall y i m pr o ve d, 
n ot i m pr o ve d, or was w orse  
c) me dical c o n diti o n res ulti n g i n c o ntrai n dicati o n t o t he sta n dar d of care a p pr o priate t o t he 
se verit y of t he i n de x k nee O A pai n.  
“ T hera pies” i ncl u de,  b ut are n ot li mite d t o , eac h of t he f oll o wi n g:  
o  n o nster oi dal a nti -i nfla m mat or y dr u gs (N S AI D s) (i ncl u di n g t o pical), o pi oi ds, 
d ul o xeti ne, ot her s yste mic t hera p y, I A c ortic oster oi ds, I A visc os u p ple me nts  
o  p h ysical t hera p y, braci n g, a n d  ort h otics.   
1 1.  Fe males n ot of c hil d beari n g p ote ntial,  defi ne d as p ost -me n o pa usal f or at least 1 year, or 
s ur gicall y sterile ( bilateral t u bal li gati o n, bilateral o o p h orect o m y, or h ysterect o m y), or 
practici n g o ne  of t he f oll o wi n g me dicall y acce pta ble met h o ds of birt h c o ntr ol t hr o u g h o u t t he 
st u d y peri o d:  
•  H or m o nal met h o ds s uc h as oral, i m pla nta ble, i njecta ble, or tra ns der mal c o n trace pti ves 
f or a mi ni m u m of 1 f ull c ycle ( base d o n t he s u bject’s us ual me nstr ual c ycle peri o d) 
bef ore I P a d mi nistrati o n 
•  T otal a bsti ne nce fr o m se x ual i nterc o urse  si nce t he last me nses bef ore I P a d mi nistrati o n  
•  I ntra uteri ne de vice 
•  D o u ble barrier met h o d (c o n d o ms, s p o n ge, dia p hra g m, wit h s per mici dal jellies or crea m)  
1 2.  A ble t o s pea k, rea d, a n d u n dersta n d t he la n g ua ge of t he st u d y use d f or t he i nf or me d c o nse nt 
a n d e P R O. 
1 3.  Willi n g a n d a ble t o : 
a) u n dersta n d t he st u d y re q uire me nts,  
b)  a bi de b y t he st u d y restricti o ns  a n d req uire me nts ,  
c) c o m plete t he st u d y pr oce d ures,  
d)  be c o m plia nt a n d i n de pe n de ntl y (ie , wit h o ut assista nce) rec or d res p o nses o n t he pai n 
scales a n d ma ke dail y e ntries usi n g e P R O (e g, ha ve t he a bilit y t o c o m pl y wit h a ns weri n g 
t he electr o nic diar y usi n g t he st u d y pr o vi de d ta blet c o m p uters), 
e) i n de pe n de ntl y c o m m u nicate mea ni n gf ull y wit h t he st u d y pers o n nel 
1 4.  Si g ne d i nf or me d c o nse nt f or m a p pr o ve d b y t he i nstit uti o nal re vie w b oar d  (I R B). 
1 5.  S u bject a grees t o sta y o n t heir c urre nt pai n me dicati o n (i ncl u di n g o ver t he c o u nter ( OT C) 
me dicati o n s) fr o m t he ti me of Pre -scree ni n g t hr o u g h W ee k 1 2. T he c urre n t pai n me dicati o n 
m ust be ta ke n o nl y f or pai n i n t he i n de x k nee, a n d n ot f or a n ot her pai n i n dicati o n. T heir 
c urre nt pai n me dicati o n m ust be o ne of  t he all o we d resc ue me dicati o ns a n d d osa ges , or 
h y dr oc o d o ne  at a d ose u p t o 1 5 m g dail y ( or a n ot her o pi oi d e q u i vale nt). T he resc ue 
Pa ge 3 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
me dicati o n is n ot all o we d t o be i n t he sa me dr u g class as t he o n g oi n g me dicati o n. F or 
e xa m ple, s u bjects will n ot be all o we d t o ta ke tra ma d ol as a resc ue me dicat i o n if t he y are 
ta ki n g a n o pi oi d as c o nc o mita nt me dicati o n, or a n N S AI D as resc ue if t he y are usi n g a n 
N S AI D as c o nc o mita nt me dicati o n.  Fr o m Wee k 1 2 t o c o m pleti o n of t he st u d y, s u bjects ma y 
sta y o n c urre nt pai n me dicati o n as prescri be d or O T C me dicati o n, b ut t his is n ot re q uire d.  If 
re d uci n g or st o p pi n g bac k gr o u n d me dicati o ns f or t he i n de x k nee O A pai n, t hat i nf or mati o n 
m ust be rec or de d b y t he site/s u bject.   
1 6.  S u bject a grees t o ta ke o nl y t he all o we d resc ue me dicati o ns f or O A k nee pai n of t he i n de x 
k nee fr o m t he ti me of t he first Treat me nt Visit t hr o u g h st u d y c o m pleti o n a n d a grees t o use n o 
t o pical me dicati o ns f or O A k nee pai n d uri n g t he trial. 
8. 2. 2  E xcl usi o n Criteri a  
A s u bject will be e xcl u de d fr o m t he st u d y if t he s u bject meets a n y of t he f oll o wi n g criteria:  
1.  J oi nt re place me nt s ur ger y of t he i n de x k nee at a n y ti me (f ull or partial), or o pe n s ur ger y of 
t he i n de x k nee i n t he past 2 4  m o nt hs.   
2.  Pri or art hr osc o pic s ur ger y of t he i n de x k nee wit hi n 6 m o nt hs of Scree ni n g.  
3.  A n y pai nf ul c o n diti o ns of t he i n de x k nee d ue t o j oi nt  disease ot her t ha n O A.  F or e xa m ple, 
ra dic ular or referre d pai n i n v ol vi n g t he i n de x k nee or fr o m j oi nt disease ot her t ha n O A 
i n v ol vi n g t he i n de x k nee s uc h as, b ut n ot restricte d t o, i nfla m mat or y diseases, e g, r he u mat oi d 
art hritis, ps oriatic art hritis,  c h o ndr o malacia patella,  meta b olic diseases, g o ut/ pse u d o g o ut, 
he m oc hr o mat osis, acr o me gal y , etc.  
4.  P eriartic ular pai n fr o m a n y ca use, i ncl u di n g referre d pai n, b ursitis, te n d o nitis, s oft tiss ue 
te n der ness, or s u bac ute/ac ute  pai n fr o m  i nj ur y.  
5.  Pai n i n t he n o n -i n de x k nee t hat is > 3 ( N P R S 0-1 0) w he n wal ki n g or at rest.  
6.  Ot her c hr o nic pai n a n y w here i n t he b o d y t hat re q uires t he use of a nal gesic me dicati o ns, 
i ncl u di n g, b ut n ot li mite d t o, l ocal pai nf ul areas, m y ofascial pai n s y n dr o mes, fi br o m yal gia, 
ge netic , meta b olic a b n or malities , he mat ol o gic or ne ur o pat hic pai n , a n d a n y ac ute or c hr o nic 
pai n t hat ma y i nterfere wit h t he st u d y pai n assess me nts b y t he s u bject . 
7.  I nsta bilit y of t he i n de x k nee (e g, cr uciate li ga me nt tear or r u pt ure, si g nifica nt pr otr u di n g 
me nisc us, s u bsta ntial li ga me nt o us la xit y).  
8.  Misali g n me nt ( > 1 0  de grees var us or val g us) of t he i n de x k nee  o n sta n di n g . 
9.  D oc u me nte d hist or y of ne ur o pat hic art hr o pat h y or fi n di n g of b o n y fra g me ntati o n i n t he i n de x 
k nee wit h i ma gi n g (ra di o gra p hic, c o m p ute d t o m o gra p h y, or ma g netic res o na nce i ma gi n g). 
1 0.  P h ys ical/ occ u pati o nal/c hir o practic t hera p y f or t he l o wer e xtre mities  or ac u p u nct ure f or t he 
l o wer e xtre mities wit hi n  3 0 da ys of Scree ni n g , or nee d f or s uc h t hera p y d uri n g t he st u d y. 
1 1.  Pla ns t o ha ve s ur ger y, ot her i n vasi ve pr oce d ures, or I A i njecti o ns ( ot her t ha n t he I P) w hile 
partici pati n g i n t he st u d y.  
1 2.  Has use d t o pical ca psaici n o n t he i n de x k nee wit hi n 9 0  da ys of Scree ni n g.  
1 3.  C urre nt use of o pi oi ds f or a n y c o n diti o n ot her t ha n f or O A  of t he i n de x k nee ( ma xi m u m d ose 
of 1 5  m g of h y dr oc o d o ne [ or e q ui vale nt] per da y). 
Pa ge 3 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 4.  C ortic oster oi d i njecti o n i nt o t he i n de x k nee wit hi n 9 0  da ys of Scree ni n g.  
1 5.  Recei ve d I A visc os u p ple me ntati o n (e g, S y n visc ® , H yal ga n® ) wit hi n 9 0 da ys of Scree ni n g. 
1 6.  Hist or y of aller gic reacti o n t o t he pla n ne d l ocal a nest hesia/ a nal gesi c re gi me ns, 
 
or ca psaici n.  
1 7.  Prese nce of a n y me dical c o n diti o n or u nsta ble healt h stat us t hat, i n t he j u d g me nt of t he 
i n vesti gat or, mi g ht a d versel y i m pact t he safet y of the s u bject , or t he c o n d uct of t he st u d y , or 
ne gati vel y affect t he res ulti n g data, i ncl u di n g c hr o nic c o n diti o ns t hat are li kel y t o alter t he 
rate of heali n g or are li kel y t o res ult i n safet y c o m plicati o ns u nrelate d t o t he st u d y 
me dicati o n, or si g nifica nt l y c o m pr o mise ke y or ga n s yste ms. F or a n y q uesti o n re gar di n g 
eli gi bilit y, it is str o n gl y rec o m me n de d t hat t he i n vesti gat or disc uss t he s u bject wi t h t he 
me dical m o nit or.  
1 8.  Is pre g na nt or is breast fee di n g. 
1 9.  Has a mali g na nc y, a hist or y of mali g na nc y, or has recei ve d treat me nt f or mali g na nc y at a n y 
ti me, wit h e xce pti o n of resecte d a n d c ure d basal cell carci n o ma a n d s q ua m o us cell carci n o ma 
of t he s ki n.   
2 0.  R e g ular use of a ntic oa g ula nt bl o o d t hi n ners (e xce pt l o w -d ose as piri n, Da bi gatra n 1 5 0  m g 
o nce dail y  [ q d], E n o xa pari n 4 0  m g q d , Ri var o xa ba n 1 0 m g q d,  A pi xa ba n 2. 5  m g t wice dail y  
[ bi d], or  cl o pi d o grel  7 5 m g q d, w hic h are all o we d).   
2 1.  Acti ve c uta ne o us disease at t he a ntici pate d site of I P i njecti o n t hat w o ul d pre ve nt t he safe 
a d mi nistrati o n of I P. 
2 2.  Ulcer or o pe n w o u n d a n y w here  o n t he i n de x k nee . 
2 3.  S pecific la b orat or y a b n or malities:  
•  He m o gl o bi n < 1 1 . 0 g/ d L  
•  W hite bl o o d cells ( W B C ) < 2 .5 X 1 0 9/ L 
•  Ne utr o p hils < 1. 5 X 1 0 9/ L 
•  Platelets < 1 0 0 X 1 0 9/ L 
•  As partate tra nsa mi nase ( A S T ) or ala ni ne tra nsa mi nase ( A L T ) > 2 X u p per li mit of n or mal  
•  Creati ni ne > 1. 6 m g/ d L  
•  Gl uc ose  (fasti n g) > 2 5 0 m g/ d L  
•  H g b A 1c > 9  
2 4.  Cli nicall y si g nifica nt a b n or mal la b orat or y res ult at t he Scree ni n g Visit (i n t he o pi ni o n of t he 
i n vesti gat or), or si g nifica nt or ga n disease t hat w o ul d p ut t he s u bject at u n d ue ris k or affect 
t he a bilit y of t he s u bject t o partici pate i n t he trial. F or a n y q uesti o n re gar di n g eli gi bilit y, it is 
str o n gl y rec o m me n de d t hat t he i n vesti gat or disc usses t he s u bject wit h t he me dical m o nit or. 
2 5.  Use of a n i n vesti gati o nal me dicati o n wit hi n 3 0 da ys of Scree ni n g or 5 p har m ac o ki netic ( P K) 
or p har mac o d y na mic ( P D) half -li ves ( w hic he ver is l o n ger), or sc he d ule d t o recei ve s uc h a n 
a ge n t w hile partici pati n g i n t he c urre nt st u d y. 
2 6.  Pri or partici pati o n i n a n A L G R X 4 9 7 5 or C N T X -4 9 7 5 st u d y . 
2 7.  Has a n y of t he f oll o wi n g c haracteristics:  
Pa ge 3 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  D oe s n ot ha ve a q ualif yi n g Baseli ne mea n k nee pai n sc ore of ≥5 a n d ≤9 o ut of 1 0 o n the 
N P R S scale i n t he i n de x k nee 
•  A cti ve or hist oric s u bsta nce use dis or der wit hi n t he pre vi o us year as defi ne d b y t he 
Dia g n ostic a n d Statistical Ma n ual f or Me ntal Healt h Dis or d ers, fift h e diti o n  
•  T est is p ositi ve u p o n uri ne dr u g scree n f or a s u bsta nce of a b use ( prescri be d o pi oi ds 
acce pta ble) 
•  H as a hist or y, at a n y ti me, or c urre ntl y, of s uici dal i deati o n, s uici de atte m pt, or i ncrease d 
ris k of s uici de 
•  Has u nacce pta ble le vel of  de pr essi o n or a n xiet y  as meas ure d b y t he H os pital  A n xiet y a n d 
De pressi o n Scale ( H A D S ) sc ore of ≥1 1  
•  Has u na cce pta ble c hr o nic pai n as meas ure d b y t he Fi br o m yal gia S y m pt o m  Scale  Sc ore 
( F S S) of ≥1 3  
•  Has a p ositi ve pre g na nc y test at t he Scree ni n g or Treat me nt Visit  
•  Has o n g oi n g liti gati o n f or w or kers’ c o m pe nsati o n  
•  Has a n y c o n diti o n, or is ta ki n g a n y me dica ti o n, t hat w o ul d be c o ntrai n dicate d f or st u d y 
partici pati o n  
8. 3.  Pre m at ure S u bject Wit h dr a w al  
All  s u bjects will be a d vise d t hat t he y are free t o wit h dra w fr o m partici pati o n i n t his st u d y at a n y 
ti me, f or a n y reas o n, a n d wit h o ut prej u dice. E ver y reas o na ble  atte mpt s h o ul d be ma de b y t he 
i n vesti gat or t o kee p s u bjects i n t he st u d y. H o we ver, s u bjects m ust be wit h dra w n fr o m t he st u d y 
if t he y wit h dra w c o nse nt t o partici pate. I n vesti gat ors m ust atte m pt t o c o ntact s u bjects w h o fail t o 
atte n d sc he d ule d visits b y tel e p h o ne  or ot her mea ns t o e xcl u de t he p ossi bilit y of a n A E bei n g t he 
ca use of wit h dra wal.  S h o ul d t his be t he ca use, t he A E m ust be d oc u me nte d, re p orte d, a n d 
f oll o we d as descri be d i n Secti o n 1 1. 2 . 
T he s p o ns or reser ves t he ri g ht t o re q uest t he wit h dra wal of a s u bject d ue t o pr ot oc ol de viati o ns  
or ot her reas o ns.  
T he i n vesti gat or als o has t he ri g ht t o wit h dra w s u bjects fr o m t he st u d y at a n y ti me f or lac k of 
t hera pe utic effect t hat is i nt olera ble or ot her wise u nacce pta ble t o t he s u bject, an d at a n y ti me f or 
i nt olera ble or u nacce pta ble A Es, i nterc urre nt ill ness, n o nco m plia nce wit h st u d y pr oce d ures, 
a d mi nistrati ve reas o ns, or i n t he i n vesti gat or’s o pi ni o n, t o pr otect t he s u bject’s best i nterest. 
If a s u bject is wit h dra w n bef ore c o m pleti n g t he st u d y, t he reas o n f or wit h dra wal a n d t he date of 
disc o nti n uati o n will be rec or de d o n t he a p pr o priate pa ge of t he electr o nic case re p ort f or m 
(eC R F).  W he ne ver p ossi ble a n d reas o na ble, t he e val uati o ns t hat were t o be c o n d ucte d at t he 
c o m pleti o n of t he st u d y  s h o ul d be perf or me d at t he ti me of pre mat ure disc o nti n uati o n. 
8. 4.  S u bject Re pl ace me nt Criteri a  
Wit h dra w n s u bjects will n ot be re place d. If a s u bsta ntial n u m ber of s u bjects are wit h dra w n fr o m 
t he st u d y, t he s p o ns or will e val uate t he nee d f or de vel o pi n g re placeme nt criteria.  
Ra n d o mize d  s u bjects wit h dra w n fr o m t he st u d y ma y n ot ree nter. The s u bject n u m ber f or a 
wit h dra w n s u bject will n ot be reassi g ne d t o a n ot her s u bject.  
Pa ge 3 8 of 1 3 3






Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  Se x of s u bject  
St u d y ce nter will be a bl oc ki n g fact or i n t he ra n d o mizati o n sc he d ule.  
T he s pecific n u meric re q uire me nts f or s o me I ncl usi o n/ E xcl usi o n criteria i nt o t he st u d y will be 
bli n de d f or t he i n vesti gat or a n d st u d y site staff. Bli n di n g o f t he s pecific n u meric re q uire me nts is 
d o ne t o re d uce bias i ntr o d uce d i nt o t he trial f or s u bjects w h o ma y  n ot  q uite meet t he st u d y 
re q uire me nts f or ra n d o mizati o n. T he st u dy sites will e nter i nt o t he I R T a set of val ues fr o m 
s pecific I ncl usi o n/ E xcl usi o n criteria, w hic h will be e val uate d b y t he Ce ntre xi o n Ra n d o mizati o n 
Al g orit h m . T h ose s u bjects w h o f ulfill t he ra n d o mizati o n re q uire me nts ma y be e nr olle d i nt o t he 
st u d y. 
T he ra n d o mizati o n sc he d ule will be  pre pare d b y 
 bef ore t he start of t he st u d y. 
N o o ne i n v ol ve d i n t he st u d y perf or ma nce will ha ve access t o t he ra n d o mizati o n sc he d ule bef ore 
t he official u n bli n di n g of treat me nt assi g n me nt. N o s u bject will be ra n d o mize d i nt o t his st u d y 
m ore t ha n o nce.  
9. 6.  Bli n di n g  a n d U n b li n di n g Tre at me nt Assi g n me nt  
Al l s u bjects, i n vesti gat ors, a n d st u d y pers o n nel i n v ol ve d i n t he c o n d uct of t he st u d y, i ncl u di n g 
data ma na ge me nt  a n d t he site p har macist , will be bli n de d t o treat me nt assi g nme nt , wit h t he 
e xce pti o n of a s pecifie d u n bli n de d statisticia n a n d pr o gra m mer fr o m 
, w h o will 
ha ve access t o t he ra n d o mizati o n c o de. T he u n bli n de d st u d y pers o n nel will n ot partici pate i n 
st u d y pr oce d ures or data a nal ysis pri or t o u n bli n di n g of t he st u d y data. If a n i nteri m a nal ysis is t o 
be c o n d ucte d, t he n u n bli n de d pers o n n el w h o are n ot ot her wise i n v ol ve d i n t he st u d y will pre pare 
t he data f or re vie w. 
St u d y pers o n nel will e n dea v or t o safe g uar d t he i nte grit y of t he st u d y bli n d t o mi ni mize bi as i n 
t he c o n d uct of t he st u d y. Treat me nt u n bli n di n g is disc o ura ge d if k n o wle d ge of the treat me nt 
assi g n me nt will n ot materiall y c ha n ge t he pla n ne d ma na ge me nt of a me dical e mer ge nc y. 
U n bli n di n g will be per mitte d i n a me dical e mer ge nc y t hat re q uires i m me dia te k n o wle d ge of t he 
s u bject’s treat me nt assi g n me nt. 
U n bli n di n g s h o ul d be disc usse d i n  a d va nce wit h t he me dical m o nit or , if p ossi ble. F or e mer ge nc y 
u n bli n di n g, st u d y pers o n nel will use t he I R T. If t he i n vesti gat or is n ot a ble t o disc uss treat me nt 
u n bli n di n g i n a d va nce, t he n he/s he m ust n otif y t he me dical m o nit or as s o o n as p ossi ble a b o ut t h e 
u n bli n di n g i nci de nt , wit h o ut re veali n g t he s u bject’s treat me nt assi g n me nt.  
T he i n vesti gat or , or desi g nee , m ust rec or d t he date a n d reas o n f or st u d y disc o nti n uati o n o n t he 
a p pr o priate C R F f or t hat s u bject. I n all cases t hat are n ot e mer ge ncies, t he i n ves ti gat or s h o ul d 
disc uss t he e ve nt wit h t he me dical m o nit or pri or t o u n bli n di n g t he s u bject’s treat me nt 
assi gn me nt.  
If treat me nt assi g n me nt is u n bli n de d f or a n i n di vi d ual s u bject, st u d y pers o n nel will be n otifie d of 
t hat s u bject’s treat me nt assi g n me nt wit h o ut u n bli n di n g t he treat me nt assi g n me nts f or t he 
re mai ni n g s u bjects i n t he st u d y. T h us, t he o verall st u d y blin d will n ot be c o m pr o mise d. If a 
s u bject’s treat me nt assi g n me nt is u n bli n de d, he/s he ma y or ma y n ot be as ke d t o wit h dra w fr o m 
t he st u d y. T he i n vesti gat or s h o ul d ma ke t his decisi o n after c o ns ultati o n wit h t he me dical 
m o nit or.  
At t he fi nal visit, s u bjects wi ll be as ke d w hic h treat me nt t he y t hi n k t he y recei ve d. 
Pa ge 4 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
9. 7.  Selecti o n of D ose i n t he St u d y  
T he o bjecti ve of t his st u d y is t o deter mi ne t he efficac y  a n d safet y of 
 of C N T X -4 9 7 5 -0 5, 
c o m pare d t o matc hi n g place b o, a d mi nistere d b y a si n gle I A i njecti o n i nt o t he  i n de x k nee of 
s u bjects wit h m o derate-t o-se vere pai n fr o m O A i n t he k nee. T he res ults of a pre vi o us O A 
P hase  2 st u d y, C N T X -4 9 7 5 -O A -5 0 2, c o n d ucte d b y t he s p o ns or, de m o nstrate d t hat 
 is a n 
effecti ve a n d well -t olerate d treat me nt f or s u bjects wit h m o derate-t o-se vere pai n fr o m O A i n t he 
i n de x k nee. A d ose of  
 res ulte d i n a si g nifica nt decrease i n pai n wit h wal ki n g relati ve t o 
place b o as earl y as  1 wee k after I P i njecti o n, a n d t he pai n re d ucti o n t y picall y c o nti n ue d be y o n d 
1 2 wee ks p ost -i njecti o n. I n ad diti o n, m ulti ple sec o n dar y a n d e x pl orat or y a nal yses s h o we d 
mea ni n gf ul i m pr o ve me nt i n k nee f u ncti o n, k nee stiff ness, a n d Baseli ne pai n. I n a d diti o n, t he 
safet y pr ofile of C N T X -4 9 7 5 -0 5 was si milar t o t hat of place b o t hr o u g h o ut t he 2 4 -wee k st u d y.  
9. 8.  D ose A dj ust me nt Criteri a  
D ose a dj ust me nt is n ot all o we d i n t his st u d y.  
9. 9.  Selecti o n of Ti mi n g of D ose f or E ac h S u bject  
All s u bjects will recei ve a si n gle cli nical or ultras o u n d -g ui de d I A i njecti o n of C N T X-4 9 7 5 -0 5  or , 
matc hi n g  place b o , i nt o t he i n de x k nee at t he st u d y site u n der t he s ur veilla nce of a p pr o priate 
st u d y pers o n nel o n St u d y Da y 1 ( Treat me nt Da y 1) a n d at Wee k 2 6  ( Treat me nt Da y 2). 
9. 1 0.  Dr u g Acc o u nt a bilit y  
T he site p har macist m ust mai ntai n a de q uate rec or ds s h o wi n g t he recei pt, dis pe nsi n g, ret ur n, or 
ot her dis p ositi o n of t he I P i ncl u di n g t he date, q ua ntit y, batc h or c o de n u m ber, a n d i de ntificati o n 
of s u bjects (s u bject n u m ber) w h o recei ve d t he I P. T he site p har macist will n ot s u p pl y t he I P t o 
a n y pers o n e xce pt t h ose na me d as  t he i n vesti gat or or s u b-i n vesti gat ors, desi g nate d st u d y 
pers o n nel, a n d s u bjects i n t his st u d y. T he site p har macist will n ot dis pe nse t he I P fr o m a n y st u d y 
sites ot her t ha n t h ose liste d. I n vesti gati o nal pr o d uct (s) ma y n ot be rela bele d or reassi g ne d f or use 
b y ot her s u bjects. If a n y of t he I P is n ot dis pe nse d , is l ost, st ole n, s pille d, u n usa ble, or is recei ve d 
i n a da ma ge d c o ntai ner, t his i nf or mati o n m ust be d oc u me nte d a n d re p orte d t o Ce ntre xi o n 
T h era pe utics C or p. a n d a p pr o priate re g ulat or y a ge ncies, as re q uire d.  
U p o n c o m pleti o n of t he st u d y, t he I P ( partl y use d, u n use d, a n d e m pt y pac ka gi n g) m ust be left i n 
t he ori gi nal pac ka gi n g a n d ret ur ne d t o t he s p o ns or or desi g nee f or destr ucti o n. 
9. 1 1.  Tre at me nt C o m pli a nce  
O n  Treat me nt Da y 1 a n d Treat me nt Da y 2  ( Wee k 2 6), all s u bjects will recei ve t he si n gle IA 
i n vesti gati o nal pr o d uct i njecti o n. It is rec o m me n de d t o use ultras o u n d -g ui de d i njecti o n , b ut it is 
n ot re q uire d. I ntra -artic ular i njecti o n wit h o ut i ma gi n g g ui da nce s h o ul d ass ure t hat t he nee dle is 
i n t he j oi nt b y as pirati n g j oi nt fl ui d bef ore i njecti n g I P. All i njecti o ns at t he st u d y site s h o ul d be 
u n der t he s ur veilla nce of a p pr o priate st u d y pers o n nel. I njecti o n pr oce d ure details will be 
rec or de d i n t he s u bject’s eC R F.   
All c o nc o mita nt me dicati o ns use d (i ncl u di n g O T C  me d icati o ns) will be rec or de d i n t he s o urce 
d oc u me nt a n d o n t he a p pr o priate e C R F . 
Pa ge 4 2 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
9. 1 2. 2  Pr o hi bite d T her a pies  
T he f oll o wi n g t hera pies are pr o hi bite d b ot h pri or t o a n d d uri n g t he st u d y:  
•  I njectio n  of  c ortic oster oids  i n t he i n de x k nee  fro m  9 0 d a ys pri o r t o Scree n i n g th r o u g h stu d y  
c om p letio n.  
•  T o p ical m e dicatio ns  a p plie d t o t he i n de x k nee  f or O A pai n  (in clu d in g  cap saicin,  lid oc aine,  
pres cript io n,  or O T C  m e dicati o ns) fr o m 9 0 da ys  pri or t o S creeni n g  th r o u g h st u d y 
c o m pleti o n . 
•  C urre nt use of o pi oi ds f or a n y c o n diti o n ot her t ha n f or O A  of t he i n de x k nee ( ma xi m u m 
d ose of 1 5  m g of h y dr oc o d o ne [ or e q ui vale nt] per da y  as bac k gr o u n d me dicati o n all o we d 
at e ntr y ). Per mitte d a nal gesics , ta ke n occasi o nall y f or c o n diti o ns ot her t ha n i n de x k nee 
O A ( n ot resc ue a nal gesics) s h o ul d be a v oi de d wit hi n 2 4 h of a n y p ost -I P treat me nt 
pla n ne d st u d y visit , a n d are t o be rec or de d as c o nc o mita nt me dicati o ns. 
•  Re g ular use of a ntic oa g ula nt bl o o d t hi n ners (e xce pt l o w -d ose as piri n, Da bi gatra n 1 5 0  m g 
o nce dail y  [ q d], E n o xa pari n 4 0 m g q d , Ri var o xa ba n 1 0 m g q d,  A pi xa ba n 2. 5  m g t wice 
dail y  [ bi d], or cl o pi d o grel 7 5 m g q d, w hic h are all o we d).   
•  Use of a n i n vesti gati o nal me dicati o n wit hi n 3 0 d a ys pri o r t o Scree n i n g, or 5 P K or P D  
half -li ves ( w hic he ver is l o n ger), or sc he d ule d t o recei ve s uc h a n a ge nt w hile partici pati n g i n t he 
st u d y.  
•  P h ysical / occ u pati o nal/c hir o practic t hera p y f or t he l o wer e xtre mities or ac u p u nct ure f or 
t he l o wer e xtre mities wit hi n 3 0 da ys of Scree ni n g , or nee d f or s uc h t hera p y d uri n g t he 
c o urse of t he st u d y.  
•  J oi nt re place me nt s ur ger y of t he i n de x k nee at a n y ti me (f ull or partial), or o pe n s ur ger y 
of t he i n de x k nee i n t he past 2 4  m o nt hs pri or t o Scree ni n g , or pri or art hr osc o pic s ur ger y 
of t he i n de x k nee wit hi n 6 m o nt hs of Scree ni n g . 
•  S ur ge r y, or ot her i n vasi ve pr oce d ures, or I A i njecti o ns ( ot her t ha n t he I P) w hile 
partici pati n g i n t he st u d y.  
T he s u bject s h o ul d be e xcl u de d fr o m st u d y partici pati o n if t he y ha ve t a ke n a n y me dicati o n p rior  to  
ra n d o mizati o n t hat w o u ld  i n dicate th at t he s u bject has a ser io us  o r u ns ta ble illn ess, is n ot  in  g o o d 
ge ner al hea lth,  or h as a c o n ditio n  that  w o u ld c o ntr ai n dicate st u d y p artici pati o n. 
S u bjects recei vi n g e xcl u de d t hera pies will be i neli gi ble f or st u d y e nr oll me n t. If s u bjects recei ve 
e xcl u de d t hera pies after e nr oll me nt, c o nti n uati o n i n t he st u d y will be at t he discreti o n of t he 
s p o ns or/i n vesti gat or/ me dical m o nit or. 
9. 1 3.  Tre at me nt After E n d of St u d y  
After t he e n d of t he st u d y, eac h s u bject will be treate d acc or di n g t o sta n dar d cli nical practice.  
Pa ge 4 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0.  S T U D Y P R O C E D U R E S  
S u bjects m ust  pr o vi de writte n i nf or me d c o nse nt bef ore a n y st u d y -relate d pr oce d ures are 
i nitiate d, i ncl u di n g t he cessati o n of pr o hi bite d c o nc o mita nt t hera p y. 
F or t he ti mi n g of assess me nts a n d pr oce d ur es t hr o u g h o ut t he st u d y, refer t o t he sc he d ule of 
e ve nts ( Secti o n  1 7. 1 ). T hr o u g h o ut t he st u d y, e ver y reas o na ble eff ort s h o ul d be ma de b y st u d y 
pers o n nel t o f oll o w t he ti mi n g of assess me nts a n d pr oce d ure s i n t he sc he d ule of e vents f or eac h 
s u bject. If a s u bject misses a st u d y visit f or a n y reas o n, t he visit s h o ul d be r esc he d ule d as s o o n as 
p ossi ble . 
1 0. 1.  St u d y Peri o ds a n d Visits  
1 0. 1. 1  Pre -Scree ni n g  a n d Scree ni n g , D a y -3 0 t o D a y 1  
O nce t he Pre -Scree ni n g Visit has bee n perf or me d, i ncl u di n g t he k nee ra di o gra p h, s u bjects s h o ul d 
be sc he d ule d t o ret ur n t o t he st u d y ce nter f or t he Scree ni n g Visit as s o o n as is feasi ble. T he 
s u bject m ust ha ve t he Scree ni n g Visit perf or me d wit hi n 3 0  da ys be f ore e nr oll me nt i nt o t he st u d y. 
T he f oll o wi n g pr oce d ures wil l be perf or me d at pre -scree ni n g a n d scree ni n g. 
1 0. 1. 1. 1  Pre -S cree ni n g  Visit  
1.  W ritte n i nf or me d c o nse nt 
2.  I n vesti gat or pre-scree ni n g assess me nt of k nee f or preli mi nar y eli gi bilit y usi n g f i xe d fle xi o n 
ra di o gra p hic i ma gi n g ( b ot h k nees)9 ,1 0 
3.  C o nfir mati o n of O A ( K -L gra de 2 , 3 or 4) of t he k nee: ra di o gra p h  K -L gra de  b y ce ntral rea der  
is t he o nl y assess me nt use d f or ra n d o mizati o n  
4.  Hei g ht a n d wei g ht ( B MI)  
5.  Hist or y of ca ncer  
6.  K nee pai n  (clinic, N P R S)  
1 0. 1. 1. 2  Scree ni n g Visit , Visit 1 
1.  C o nfir mati o n of O A of t he i n de x k nee: A merica n C olle ge of R he u mat ol o g y ( A C R) dia g n ostic 
criteria 
2.  Incl usi o n/e xcl usi o n criteria  
3.  De m o gra p hics  
4.  Me dical hist or y, c urre nt k nee 
O A 
me dicati o ns (e g, prescri pti o n a n d n o n prescr i pti on 
me dicati o ns) a n d treat me nt hist or y (i ncl u di n g all pre vi o us p har mac ol o gic, n o ni n vasi ve or 
i n vasi ve treat me nts) 
5.  H A D S  
6.  F S S  
7.  K nee circ u mfere nce  
8.  A b d o mi nal girt h  
9.  C o m plete p h ysical e xa mi nati o n  
1 0.  E C G  
1 1.  Cli nical la b orat or y testi n g (fasti n g f or at least 8 h o urs) 
Pa ge 4 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 2.  Uri ne d r u g scree n 
1 3.  Uri ne pre g na nc y test  
1 4.  Vital si g ns  
1 5.  Set u p s u bject’s acc o u nt i n e P R O t o rec or d d ail y k nee pai n diar y ( N P R S)  
1 6.  Trai ni n g a n d assess me nt of k n o wle d ge o n pai n  rati n gs, all o wa ble resc ue me dicati o n, ot her 
patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g da ta i nt o t he e P R O s yste m 
1 7.  A Es  
1 8.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 2  Tre at me nt 1, D a y 1, Visit 2  
As 2 cases of se vere aller gic reacti o ns ha ve occ urre d i n t he e ntire C N T X -4 9 7 5 pr o gra m, a cras h 
cart a n d pers o n nel certifie d i n a d va nce d car diac life s u p p ort ( A C L S ) s h o ul d be i m me diatel y 
a vaila ble. See S ecti o n 1 1. 2. 1  f or details. 
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 1:  
1.  Verif y t hat  e P R O c o m plia nce meets re q uire me nts f or ra n d o mizati o n  
2.  Incl usi o n/e xcl usi o n criteria  
3.  Partial p h ysic al e xa mi nati o n  
4.  Cli nical la b orat o r y testi n g 
5.  Uri ne dr u g scree n  
6.  Uri ne pre g na nc y test  
7.  Vital si g ns  (sta n di n g a n d sitti n g vital si g ns wit hi n a p pr o xi matel y 5 mi n utes bef ore t he 
i njecti o n of I P, a n d sitti n g-o nl y vital si g ns wit hi n a p pr o xi matel y 5 , 1 5, a n d 3 0 mi n ut es after 
i njecti o n of I P) a n d wei g ht  
8.  Se ns or y testi n g at t he k nee a n d f o ot usi n g a 5-p oi nt Li kert scale  
9.  Ra n d o mizati o n  
1 0.  Dail y k nee pai n diar y ( N P R S) b y e P R O  
1 1.  Re vie w dail y e P R O pai n sc ores ( N P R S)  
1 2.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
1 3.  K nee pai n , stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B, a n d C) 
1 4.  J oi nt re place me nt q uesti o n naire 
1 5.  K O O S  
1 6.  M O S slee p scale  
1 7.  Healt h stat us q uesti o n naire ( S F -3 6)  
1 8.  Q ualit y of life E Q -5 D -5 L  
1 9.  W P AI q uesti o n naire  
2 0.  I njecti o n site assess me nts (er yt he ma, e de ma) bef ore i njecti o n, a n d after t he i njecti o n 1 a n d 2 
h o urs p ost -d ose  I P 
2 1.  S u bject pr oce d ure pai n assess me nt s ( 1) at rest pri or t o pre-me dicati o n; ( 2) pri or t o  f ull 1 5 ml 
of  i ntra-artic ular 2 % li d ocai ne ( wit h o ut e pi ne p hri ne); ( 3)  at rest 1 0 mi n utes ( ± 2 mi n utes) 
after f ull 1 5 m L i ntra-artic ular 2 % li d ocai ne ( wit h o ut e pi ne p hri ne); ( 4) at 3 0  mi n utes 
Pa ge 4 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
( ± 5  mi n utes) after i ntra -artic ular i njecti o n of 2 m L of t he I P a n d ( 5) at rest at t he 1 h a n d 2 h 
ti me p oi nts after i ntra -artic ular i njecti o n of t he  I P ( ± 1 0 mi n utes)  
2 2.  Treat me nt pr oce d ure, i ncl u di n g c o oli n g, i ntra -artic ular 1 5 m L 2 % li d ocai ne ( wit h o ut 
e pi ne p hri ne), i ntra -artic ular I P i njecti o n , a n d p ost-i njecti o n c o oli n g 
2 3.  All s u bjects m ust be m o nit ore d f or at least 3 0 mi n utes ( or l o n ger, as re q uire d b y t he pr ot oc ol) 
after st u d y dr u g i njecti o n t o e ns ure t hat t he y d o n ot ha ve a h y perse nsiti vit y 
reacti o n/a na p h yla xis 
2 4.  A Es  
2 5.  Trai ni n g a n d assess me nt of k n o wle d ge o n resc ue me dicati o n use a n d l o g gi n g of resc ue 
me dicati o n i nt o e P R O s yste m  
2 6.  C o nc o mita nt me d icati o ns a n d t hera pies 
1 0. 1. 3   D o u ble -bli n d  P ost -tre at me nt 1 Assess me nt a n d O bser v ati o n Peri o d, D a y 3 t o 
Wee k  1 8, Visit 3 t o Visit 7  
1 0. 1. 3. 1  D a y 3, Tele p h o ne Visit 3  
1.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
2.  Re mi n d s u bject t o c o nti n ue dail y e ntr y of e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n 
use  ( 9: 0 0 P M ± 3 h o urs)  
3.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
4.  Re vie w e P R O c o m plia nce wit h s u bject; r etrai n as nee de d  
5.  S u bject assess me nt of satisfacti o n wit h t he treat me nt pr oce d ure  
6.  P atie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) i n t he i n de x k nee 
7.  A Es  
8.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 3. 2  Wee k 4, Visit 4  
1.  Partial p h ysical e xa mi nati o n  
2.  Vital si g ns  a n d wei g ht 
3.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
4.  I njecti o n site assess me nt (er yt he ma, e de ma) 
5.  Dail y k nee pai n diar y ( N P R S) b y e P R O 
6.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
7.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
8.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
9.  P GI C  
1 0.  K O O S  
1 1.  Assisti ve  de vice usa ge  
Pa ge 4 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 2.  A Es  
1 3.  Resc ue me dicati o n use  
1 4.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 3. 3  Wee k 8, Visit 5  
1.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
2.  Dail y k nee pai n diar y ( N P R S) b y e P R O  
3.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
4.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
5.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A,  B , a n d C) 
6.  P GI C  
7.  M O S slee p scale  
8.  Healt h sta t us q uesti o n naire ( S F-3 6)  
9.  W P AI  q uesti o n naire  
1 0.  Assisti ve  de vice usa ge  
1 1.  A Es  
1 2.  Resc ue me dicati o n use  
1 3.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 3. 4  Wee k 1 2, Visit 6  
1.  C o m plete p h ysical e xa mi nati o n  
2.  Cli nical la b orat or y testi n g  
3.  Uri ne dr u g scree n  
4.  Uri ne pre g na nc y test 
5.  Vital si g ns  a n d wei g ht 
6.  Se ns or y testi n g at t he k nee a n d f o ot usi n g a 5-p oi nt Li kert scale  
7.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
8.  Dail y k nee pai n diar y ( N P R S) b y e P R O  
9.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
1 0.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
1 1.  K nee pai n , stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B, a n d C) 
1 2.  P GI C  
1 3.  J oi nt re place me nt q uesti o n naire  
1 4.  K O O S  
1 5.  E Q -5 D -5 L  
1 6.  Assisti ve  de vice usa ge  
Pa ge 4 8 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 7.  A Es  
1 8.  Resc ue me dicati o n use  
1 9.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 3. 5  Wee k 1 8, Visit 7  
1.  Vital si g ns  
2.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all other patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
3.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
4.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
5.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
6.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
7.  P GI C  
8.  J oi nt re place me nt q uesti o n naire 
9.  K O O S  
1 0.  M O S slee p scale  
1 1.  S F -3 6  
1 2.  E Q -5 D -5 L  
1 3.  W P AI  
1 4.  Assisti ve  de vice usa ge  
1 5.  A Es  
1 6.  Resc ue me dicati o n use  
1 7.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 4  Tre at me nt 2, Wee k 2 6, Visit 8  
As 2 cases of se vere aller gic reacti o ns ha ve occ urre d i n t he e ntire C N T X -4 9 7 5 pr o gra m, a cras h 
cart a n d pers o n nel certifie d i n a d va nce d car diac life  s u p p ort ( A C L S) s h o ul d be i m me diatel y 
a vaila ble. See secti o n 1 1. 2. 1  f or details. 
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 1 of Treat me nt 2:  
1.  C o m plete p h ysical  e xa mi nati o n 
2.  E C G  
3.  Cli nical la b orat or y testi n g 
4.  Uri ne dr u g scree n  
5.  Uri ne pre g na nc y test  
6.  Vital si g ns  (sta n di n g a n d sitti n g vital si g ns wit hi n a p pr o xi matel y 5 mi n utes bef ore t he 
i njecti o n of I P, a n d sitti n g-o nl y vital si g ns wit hi n a p pr o xi matel y 5 , 1 5, a n d 3 0 mi n utes  after 
i njecti o n of I P) a n d wei g ht  
7.  Se ns or y testi n g at t he k nee a n d f o ot usi n g a 5-p oi nt Li kert scale  
Pa ge 4 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
8.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
9.  Dail y k nee pai n diar y ( N P R S) b y e P R O  
1 0.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
1 1.  Re vie w e P R O c o m plia nce wit h s u bje ct; retrai n as nee de d  
1 2.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
1 3.  P GI C  
1 4.  J oi nt re place me nt q uesti o n naire 
1 5.  K O O S  
1 6.  M O S slee p scale  
1 7.  S F -3 6  
1 8.  E Q -5 D -5 L  
1 9.  W P AI   
2 0.  Assisti ve  de vice usa ge  
2 1.  I njecti o n site assess me nts (er yt he ma, e de ma) bef ore injecti o n , a n d after t he i njecti o n 1 a n d 2 
h o urs p ost -d ose  I P 
2 2.  S u bject pr oce d ure pai n assess me nts ( 1) at rest pri or t o pre-me dicati o n ; ( 2) pri or t o f ull 1 5 m L 
of i ntra-artic ular 2 % li d ocai ne ( wit h o ut e pi ne p hri ne); ( 3)  at rest 1 0 mi n utes ( ± 2 mi n utes) 
after full 1 5  m L of  i ntra-artic ular 2 % li d ocai ne ( wit h o ut e pi ne p hri n e); ( 4) at 3 0  mi n utes 
( ± 5  mi n utes) after i ntra -artic ular i njecti o n of 2  m L of  t he I P a n d ( 5) at rest at t he 1 h a n d 2 h 
ti me p oi nts after i ntra-artic ular i njecti o n of t he I P ( ±  1 0 mi n utes)  
2 3.  Treat me nt pr oce d ure, i ncl u di n g c o oli n g, i ntra -artic ular 1 5 m L 2 % l i d ocai ne ( wit h o ut 
e pi ne p hri ne), i ntra -artic ular I P i njecti o n, a n d p ost -i njecti o n c o oli n g 
2 4.  All s u bjects m ust be m o nit ore d f or at least 3 0 mi n utes ( or l o n ger, as re q uire d b y t he pr ot oc ol) 
after st u d y dr u g i njecti o n t o e ns ure t hat t he y d o n ot ha ve a h y perse nsi ti vit y 
reacti o n/a na p h yla xis 
2 5.  A Es  
2 6.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 5  D o u ble -bli n d  P ost -tre at me nt 2  Assess me nt a n d O bser v ati o n Peri o d, D a y 3 t o Wee k 
4 6 , Visit 9  t o Visit 1 2  
1 0. 1. 5. 1  D a y 3, Tele p h o ne Visit  9  
1.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
2.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
3.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
4.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
5.  P GI C  i n i n de x k nee  
6.  A Es  
Pa ge 5 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
7.  Resc ue me dicati o n use  
8.  C o nc o mita nt me dicati o ns a n d t hera pies  
9.  S u bject assess me nt of satisfacti o n wit h t he treat me nt pr oce d ure   
1 0. 1. 5. 2  Wee k 3 0 , Visit 1 0  
1.  V ital si g ns 
2.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
3.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
4.  Re vie w dail y e P R O pai n sc ores  ( N P R S) a n d resc ue me dicati o n use recall 
5.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
6.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
7.  P GI C  
8.  J oi nt re place me nt q uesti o n naire 
9.  K O O S  
1 0.  I njecti o n site assess me nt (er yt he ma, e de ma) 
1 1.  Assisti ve  de vice usa ge  
1 2.  A Es  
1 3.  Resc ue me dicati o n use  
1 4.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 5. 3  Wee k 3 8 , Visit 1 1  
1.  Partial p h ysical e xa mi nati o n  a n d wei g ht  
2.  Cli nical la b orat or y testi n g  
3.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
4.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
5.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall  
6.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
7.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
8.  P GI C  
9.  J oi nt re place me nt q uesti o n naire 
1 0.  M O S slee p scale  
1 1.  S F -3 6  
1 2.  E Q -5 D -5 L  
1 3.  W P AI  
1 4.  Assisti ve  de vice usa ge  
1 5.  A Es  
Pa ge 5 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 6.  Resc ue me dicati o n use  
1 7.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 5. 4  Wee k 4 6 , Visit 1 2  
1.  Vital si g ns  
2.  Trai ni n g a n d assess me nt of k n o wle d ge, as nee de d, o n pai n  rati n gs, all o wa ble resc ue 
me dicati o n , all ot her patie nt -re p orte d o utc o mes rati n gs, a n d e nteri n g data i nt o t he e P R O 
s yste m 
3.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
4.  Re vie w dail y e P R O  pa i n sc ores ( N P R S) a n d resc ue me dicati o n use recall 
5.  Re vie w e P R O c o m plia nce wit h s u bject; retrai n as nee de d  
6.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
7.  P GI C  
8.  J oi nt re place me nt q uesti o n naire 
9.  K O O S  
1 0.  Assisti ve  de vice usa ge  
1 1.  A Es  
1 2.  Res c ue me dicati o n use  
1 3.  C o nc o mita nt me dicati o ns a n d t hera pies  
1 0. 1. 6  Fi n al/ E arl y Ter mi n ati o n ( E T) Visit, Wee k 5 2, Visit 1 3  
1.  Fi xe d fle xi o n ra di o gra p hic  i ma gi n g ( b ot h k nees)9 ,1 0 
2.  A b d o mi nal girt h  
3.  C o m plete p h ysical  e xa mi nati o n 
4.  E C G  
5.  Cli nical la b orat or y testi n g   
6.  Uri ne dr u g scree n  
7.  Uri ne pre g na nc y test  
8.  Vital si g ns  a n d wei g ht 
9.  Se ns or y testi n g at t he k nee a n d f o ot usi n g a 5-p oi nt Li kert scale  
1 0.  Dail y  k nee pai n diar y ( N P R S) b y e P R O  
1 1.  Re vie w dail y e P R O pai n sc ores ( N P R S) a n d resc ue me dicati o n use recall 
1 2.  Re vie w e P R O c o m plia nce wit h s u bject  
1 3.  K nee pai n, stiff ness a n d p h ysical f u ncti o n at st u d y visits ( W O M A C A, B , a n d C) 
1 4.  P GI C  
1 5.  J oi nt re place me nt q uesti o n naire 
1 6.  K O O S  
1 7.  M O S slee p scale  
1 8.  S F -3 6  
1 9.  E Q -5 D -5 L  
Pa ge 5 2 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
2 0.  W P AI  
2 1.  Assist i ve de vice usa ge  
2 2.  A Es  
2 3.  Resc ue me dicati o n use  
2 4.  C o nc o mita nt me dicati o ns a n d t hera pies  
2 5.  S u bject ter mi nati o n f or m  
2 6.  A  q uesti o n as ki n g s u bjects w hic h treat me nt t he y t hi n k t he y recei ve d 
2 7.  A q uesti o n as ki n g if t he s u bject w o ul d u n der g o t he pr oce d ure a gai n if t heir k nee p ai n ret ur ne d 
1 0. 2.  St u d y  D ur ati o n  
1 0. 2. 1  O ver all St u d y Sc he d ule  
T he  o verall  st u d y d urati o n is e x pecte d t o be 2 5  m o nt hs , wit h 1 2 m o nt hs of acti ve e nr ol lme nt.  
T he pla n ne d se q ue nce a n d ma xi m u m d urati o n of t he st u d y peri o ds will be as f oll o ws:  
1.  Pre -Scree ni n g Peri o d  (after the Pre -Scree ni n g Visit has bee n perf or me d, i ncl u di n g t he k nee 
ra di o gra p h, s u bjects s h o ul d be sc he d ule d t o ret ur n t o t he st u d y ce nter t o ha ve t he Scree ni n g 
Visit perf or me d as s o o n as is feasi ble)  
2.  Scree ni n g Peri o d : u p t o 3 0 da ys  + 3 -da y wi n d o w  
3.  Treat m e nt Peri o d (d o u ble -bli n d, place b o -c o ntr olle d): first d ose at Da y 1 (1 da y ); sec o n d d ose 
at Wee k 2 6 (1 da y ) 
4.  P ost -T reat me nt D o u ble -B li n d peri o d: 5 2 wee ks  
T he ma xi m u m treat me nt d urati o n f or eac h s u bject is 2 da ys.   
T he ma xi m u m st u d y d urati o n f or eac h s u bject is a p pr o xi matel y 5 8 wee ks . 
1 0. 3.  Assess me nts  
1 0. 3. 1  Effic ac y  
1 0. 3. 1. 1  K nee P ai n, Stiff ness a n d F u ncti o n: Wester n O nt ari o a n d Mc M aster U ni versities 
Art hritis I n de x ( W O M A C)  
T he Wester n O ntari o a n d Mc Master U ni versities de vel o pe d t he W O M A C sc ore i n use a m o n g 
patie nts wit h k nee a n d/ or hi p  O A.  T he W O M A C is a vali date d, m ulti di me nsi o nal meas ure of 
pai n, stiff ness, a n d p h ysical f u ncti o nal disa bilit y t hat is se nsiti ve t o t he effects of dr u gs or ot her 
i nter ve nti o n. It is a vailable i n 5 -p oi nt Li kert, 1 0 0 m m Vis ual A nal o g ue a n d 1 1 -b o x N u merical 
R ati n g Scale f or mats.  T his st u d y will use t he 1 1 -b o x N u merical Pai n Rati n g Scale ( N P R S) 
f or mat (see A p pe n di x A ). T he N R S uses e n d p oi nts of 0 =“ N o ne” ( or “ N o 
pai n/stiff nes s/ diffic ult y”) a n d 1 0 =“ E xtre me.” 
T he W O M A C is a self-a d mi nistere d i n de x a n d c o ntai ns 2 4 ite ms as ke d i n relati o n t o t he i n de x 
k nee j o i nt. T he W O M A C has 3 di me nsi o ns: Pai n ( Secti o n A), Stiff ness ( Secti o n B), a n d P h ysical 
F u ncti o n ( Secti o n C).  
•  T he pai n secti o n i ncl u des 5  ite ms a b o ut t he a m o u nt of pai n e x perie nce d d oi n g vari o us 
acti vities ( wal ki n g, stair cli m bi n g, n oct ur nal, at rest, wei g h t beari n g). 
Pa ge 5 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  T he stiff ness secti o n has 2  ite ms: j oi nt stiff ness u p o n wa ke ni n g a n d j oi nt stiff ness later i n 
t he da y.  
•  T he f u ncti o n secti o n as ks a b o ut t he de gree of dif fic ult y i n d oi n g 1 7 acti vities d ue t o t he 
refere nce j oi nt ( desce n di n g stairs, asce n di n g stairs, risi n g fr o m sitti n g p ositi o n, sta n di n g, 
be n di n g t o t he fl o or, wal ki n g o n a flat s urface, getti n g i nt o or o ut of a car, g oi n g 
s h o p pi n g, p utti n g o n s oc ks, l yi n g in be d, ta ki n g off s oc ks, risi n g fr o m be d, getti n g i nt o or 
o ut of t he bat h, sitti n g, getti n g  o nt o or off t he t oilet, hea v y d o mestic d uties, a n d li g ht 
d o mestic d uties).   
1 0. 3. 1. 2  P atie nt Gl o b al I m pressi o n of C h a n ge i n K nee P ai n  
S u bjects will rate t heir c ha n ge i n k nee  pai n as c o m pare d t o Baseli ne ( bef ore I P i njecti o n) b y 
c o m pleti n g t he P GI C .  
T he P GI C is a 7 -p oi nt cate g orical scale, w here t he patie nt rates t heir c ha n ge i n o verall stat us 
c o m pare d t o B aseli ne as f oll o ws:  1 = Ver y m uc h i m pr o ve d; 2 = M uc h i m pr o ve d; 3 = Mi n i mall y 
i m pr o ve d; 4 = N o c ha n ge; 5 = Mi ni mall y w orse; 6 = M uc h w orse; a n d 7 = Ver y m uc h w ors e. 
1 0. 3. 1. 3  A ver a ge W al ki n g O A K nee P ai n ( N P R S)  
Fr o m t he Scree ni n g Visit u ntil t he Wee k 5 2 Visit, s u bjects will use a n e P R O at be dti me ( 9: 0 0 
P M ± 3 h o urs) t o rec or d o n a dail y basis t heir a vera ge dail y O A k nee pai n sc ore wit h wal ki n g 
d uri n g t he pre vi o us 2 4 h o urs. A vera ge dail y O A k nee pai n wit h wal ki n g will be e val uate d usi n g 
a 0-1 0 N P R S ( 0 = “ n o pai n” a n d 1 0 = “ w orst p ossi ble pai n”).  
1 0. 3. 1. 4  K nee I nj ur y a n d Oste o art hritis O utc o me Sc o re ( K O O S) 
T he K O O S  was de vel o pe d as a n e xte nsi o n of t he W O M A C Oste oart hritis I n de x wit h t he p ur p ose 
of e val uati n g s h ort -ter m a n d l o n g-ter m s y m pt o ms a n d f u ncti o n i n s u bjects wit h k nee i nj ur y a n d 
O A . T he K O O S h ol ds 5 se paratel y sc ore d s u bscales: Pai n, ot her sy m pt o ms, F u ncti o n  i n Dail y 
Li vi n g ( A D L), F u ncti o n i n S p ort a n d Recreati o n ( S p ort/ Rec), a n d k nee-relate d Q ualit y of Life 
( Q O L). T he K O O S has bee n vali date d f or se veral ort h o pe dic i nter ve nti o ns s uc h as a nteri or 
cr uciate li ga me nt rec o nstr ucti o n, me niscect o m y , a n d t otal k nee r e place me nt. I n a d diti o n, t he 
i nstr u me nt has bee n use d t o e val uate p h ysical t hera p y, n utriti o nal s u p ple me ntati o n, a n d 
gl uc osa mi ne s u p ple me ntati o n. T he effect size is ge nerall y lar gest f or t he s u bscale Q O L f oll o we d 
b y t he s u bscale Pai n. T he  K O O S is a vali d, relia ble, a n d res p o nsi ve self -a d mi nistere d i nstr u me nt 
t hat ca n be use d f or s h ort-ter m a n d l o n g-ter m f oll o w-u p of se veral t y pes of k nee i nj ur y , i ncl u di n g 
O A.   
1 0. 3. 1. 5  Me dic al O utc o mes St u d y ( M O S) Slee p Sc ale  
I nte n de d t o assess t he e xte nt of slee p pr o ble ms, t he M O S  slee p scale meas ures 6 di me nsi o ns of 
slee p, i ncl u di n g i nitiati o n, mai nte na nce (e g, sta yi n g aslee p), q ua ntit y, a de q uac y, s o m n ole nce (e g, 
dr o wsi ness) , a n d res pirat or y i m pair me nts (e g , s h ort ness of breat h, s n ori n g). Dist ur be d slee p has a 
maj or i m pact o n q ualit y of life a n d is ofte n a c o m m o n s y m pt o m of ma n y ot her c hr o nic 
c o n diti o ns, s uc h as c hr o nic pai n a n d m o o d dis or ders.  
T he relia bilit y a n d vali dit y of t he M O S slee p scale ha ve bee n e va l uate d i n a n u m ber of disease 
areas, i ncl u di n g ne ur o pat hi c pai n, restless le g s y n dr o me, o veracti ve bla d der , a n d r he u mat oi d 
art hritis.  
Pa ge 5 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
I nte n de d f or a d ults 1 8 years of a ge a n d ol der, t he f or ms are a vaila ble i n a  fi xe d f or m m o de of 
a d mi nistrati o n, wit h a sta n dar d 4 -wee k recall peri o d ( A p pe n di x A ). 
1 0. 3. 1. 6  Q u alit y of Life ( E Q -5 D -5 L ) 
T he E Q -5 D -5 L is a ge neric, prefere nce -base d patie nt -re p orte d o utc o me meas ure, w hic h 
meas ures healt h -relate d q ualit y of life.1 1 I n patie nts wit h c hr o nic pai n, t he c o nstr uct vali dit y of 
t he E Q-5 D -5 L differe ntiates bet wee n patie nt s u b gr o u ps wit h differe nt se verities of A Es  a n d 
a nal gesic efficac y.  W he n a nc h ori n g t he E Q -5 D -5 L meas ures t o a disease -s pecific q uestio n naire 
s uc h as t he W O M A C, b ot h q uesti o n naires c oul d differe ntiate bet wee n W O M A C se verit y 
le vels.1 2  
•  T he first part of t he E Q -5 D -5 L as ks t he s u bject t o gra de t he de gree of pr o ble ms 
ass ociate d wit h perf or mi n g a series of 5 as pects of dail y f u ncti o ni n g ( m o bilit y, self -care, 
us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n) b y selecti n g 1  of 5 descri pti ve 
cate g ories: n o/ n o ne, sli g ht, m o derate, se vere, or e xtre mel y.  
•  T he sec o n d part of t he E Q -5 D -5 L as ks t he s u bject t o a ns wer t he q uesti o n “ We w o ul d li ke 
t o k n o w h o w g o o d or ba d y o ur healt h  is T O D A Y” b y mar ki n g a n X o n a 1 0 0-c m, 
gra d uate d scale, w here 1 0 0 c orres p o n ds t o “t he best healt h y o u ca n i ma gi ne” a n d 0 
c orres p o n ds t o “t he w orst healt h y o u ca n i ma gi ne .” T he scale is gra d uate d b y u nits, wit h 
eac h 5-u nit i ncre me nt fr o m zer o la bele d wit h t he c orres p o n di n g val ue (ie, 0, 5, 1 0, 1 5, 
etc.). T he s u bject is t he n as ke d t o rec or d t he val ue f or t he l ocati o n of X o n t he scale.  
Q ualit y of life will be assesse d usi n g t he E Q -5 D -5 L  scale (A p pe n di x  A ) acc or di n g t o t he 
sc he d ule of e ve nts, Ta ble 1 7 -1 . 
1 0. 3. 1. 7  S h ort F or m -3 6  He alt h St at us Q uesti o n n aire  
T he S h ort F or m -3 6 Healt h S ur ve y  is a 3 6-ite m, patie nt-re p orte d s ur ve y of patie nt healt h, a n d is 
co m m o nl y use d i n  healt h ec o n o mics  as a varia ble i n t he  q ualit y -a dj uste d life year calc ulati o n t o 
deter mi ne t he  c ost -effecti ve ness  of a healt h treat me nt. T he ori gi nal S F -3 6 ca me o ut fr o m t he 
M O S.   
T he S F -3 6  meas ures 8 healt h d o mai ns: p h ysical f u ncti o ni n g, r ole p h ysical, b o dil y pai n, ge neral 
healt h, vitalit y, s ocial f u ncti o ni n g, r ole e m oti o nal, a n d me ntal healt h. P h ysical f u ncti o ni n g c o vers 
li mitati o ns i n dail y life d ue t o healt h pr o ble ms. T he r ole p h ysical scale meas ures r ole li mitati o ns 
d ue t o p h ysical healt h pr o ble ms. T he b o dil y pai n scale assesses pai n fre q ue nc y a n d pai n 
i nterfere nce wit h us ual r oles. T he ge neral healt h scale meas ures i n di vi d ual perce pti o ns of ge neral 
healt h. T he vitalit y scale assesses e ner g y le vels a n d fati g ue. T he s ocial f u ncti o ni n g scale 
m eas ures t he e xte nt t o w hic h ill healt h i nterferes wit h s ocial acti vities. T he r ole e m oti o nal scale 
assesses r ole li mitati o ns d ue t o e m oti o nal pr o ble ms, a n d t he me ntal healt h scale meas ures 
ps yc h ol o gical distress ( A p pe n di x  A ). 
1 0. 3. 1. 8  W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Sc ale ( W P AI)  
T he W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt ( W P AI) q uesti o n naire is a n i nstr u me nt t o 
meas ure i m pair me nts i n b ot h pai d w or k a n d u n pai d w or k. It meas ures a bse n teeis m, prese nteeis m 
as well as t he i m pair me nts i n u n pai d acti vit y beca use of healt h pr o ble m d uri n g t he past se ve n 
da ys ( A p pe n di x A ). T he W P AI is a vali d q uesti o n naire f or assessi n g i m pair me nts i n pai d w or k 
a n d acti vities i n O A  patie nts a n d f o r meas uri n g t he relati ve differe nces bet wee n O A  patie nts wit h 
differe nt healt h stat us.  
Pa ge 5 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0. 3. 1. 9  Assisti ve  De vice Us a ge  
T he Assisti ve De vice Usa ge q uesti o n naire is a n i nstr u me nt t o meas ure a n y c ha n ges i n t he t y pes 
of de vices use d t o  assist wit h wal ki n g d uri n g t he s t u d y peri o d. S u bjects w h o use assisti ve de vices 
at t he start of t he st u d y are as ke d t o i de ntif y t he t y pe of de vice use d. T his q uesti o n is t he n as ke d 
a gai n at s pecifie d visits d uri n g t he st u d y. T he fre q ue nc y of de vice use is  als o ca pt ure d ( Ofte n; 
Sel d o m; or  N ot at All).  
T he c h oice of de vices is as f oll o ws:  
•  
Ca ne  
•  Cr utc h  
•  Wal ker  
•  Gait Trai ner  
•  Seate d wal ki n g sc o oter  
•  W heelc hair  
•  Stairlift  
•  Ot her (if ot her, s pecif y i n t he s pace pr o vi de d)  
1 0. 3. 1. 1 0  Resc ue Me dic ati o n Use  
S u bjects ma y ta ke all o we d resc ue me dicati o n f or pai n of t he i n de x k nee as nee de d, e xce pt t hat 
t he y s h o ul d n ot use resc ue me dicati o n wit hi n 2 4 h o urs of a pla n ne d st u d y visit.  Per mitte d resc ue 
me dicati o ns  are liste d i n Secti o n 9. 1 2. 1 . Data o n t he t y pe of  resc ue me dicati o n, a n d t he dail y 
d ose, will be re p orte d dail y b y t he s u bject usi n g t he e P R O fr o m Scree ni n g t hr o u g h Wee k  5 2 or 
f or Earl y Ter mi nati o n. A d diti o nal resc ue  me dicati o n details will be c ollecte d at st u d y visits a n d 
f oll o w-u p tele p h o ne calls i n t h e s o urce d oc u me nts a n d i n t he e C R F. 
1 0. 3. 2  Cli nic al P h ar m ac ol o g y  
N ot a p plica ble f or t his st u d y.  
1 0. 3. 3  S afet y  
Safet y will be assesse d b y i njecti o n site assess me nt (er yt he ma a n d e de m a), assess me nt of 
pr oce d ure pai n , A Es, p h ysical e xa mi nati o n fi n di n gs, se ns or y testi n g, vital si g n meas ure me nts, 
1 2 -lea d E C G, cli nical la b orat or y test res ults , a n d t he sta bilit y of t he ra di o gra p hic k nee O A, base d 
o n Pre -scree ni n g a n d Wee k 5 2 ra di o gra p hs.  
1 0. 3. 3. 1  L a b or at or y S afet y Assess me nts  
1 0. 3. 3. 1. 1  L a b or at or y Tests t o be Perf or me d  
Sa m ples f or t he f oll o wi n g la b orat or y tests will be c ollecte d at t he ti me p oi nts s pecifie d i n t he 
sc he d ule of e ve nts ( Secti o n  1 7. 1 ). 
He mat ol o g y  
he m o gl o bi n, he mat ocrit, re d bl o o d cell ( R B C) c o u nt, R B C i n dices, mea n 
c or p usc ular he m o gl o bi n, mea n c or p usc ular he m o gl o bi n c o nce ntrati o n, 
platelet c o u nt ( or esti mate), w hite bl o o d cell c o u nt i ncl u di n g differe ntial  
Ser u m C he mistr y  
al b u mi n, t otal bilir u bi n, t otal pr otei n, calci u m, al kali ne p h os p hatase, 
ala ni ne a mi n otra nsferase, as partate a mi n otra nsferase, bl o o d urea 
Pa ge 5 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
nitr o ge n, creati ni ne, gl uc ose, s o di u m, p otassi u m, c hl ori de, bicar b o nate, 
lactate de h y dr o ge nase, uric aci d 
C oa g ulati o n Pa nel  
Pr ot hr o m bi n ti me, partial t hr o m b o plasti n ti me, fi bri n o ge n  
Uri nal ysis  
p H, s pecific gra vit y, occ ult bl o o d, le u k oc yte esterase, gl uc o se, pr otei n, 
ket o nes  
Uri ne Pre g na nc y 
T est 
f or all fe male s u bjects 
Uri ne Dr u g Scree n  a m p heta mi nes, bar bit urates, be nz o diaze pi nes, c ocai ne, o piates, 
p he nc ycli di ne, a n d tetra h y dr oca n na bi n ol  
Ot her  
H b A 1c, ser u m pre g na nc y test f or fe male s u bjects  
K nee Ra di o g ra p hs 
Sta bilit y of t he ra di o gra p hic k nee O A j oi nt da ma ge, c o m pare d t o place b o 
o r n o treat me nt, base d o n Pre -scree ni n g a n d Wee k 5 2 ra di o gra p hs.  
Sc ori n g will use t he O A R SI criteria 
Bl o o d a n d uri ne sa m ples f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis will  be se nt t o a 
ce ntral la b orat or y f or a nal yses. Uri ne dr u g scree ns a n d uri ne pre g na nc y tests ma y be c o n d ucte d 
at t he st u d y sites. K nee ra di o gra p hs will be o btai ne d at t he sites, a n d i ma ges will be e val uate d b y 
a ce ntral rea der.  
1 0. 3. 3. 1. 2  S peci me n H a n dli n g Re q uire me nt s 
T he tra ns missi o n of i nfecti o us a ge nts ma y occ ur t hr o u g h c o ntact wit h c o nta mi n ate d nee dles a n d 
bl o o d or bl o o d pr o d ucts. C o nse q ue ntl y, a p pr o priate bl o o d a n d b o d y fl ui d preca uti o ns s h o ul d be 
e m pl o ye d b y all st u d y pers o n nel i n v ol ve d i n t he c ollecti o n  of bl o o d a n d ha n dli n g of s peci me ns 
i n b ot h t he cli nic a n d la b orat or y setti n gs. Refer t o c urre nt rec o m me n dati o ns of t he a p pr o priate 
a ut h orities . 
1 0. 3. 3. 1. 3  E v al u ati o n of L a b or at or y V al ues  
T he n or mal ra n ges of val ues f or t he la b orat or y assess me nts i n t his st u d y will b e pr o vi de d b y t he 
res p o nsi ble la b orat or y a n d s u b mitte d t o Ce ntre xi o n T hera pe utics C or p.  pri o r t o t he be gi n ni n g of 
t he st u d y. T he y will be re gar de d as t he refere nce ra n ges o n w hic h decisi o ns will be ma de.  
If a la b orat or y val ue is o ut of t he refere nce ra n ge, it is not necessaril y cli nicall y rele va nt. T he 
i n vesti gat or m ust e val uate t he o ut-of -ra n ge val ues a n d rec or d his/ her assess me nt of t he cli nical 
rele va nce i n t he a p pr o priate eC R F.  
All la b orat or y val ues w hic h, i n t he i n vesti gat or’s o pi ni o n, s h o w cli nicall y rele va nt or 
pat h ol o gical c ha n ges d uri n g or after ter mi nati o n of t he treat me nt ha ve t o be re p orte d as A Es a n d 
f oll o we d as descri be d i n Secti o n 1 1. 2. 6 . 
All meas ure m e nts descri be d i n t his secti o n are rec o g nize d sta n dar d met h o ds.  
Pa ge 5 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0. 3. 3. 2  Cli nic al  E x a mi n ati o ns  
1 0. 3. 3. 2. 1  Vit al Si g ns  
Vital si g ns  meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure , heart rate ( H R) a n d 
res pirat or y rate ( R R). At eac h office visit, e xce pt o n t he day s of i njecti o n, vital si g ns  will be 
meas ure d after t he s u bject has bee n  sta n di n g f or a p pr o xi matel y 2 mi n utes, a n d after t he s u bject 
has bee n i n a sitti n g p ositi o n f or a p pr o xi matel y 5  mi n utes . O n t he da y s of i njecti o n, b ot h 
sta n di n g a n d sitti n g vital si g ns will be meas ure d wit hi n a p pr o xi matel y 5 mi n utes bef ore t he 
i njecti o n of I P, a n d sitti n g-o nl y vital si g ns will be meas ure d wit hi n a p pr o xi matel y 5 , 1 5, a n d 3 0 
mi n utes after t he i njecti o n.  
Te m perat ure will als o be meas ure d  at all office visits , e xce pt t he Pre-Scree ni n g Visit . 
1 0. 3. 3. 2. 2  Electr oc ar di o gr a m  
A sta n dar d 1 2 -lea d E C G will be perfor me d at rest, wit h t he s u bject l yi n g d o w n f or a p pr o xi matel y 
5  mi n utes bef ore t he E C G is o btai ne d . T he  E C G  will be e val uate d at t he i n vesti gati o nal site t o 
deter mi ne t he s u bject’s eli gi bilit y a n d t o m o nit or safet y d uri n g t he trial.  T he pri nci pal 
i n vesti gator or q ualifie d desi g nee will re vie w, si g n, a n d date eac h E C G rea di n g, n oti n g w het her 
or n ot a n y a b n or mal res ults are of cli nical si g nifica nce.  T he E C G will be re peate d if a n y res ults 
are c o nsi dere d t o be cli nicall y si g nifica nt. All E C G rec or di n gs will be i de ntifie d wit h t he s u bject 
n u m ber, i nitials, date, a n d ti me of t he rec or di n g . 
1 0. 3. 3. 2. 3  P h ysic al E x a mi n ati o n  
C o m plete  (e xcl u di n g a ge nit o uri nar y e xa m) or partial  p h ysical e xa mi nati o n s will be c o n d ucte d 
acc or di n g t o t he sc he d ule of e ve nts , Ta ble 1 7 -1 . T he i n vesti gat or s h o ul d als o ass ess periartic ular 
te n der ness a n d pai n i n t he s oft tiss ue of t he i n de x k nee at eac h p h ysical e xa m a n d rec or d t he 
res ults o n t he eC R F. Hei g ht will be meas ure d at t he Pre -scree ni n g Visit.  B o d y wei g ht will be 
meas ur e d at Pre -scree ni n g, Da y 1 ( pre -d ose), a n d We e ks 4, 1 2, 2 6, 3 8 , a n d 5 2/ Earl y Ter mi nati o n 
Visit . K nee circ u mfere nce will be meas ure d at Scree ni n g  a n d pre -d ose at Wee k 2 6 , a n d 
a b d o mi nal girt h will be meas ure d at Scree ni n g a n d at t he E n d -of -St u d y Visit ( Wee k  5 2).   
I n a d diti o n t o periartic ular pai n (assesse d at all visits), t he partial p h ysical e xa mi nati o n s h o ul d 
i ncl u de vital si g ns ( bl o o d press ure a n d heart rate) a n d te m perat ure. T he i n vesti gat or s h o ul d als o 
liste n t o t he heart a n d l u n gs at a mi ni m u m a n d f oll o w u p a n y s y m pt o ms wit h a tar gete d p h ysical 
e xa m, as a p pr o priate . 
T he pri nci pal i n vesti gat or or his/ her a p p oi nte d desi g nee is pri maril y res p o nsi ble f or perf or mi n g 
t he p h ysical e xa mi nati o n. W he ne ver p ossi ble, t he sa me i n di vi d ual s h o ul d perf or m all p h ys ical 
exa mi na ti o ns if feasi ble.  
1 0. 3. 3. 2. 4  I njecti o n Site Assess me nt 
T he i njecti o n site will be e xa mi ne d a n d assesse d f or er yt he ma a n d e de ma (se paratel y b y a n 
i n vesti gat or usi n g a cate g orical scale of n o ne, mil d, m o derate, or se vere) o n Treat me nt Da y 1 
bef ore i njecti o n, after t he i njecti o n at 1 a n d 2 h o urs p ost -d ose, a n d at t he Wee k 4  st u d y visit. T he 
pr oce d ure will be re peate d o n  Treat me nt Da y 2 (Wee k 2 6 ) a n d Wee k 3 0. Si g nifica nt br uisi n g  or 
ot her cli nicall y si g nifica nt i njecti o n site reacti o ns  ( ot her t ha n er yt he ma or e de ma) wil l be 
rec or de d as A Es. 
Pa ge 5 8 of 1 3 3




Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 0. 3. 3. 6  A d verse E ve nts  
T he defi niti o ns a n d ma na ge me nt of a n d s pecial c o nsi derati o ns f or A Es are pr o vi de d  i n 
Secti o n  1 1 .  
Pa ge 6 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 1.  A D V E R S E E V E N T S  
1 1. 1.  Defi niti o n s 
1 1. 1. 1  A d verse E ve nts  
A n A E  is defi ne d as a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t he 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 
(i ncl u di ng a ne w, cli nicall y i m p orta nt a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease, 
te m p orall y ass ociate d wit h t he pr o d uct, w het her or n ot relate d t o t he pr o d uct. 
Pre -e xisti n g diseases or c o n diti o ns will n ot  be c o nsi dere d A Es u nless  t here is a n i ncrease i n t he 
fre q ue nc y or se verit y, or a c ha n ge i n t he q ualit y of t he disease or c o n diti o n (w orse ni n g of a 
pre -e xisti n g c o n diti o n is c o nsi dere d a n A E) . 
E ve nts occ urri n g i n s u bjects treate d wit h place b o or acti ve c o m parat or or d uri n g treat me n t-free 
peri o ds of t he st u d y are als o c o nsi dere d A Es.  
1 1. 1. 2  A d verse Dr u g Re acti o n  
All n o xi o us a n d u ni nte n de d res p o nses t o a n i n vesti gati o nal  pr o d uct relate d t o a n y d ose s h o ul d be 
c o nsi dere d ad verse dr u g r eacti o ns ( A D Rs).  
T he p hrase “res p o nses t o a n  i n vesti gati o nal pr o d uct” mea ns t hat a ca usal relati o ns hi p bet wee n a n  
i n vesti gati o nal pr o d uct a n d a n A E is at least a reas o na ble p ossi bilit y, i .e., t he relati o ns hi p ca n n ot 
be r ule d o ut. All A Es j u d ge d b y ei t her t he re p orti n g i n vesti gat or or t he s p o ns or as ha vi n g a 
reas o na ble ca usal relati o ns hi p t o an  i n vesti gati o nal pr o d uct q ualif y as A D Rs.  
All A E s f or w hic h t he j u d g me nt of relati o ns hi p t o I P is “ p ossi ble” or hi g her will be c o nsi dere d 
A D Rs. If a relati o ns hi p  t o I P is n ot gi ve n, t he n t he A E m ust be treate d as if t he relati o ns hi p t o IP 
were  “ p ossi ble .”  
1 1. 1. 3  U ne x pecte d A d verse E ve nt / A d verse Dr u g Re acti o n 
A n e x pecte d A E or A D R is o ne f or w hic h t he nat ure or se verit y is c o nsiste nt wit h t he k n o w n A E 
pr ofile of t he pr o d uct. F or a n  I P, t he k n o w n i nf or mati o n is c o ntai ne d i n t he I B. F or a mar kete d 
pr o d uct, t he k n o w n i nf or mati o n is c o ntai ne d i n t he c urre nt pac ka ge i nsert f or t he pr o d uct.  
A n u ne x pecte d a d verse e ve nt ( U A E) or u ne x pecte d ad verse d r u g reacti o n ( U A D R) is o ne f or 
w hic h t he s pecificit y or se verit y is n ot c o nsist e nt wit h t he c urre nt I B. F or e xa m ple, he patic 
necr osis w o ul d be u ne x pecte d ( greater se verit y) if t he I B o nl y liste d ele vate d he patic e nz y mes or 
he patitis. Li ke wise, cere bral t hr o m b oe m b olis m a n d cere bral vasc ulitis w o ul d be u ne x pecte d 
( greater s pecificit y) if t he I B o nl y liste d cere bral vasc ular acci de nts.  
F urt her m ore , re p orts t hat a d d si g nifica nt i nf or mati o n o n s pecificit y or se verit y of a k n o w n, 
alrea d y d oc u me nte d a d verse reacti o n c o nstit ute u ne x pecte d e ve nts. E xa m ples w o ul d be (a) ac ute 
re nal fail ure as a n e x pecte d a d verse reacti o n wit h a s u bse q ue nt ne w occ urre nce of i nterstitial 
ne p hritis (i nterstitial ne p hritis w o ul d be u ne x pecte d) a n d ( b) he patitis wit h a first occ urre nce of 
f ul mi nan t he patitis (f ul mi na nt he patitis w o ul d be u ne x pecte d). 
Pa ge 6 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 1. 1. 4  Seri o us A d verse E ve nts / Dr u g Re acti o n 
A seri o us a d verse e ve nt ( S A E) is a n y u nt o war d me dical occ urre nce t hat at a n y d ose 
•  res ults i n deat h 
•  is life-t hreate ni n g 
N O T E: T he ter m “life -t hre ate ni n g ” i n t he defi niti o n of “seri o us ” refers t o a n eve nt i n 
w hic h t he p atie nt w as at risk of de at h at t he ti me of t he  eve nt; it d oes n ot refer t o a n eve nt 
w hic h hy p ot hetic ally mi g ht h ave c a use d de at h if it were m ore severe.  
•  re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
N O T E: I n p atie nt hos pit aliz ati o n is defi ne d as 2 4  h o urs i n a h os pit al o r a n over ni g ht st ay. 
A n elective h os pit al a d missi o n t o tre at a c o n diti o n prese nt bef ore ex p os ure t o t he test 
dr u g, or a h os pit al a d missi o n f or a di a g n ostic ev al u ati o n  of a n A E, d oes n ot  q u alify t he 
c o n diti o n or eve nt as a n S A E. F urt her, a n over ni g ht st ay i n t he h os pit al t h at is o nly d ue 
t o tr a ns p ort ati o n, or g a niz ati o n, or acc o m m o d ati o n pr o ble ms a n d wit h o ut me dic al 
b ack gr o u n d d oes n ot nee d t o be c o nsi dere d a n S A E . 
•  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 
N O T E: A c o n g e nit al a n o m aly i n a n i nf a nt b or n t o a m ot her w h o w as ex p ose d t o t he I P 
d uri n g pre g n a ncy is a n S A E. H o wever, a  ne wly di a g n ose d pre g n a ncy i n a s u bject t h at 
h as receive d a n I P  is n ot  c o nsi dere d a n S A E u nless it is s us pecte d t h at t he I P(s) 
i nter acte d wit h a c ontr ace ptive met h o d a n d le d t o t he pre g n a ncy.  
•  is a n i m p orta nt me dical e ve nt 
N O T E: Me dic al a n d scie ntific j u d g me nt s h o ul d be exercise d i n deci di n g w het her it is 
a p pr o pri ate t o c o nsi der ot her sit u ati o ns seri o us, s uc h as i m p ort a nt me dic al eve nts t h at 
m ay n ot be i m me di ately life -t hre ate ni n g or res ult i n de at h or h os pit aliz ati o n b ut m ay 
je o p ar dize t he p atie nt or m ay re q uire i nterve nti o n t o preve nt o ne of t he ot her o utc o mes 
liste d i n t he defi niti o n a b ove. Ex a m ples of s uc h eve nts are i nte nsive tre at me nt i n a n 
e merge ncy r o o m or at h o me f or aller gic br o nc h os p as m, bl o o d dyscr asi as , or c o nv ulsi o ns 
t h at d o n ot res ult i n h os pit aliz ati o n, devel o p me nt of dr u g de pe n de ncy, or dr u g a b use. T he 
occ urre nce of m ali g n a nt t u m ors is als o t o be c o nsi dere d seri o us.   
1 1. 1. 5  Si g nific a nt A d vers e E ve nts 
Ot her si g nifica nt A Es are defi ne d as mar ke d he mat ol o gical a n d ot her la b orat or y a b n or malities 
( ot her t ha n t h ose meeti n g t he defi niti o n of seri o us) a n d a n y e ve nts t hat le d t o a n i nter ve nti o n, 
i ncl u di n g wit h dra wal of I P, d ose re d ucti o n, or si g nifica nt a d diti o nal c o nc o mita nt t hera p y. 
1 1. 1. 6  Tre at me nt -E mer ge nt A d verse E ve nts  
A n A E is defi ne d as treat me nt e mer ge nt if  t he first o nset or w orse ni n g is after t he first 
a d mi nistrati o n of I P.  
1 1. 2.  M a n a ge me nt of A d verse E ve nts  
A d verse e ve nts will be c ollecte d fr o m t he ti me of si g ni n g t he I C F t hr o u g h t he F oll o w -u p Visit or  
Earl y Ter mi nati o n Visit, w hic he ver occ urs first.  
Pa ge 6 2 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 1. 2. 1  A d verse 
E ve nt of S peci al I nterest : Se vere 
Aller gic 
Re acti o n –  A n a p h yl a xis/ 
A n a p h yl act oi d Re acti o n  
O nly st u dy sites wit h cr as h c arts or e q uiv ale nt a n d A C L S -ce rtifie d pers o n nel i m me di ately 
av ail a ble are per mi tte d t o tre at s u bjects wit h st u dy dr u g. 
A case of lar y n g os pas m was o bser ve d d uri n g a hi p re place me nt o perati o n after ca psaici n was 
i nstille d i nt o t he s ur gical w o u n d, re q uiri n g t he s u bject t o be i nt u bate d d uri n g t he pr oce d ure.  
A case of se vere aller gic rea cti o n was see n i m me diatel y after C N T X -4 9 7 5 -0 5 was i njecte d i nt o 
t he k nee of a s u bject i n st u d y C N T X-4 9 7 5i -O A -3 0 3, wit h t he s u bject c o m plai ni n g of d ys p nea 
a n d tac h ycar dia. E pi ne p hri ne 0. 5 m g a n d I M s ol u me dr ol  were gi ve n, a n d t he s u bject rec o vere d 
i n mi n utes, wit h n o s u bse q ue nt a d verse e ve nts. 
A n a p h yl actic Re acti o n  
A n a na p h ylactic reacti o n is a ra pi d o nset seri o us aller gic reacti o n t hat has a variet y of s y m pt o ms 
a n d o utc o mes, w hic h ca n i ncl u de deat h. A n a na p h y lactic reacti o n t y picall y has s y m pt o ms a n d 
si g ns starti n g o ver mi n utes t o h o urs. A na p h yla xis ca uses m ore t ha n o ne of t he f oll o wi n g: l o w 
bl o o d press ure, li g ht hea de d ness, s h ort ness of breat h, a n itc h y ras h, t hr oat or t o n g ue s welli n g, a n d 
v o miti n g.  
A n a p h yl ac t oi d re acti o n  
T hese reacti o ns pr o d uce t he sa me c li nical si g ns a n d s y m pt o ms a na p h ylactic reacti o ns, b ut are n ot 
I g E me diate d, b ut i nstea d occ ur t hr o u g h a direct n o n-i m m u ne-me diate d release of me diat ors 
fr o m bas o p hils a n d/ or mast cells or ca n ma nifest fr o m direct c o m ple me nt acti vati o n.  
All s u bjects m ust b e m o nit ore d f or at least 3 0 mi n utes ( or l o n ger, as re q uire d b y t he pr ot oc ol) 
after st u d y dr u g i njecti o n t o e ns ure t hat t he y d o n ot ha ve a h y perse nsiti vit y reacti o n/a na p h yla xis. 
Vital si g ns ( V S) are t o be d o n e pre-i njecti o n a n d 5 mi n utes after t he i njecti o n, sta n di n g a n d 
sitti n g, a n d t he n vital si g ns m ust n o w be ta ke n at 1 5 a n d 3 0 mi n utes (sitti n g o nl y) after i njecti o n 
of st u d y dr u g  
A n y s u bject t hat meets t he criteria f or a na p h yla xis or a na p h ylact oi d reacti o ns , as descri be d i n t he 
pa per b y Sa m ps o n et al. ( 2 0 0 6 )1 3 (see A p pe n di x C ) f oll o wi n g t he first/ pri or i njecti o n is 
pr o hi bite d fr o m bei n g re -treate d wit h st u d y dr u g. 
Cli nic a l Criteri a f or Di a g n osi n g A n a p h yl a xis  
A na p h yla xis is hi g hl y li kel y w he n a n y o ne  of t he f oll o wi n g 3 criteri a  are f ulfille d:  
1.  Ac ute o nset of a n ill ness ( mi n utes t o se ver al h o urs) wit h i n v ol ve me nt of t he s ki n, m uc os al 
tiss ue, or b ot h (e g, ge ner alize d hi ves, pr urit us or fl us hi n g, s w olle n li ps-t o n g ue-u v ul a), A N D 
A T L E A S T O N E O F T H E F O L L O WI N G : 
a. Res pi rat or y c o m pr o mise (e g, d ys p nea, w heeze-br o nc h os pas m, stri d or, re d uce d P E F, h y p o xe mia)  
b.  Re d uce d B P or ass ociate d s y m pt o ms of e n d -or ga n d ysf u ncti o n (e g, h y p ot o ni a [c olla pse], 
s y nc o pe, i nc o nti ne nce) 
2.  T w o or m ore of t he f oll o wi n g t h at occ ur r a pi dl y after e x p os ure t o a li kel y aller ge n f or t h at 
p atie nt ( mi n utes t o se ver al h o urs) : 
a. I n v ol ve me nt of t he s ki n-m uc osal tiss ue (e g, ge neralize d hi ves, itc h -fl us h, s w olle n li ps-t o n g ue-
u v ula)  
Pa ge 6 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
b.  Res pirat or y c o m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, stri d or, re d uce d P E F, h y p o xe mia) 
c. Re d uce d B P or ass ociate d s y m pt o ms (e g, h y p ot o nia [c olla pse], s y nc o pe, i nc o nti ne nce)  
d.  Persiste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o m i nal pai n, v o miti n g) 
3.  Re d uce d B P after e x p os ure t o k n o w n aller ge n f or t h at p atie nt ( mi n utes t o se ver al h o urs) : 
a. I nfa nts a n d c hil dre n: l o w s yst olic B P (a ge s pecific) or greater t ha n 3 0 % decrease i n s yst olic B P∗ 
b.  A d ults: s yst olic B P of less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease fr o m t hat pers o n's 
baseli ne  
S o urce: Sa m ps o n et al. ( 2 0 0 6) 
A b bre viati o ns: P E F, Pea k e x pirat or y fl o w; B P, bl o o d press ure.  
∗ L o w s yst olic bl o o d press ure f or c hil dre n is defi ne d as less t ha n 7 0 m m H g fr o m 1 m o nt h t o 1  year, 
less t ha n ( 7 0 m m H g + [ 2 × a ge]) fr o m 1 t o 1 0 years, a n d less t ha n 9 0 m m H g fr o m 1 1 t o 1 7 years.  
I n t he e ve nt of a n a na p h ylactic reacti o n or a na p h ylact oi d e ve nt, i nstit ute treat me nt i m me diatel y, 
as o utli ne d i n A p pe n di x C . N ote als o t hat a ser u m tr y ptase bl o o d le vel m ust be o btai ne d usi n g 
t he Vac utai ner t u be pr o vi de d. 
All a na p h ylactic a n d a na p h ylact oi d e ve nts (e. g. ras h, d ys p nea, gastr oi ntesti nal s y m pt o ms) m ust 
be rec or de d wit h t he ti me t hat t he e ve nts occ urre d a n d res o l ve d, a n d treat me nts (e. g. 
e pi ne p hri ne) s h o ul d be rec or de d wit h t heir ti me of a d mi nistrati o n.  
1 1. 2. 2  C ollecti o n  
T he i n vesti gat or is res p o nsi ble f or t he detecti o n a n d d oc u me ntati o n of e ve nts meeti n g t he criteria 
a n d defi niti o n of a n A E or S A E descri be d pre vi o usl y.  A t eac h visit, t he s u bject will be all o we d 
ti me t o s p o nta ne o usl y re p ort a n y iss ues si nce t he last visit or e val uati o n. T he i n vesti gat or will 
t he n m o nit or a n d/ or as k a b o ut or e val uate A Es usi n g n o nlea di n g q uesti o ns , s uc h as 
•  “ H o w are y o u feeli n g?”  
•  “ Ha ve y o u  e x perie nc e d a n y iss ues si nce y o ur last visit? ” 
•  “ Ha ve y o u ta ke n a n y ne w me dicati o ns si nce y o ur last visit?”  
A n y cli nicall y rele va nt o bser vati o ns ma de d uri n g t he visit will als o be c o nsi dere d  A Es.  
1 1. 2. 3  E v al u ati o n  
1 1. 2. 3. 1  Se verit y of A d verse E ve nts  
T he cli nical se verit y of a n A E will be classifie d as  
Mil d  
Us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt or t hera pe utic 
i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual acti vities of 
dail y li vi n g.  
M o derate  
Us uall y alle viate d wit h a d diti o nal s pecific t h era pe utic  i nter ve nti o n. T he e ve nt 
i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort b ut p oses n o 
si g nifica nt or per ma ne nt ris k of har m t o t he s u bject. 
Pa ge 6 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
Se vere  
I nterr u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y affects cli nical 
stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter ve nti o n. 
It is i m p orta nt t o disti n g uis h bet wee n se vere A Es a n d S A Es. Se verit y is a classificati o n of 
i nte nsit y, w hereas a n S A E is a n A E t hat meets seri o us criteria, as descri be d i n Secti o n  1 1. 1. 4 . 
1 1. 2. 3. 2  Seri o us ness  
T he i n vesti gat or i s t o e val uate w het her t he A E meets seri o us criteria , as descri be d i n 
Secti o n  1 1. 1. 4 . 
1 1. 2. 3. 3  Acti o n(s) T a ke n  
Acti o n(s) ta ke n wit h re gar d t o I P ma y c o nsist of  t he f oll o wi n g: 
D ose i nc rease d 
A n i n dicati o n t hat a me dicati o n sc he d ule was m o difie d b y a d diti o n; eit her 
b y c ha n gi n g t he fre q ue nc y, stre n gt h or a m o u nt. 
D ose n ot 
c ha n ge d 
A n i n dicati o n t hat a me dicati o n sc he d ule was mai ntai ne d.  
D ose re d uce d  
A n i n dicati o n t hat a me dicati o n sc he d ul e was m o difie d b y s u btracti o n, eit her 
b y c ha n gi n g t he fre q ue nc y, stre n gt h or a m o u nt.  
Dr u g 
i nterr u pte d 
A n i n dicati o n t hat a me dicati o n sc he d ule was m o difie d b y te m p oraril y 
ter mi nati n g a prescri be d re gi me n of me dicati o n. 
Dr u g 
wit h dra w n  
A n i n dicati o n t hat a  me dicati o n sc he d ule was m o difie d t hr o u g h ter mi nati o n 
of a prescri be d re gi me n of me dicati o n.  
N ot a p plica b le 
Deter mi nati o n of a val ue is n ot rele va nt i n t he c urre nt c o nte xt.  
U n k n o w n  
N ot k n o w n, n ot o bser ve d, n ot rec or de d, or ref use d.  
1 1. 2. 3. 4  O utc o me at t he Ti me o f L ast O bser v ati o n 
T he o utc o me at t he ti me of last o bser vati o n will be classifie d as  
•  Rec o vere d/res ol ve d  
•  Rec o vere d/res ol ve d wit h se q uelae  
•  Rec o veri n g/res ol vi n g  
•  N ot rec o vere d/ n ot res ol ve d  
•  Fatal *  
•  U n k n o w n  
* O nl y select fatal as a n o utc o me w he n t he A E res ults i n deat h. If m ore t ha n o ne A E is p ossi bl y 
relate d t o t he s u bject’s deat h, t he o utc o me of deat h s h o ul d be i n dicate d f or eac h s uc h A E. 
Alt h o u g h “fatal” is us uall y a n e ve nt o utc o me, e ve nts s uc h as s u d de n deat h or u ne x plai ne d deat h 
s h o ul d be re p orte d as S A Es. 
Pa ge 6 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 1. 2. 3. 5  A d v erse E ve nt Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct  
T he i n vesti gat or m ust ma ke a n assess me nt of eac h A E’s  relati o ns hi p t o t he I P. T he cate g ories f or 
classif yi n g t he i n vesti gat or’s o pi ni o n of t he relati o ns hi p are liste d bel o w . 
N ot relate d  
A n A E wit h s ufficie nt e vi de nce t o acce pt t hat t here is n o ca usal relati o ns hi p 
t o I P a d mi nistrati o n (e g, n o te m p oral relati o ns hi p t o dr u g a d mi nistrati o n, 
beca use t he dr u g was a d mi nistere d after o nset of e ve nt; i n vesti gati o n s h o ws 
t hat t he dr u g was n ot a d mi nistere d; a n ot her cause was pr o ve n) . 
U nli kel y 
relate d 
A n A E, i ncl u di n g la b orat or y test a b n or malit y, wit h a te m p oral relati o ns hi p 
t o I P a d mi nistrati o n t hat ma kes a ca usal relati o ns hi p i m pr o ba ble, a n d i n 
w hic h ot her dr u gs, e ve nts or u n derl yi n g disease pr o vi de pla usi ble 
e x pla nati o ns. 
P ossi bl y 
relate d 
A n A E wit h a reas o na ble ti me se q ue nce t o a d mi nistrati o n of t he I P, b ut 
w hic h c o ul d als o be e x plai ne d b y c o nc urre nt disease or ot her dr u gs or 
e ve nts. I nf or mati o n o n dr u g wit h dra wal ma y be lac ki n g or u nclear.  
Relate d  
A n A E occ urri n g  i n a pla usi ble ti me relati o ns hi p t o I P a d mi nistrati o n a n d 
w hic h ca n n ot be e x plai ne d b y a c o nc urre nt disease or ot her dr u gs or e ve nts. 
T he res p o nse t o wit h dra wal of t he dr u g ( dec halle n ge) is cli nicall y 
reas o na ble. 
1 1. 2. 4  D oc u me nt ati o n  
All  A Es occ urri n g wit hi n t h e peri o d of o bser vati o n f or t he st u d y m ust  be d oc u me nte d i n t he C R F 
wit h t he f oll o wi n g i n f ormati o n, w here a p pr o priate. (T he peri o d of o bser vati o n f or t he st u d y is 
descri be d i n Secti o n  1 1. 2 .) 
•  A E na me or ter m  
•  W he n t he A E first o cc urre d (start date a n d ti me ) 
•  W he n t he A E st o p pe d (st o p date a n d ti me or a n i n dicati o n of “ o n g oi n g”)  
•  Se verit y of t he A E  
•  Seri o us ness  ( h os pitalizati o n, deat h, etc.) 
•  Acti o ns ta ke n  
•  O utc o me  
•  I n vesti gat or o pi ni o n re gar di n g t he A E relati o ns hi p t o t he I P(s) 
1 1. 2. 5  Tre at me nt  of A d verse E ve nts  
A d verse e ve nts t hat occ ur d uri n g t he st u d y will be treate d, if necessar y, b y esta blis he d sta n dar ds 
of care. T he decisi o n a b o ut w het her t he s u bject ma y c o nti n ue i n t he st u d y will be ma de b y t he 
s p o ns or after c o ns ultati o n wit h t he i n vesti gat or a n d/ or me dical m o nit or.  
If A Es occ ur i n a s u bject t hat are n ot t olera ble, t he i n vesti gat or m ust deci de w het her t o st o p t he 
s u bject’s i n v ol ve me nt i n t he st u d y a n d/ or treat t he s u bject. S pecial pr oce d ures ma y be 
rec o m me n de d f or t he s pecific I P, s uc h as t he c ollecti o n of a ser u m sa m ple f or deter mi ni n g  bl o o d 
c o nce ntrati o ns of I P , s pecific ta peri n g pr oce d ures, or treat me nt re gi me ns, as a p pr o priate. 
Pa ge 6 6 of 1 3 3






Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
t he Pre g na nc y Data C ollecti o n F or m via t he sa me fa x n u m ber a n d/ or e mail a d dress as f or S A E 
re p ortin g . T he i n vesti gat or s h o ul d c o ntact t he desi g nate d i n di vi d ual(s)  w h o recei ve S A E 
n otificati o n a n d rec or d  i nf or mati o n relate d t o t he pre g na nc y on a n S A E a n d A E f or m  (e nteri n g 
t he e ve nt te m p oraril y as n o n-seri o us o n b ot h f or ms)  pr o vi de d b y t he s p o ns or or its desi g nee. 
Earl y Ter mi nati o n Visit assess me nts are re q uire d as s o o n as p ossi ble after lear ni n g of t he 
pre g na nc y . T he i n vest i gat or is als o res p onsi ble f or  f oll o wi n g t he pre g na nc y u ntil deli ver y or 
ter mi nati o n. T hese fi n di n gs m ust be re p orte d o n t he S A E a n d A E f or m  a n d f or war de d t o t he 
desi g nate d i n di vi d ual(s) . T he e ve nt meets t he S A E  criteri o n o nl y if it res ults i n a s p o nta ne o us 
a b orti o n or a c o n ge nital a n o mal y . 
1 1. 3. 2  O ver d ose  
T he ma xi mal d ose of I P s h o ul d n ot be e xcee de d d uri n g t he st u d y . 
O ver d ose t hat occ urs d uri n g t he st u d y will be  treate d a n d d oc u me nte d as a n A E /U A E /S A E  if it 
f ulfills t he criteria. If t he o ver d ose d oes n ot res ult i n a n A E , it s h o ul d be re p orte d i n writte n f or m 
t o t he desi g nate d i n di vi d ual(s) w h o recei ve S A E n otificati o n. T he i nf or mati o n c o ntai ne d t herei n 
s h o ul d i ncl u de st u d y site i de ntificati o n, re p orter i de ntificati o n, s u bject i de ntificati o n, I P, d ose, 
acti o n ta ke n , a n d a n y c o m me nts.  
1 2.  D A T A S A F E T Y M O NI T O RI N G B O A R D  
A Data Safet y M o nit ori n g B oar d ( D S M B) will n ot be use d i n t his st u d y.  
Pa ge 6 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 3.  S T A TI S TI C S  
T he statistical a nal ysis was de vel o pe d t o meet t he re q uire me nts of t he U nite d States F D A  a n d t he 
E M A . 
1 3. 1.  St u d y E n d p oi nts  
1 3. 1. 1  Pri m ar y Effic ac y E n d p oi nt s 
T he pri mar y efficac y e n d p oi nt of t his st u d y, c o m pari n g res ults i n s u bjects treate d wit h  
 of 
C N T X -4 9 7 5 -0 5 or  place b o, is as f oll o ws:  
•  C ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n t he a vera ge pai n i n t he i n de x k nee, usi n g t he 
W O M A C A ( pai n) s u bscale.  
1 3. 1. 2  Ke y Sec o n d ar y  E ffic ac y E n d p oi nts:  
T he ke y sec o n dar y efficac y e n d p oi nts of t his st u d y, c o m pari n g res ults i n s u bjects treate d wit h  
 
 of C N TX -4 9 7 5 -0 5 or place b o, are as f oll o ws:  
• 
First Key Sec o n d ary:  C ha n ge fr o m st u d y baseli ne t o Wee k 3 8 i n t he a vera ge pai n i n t he 
i n de x k nee, usi n g t he W O M A C A ( pai n) s u bscale.  
• 
Sec o n d Key Sec o n d ary : C ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n t he a vera ge f u ncti o n 
i n t he i n de x k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale. 
1 3. 1. 3  Sec o n d ar y Effic ac y E n d p oi nts  
T he sec o n dar y efficac y e n d p oi n ts of t his st u d y, c o m pari n g res ults i n s u bjects treate d wit h  
 
of C N T X -4 9 7 5 -0 5 or  place b o, i ncl u de t he f oll o wi n g:  
 
•  P GI C res p o n ders (sc ores of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) f or t he i n de x k nee 
at Wee k 1 2.  
•  Area u n der  t he c ur ve ( A U C) calc ulate d base d o n t he c ha n ge fr o m st u d y baseli ne t hr o u g h 
Wee k 1 2 ( Da y 8 4) (i.e., Sta n dar dize d A U C
Dail y -W k 1 2 ) i n t he a vera ge pai n wit h wal ki n g i n 
t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0-1 0)  
•  C ha n ge fr o m st u d y baseli ne ( mea n of m ost rece nt n o n-missi n g 8 o ut of 1 4 da ys, fr o m 
Da y -1 4 t hr o u g h Da y -1) t o Wee k 1 2 ( mea n of Da y 7 8 t hr o u g h Da y 8 4) i n t he a vera ge 
pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
•  A U C calc ulate d o n c ha n ge fr o m s t u d y baseli ne t hr o u g h Wee k 2 6 ( Da y 1 8 2) (i.e., 
Sta n dar dize d A U C Dail y -W k 2 6 ) i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he 
pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
•  C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a vera ge pai n i n t he i n de x k nee, us i n g t he 
W O M A C A ( pai n) s u bscal e. 
•  C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a vera ge f u ncti o n i n t he i n de x k nee, usi n g 
t he W O M A C C (f u ncti o n) s u bscale.  
•  C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n t he a vera ge pai n i n t he i n de x k nee wit h 
wal ki n g o ver t he pre v i o us 2 4 h o urs, usi n g t he N P R S ( 0-1 0).  
Pa ge 7 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  P GI C res p o n ders (sc ores of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) f or t he i n de x k nee 
at Wee k 2 6.  
1 3. 1. 4  E x pl or at or y  Effic ac y E n d p oi nts  
E x pl orat or y  efficac y e n d p oi nts of t his st u d y, c o m pari n g res ults i n s u bjects treate d wit h  
 of 
C N T X -4 9 7 5 -0 5 or  place b o, i ncl u de t he f oll o wi n g:  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k  5 2 i n t he a vera ge pai n i n 
t he i n de x k nee, usi n g t he W O M A C A ( pai n) s u bscale. 
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge stiff ness 
i n t he i n de x k nee, usi n g t he W O M A C B (stiff ness) s u bscale. 
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge f u ncti o n 
i n the i n de x k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale.  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y wee k t hr o u g h W ee k 5 2 i n t he a vera ge pai n 
wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
•  A U C calc ulate d o n c ha n ge fr o m st u d y ba seli ne t hr o u g h Wee k 3 8 ( Da y 2 6 6) (i.e., 
Sta n dar dize d A U C Dail y -W k 3 8 ) a n d Wee k 5 2 ( Da y 3 6 4) (i.e., Sta n dar dize d A U C Dail y -W k 5 2 ) i n 
t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he 
N P R S ( 0 -1 0).  
•  T otal dail y, sta n dar dize d wee kl y, t otal wee kl y, resc ue -a dj uste d t otal dail y, a n d 
resc ue-a dj uste d t otal dail y A U C calc ulate d o n c ha n ge fr o m  st u d y baseli ne t hr o u g h 
Wee ks  1 2, 2 6, 3 8, a n d 5 2 i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he 
pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
•  P GI C f or t he i n de x k nee f or eac h st u d y visit t hr o u g h Wee k 5 2.  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y v isit t hr o u g h Wee k 5 2 i n t he q ualit y of life 
( Q O L), as meas ure d b y t he S F-3 6 Healt h S ur ve y.  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h W ee k 5 2 i n Q O L, as meas ure d b y 
t he fi ve-le vel versi o n of t he E Q-5 D -5 L.  
•  D ura bilit y of efficac y of a first ( u p t o Wee k 2 6) a n d a re peat I A i njecti o n ( u p t o 
Wee k  5 2), as meas ure d b y t he ti me fr o m Da y 1 (st u d y baseli ne) t o t he ret ur n of st u d y 
baseli ne ( N P R S pai n wit h wal ki n g) pai n.  
•  C u m ulati ve res p o n der a nal ysis f or all s u bjects at eac h st u d y visit, base d o n W O M A C A 
(pai n), W O M A C B (stiff ness),  a n d W O M A C C (f u ncti o n) sc ores. Res p o n ders at eac h 
st u d y visit ( W O M A C) / st u d y wee k ( N P R S) will be defi ne d usi n g 1) perce nt c ha n ge fr o m 
st u d y baseli ne, 2) t he a bs ol ute c ha n ge fr o m st u d y baseli ne, a n d 3) t he o bser ve d val ue.  
•  Fre q ue nc y of use of resc ue a n d bac k gr o u n d a nal gesic me dicati o n f or t he i n de x k nee pai n 
t hr o u g h o ut t he st u d y peri o d. 
•  O M E R A C T -O A R SI criteria res p o n ders at eac h st u d y visit t hr o u g h Wee k 5 2 ( base d o n 
st u d y baseli ne). 
Pa ge 7 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t h r o u g h Wee k 5 2 i n q ualit y of slee p, as 
meas ure d b y t he M O S slee p scale.  
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n K O O S . 
•  C ha n ge fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n wei g ht a n d b o d y 
mass i n de x ( B MI).  
•  C ha n ge fr o m s t u d y baseli ne t o Wee k 5 2 i n a b d o mi nal girt h a n d H b A 1c. 
•  Li keli h o o d of s u bject nee d f or j oi nt re place me nt s ur ger y, base d o n pai n, f u ncti o n, a n d 
o t her patie nt-re p orte d o utc o mes, fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h 
Wee k  5 2.  
•  C ha n ge fr o m st u d y basel i ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n W P AI: O A res ults. 
•  T o e x pl ore t he effect of K -L gra de, se x, B MI, a n d a ge o n t he a nal gesic efficac y of 
C N T X -4 9 7 5 -0 5, meas ure d b y W O M A C A ( pai n) scale, W O M A C C (f u ncti o n) scale, a n d 
a vera ge wee kl y pai n wit h wal ki n g N P R S ( 0 -1 0) sc ore, t hr o u g h Wee k 5 2.  A d diti o nall y, 
s u bjects wit h ra di o gra p hic e vi de nce of O A i n t he n o n-i n de x ( o p p osite) k nee ( K-L = 2, 3, 
or 4) vs s u bjects wit h n o ra di o gra p hic e vi de nce of O A i n t he n o n-i n de x k nee ( K-L = 0 or 
1) will be a nal yze d.  
•  S u bject’s g uess  as t o w hic h treat me nt t he y t hi n k t he y recei ve d.  
•  S hift fr o m st u d y baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n w orst case assisti ve 
de vice u sa ge. 
•  S u bject satisfacti o n wit h treat me nt pr oce d ure.  
1 3. 1. 5  S u p p orti ve Effic ac y  E n d p oi nts  
S u p p orti ve  efficac y e n d p oi nts  f or t he re peat i njecti o n, c o m pari n g res ults i n s u bjects treate d wit h 
 of C N T X -4 9 7 5 -0 5  or  place b o , i ncl u de t he f oll o wi n g: 
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge pai n 
i n t he i n de x k nee, usi n g t he W O M A C A ( pai n) s u bscale. 
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge 
stiff ness i n t he i n de x k nee, usi n g t he W O M A C B (stiff ness) s u bscale. 
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he a vera ge 
f u ncti o n i n t he in de x k nee, usi n g t he W O M A C C (f u ncti o n) s u bscale.  
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y wee k t hr o u g h Wee k 5 2 i n t he a vera ge pai n 
wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, usi n g t he N P R S ( 0 -1 0).  
•  A U C calc ulate d base d o n t he c ha n ge fr o m Wee k 2 6 baseli ne t hr o u g h Wee k 3 8 a n d 
t hr o u g h Wee k 5 2 (i.e., Sta n dar dize d A U CDail y -W k 2 6 W k 3 8  a n d Sta n dar dize d 
A U C Dail y -W k 2 6 W k 5 2 ) i n t he a verage pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 
2 4 h o urs, usi n g t he N P R S) ( 0 -1 0).  
•  T otal dail y, sta n dar dize d wee kl y, t otal wee kl y, resc ue -a dj uste d t otal dail y, a n d resc ue -
a dj uste d t otal dail y A U C calc ulate d o n c ha n ge fr o m Wee k 2 6 baseli ne t hr o u g h W ee ks 3 8 
Pa ge 7 2 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
a n d 5 2 i n t he a vera ge pai n wit h wal ki n g i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs, 
usi n g t he N P R S ( 0 -1 0).  
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n t he Q O L, as 
meas ure d b y t he S F -3 6 Healt h S ur ve y.  
•  C ha n ge fr o m Wee k 2 6 ba seli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n Q O L, as 
meas ure d b y E Q -5 D -5 L.  
•  O M E R A C T -O A R SI criteria res p o n ders at eac h  st u d y visit t hr o u g h Wee k 5 2 ( base d o n 
Wee k 2 6 baseli ne).  
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n q ualit y of sl ee p, 
as meas ure d b y t he M O S slee p scale.  
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n K O O S.  
•  C h a n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 i n wei g ht a n d B MI.  
•  C ha n ge fr o m Wee k 2 6 baseli ne t o eac h st u d y visit t hr o u g h Wee k 5 2 o n t he W P AI: O A.  
1 3. 1. 6  S afet y E n d p oi nts  
Safet y e n d p oi nts i n s u bjects treate d wit h 1. 0 m g of C N T X -4 9 7 5 -0 5  or  place b o , i ncl u de t he 
f oll o wi n g: 
•  A Es  
•  Vital si g ns  
•  Cli nical la b orat or y e val uati o ns ( he mat ol o g y, c he mistr y, a n d uri nal ysis)  
•  1 2 -lea d E C G  
•  P h ysical e xa mi nati o n (i ncl u di n g t he prese nce or a bse nce of a n eff usi o n i n t he i n de x k nee , 
periartic ular pai n/te n der ness ) 
•  Se ns or y tes ti n g usi n g a 5-p oi nt Li kert scale  
•  C o nc o m ita nt me dicati o ns a n d t hera pies (i ncl u di n g bac k gr o u n d me dicati o ns) 
•  De gree of pr oce d ure pai n  i n t he i n de x k nee o n Da y 1 a n d Wee k 2 6 ( n ot rec or de d as A Es ) 
•  L ocal p h ysical fi n di n gs after i njecti o n of t he i n de x k nee  
•  I njecti o n site assess me nt of er yt he ma a n d e de ma  
•  Sta bilit y of k nee ra di o gra p hs  fr o m P re-scree ni n g t o Wee k 5 2, eval uate d usi n g O A R SI 
sc ori n g criteria 
1 3. 2.  S a m ple Size Deter mi n ati o n  
A p pr o xi matel y 3 2 5  s u bjects will be ra n d o mize d t o place b o (a p pr o xi matel y 1 2 5  s u bjects) a n d t o 
C N T X -4 9 7 5 -0 5 (a p pr o xi matel y 2 0 0  s u bjects).  
I n t he pre vi o us versi o ns of t he pr ot oc ol ( Versi o n s 1. 0 a n d 2. 0), t he pri mar y e n d p oi nt was a vera ge 
wee kl y pai n wit h wal ki n g N P R S ( 0 -1 0) t o Wee k 1 2. T he sa m ple size a n d p o wer calc ulati o ns 
were base d u p o n t ha t e n d p oi nt. 
Pa ge 7 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
Res ults fr o m st u d y C N T X-4 9 7 5 -O A -5 0 2 pr o vi de d a sta n dar d de viati o n  ( S D) of 2. 5 5 a n d mea n 
c ha n ges f r o m baseli ne of -3. 0 2 a n d -4. 4 2 f or place b o a n d 
 of C N T X -4 9 7 5, res pecti vel y. 
Ass u mi n g a n effect size of 0. 5, a sa m ple size of 2 9 3 e val ua ble s u bjects at Wee k 1 2 wit h a 2: 3 
all ocati o n ( place b o t o acti ve) will ac hie ve 9 8 % statistical p o wer f or ha vi n g a si g nifica nt C N T X-
4 9 7 5 -0 5 a n d place b o c o m paris o n, usi n g a t w o -si de d test at t he 5 % si g nifica nce le vel. A p o wer of 
9 8 % was use d f or t he pri mar y a nal y sis at Wee k 1 2 i n or der t o mai ntai n a de q uate p o wer f or 
c o m paris o ns at later ti me p oi nts  o n t he pri mar y o utc o m e a n d ke y sec o n dar y o utc o me meas ures . 
Pre vi o usl y k e y sec o n dar y o utc o mes, W O M A C  B  (stiff ness) a n d W O M A C C (f u ncti o n), are 
p o were d at 7 5 % a n d 7 1 %, re s pecti vel y, at Wee k 1 2 (t he pri mar y e n d p oi nt) usi n g a n N of 2 9 3  f or 
t he trial. T o acc o u nt f or dr o p o uts  a n d s ubjects f or safet y e val uati o n , t he i nitial pla n ne d 
e nr oll me nt is a p pr o xi matel y 3 2 5  s u bjects (a p pr o xi matel y 1 2 5 s u bjects i n p lace b o a n d 2 0 0 
s u bjects i n C N T X-4 9 7 5 -0 5 ). 
I n t his versi o n of t he pr ot oc ol ( Versi o n 3. 0), t he pri mar y e n d p oi nt is t he c ha n ge fr o m st u d y 
baseli ne t o Wee k 1 2 i n W O M A C A ( pai n). I n or der t o deter mi ne t he a p pr o xi mate p o wer f or t his 
pri mar y e n d p oi nt, a p ost h oc a nal ysis f or c ha n ge fr o m  baseli ne t o Wee k 1 2 i n W O M A C A ( pai n) 
fr o m Ce ntre xi o n’s P hase 3 st u d y i n k nee O A, C N T X 4 9 7 5i-O A -3 0 1, was  perf or me d. T he mea n 
c ha n ges fr o m baseli ne t o Wee k 1 2 were -1 3. 4 3 a n d -1 6. 4 4 f or place b o a n d  
 
C N T X -4 9 7 5 -0 5, res pecti vel y, wit h a p o ole d S D of t he  p o p ulati o n of 1 1. 7 7 9 4. Wit h a calc ulate d 
effect size of 0. 2 5 6, a statistical p o wer of 5 6 % is pre dicte d t o detect a si g nifica nt C N T X -4 9 7 5 -0 5 
a n d place b o c o m paris o n, usi n g a 2 -si de d test at t he 5 % si g nifica nce le vel. 
1 3. 3.  A n al ysis P o p ul ati o ns  
T he f oll o wi n g a nal y sis p o p ulati o ns are pla n ne d f or t his st u d y: T he f oll o wi n g a nal ysis 
p o p ulati o ns are pla n ne d f or t his st u d y :  
•  Safet y: all s u bjects w h o recei ve a n y a m o u nt of pla n ne d I P.  
•  Safet y ( Si n gle I njecti o n Recei ve d) P o p ulati o n: all s u bjects w h o recei ve o nl y 1 I P 
i njecti o n b ut c o nti n ue i n t he st u d y past Wee k 2 6. 
•  Wee k 2 6 Safet y P o p ulati o n: all s u bjects w h o recei ve a n y a m o u n t of I P fr o m a re peat I P 
i njecti o n at t he Wee k 2 6 visit. 
•  I nte nt-to -Treat (I T T): all ra n d o mize d s u bjects  w h o recei ve a n y a m o u nt of I P . A d diti o nal 
s u b gr ou ps of t he I T T ma y  be s pecifie d acc or di n g t o K -L gra des , B MI val ues , se x, a n d 
ot her s u b gr o u ps as i n dicate d.  
•  Wee k 2 6 I nte nt -t o-Treat P o p ulati o n; all ra n d o mize d s u bjects w h o recei ve t he re peat I P 
i njecti o n at t he Wee k 2 6 visit. 
•  Per Pr ot oc ol f or Wee k 1 2: all  s u bjects i n t he I T T p o p ulati o n w h o recei ve I P a n d d o n ot 
ha ve a n y critical pr ot oc ol vi olati o ns a s deter mi ne d pri or t o data base l oc k. Critical 
vi olati o ns will i ncl u de ge neral critical vi olati o ns (e. g., pr o hi bite d me dicati o n t hat c o ul d 
affect t he pri mar y e n d p oi nt o utc o mes) or critical vi olati o ns s pecificall y relate d t o t he 
Wee k 1 2 W O M A C A ( pai n) or C ( f u ncti o n) pri mar y e n d p oi nts. 
•  Per Pr ot oc ol f or Wee k 3 8: all s u bjects i n t he Wee k 2 6 I T T p o p ulati o n w h o recei ve a 
re peat I P i njecti o n a n d d o n ot ha ve a n y critical pr ot oc ol vi olati o ns as deter mi ne d pri or t o 
Pa ge 7 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
data base l oc k. Critical vi olati o ns will i ncl u de ge ne ral critical vi olati o ns (e. g., pr o hi bite d 
me dicati o n t hat c o ul d affect t he pri mar y e n d p oi nt o utc o mes) or critical vi olati o ns 
s pecificall y relate d t o t he Wee k 38 W O M A C A ( pai n) pri mar y e n d p oi nt.  
Me m bers hi p i n t he a nal ysis p o p ulati o ns will be deter mi ne d pri or t o data base  l oc k. 
If a s u bject is ra n d o mize d i nc orrectl y or is a d mi nistere d t he i nc orrect I P, a nal yses of t he I T T a n d 
Wee k 2 6 I T T  p o p ulati o n s will be base d o n t he assi g ne d treat me nt w hereas all ot her a nal yses will 
be base d o n t he act ual treat me nt.  
1 3. 4.  St ati stic al A n al yses 
T his secti o n prese nts a s u m mar y of t he pla n ne d statistical a nal yses. A statistical a nal ysis pla n 
( S A P) t hat descri bes t he details of t he a nal yses t o be c o n d ucte d will be writte n pri or t o data base 
l oc k.  
F or a nal yses i n v ol vi n g st u d y site, if t he n u m ber of s u bjects per site is s mall, sites ma y be p o ole d 
f or a nal ysis, or o mitte d fr o m statistical m o dels. T he fi nal deter mi nati o n will be ma de pri or t o 
data base l oc k .  
S u m mar y statistics will be pr o vi de d f or t he varia bles descri be d bel o w. F o r c o nti n u o us varia bles, 
t hese statistics will t y picall y i ncl u de t he n u m ber of s u bjects, 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 cate g orical va ria bles, t hese statistics will t y picall y i ncl u de 
t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y.  
St u d y baseli ne will be defi ne d wit h res pect t o t he first i njecti o n; Wee k 2 6 baseli ne will be 
defi ne d wit h res pect t o t he re peat i njecti o n. St u d y baseli ne is t he pri mar y baseli ne defi niti o n use d 
i n a nal yses, w hereas Wee k 2 6 baseli ne is s u p p orti ve. M ore details will be pr o vi de d i n t he S A P. 
1 3. 4. 1  St u d y S u bjects a n d De m o gr a p hics  
1 3. 4. 1. 1  Dis p ositi o n a n d Wit h dr a w als  
T he n u m bers of s u bjects ra n d o mize d, c o m pleti n g, a n d wit h dr a wi n g, al o n g wit h reas o ns f or 
wit h dra wal, will be ta b ulate d o verall a n d b y treat me nt gr o u p. T he n u m ber of s u bjects i n eac h 
a nal ysis p o p ulati o n will be re p orte d.  
1 3. 4. 1. 2  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns will be i de ntifie d a n d classifie d as mi n or or maj or f or  statistical a nal ysis 
p ur p oses  bef ore u n bli n di n g, a n d will be s u m marize d or liste d as a p p r o priate. Critical pr ot oc ol 
de viati o ns will be use d t o e xcl u de s u bjects fr o m t he per pr ot oc ol  p o p ulati o ns  f or Wee k 1 2 a n d/ or 
Wee k 3 8  a nal ys es. 
1 3. 4. 1. 3  De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics  
T hese a nal yses will be c o n d ucte d f or all a nal ysis p o p ulati o ns .  
D e m o gra p h ic varia bles will i ncl u de a ge, se x , hei g ht, a n d wei g ht. I nf or mati o n o n race a n d 
et h nicit y will be c ollecte d f or a n y e ve nt ual a nal ysis of differe nces i n res p o ns e t o t he I P[s], i n 
acc or da nce wit h l ocal re g ulat or y re q uire me nts. Baseli ne s u bjec t c haracteristics will i ncl u de 
Pa ge 7 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
me dical hist or y , i ncl u di n g c o nfir mati o n of O A dia g n osis a n d ti me si nce dia g n osis, a n d p h ysical 
e xa mi nati o n fi n di n gs .  
Pri or a n d c o nc o mita nt me di cati o ns will be s u m marize d b y treat me nt gr o u p, b y t he n u m ber a n d 
perce nta ge of s u bjects t a ki n g eac h me dicati o n, classifie d usi n g W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O -D D) A nat o mical T hera pe utic C he mical ( A T C) classes a n d preferre d ter ms.  
1 3. 4. 2  E x p os ure a n d C o m pli a nce  
All  s u bjects will recei ve 1 or 2 I P i njecti o ns at t he st u d y site u n der t he  s ur veilla nce of 
a p pr o priate st u d y pers o n nel  a n d, t heref ore, n o c o m plia nce will be calc ulate d . Injecti o n pr oce d ure  
details a n d I P batc h or l ot n u m ber(s) will be  rec or de d i n t he s u bject’s e C R F/electr o nic data 
ca pt ure ( E D C) s yste m a n d s u m marize d or liste d as  a p pr o priate. 
1 3. 4. 3  Effic ac y A n al yses  
Efficac y varia bles will be s u m marize d a n d a nal yze d usi n g t he I T T p o p ulati o n, u nless ot her wise 
s pecifie d i n t he statistical a nal ysis plan ( S A P ).  
T he t y pe I err or rate of α = 0. 0 5 will be mai ntai ne d f or t he st u d y b y usi n g a fi xe d -se q ue nce 
testi n g strate g y f or pri mar y, ke y sec o n dar y, a n d sec o n dar y e n d p oi nt s. If t he pri mar y e n d p oi nt has 
P  ≤ 0. 0 5, t he n t he f ull α = 0. 0 5 will be passe d t o t he  ke y  sec o n dar y e n d p oi nt s t he n sec o n dar y 
e n d p oi nts f or c o nti n ue d fi xe d-se q ue nce testi n g i n t he or der liste d; testi n g will st o p at t he first P  
val ue > 0. 0 5. T he fi xe d -se q ue nce testi n g will be base d o n t he or der liste d i n t he pri mar y, ke y 
sec o n dar y, a n d sec o n dar y e n d p oi nts, i n or der t o meet re g ulat or y re q uire me nts.   
Sites will be p o ole d f or statistical a nal ysis as f oll o ws: sites s h o ul d ha ve a mi ni m u m of 2 0 
ra n d o mize d s u bjects. T he s mallest sites will be gr o u pe d se q ue ntiall y i n or der of s mallest t o 
lar gest, u ntil eac h p o ole d site has a mi ni m u m of 2 0 s u bjects. If a site ha d 2 site n u m bers d ue t o 
a d diti o nal ra n d o mizati o n n u m bers re q uire d (if nee de d), t h ose site n u m bers will be c o nsi dere d as 
1 site bef ore p o oli n g.  
1 3. 4. 3. 1  Pri m ar y Effic ac y E n d p oi nt A n al ys is 
T he pri mar y  e n d p oi nt effica c y a nal ysis, t he c ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n W O M A C 
A ( pai n) sc ores,  will be base d o n t he I T T p o p ulati o n.  
A mi xe d m o del f or re peate d meas ures ( M M R M) a nal ysis will be perf or me d t hat i ncl u des c ha n ge 
fr o m st u d y baseli ne i n W O M A C A ( pai n) sc ores as t he de pe n de nt varia ble a n d ter ms f or 
treat me nt, p o ole d site, baseli ne K -L gra de cate g or y, st u d y baseli ne B MI cate g or y, st u d y baseli ne 
O A t y pe, se x, st u d y wee k, treat me nt b y visit st u d y wee k i nteracti o n, a n d st u d y baseli ne 
W O M A C A ( pai n) sc ore as a c o varia te, usi n g a n u nstr uct ure d c o varia nce str uct ure. Least s q uares 
esti mate s of t he treat me nt differe nce s at Wee k 1 2, al o n g wit h 9 5 % c o nfi de nce i nter vals , will be 
deri ve d fr o m t his m o del a n d re p orte d . M ore details will be pr o vi de d i n t he S A P o n h o w t o ha n dle 
p o te ntial c o n ver ge nce iss ues.  
S e nsiti vit y a nal yses of t he pri mar y e n d p oi nts  will be perf or me d o n ot her p o p ulati o ns, as 
s pecifie d i n t he S A P. F urt her se nsiti vit y a nal yses o n t he pri mar y e n d p oi nt s t o e x pl ore t he i m pact 
of missi n g data will  be perf or me d a n d wil l be descri be d i n a detaile d S A P . Descri pti ve 
s u m maries (s uc h as mea n, sta n dar d err or, me dia n, mi ni m u m, a n d ma xi m u m) will als o be 
Pa ge 7 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
pr o vi de d f or t he pri mar y e n d p oi nt . Res ults fr o m t he M M R M pri mar y a nal yses will be use d t o 
deter mi ne st u d y s uccess  base d o n t he  fi xe d-se q ue nce a p pr oac h. 
1 3. 4. 3. 2  Ke y Sec o n d ar y Effic ac y E n d p oi nt s A n al yses  
T he ke y  e n d p oi nt efficac y a nal ys es, c ha n ge fr o m st u d y baseli ne t o Wee k 3 8 i n W O M A C A 
( pai n) sc ores a n d c ha n ge fr o m st u d y baseli ne t o Wee k 1 2 i n W O M A C C (f u ncti o n) sc ores, will 
be base d o n t he I T T p o p ulati o n. 
T he ke y sec o n dar y  efficac y e n d p oi nt s will be a nal yze d i n a ma n ner si milar t o c ha n ge fr o m st u d y 
baseli ne t o Wee k 1 2 i n W O M A C A ( pai n) sc ores.  
S e nsiti vit y a nal yses of t he pri mar y e n d p oi nts  will be perf or me d o n ot her p o p ulati o ns, as 
s pecifie d i n t he S A P. F urt her se nsiti vit y a nal yses o n t he pri mar y e n d p oi nt s t o e x pl ore t he i m pact 
of missi n g data will  be perf or me d a n d will  be descri be d i n a detaile d S A P . Descri pti ve 
s u m maries (s uc h as mea n, sta n dar d err or, me dia n, mi ni m u m, a n d ma xi m u m) will a ls o be 
pr o vi de d f or t he pri mar y e n d p oi nt . Res ults  fr o m t he M M R M pri mar y a nal yses will be use d t o 
deter mi ne st u d y s uccess  base d o n t he fi xe d -se q ue nce a p pr oac h. 
1 3. 4. 3. 3  Sec o n d ar y Effic ac y E n d p oi nt s A n al yses  
T he P GI C will be s u m marize d descri pti vel y usi n g fre q ue ncies  a n d perce nta ges b y st u d y wee k 
a n d treat me nt gr o u p. A res p o n der a nal ysis will be perf or me d f or eac h visit f or t he P GI C i n w hic h 
res p o n ders ( P GI C of Ver y M uc h I m pr o ve d or M uc h I m pr o ve d) will be c o m pare d t o n o n-
res p o n ders. T he res p o n der a nal ysis will be pres e nte d f or all st u d y visits ; h o we ver, o nl y res ults at 
Wee k 1 2 a n d Wee k 2 6 will be i ncl u de d i n t he fi xe d -se q ue nce testi n g strate g y. 
A nal ysis of t he c ha n ge fr o m st u d y baseli ne t o eac h st u d y wee k  i n t he a vera ge pai n wit h wal ki n g 
i n t he i n de x k nee o ver t he pre vi o us 2 4 h o urs (a vera ge wee kl y pai n wit h wal ki n g N P R S [ 0-1 0]), 
will c o me fr o m t he M M R M use d f or t he pri mar y a nal ysis a n d will be deri ve d usi n g c o ntrast 
state me nts wit hi n t hat m o del. T he M M R M a nal ysis will be prese nte d s h o wi n g all st u d y wee ks; 
h o we ver, o nl y res ults at Wee k 1 2 a n d Wee k 2 6 will be i ncl u de d i n t he fi xe d-se q ue nce testi n g 
strate g y. T his a nal ysis will be base d o n a w orst o bser vati o n carrie d f or war d ( W O C F) a p pr oac h 
t hat will re place sc ores occ urri n g o n a da y w here resc ue me dicati o n was ta ke n wit h t he w orst 
o bser vati o n starti n g at Da y 2. Det ails will be s pecifie d i n t he S A P. Area u n der t he c ur ve ( A U C) 
as calc ulate d o n c ha n ge fr o m st u d y baseli ne t hr o u g h Wee k  1 2 ( Da y 8 4) a n d t hr o u g h Wee k 2 6 
( Da y 1 8 2) i n t he a vera ge pai n i n t he i n de x k nee wit h wal ki n g o ver t he pre vi o us 2 4  h o urs , usi n g 
t he N P R S (0 -1 0), i n s u bjects treate d wit h  
 of C N T X -4 9 7 5 -0 5,  c o m pare d wit h place b o, 
will be a nal yze d usi n g a n a nal ysis of c o varia nce  ( A N C O V A) m o del wit h ter ms f or p o ole d site, 
baseli ne K -L gra de cate g or y, st u d y baseli ne  B MI cate g or y, se x, treat me nt, a n d st u d y b aseli ne 
dail y pai n wit h wal ki n g N P R S ( 0 -1 0) sc ore as a c o variate , base d o n t he I T T p o p ulati o n . 
C ha n ge fr o m st u d y baseli ne t o Wee k 2 6 i n W O M A C A ( pai n) a n d C (f u ncti o n) sc ores will be 
a nal yze d usi n g a n M M R M wit h t he  sa me ter ms as t hat descri be d f or t he pri mar y a nal ysis. 
All sec o n dar y efficac y a nal yses will be perf or me d usi n g t he I T T p o p ulati o n, u nless ot her wise 
s pecifie d. Se nsiti vit y a nal yses of sec o n dar y efficac y e n d p oi nts will be s pecifie d i n t he S A P  if 
re q uire d. 
Pa ge 7 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 3. 4. 3. 4  E x pl or at or y Effic ac y A n al yses  
All c o nti n u o u s e x pl orat or y  efficac y e n d p oi nt s will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p a n d wee k/ visit, as a p pr o priate , a n d a nal yze d usi n g a n M M R M a nalysis or b y 
A N C O V A , as a p pr o priate. Cate g orical e n d poi nts (res p o n der a nal yses) will be c o m pare d bet wee n  
treat me nts usi n g Pears o n’s c hi-s q uare or Fis her’s e xact test, as a p pr o priate ; ot her cate g orical 
e n d p oi nts (i ncl u di n g s hift fr o m st u d y baseli ne) will be s u m marize d descri p ti vel y usi n g 
fre q ue ncies a n d percenta ges . P  val ues fr o m s u p p orti ve efficac y e n d p oi nts will be c o nsi dere d 
n o mi nal a n d n o a dj ust me nts f or m ulti plicit y will be ma de . 
1 3. 4. 3. 5  S u p p orti ve Effic ac y A n al yses  
U nless ot her wise s pecifie d i n t he S A P, all s u p p orti ve efficac y a nal yses f or t he re peat i njecti o n 
w ill be base d o n t he Wee k 2 6 baseli ne, t o assess t he effect of t he re peat i njecti o n o n efficac y. All 
c o nti n u o us e x pl orat or y  efficac y e n d p oi nt s will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p a n d wee k/ visit, as a p pr o priate , a n d a nal yze d us i n g an M M R M a nalysis or b y 
A N C O V A , as a p pr o priate. Cate g orical e n d p oi nts (res p o n der a nal yses) will be c o m pare d bet wee n  
treat me nts usi n g Pears o n’s c hi-s q uare or Fis her’s e xact test, as a p pr o priate ; ot her cate g orical 
e n d p oi n ts (i ncl u di n g s hift fr o m Wee k 2 6 baseli ne) will be s u m marize d descri pti vel y usi n g 
fre q ue ncies a n d perce nta ges. P  val ues fr o m e x pl orat or y efficac y  e n d p oi nts will be c o nsi dere d 
n o mi nal a n d n o a dj ust me nts f or m ulti plicit y will be ma de.  
1 3. 4. 4  S afet y a n d T oler a bilit y A n al yses  
Safet y a nal yses will be c o n d ucte d usi n g data fr o m t he safet y p o p ulati o n (as defi ne d i n 
Secti o n  1 3. 3 ). Safet y varia bles i ncl u de i njecti o n site assess me nt (er yt he ma a n d e de ma), 
assess me nt of pr oce d ure  pai n, A Es , p h ysical e xa mi nati o n fi n di n gs, se ns or y testi n g, vital si g n 
meas ure me nts, 1 2 -lea d E C G fi n di n gs , cli nical la b orat or y test res ults , a n d sta bilit y of k nee 
ra di o gra p hs o ver ti me . N o f or mal i nfere ntial a nal yses will be c o n d ucte d f or safet y varia bles 
u nless ot her wise n ote d.  
1 3. 4. 4. 1  A d verse E ve nts  
All A Es will be c o de d usi n g Me d D R A, Versi o n 2 0 . 0.  
Tre at me nt-e mer ge nt A Es are defi ne d as : 
•  A Es wit h o nset at t he ti me of or f oll o wi n g t he start of treat me nt wit h I P t hr o u g h t he  
F oll o w -u p Visit or Earl y Ter mi nati o n Visit, w hic he ver occ urs first  
T he n u m ber a n d perce nta ge  of s u bjects wit h A Es will be dis pla ye d f or eac h treat me nt gr o u p b y 
s yste m or ga n class ( S O C) a n d preferre d ter m ( P T). S u m maries of A Es b y se verit y a n d 
relati o ns hi p t o I P will als o be pr o vi de d. Seri o us a d verse e ve nts a n d A Es res ulti n g i n 
disc o nti n uati o n  of I P will be s u m marize d se paratel y i n a si m ilar ma n ner. S u bject listi n gs of A Es, 
S A Es a n d A Es ca usi n g disc o nti n uati o n of I P will be pr o d uce d.  
1 3. 4. 4. 2  Cli nic al L a b or at or y E v al u ati o ns  
Descri pti ve s u m maries ( mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) of act ual (a bs ol ute) val ues 
a n d c ha n ges fr o m Baseli ne val ues will be prese nte d f or cli nical la b orat or y val ues f or eac h 
treat me nt gr o u p at eac h ti me p oi nt. 
Pa ge 7 8 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
T he n u m ber of s u bjects wit h cli nical l a b orat or y val ues cate g orize d as bel o w, wit hi n, or a b o ve 
n or mal ra n ges, will be ta b ul ate d s h o wi n g c ha n ge fr o m st u d y baseli ne  a n d Wee k 2 6 baseli ne  
(s hift ta bles) f or eac h cli nical la b orat or y a nal yte b y treat me nt gr o u p a n d b y st u d y visit . Pre- a n d 
p ost -treat me nt val ues will als o be prese nte d wit h a nal ysis s u m mar y  of mea n c ha n ges fr o m st u d y 
an d Wee k 2 6 b aseli ne .  
La b orat or y val ues t hat are o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he data listi n gs, 
al o n g wit h c orres p o n di n g n or mal ra n ges. A n y o ut -of -ra n ge val ues t hat are i de ntifie d b y t he 
i n vesti gat or as bei n g cli nicall y si g nifica nt will be re p orte d as A Es . 
1 3. 4. 4. 3  Vit al Si g ns  
Descri pti ve s u m maries ( mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d 
c ha n ges fr o m st u d y a n d Wee k 2 6 baseli ne will be calc ul ate d f or s yst olic bl o o d press ure ( S B P), 
diast olic bl o o d press ure ( D B P), heart rate ( H R), a n d res pirat or y rate ( R R) . 
Vital si g ns  will be ta b ulate d  s h o wi n g c ha n ge fr o m st u d y a n d Wee k 2 6 baseli ne (s hift ta bles) f or 
eac h para meter b y treat me nt gr o u p  a n d b y st u d y visit. Pre - a n d p ost -treat me nt val ues ma y als o be 
prese nte d wit h a  s u m mar y of mea n c ha n ges fr o m st u d y a n d Wee k 2 6 baseli ne. 
1 3. 4. 4. 4  Electr oc ar di o gr a ms  
T he n u m ber a n d perce nta ge of s u bjects wit h n or mal a n d a b n or mal E C G fi n di n gs will be 
s u m marize d f or eac h treat me nt gr o u p at eac h ti me p oi nt. A c o m paris o n of Q T res ults will be 
prese nte d. S u m mar y statistics f or st u d y baseli ne val ues a n d at st u d y visits acc or di n g t o t he 
sc he d ule of e ve nts will be dis pla ye d b y treat me nt gr o u p f or Q T a n d t he Q T i nter val c orrecte d f or 
h eart rate ( Q Tc) calc ulate d usi n g Bazett’s a n d Fri dericia’s Q T c orrecti o n met h o ds. I n  a d diti o n, 
t he n u m ber a n d perce nt of s u bjects i n eac h treat me nt gr o u p w h o e x perie nce d a c ha n ge > 3 0 ms or 
a c ha n ge > 6 0  ms will be prese nte d . 
Descri pti ve s u m maries ( mea n, S D,  me dia n, mi ni m u m, a n d ma xi m u m) will be prese nte d f or E C G 
meas ures of P R i nter val, Q R S i nter val, Q T i nter val, Q Tc i nter val ( b ot h c orrecti o n met h o ds), a n d 
H R f or eac h treat me nt gr o u p at eac h ti me p oi nt.  
1 3. 4. 4. 5  P h ysic al E x a mi n ati o n Fi n di n gs  
T he n u m ber a n d perce nta ge  of s u bjects wit h n or mal a n d a b n or mal fi n di n gs i n t he c o m plete 
p h ysical e xa mi nati o n will be dis pla ye d f or eac h treat me nt gr o u p.  
1 3. 4. 4. 6  I njecti o n Site Assess me nt 
T he n u m ber a n d perce nta ge of s u bjects wit h er yt he ma a n d e de ma  fi n di n gs se paratel y cate g orize d 
as n o ne, mil d, m o derate, or se vere  will be s u m marize d f or eac h treat me nt gr o u p at eac h ti me 
p oi nt.   
1 3. 4. 4. 7  Se ns or y Testi n g  
T he n u m ber a n d perce nta ge of s u bjects wit h eac h se ns or y assess me nt , cate g orize d fr o m n or mal 
t o a bse nt, usi n g t he 5 -p o i nt Li kert scale , w here 0 is a bse nt se nsati o n a n d 4 is n or mal se nsati o n 
(see S ecti o n 1 0. 3. 3. 2. 5 ), will be s u m marize d f or eac h treat me nt gr o u p at eac h ti me p oi nt.   
Pa ge 7 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 3. 4. 4. 8  Pr oce d ure P ai n   
T he n u m ber a n d perce nta ge of s u bjects wit h pai n assess me nt s cate g orize d as n o ne, mil d, 
m o derate, m o deratel y se vere, or se vere  ( 0-4)  will be s u m marize d b y  treat me nt gr o u p at eac h ti me 
p oi nt.  
1 3. 4. 4. 9  S atisf acti o n  wit h t he Tre at me nt  Pr oce d ure  
T he n u m ber a n d perce nta ge of s u bjects wit h eac h satisfacti o n assess me nt cate g orizati o n  ( 1-7)  
will be s u m marize d f or  eac h treat me nt gr o u p at eac h ti me p oi nt.  
1 3. 4. 4. 1 0  K nee R a di o gr a p hs  
Assess me nts  of a b n or malit y ( n or mal or a b n or mal) will be pr o vi de d b y a c e ntral rea der f or 
s u bc h o n dral i ns ufficie nc y, oste o necr osis, attriti o n, a n d scler osis i n t he me dial fe m oral, lateral 
fe m oral, me dial ti bial, a n d lateral ti bial l ocati o ns; a d diti o nall y, a n assess me nt of j oi nt s pace 
narr o wi n g ( n o ne, mil d, m o derate, or se vere)  will be pr o vi de d f or me dial a n d lateral l ocati o ns.  
T he n u m ber a n d perce nta ge of s u bjects wit h eac h k nee ra di o gra p h  a b n or malit y assess me nt will 
be s u m marize d f or eac h treat me nt gr o u p.  
1 3. 4. 5  I nteri m A n alysis  
N o i nteri m a nal ysis is pla n ne d f or t his st u d y.  
Pa ge 8 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 4.  S T U D Y C O N D U C T  
Ste ps t o e ns ure t he acc urac y a n d relia bilit y of data i ncl u de t he selecti o n of q ualifie d i n vesti gat ors 
a n d a p pr o priate st u d y sites, re vie w of pr ot oc ol pr oce d ures wit h t he i n vesti gat or a n d as s ociate d 
pers o n nel bef ore  t he st u d y, peri o dic m o nit ori n g visits, a n d metic ul o us data ma na ge me nt. 
1 4. 1.  S p o ns or a n d I n vesti g at or Res p o nsi bilities  
1 4. 1. 1  S p o ns or Res p o nsi bilities  
T he s p o ns or is o bli gate d t o c o n d uct t he st u d y i n acc or da nce wit h strict et hical pri nci ples 
(Secti o n  1 5 ). T he s p o ns or reser ves t he ri g ht t o wit h dra w a s u bject fr o m t he st u d y, t o ter mi nate 
partici pati o n of a st u d y site at a n y ti me ( Secti o n  1 4. 7 ), a n d/ or t o disc o nti n ue t he st u d y 
( Secti o n 1 4. 6 ). 
Ce ntre xi o n T hera pe utics C or p. a grees t o pr o vi de t he i n vesti gat or wit h  s ufficie nt material a n d 
s u p p ort t o per mit t he i n vesti gat or t o c o n d uct t he st u d y acc or di n g t o t he st u d y pr ot oc ol . 
1 4. 1. 2  I n vesti g at or Res p o nsi bilities 
B y si g ni n g t he I n vesti gat or’s A gree me nt ( Secti o n  1 7. 2 ), t he i n vesti gat or i n dicates t hat he/she has 
caref ull y rea d t he pr ot oc ol, f ull y u n dersta n ds t he re q uire me nts, a n d a grees t o c o n d uct t he st u d y 
i n acc or da nce wit h t he pr oce d ures a n d re q uire me nts descri be d i n t his pr ot oc ol. 
T he i n vesti gat or als o a grees t o c o n d uct t his st u d y i n acc or da nce wit h all la ws, re g ulati o ns, a n d 
g ui deli nes of t he perti ne nt re g ulat or y a ut h orities, i ncl u di n g t he A pril 1 9 9 6 I nter nati o nal C o u ncil 
f or Har m o nisati o n (I C H) G ui da nce f or I n d ustr y E 6 G o o d  Cli nical Practice ( G C P ), a n d i n 
a gree me nt wit h t he 2 0 1 3  v ersi o n of t he Declarati o n of Helsi n ki. W hile dele gati o n of certai n 
as pects of t he st u d y t o s u b  i n vesti gat ors a n d st u d y c o or di nat ors is a p pr o priate, t he i n vesti gat or 
will re mai n pers o nall y acc o u nta bl e f or cl osel y o verseei n g t he st u d y a n d f or e ns uri n g c o m plia nce 
wit h t he pr ot oc ol a n d all a p plica ble re g ulati o ns a n d g ui deli nes. T he i n vesti gat or is res p o nsi ble 
f or mai ntai ni n g a list of all pers o ns t hat ha ve bee n dele gate d st u d y-relate d res p o nsi bilities (e.g ., 
s u b i n vesti gat ors a n d st u d y c o or di nat ors) a n d t heir s pecific st u d y-relate d d uties. 
I n vesti gat ors s h o ul d e ns ure t hat all pers o ns w h o ha ve bee n dele gate d st u d y-relate d 
res p o nsi bilities are a de q uatel y q ualifie d a n d i nf orme d a b o ut t he pr ot oc ol, I Ps, a n d t heir s pecific 
d uties wit hi n t he c o nte xt of t he st u d y. I n vesti gat ors are res p o nsi ble f or pr o vi di n g Ce ntre xi o n 
T hera pe utics C or p. wit h d oc u me ntati o n of t he q ualificati o ns, G C P trai ni n g, a n d researc h 
e x perie nce f or t he msel ves  a n d t heir staff as re q uire d b y t h e s p o ns or a n d t he rele va nt g o ver ni n g 
a ut h orities. 
T o e ns ure c o m plia nce wit h t he g ui deli nes, t he st u d y ma y  be a u dite d b y a n i n de pe n de nt pers o n. 
T he i n vesti gat or a grees, b y writte n c o nse nt t o t his pr ot oc ol, t o c o o perate f ull y wit h c o m plia nce 
c hec ks b y all o wi n g access t o all st u d y d oc u me ntati o n b y a ut h orize d i n di vi d uals.  
1 4. 2.  Site I niti ati o n  
St u d y pers o n nel  ma y n ot scree n or e nr oll s u bjects i nt o t he st u d y u ntil after recei vi n g n otificati o n 
fr o m t he s p o ns or or its desi g nee t hat t he st u d y ca n be i nitiate d at t he st u dy site. T he st u d y site 
will n ot be a ut h orize d f or st u d y i nitiati o n u ntil:  
Pa ge 8 1 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1.  T he st u d y site has recei ve d t he a p pr o priate  I R B a p pr o val f or t he pr ot oc ol a n d t he a p pr o priate 
I C F. 
2.  All G C P  d oc u me nts ha ve bee n s u b mitte d t o a n d a p pr o ve d b y t he s p o ns or or its desi g nee . 
3.  T he st u d y site has a Cli nical Trial A gree me nt i n place . 
4.  St u d y site pers o n nel, i ncl u di n g t he i n vesti gat or, ha ve partici pate d i n a st u d y i nitiati o n meeti n g.  
1 4. 3.  Scree n F ail ures  
S u bjects w h o fail i ncl usi o n a n d/ or e xcl usi o n cri teria ma y be rescree ne d f or t he st u d y. S u bjects 
ma y o nl y be rescree ne d o nce 3 0  da ys  or m ore after t he ori gi nal Scree ni n g Visit. If a s u bject is 
eli gi ble t o e nter t he st u d y after ha vi n g pre vi o usl y faile d Scree ni n g , t he s u bject will be assi g ne d a 
ne w s u bject  i de ntificati o n n u m ber. 
1 4. 4.  St u d y D oc u me nts  
All d oc u me ntati o n a n d material pr o vi de d b y Ce ntre xi o n T hera pe utics C or p.  f or t his st u d y are t o 
be retai ne d i n a sec ure l ocati o n a n d treate d as c o nfi de ntial material.  
1 4. 4. 1  G o o d Cli nic al Pr actice  D oc u me nts  
T he G C P  d oc u me nts  are liste d bel o w : 
•  Si g ne d ori gi nal pr ot oc ol (ie, I n vesti gat or’s A gree me nt)  
•  C urric ul a vitae of all i n vesti gat ors a n d  s u b i n vestig ators  
•  Na me a n d a d dress of t he la b orat ories  
•  List of la b orat or y refere nce ra n ges, a n d if a vaila ble, a q ualit y certificate 
•  F or m Si g nat ure L o g/ Dele gati o n of St u d y -relate d D uties 
•  A n y ot her rele va nt G C P d oc u me nts  
T he G C P d oc u me nts  m ust be recei ve d fr o m t he i n vesti gat or a n d re vie we d a n d a p pr o ve d b y 
Ce ntre xi o n T hera pe utics C or p. or it s desi g nee bef ore t he st u d y site ca n i nitiate t he st u d y a n d 
bef ore Ce ntre xi o n T hera pe utics C or p. will a ut h orize s hi p me nt of I P t o t he st u d y site. C o pies of 
t he i n vesti gat or’s G C P  d oc u me nts m ust be retai ne d at t he st u d y site i n a sec ure l ocati o n. 
A d diti o nal  d oc u me nts, i ncl u di n g a c o p y of t he pr ot oc ol a n d a p plica ble a me n d me nt(s), t he I P I B, 
e C R F c o m pleti o n g ui deli nes, c o pies of re g ulat or y refere nces, c o pies of I R B  c orres p o n de nce, a n d 
I P acc o u nta bilit y rec or ds s h o ul d als o be retai ne d as part of t he i n vesti gat or’s G C P  d oc u me nts. It 
is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat c o pies of all re q uire d G C P  d oc u me nts are 
or ga nize d , c urre nt, a n d a vaila ble f or i ns pecti o n. 
1 4. 4. 2  C ase Re p ort F or ms  
B y si g ni n g t he I n vesti gat or’s A gree me nt ( Secti o n  1 7. 2 ), t he i n vesti gat or a grees t o mai ntai n 
acc urat e e C R Fs a n d s o urce d oc u me ntati o n as part of t he case hist ories f or all s u bjects w h o si g n 
a n I C F.  
Case re p ort for ms are c o nsi dere d c o nfi de ntial d oc u me nts a n d s h o ul d be ha n dle d a n d st ore d 
acc or di n gl y. T he s p o ns or or its desi g nee will pr o vi de t he necessar y tr ai ni n g o n t he use of t he 
Pa ge 8 2 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
s pecific e C R F s yste m use d d uri n g t he st u d y t o e ns ure t hat t he st u d y i nf or mati o n is ca pt ure d 
acc uratel y a n d a p pr o priatel y.  
T o e ns ure data acc urac y, e C R F data f or i n di vi d ual s u bject visits s h o ul d be c o m plete d as s o o n as 
p ossi ble after t he visit. All re q ueste d i nf or mati o n m ust be e ntere d i n t he C R F/ E D C s yste m  
acc or di n g t o t he c o m pleti o n g ui de li nes pr o vi de d b y t he s p o ns or or its desi g nee. 
T he e C R Fs m ust  be si g ne d b y t he i n vesti gat or or a s u b  i n vesti gat or. T hese si g nat ures ser ve t o 
attest t hat t he i nf or mati o n c o ntai ne d i n t he e C R F is acc urate a n d tr ue. 
1 4. 4. 3  S o urce D oc u me nts  
Inf or mati o n rec or de d i n t he C R F/ E D C s yste m s h o ul d be s u p p orte d b y c orres p o n di n g s o urce 
d oc u me ntati o n. E xa m ples of acce pta ble s o urce d oc u me ntati o n i ncl u de , b ut are n ot li mit e d t o, 
h os pital rec or ds, cli nic a n d office c harts, la b orat or y n otes, a n d rec or de d data fr o m a ut o mate d 
i nstr u me nts, me m ora n da, a n d p har mac y dis pe nsi n g rec or ds. 
Cli nical la b orat or y data re q uire d b y t he pr ot oc ol will be electr o nicall y tra nsferre d fr o m t he 
ce ntral/l ocal la b orat or y t o t he s p o ns or or its desi g nee. A pa per c o p y of t he la b orat or y res ults will 
be pr o vi de d t o t he st u d y site a n d s h o ul d be retai ne d w it h eac h s u bject’s s o urce data. 
1 4. 5.  D at a Q u alit y C o ntr ol  
Ce ntre xi o n T hera pe utics C or p. a n d its desi g nees wil l perf or m q ualit y c o ntr ol c hec ks o n t his 
cli nical st u d y . 
1 4. 5. 1  M o nit ori n g Pr oce d ures  
Ce ntre xi o n T hera pe utics C or p. a n d/ or its desi g nee will c o n d uct site visits t o m o nit or t he st u d y 
a n d e ns ure c o m plia nce wit h t he pr ot oc ol, G C P, a n d a p plica ble re g ulati o ns a n d g ui d eli nes. T he 
assi g ne d cli nical researc h ass ociate(s) (C R As) will visit t he i n ves ti gat or a n d st u d y site at peri o dic 
i nter vals a n d mai ntai n peri o dic c o m m u nicati o n. T he i n vesti gat or a grees t o all o w t he C R A(s) a n d 
ot her a ut h orize d Ce ntre xi o n T hera pe utics C or p. pers o n nel access. T he C R A(s) will mai ntai n 
c urre nt pers o nal k n o wle d ge of t he st u d y t hr o u g h o bser vati o n, re vie w of st u d y rec or ds a n d s o urce 
d oc u me ntati o n, a n d disc ussi o n of t he  c o n d uct of t he st u d y wit h t he i n vesti gat or a n d staff. W hile 
o n site, t he C R A(s) will re vie w  
•  re g ulat or y d oc u me nts, directl y c o m pari n g e ntries i n t he C R F/ E D C s ys te m wit h t he s o urce 
d oc u me nts  
•  c o nse nti n g pr oce d ures  
•  A E pr oce d ures  
•  st ora ge a n d acc o u nta bilit y of I P a n d st u d y materials  
T he C R A will as k f or clarificati o n a n d/ or c orrecti o n of a n y n ote d i nc o nsiste ncies. Pr oce d ures f or 
c orrecti n g e C R F are descri be d i n t he st u d y ma n ual. As re prese ntati ves of t he s p o ns or, C R As are 
res p o nsi ble f or n otif yi n g pr oject ma na ge me nt of a n y n ote d pr ot oc ol de viati o ns. 
B y si g ni n g t he I n vesti gat or’s A gree me nt ( Secti o n 1 7. 2 ), t he i n vesti gat or a grees t o meet wit h t he 
C R A (s) d uri n g st u d y site visits ; t o e ns ure t hat st u d y staff is a vaila ble t o t he C R A(s) as nee de d; t o 
pr o vi de t he C R A(s) access t o all st u d y d oc u me nt ati o n, t o t he cli nical s u p plies dis pe nsi n g a n d 
st ora ge area; a n d t o assist t he m o nit ors i n t heir acti vities, if re q ueste d. F urt her, t he i n vesti gat or 
Pa ge 8 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
a grees t o all o w Ce ntre xi o n T hera pe utics C or p. or desi g nee a u dit ors or i ns pect ors fr o m re g ulat or y 
a ge ncies t o re vie w rec or ds a n d t o  assist t he i ns pect ors i n t heir d uties, if re q ueste d.  
1 4. 5. 2  D at a M a n a ge me nt  
Ce ntre xi o n T hera pe utics C or p. or desi g nee will be res p o nsi ble f or acti vities ass ociate d wit h t he 
data ma na ge me nt of t his st u d y. T he sta n dar d pr oce d ures f or ha n dli n g a n d pr ocessi n g rec or d s will 
be f oll o we d per G C P a n d 
 sta n dar d o perati n g p r oce d ures ( S O Ps). A 
c o m pre he nsi ve data ma na ge me nt p la n ( D M P) will be de vel o pe d i ncl u di n g a data ma na ge me nt 
o ver vie w, descri pti o n of data base c o nte nts, a n n otate d C R F, pre -e ntr y r e vie w list, self-e vi de nt 
c orrecti o n c o n ve nti o ns, q uer y c o ntacts, a n d c o nsiste nc y c hec ks.  
St u d y site pers o n nel will be res p o nsi ble f or pr o vi di n g res ol uti o ns t o all data q ueries. T he 
i n vesti gat or will be re q uire d t o d oc u me nt electr o nic data re vie w t o e ns ure t he acc urac y of t he 
c orrecte d a n d/ or clarifie d data. Pr oce d ures f or s oliciti n g a n d d oc u me nti n g res ol uti o n t o data 
q ueries are descri be d  i n t he st u d y ma n ual. 
1 4. 5. 3  Q u alit y Ass ur a nce/ A u dit  
T his st u d y will be s u bject t o a u dit b y Ce ntre xi o n T hera pe utics C or p. or  its desi g nee . A u dits ma y 
be u n derta ke n t o c hec k c o m plia nce wit h G C P g ui deli nes , a n d ca n i ncl u de: 
•  site a u dits 
•  T rial M aster F ile a u dit s 
•  data base a u dits  
•  d oc u me nt a u dits (e g, pr ot oc ol a n d/ or cli nical st u d y re p ort [ C S R ]) 
Ce ntre xi o n T hera pe utics C or p. or its desi g nee ma y c o n d uct a d diti o nal a u dits o n a selecti o n of 
st u d y sites, re q uiri n g access t o s u bject n otes, st u d y d oc u me ntati o n, a n d facilities or la b orat ories 
use d f or t he st u d y.  
T he st u d y site, facilities, all data (i ncl u di n g s o urce data) , a n d d oc u me ntati o n will be ma de 
availa ble f or a u dit b y q ualit y ass ura nce a u dit ors a n d f or I R B or re g ulat or y a ut h orities acc or di n g 
t o G C P g ui deli ne s. T he i n vesti gat or a grees t o c oo perate wit h t he a u dit or d uri n g t he visit a n d will 
be a vaila ble t o s u p pl y t he a u dit or wit h C R Fs or ot her files necessar y t o c o n d uct t hat a u dit. A n y 
fi n di n gs will be strictl y c o nfi de ntial. 
If a re g ulat or y a ut h orit y i nf or ms t he i n vesti gat or t hat it i nte n ds t o c o n d uct a n i ns pecti o n, t he 
i n vesti gat or s hall n otif y Ce ntre xi o n T hera pe utics C or p. i m me diatel y.  
1 4. 6.  St u d y Ter mi n ati o n  
T he st u d y ma y be ter mi nate d t he discreti o n of Ce ntre xi o n T hera pe utics C or p. at a n y ti me a n d f or 
a n y reas o n.  
1 4. 7.  St u d y Site Cl os ure  
At t he e n d  of t he st u d y, all st u d y sites will be cl ose d. Ce ntre xi o n T hera pe utics C or p. ma y 
ter mi nate partici pati o n of a st ud y site at a n y ti me. E xa m ples of c o n diti o ns t hat ma y re q uire 
pre mat ure ter mi nati o n of a st u d y site i ncl u de, b ut are n ot li mite d t o , t he f oll o wi n g: 
Pa ge 8 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
•  N o nc o m plia nce wit h t he pr ot oc ol a n d/ or a p p lica ble re g ulati o ns a n d g ui deli nes 
•  I na de q uate patie nt e nr oll me nt 
1 4. 7. 1   R ec or d Rete nti o n  
T he i n vesti gat or s hall retai n a n d preser ve 1 c o p y of all data ge nerate d i n t he c o urse of t he st u d y, 
s pecificall y i ncl u di n g, b ut n ot li mite d t o, t h ose defi ne d b y G C P as esse ntial u ntil 
•  At least 2  years after t he last mar keti n g a ut h orizati o n f or t he I P has bee n a p pr o ve d or t he 
s p o ns or has disc o nti n ue d its researc h wit h t he I P, or 
•  At least 2  years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of 
t he I P 
T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if r e q uire d b y t he a p plica ble 
re g ulat or y re q uire me nt(s) or if nee de d b y t he s p o ns or. 
At t he e n d of s uc h peri o d, t he i n vesti gat or s hall n otif y t he s p o ns or i n writi n g of her/ his i nte nt t o 
destr o y all s uc h material. T he s p o ns or s hall ha ve 3 0  da ys t o res p o n d t o t h e i n vesti gat or’s n otice, 
a n d t he s p o ns or s hall ha ve a f urt her o p p ort u nit y t o retai n s uc h materials at t he s p o ns or’s e x pe nse.  
1 4. 8.  C h a n ges t o t he Pr ot oc ol  
T his pr ot oc ol ca n n ot be altere d or c ha n ge d e xce pt t hr o u g h a f or mal pr ot oc ol a me n d me nt, w hic h 
re q uires t he writte n a p pr o val of Ce nt re xi o n T hera pe utics C or p. T he pr ot oc ol a me n d me nt m ust be 
si g ne d b y t he i n vesti gat or a n d a p pr o ve d b y t he I R B bef ore it ma y be i m ple me nte d. Pr ot oc ol 
a me n d me nts will b e file d wit h t he a p pr o priate re g ulat or y a ge nc y( ies) ha vi n g j uris dictio n o ver t he 
c o n d uct of t he st u d y.  
1 4. 9.  Use of I nf or m ati o n a n d P u blic ati o n  
All i nf or mati o n c o ncer ni n g I P, Ce ntre xi o n T hera pe utics C or p.’s o perati o ns, pate nt a p plicati o ns, 
f or m ulae, ma n ufact uri ng pr ocesses, basic scie ntific data, a n d f or m ulati o n i nf or mati o n s u p pl ie d 
b y Ce ntre xi o n T hera pe utics C or p. or  its desi g nee  t o t he i n vesti gat or a n d n ot pre vi o usl y 
p u blis he d, is c o nsi dere d c o nfi de ntial a n d re mai ns t he s ole pr o pert y  of  Ce ntre xi o n T hera pe utics 
C or p.  Case rep ort f or ms  als o re mai n t he pr o pert y of Ce ntre xi o n T hera p e utics C or p. T he 
i n vesti gat or a grees t o use t his i nf or mati o n f or p ur p oses of st u d y e xec uti o n t hr o u g h fi nalizati o n 
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 t he  s p o ns or. 
T he i nf or mati o n de vel o pe d i n t his st u d y will be use d b y Ce n tre xi o n T hera pe utics C or p. i n 
c o n necti o n wit h t he c o nti n ue d de vel o p me nt of I P a n d t h us ma y be discl ose d as re q uire d t o ot her 
cli nical i n vesti gat ors or g o ver n me nt re g ulat or y a ge ncies.  
T he i nf or mati o n ge nerate d b y t his st u d y is t he pr o pert y of Ce ntre xi o n T he ra pe utics C or p. 
P u blicati o n or ot her p u blic prese ntati o n of I P data res ulti n g fr o m t his st u d y re q uires pri or re vie w 
a n d writte n a p pr o val of Ce ntre xi o n T hera pe utics C or p . A bstracts, ma n uscri pts, a n d prese ntati o n 
materials s h o ul d be pr o vi de d t o Ce ntre xi o n T h era pe utics C or p. f or re vie w a n d a p pr o val at least 
3 0  da ys pri or t o t he rele va nt s u b missi o n dea dli ne.  Data fr o m i n di vi d ual st u d y sites m ust n ot be 
p u blis he d se paratel y.  
Pa ge 8 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
It is a gree d t hat t he res ults of t he st u d y will n ot be s u b mitte d f or prese ntati o n, a bstract, p oster 
e x hi biti o n or p u blicati o n b y t he i n vesti gat or u ntil Ce ntre xi o n T hera pe utics C or p. has re vie we d 
a n d c o m me nte d o n s uc h a prese ntati o n or ma n uscri pt f or p u blic ati o n. 
Pa ge 8 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 5. E T HI C A L A N D L E G A L C O N SI D E R A TI O N S
1 5. 1.  Decl ar ati o n of Helsi n ki a n d G o o d Cli nic al Pr acti ce 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he A pril 1 9 9 6 I C H G ui da nce f or I n d ustr y E 6 
G C P (i ncl u di n g arc hi vi n g of esse ntial st u d y d oc u me nts), t he 2 0 1 3  versi o n of t he Declarati o n of 
Helsi n ki, t he a p plica ble re g ulati o ns of t he c o u ntr y(ies) i n w hic h t he st u d y is c o n d ucte d, a n d wit h 
t he C o m missi o n Directi ves 2 0 0 1/ 2 0/ E C a n d 2 0 0 5/ 2 8/ E C. 
See A p pe n di x B  f or re g ulati o n a n d g ui deli nes. 
1 5. 2.  S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
A pr o perl y c o nstit ute d, vali d I R B m us t re vie w a n d a p pr o ve t he pr ot oc ol, t he i n vesti gat or’s 
i nf or me d c o nse nt d oc u me nt, a n d relate d s u bject i nf or mati o n a n d recr uit me nt materials bef ore t he 
start of t he st u d y. 
It is t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat writte n i nf or me d c o nse nt an d/ or asse nt is 
o btai ne d fr o m t he s u bject bef ore a n y acti vit y or pr oce d ure is u n derta ke n t ha t is n ot part of 
r o uti ne care. 
1 5. 3.  A p pr o v al b y I nstit uti o n al Re vie w B o ar d 
F or I n vesti gati o nal Ne w Dr u g (I N D) st u dies, t he mi ni m u m sta n dar ds of c o n d uct a n d 
re q uire me nts f or i nf or me d c o nse nt are defi ne d i n t he F D A re g ulati o ns. 
A vali d I R B m ust re vie w a n d a p pr o ve  this pr ot oc ol bef ore st u d y i nitiati o n. Writte n n otificati o n 
of a p pr o val is t o be pr o vi de d  b y t he i n vesti gat or t o t he s p o ns or ’s m o nit or  bef ore s hi p me nt of 
i n vesti gati o nal dr u g s u p plies, a n d will i ncl u de t he date of t he c o m mittee’s a ppr o val a n d t he 
c hair pers o n’s si g nat ure. T his writte n a p pr o val m ust c o nsist of a c o m plete d I R B a p pr o val f or m , 
or writte n d oc u me ntati o n fr o m t he I R B c o ntai ni n g t he sa me i nf or mati o n.  
U ntil w ritte n a p pr o val b y t he I R B has bee n recei ve d b y t he i n vesti gat or, n o s u bject ma y u n der g o 
a n y pr oce d ure n ot part of r o uti ne care f or t he patie nt ’s c o n diti o n. 
Pr ot oc ol a me n d me nts m ust als o be re vie we d a n d a p pr o ve d b y t he I R B. Writte n a p pr o val fr o m 
t he I R B, or a desi g nee, m ust be recei ve d b y Ce ntre xi o n T hera pe utics C or p. bef or e 
i m ple me ntati o n. T his writte n a p pr o val will c o nsist of a c o m plete d I R B ap pr o val f or m or writte n 
d oc u me ntati o n fr o m t he I R B c o ntai ni n g t he sa me i nf or mati o n.  
1 5. 4.  Fi n a nce a n d I ns ur a nce  
Details o n fi na nce a n d i ns ura nce will be pr o vi de d  i n a se parate a gree me nt bet wee n t he 
i n vesti gat or a n d t he s p o ns or. 
Pa ge 8 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
Versi o n 3. 0 
Pa ge 8 8  of 1 3 3  
1 6. R E F E R E N C E S
1.
Ma mli n  L. A., C. A. Melfi, M. L. Parc h ma n, B. G utierrez, D. I. Alle n, B.P. Katz, R. S. Ditt us, D. A.
Hec k a n d D. A. Fre u n d ( 1 9 9 8). " Ma na ge me nt of oste oart hritis of t he k nee b y pri mar y care
p h ysicia ns." Arc h Fa m M e d  7 ( 6): 5 6 3-5 6 7.
2.
Ca b or n, D., J. R us h, W. La nzer, D. Pare nti, C. M urra y a n d G. S y n visc 9 0 1 St u d y ( 2 0 0 4). " A
ra n d o mize d, si n gle-bli n d c o m paris o n of t he efficac y a n d t olera b ilit y of h yla n G-F 2 0 a n d
tria mci n ol o ne he xacet o ni de i n patie nts wit h oste oart hritis of t he k nee." J R he u mat ol 3 1 ( 2): 3 3 3-
3 4 3.
3.
Ce ntre xi o n T hera pe utics ( 2 0 1 5). I n vesti gati o nal Dr u g Br oc h ure, C N T X -4 9 7 5 ( P E G 3 0 0 -ca psaici n)
f or I njecti o n. Balti m ore, M D 2 1 2 0 2, U nite d States, Ce ntre xi o n C or p orati o n.
4.
Cateri na, M. J. a n d D. J uli us ( 2 0 0 1). " T he va nill oi d rece pt or: a m olec ular gate wa y t o t he pai n
pat h wa y." A n n u Re v Ne ur osci  2 4 : 4 8 7-5 1 7.
5.
Bre ders o n, J. D., P. R. K y m a n d A. Szallasi ( 2 0 1 3). " Tar geti n g T R P c ha n nels f or p ai n relief." E ur J
P har mac ol  7 1 6 ( 1-3): 6 1 -7 6.
6.
Si m o ne, D. A., M. N ola n o, T. J o h ns o n, G. We n delsc hafer -Cra b b a n d W. R. Ke n ne d y ( 1 9 9 8).
"I ntra der mal i njecti o n of ca psaici n i n h u ma ns pr o d uces de ge nerati o n a n d s u bse q ue nt rei n ner vati o n
of e pi der mal ner ve fi bers:  c orrelati o n wit h se ns or y f u ncti o n." J Ne ur osci 1 8 ( 2 1): 8 9 4 7-8 9 5 9.
7.
Bara ni d hara n, G., S. Das a n d A. B has kar ( 2 0 1 3). " A re vie w of t he hi g h -c o nce ntrati o n ca psaici n
patc h a n d e x perie nce i n its use i n t he ma na ge me nt of ne ur o pat hic pai n." T her A d v Ne ur ol Dis or d
6 ( 5): 2 8 7-2 9 7.
8.
Ac or da T hera pe utics, I. ( 2 0 0 9). Q U T E N Z A ® (ca psaici n) 8 % patc h F ull Prescri bi n g I nf or mati o n.
Ar dsle y, N Y 1 0 5 0 2, U S A, Ac or da T hera pe utics, I nc.
9.
Alt ma n, R. D. a n d G ol d, G. E ( 2 0 0 7). “ Atlas of i n di vi d ual ra di o gra p hic feat ures i n oste oart hritis,
re vise d.” Oste oart hritis a n d Cartila ge 1 5 : A 1-A 5 6.
1 0.
H u nter, D.J., Alt ma n, R. D., Cic utti ni, F., Cre ma, M. D., D ur yea, J. Ec kstei n, F., G uer mazi, A., et al .
( 2 0 1 5). “ O A R SI Cli nical Trials Rec o m me n dati o ns: K nee i ma gi n g i n cli nical trials i n
oste oart hritis.” Oste oart hritis a n d Cartila ge  2 3 : 6 9 8-7 1 5.
1 1.
Her d ma n, M., C. G u de x, A. Ll o y d, M. Ja nsse n, P. Ki n d, D. Par ki n, G. B o nsel a n d X. Ba dia ( 2 0 1 1).
" De vel o p me nt a n d preli mi nar y testi n g of t he ne w fi ve -le vel versi o n of E Q-5 D ( E Q -5 D -5 L)." Q ual
Life Res  2 0 ( 1 0): 1 7 2 7 -1 7 3 6.
1 2.
O bra d o vic, M., A. Lal a n d H. Lie d ge ns ( 2 0 1 3). " Vali dit y a n d res p o nsi ve ness of E ur o Q ol -5
di me nsi o n ( E Q -5 D) vers us S h ort F or m -6 di me nsi o n ( S F -6 D) q uesti o n naire i n c hr o nic pai n." Healt h
Q ual Life O utc o mes  1 1 : 1 1 0.
1 3.
Sa m ps o n H .A ., M u ñ oz-F url o n g A ., Cam p bell R .L ., et al. ( 2 0 0 6). "Sec o n d s y m p osi u m o n t he
defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort --Sec o n d Nati o nal I nstit ute of Aller g y
a n d I nfecti o us Disease/ F o o d Aller g y a n d A na p h yla xis Net w or k s y m p osi u m ." J Aller g y Cli n
I m m u n ol 1 1 7 ( 2): 3 9 1 -3 9 7.
1 4.
E va ns , S . (2 0 0 7 ). "W he n a n d h o w ca n e n d p oi nts be c ha n ge d after i nitiati o n of a ra n d o mize d cli nical
trial?" P L o S Cli n Trials  2 ( 4): e 1 8.
1 5.
Alt ma n,  R.,  E. Asc h, D. Bl oc h, G. B ole, D. B ore nstei n, K. Bra n dt, et al. (1 9 8 6 ). "T he A merica n
C olle ge of R he u mat ol o g y criteria f or t he  classificati o n a n d re p orti n g of oste oart hritis of t he k nee. "
Art hritis R he u m  2 9 : 1 0 3 9-1 0 4 9 .










Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
8.  S u bjects are t o fast f or at least 8 h o urs pri or t o t he la b orat or y sa m ple c ollecti o ns perf or me d at t he Scree ni n g Visit . O n Da y 1, la b orat or y tests will be 
perf or me d pri or t o ra n d o mizati o n.  H o we ver, t he res ults of t hese tests are n ot re q uire d pri or t o ra n d o mizati o n a n d d osi n g if t he Scree ni n g test res ults were 
wit hi n t he a cce pta ble pr ot oc ol ra n ges.   
9.  Uri ne dr u g scree n test res ults m ust be c o nfir m e d as ne gati ve f or dr u gs of a b use pri or t o ra n d o mizati o n.   
1 0.  S u bjects will be teste d f or pre g na nc y if t he y are w o me n of c hil d beari n g p ote ntial.  A ser u m pre g na nc y test will be perf or me d  if t he uri ne pre g na nc y test is 
p ositi ve.  S u bjects wit h p ositi ve uri ne pre g na nc y test res ults will n ot be ra n d o mize d or will be disc o nti n ue d fr o m st u d y partici pati o n.  T hese s u bjects will be 
f oll o we d u ntil t he pre g na nc y is c o m plete d, a n d t he healt h of t he fet us is k n o w n. 
1 1.  O n Da y 1 a n d Wee k 2 6, sta n di n g a n d sitti n g vital si g ns t o be meas ure d wit hi n a p pr o xi matel y 5 mi n utes bef ore t he i njecti o n of I P, a n d sitti n g -o nl y vital si g ns 
wit hi n a p pr o xi matel y 5 , 1 5, a n d 3 0 mi n utes after t he i njecti o n of I P. 
1 2.  Eli gi ble s u bj ects will be ra n d o mize d t o t heir treat me nt assi g n me nt usi n g t he Ce ntre xi o n  Ra n d o mizati o n Al g orit h m after t he res ults of all Scree ni n g a n d 
a p plica ble pre -d ose assess me nts ha ve bee n o btai ne d a n d all i ncl usi o n a n d e xcl usi o n criteria ha ve bee n met.  F or treat me nt 2, s u bjects will be i njecte d per 
t heir ra n d o mize d treat me nt assi g n me nt f or treat me nt 1. 
1 3.  Fr o m t he Scree ni n g Visit t o Wee k 5 2, s u bjects will use a n e P R O s yste m dail y t o rate t heir i n de x k nee pai n at be dti me ( 9: 0 0 P M ± 3 h) f or a vera ge pai n wit h 
wal ki n g o ver t he pre vi o us 2 4 h, usi n g t he N P R S q uesti o n.  S u bjects will als o nee d t o rec or d t heir resc ue me dicati o n usa ge i n e P R O at t he sa me ti me. E ns ure 
t he s u bject is set-u p i n t he s yste m, trai ne d , a n d u n dersta n ds h o w t o e nter t heir N P R S sc ore a n d t heir resc ue me dicati o n usa ge. I n case of tec h nical iss ues, 
pa per c o pies of t he P R Os will be pr o vi de d f or s u bject c o m pleti o n a n d file d at t he site.  
1 4.  T he I P i njecti o n pr oce d ure will be sta n dar dize d acr oss all cli nical sites. It is rec o m me n de d t hat t he I P i njecti o n be a d mi nistere d usi n g ultras o u n d -g ui de d 
nee dle place me nt , b ut is n ot re q uire d. If ima gi n g -g ui de d i njecti o n is n ot use d, t he n c o nfir mati o n of l ocati o n of t he nee dle wit hi n t he i n de x k nee j oi nt m ust be 
verifie d b y as pirati n g j oi nt fl ui d.  If n o j oi nt fl ui d is as pirate d, t he I P s h o ul d n ot be i njecte d. If t here is a s u bsta ntial eff usi o n wit hin t he k nee j oi nt, t he eff usi o n 
s h o ul d be as pirate d, w he n p ossi ble, s uc h t hat t he esti mate d re mai ni n g j oi nt fl ui d i n t he k nee is a p pr o xi matel y 5 -1 0 m L. Rec or d t he a m o u nt of j oi nt fl ui d 
as pirate d.  It is rec o m me n de d, b ut at t he i n vesti gat or’s discreti o n, t o pre-me dicate s u bjects wit h a n o pi oi d, N S AI D, or l ocal a nal gesic (s uc h as et h yl c hl ori de, 
t o pical li d ocai ne, a n d/ or s u bc uta ne o us li d ocai ne –  b ut a rec o m me n de d ma xi m u m of 2 pr e-me dicati o ns ma y be use d pri or t o treat me nt (e xcl u di n g i njecti o n of 
1 5 m L  2 % li d oca i ne [ wit h o ut e pi ne p hri ne] i nt o t he i n de x k nee). L ocal a nest hesia of t he i n de x k nee will be perf or me d wit h 1 5  m L I A of 2 % li d ocai ne 
( wit h o ut e pi ne p hri ne) 3 0 mi n utes pri or t o i njecti o n of t he I P. A dj u nct use of c o ntr olle d j oi nt c o oli n g will be a p plie d a p pr o x i matel y 1 5 mi n utes pri or t o 
i ntra-artic ular i njecti o n of 2 % li d ocai ne ( wit h o ut e pi ne p hri ne); c o ntr olle d c o oli n g will be re m o ve d a n d t he n 2 % li d ocai ne ( wit h o ut e pi ne p hri ne) will be 
a d mi nistere d i nt o t he i n de x k nee i m me diatel y f oll o we d b y a dj u nct c o ntr olle d c o oli n g f or 3 0 mi n utes.  At 3 0 mi n utes after 2 % li d ocai ne ( wit h o ut e pi ne p hri ne) 
a d mi nistrati o n, t he c o oli n g de vice will be re m o ve d a n d I P i njecti o n will be a d mi nistere d i nt o t he i n de x k nee. I m me diatel y after I P i njecti o n, t he i n de x k nee 
j oi nt will be passi vel y fle xe d a n d e xte n de d 5 ti mes o ver a 1  mi n ute i nter val t o facilitate distri b uti o n of t he I P wit hi n t he i n de x k nee . T he n c o ntr olle d c o oli n g 
will be rea p plie d i m me diatel y f oll o wi n g t he passi ve fle xi o n a n d e xte nsi o n f or a mi ni m u m of 3 0 mi n utes, f or u p t o 1  h o ur after st u d y me dicati o n i njecti o n. 
T he c o oli n g ma y be disc o nti n ue d a fter a mi ni m u m of 3 0  mi n utes, a p plicati o n after I P I A i njecti o n, if t he s u bject has a pai n le vel t hat is acce pta ble f or t he 
s u bject a n d i n vesti gat or ( N P R S 0-4  scale: n o ne, mil d, m o derate, m o deratel y se vere a n d se vere). H o we ver, a n a d diti o nal 3 0 mi n utes of c o ntr olle d c o oli n g 
(t otal 1. 5 h o urs after I P a d mi nistrati o n) ma y be use d if t here c o nti n ues  t o be m o derate-t o-se vere pai n i n t he i n de x k nee, at t he i n vesti gat or’s discreti o n. 
1 5.  T he i njec ti o n site will be e xa mi ne d a n d assesse d f or er yt he ma a n d e de ma b y bli n de d site pers o n nel ( usi n g a cate g orical scale of n o ne, mil d, m o derate, 
m o deratel y se vere, or se vere [ 0-4]) o n Treat me nt Da y 1 a n d Treat me nt Da y 2 ( Wee k 2 6 ) bef ore t he i njecti o n, after t h e i njecti o n at 1 a n d 2 h, a n d at t he 
Wee k  4  a n d Wee k  3 0  st u d y visits. Si g nifica nt br uisi n g or ot her cli nicall y si g nifica nt i njecti o n site reacti o ns will be rec or de d as A Es.   
1 6.  Pr oce d ure  pai n will be assesse d b y as ki n g s u bjects t o rate t heir i n de x k nee f or pa i n ( 1) at rest pri or t o pre-me dicati o n ; ( 2) pri or t o i ntra-artic ular 2 % li d ocai ne 
( wit h o ut e pi ne p hri ne); ( 3) at rest 1 0 mi n utes ( ± 2 mi n utes) after i ntra-artic ular  2 % li d ocai ne ( wit h o ut e pi ne p hri ne); ( 4) at 3 0 mi n utes ( ± 5 mi n utes) after 
i ntra-artic ular i n jecti o n of t he I P a n d ( 5) at rest at t he 1 h a n d 2 h ti me p oi nts after i ntra -artic ular i njecti o n of t he I P ( ± 1 0 mi n utes).  
1 7.  Fr o m t he Scree ni n g Visit f or war d, t he e P R O s yste m will be use d dail y t o c ollect res p o nses fr o m s u bjects o n i n de x k nee pai n wit h wal k i n g o ver t he pre vi o us 
2 4 h o urs . Fr o m t he Treat me nt Visit t h o u g h Wee k 5 2, s u bjects will als o be as ke d t o rec or d i nt o t he e P R O de vice t heir dail y usa ge of a ny resc ue me dicati o ns. 
Pa ge 9 3 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
Site s s h o ul d m o nit or s u bject c o m plia nce of diar y e ntries re g ularl y t hr o u g h o ut the 5 2 wee ks.  If a s u bject is n ot c o m plia nt t he site s h o ul d reac h o ut t o t he 
s u bject as s o o n as n o nc o m plia nce is o bser ve d . I n case of tec h nical iss ues, pa per c o pies of t he P R Os will be pr o vi de d f or s u bject c o m pleti o n a n d file d at t he 
site. 
1 8.  S u bjects will be as ke d t o c o m plete t he W O M A C q uesti o n naire ( Parts A, B , a n d C) o n St u d y Da y 1 ( Treat me nt 1) a n d Wee k 2 6 ( Treat me nt 2) pri or t o 
recei vi n g pre-me dicati o ns a n d a t sc he d ule d St u d y Visits ( Wee ks 4, 8, 1 2, 1 8, 3 0, 3 8, 4 6 , a n d 5 2).  
1 9.  T he  q uesti o n naires n ote d i n t he  ta ble a b o ve will be c ollecte d via a n e P R O s yste m at eac h site visit i n dicate d i n t he ta ble of assess me nts.  
2 0.  T he Assisti ve De vice Usa ge q uesti o n naire is a n i nstr u me nt t o meas ure a n y c ha n ges i n t he t y pes of de vices use d t o assist wit h wal ki n g d uri n g t he st u d y 
peri o d. S u bjects w h o use assisti ve de vices at t he start of t he st u d y are as ke d t o i de ntif y t he t y pe of de vice use d. T his q ues ti o n is t he n as ke d a gai n at specifie d 
visits d uri n g t he st u d y. T he fre q ue nc y of de vice use is als o ca pt ure d ( Ofte n; Sel d o m ; or N ot at All).  
2 1.  C ollecti o n of A Es will be gi n fr o m t he ti me of si g ni n g t he I C F t hr o u g h t he F oll o w-U p Visit or Earl y Ter mi nati o n Visit, w hic he ver occ urs first . O n Da y 1 , t he 
A E assess me nt m ust be perf or me d at t he pre -d ose Baseli ne . Treat me nt -e mer ge nt A Es will be  c ollecte d fr o m t he ti me of t he i njecti o n of I P t hr o u g h t he Wee k 
5 2 Visit.  P ote ntiall y relate d A Es t hat are o n g oi n g at t he Wee k 5 2 cli nic visit will be f oll o we d u ntil t he y are sta ble, res ol ve d, or n o l o n ger cli nicall y 
si g nifica nt, i n t he o pi ni o n of t he i n vesti gat or, or u ntil 4 wee ks after t he st u d y is c o m plete d.   
2 2.  S u bjects ma y ta ke a si n gle resc ue me dicati o n f or pai n of t he i n de x k nee as nee de d. T hese  resc ue me dicati o ns ma y i ncl u de eit her 
aceta mi n o p he n/ paraceta m ol, a si n gle N S AI D at a ti me (s u bjects ma y s wit c h a p pr o ve d N S AI Ds), or tra ma d ol ( u p t o 2 0 0 m g dail y).  S u bjects s h o ul d n ot ta ke 
resc ue me dicati o n wit hi n 2 4 h pri or t o a cli nic visit.  Data o n t he t y pe of resc ue me dicati o n, a n d t he dail y d ose of resc ue me dicati o n, will be c ollecte d a n d 
will be rec or de d ea c h da y i n t he e P R O s yste m fr o m Scree ni n g u p t o Wee k 5 2 or Earl y Ter mi nati o n ; data o n t he t y pe of resc ue me dica ti o n, a n d t he dail y d ose 
will be re p orte d dail y  b y t he s u bject usi n g e P R O.  A d diti o nal resc ue me dicati o n details will be c ollecte d at st u d y visits a n d f oll o w -u p tele p h o ne calls i n t he 
s o urce d oc u me nts a n d e C R F. 
2 3.  S u bjects m ust  sta y o n t heir c urre nt pai n me dic ati o n as prescri be d, or o ver t he c o u nter m e dicati o n, fr o m t he ti me of Pre -scree ni n g t hr o u g h Wee k 1 2.  T he 
c urre nt pai n me dicati o n m ust be ta ke n o nl y f or pai n i n t he i n de x k nee, a n d n ot f or a n ot her pai n i n dicati o n. T heir c urre nt pai n me dicati o n m ust be eit her o ne 
of  t he all o we d resc ue me dicati o ns a n d d osa ges, or h y dr oc o d o ne at a d ose u p t o 1 5 m g dail y ( or a n ot her o pi oi d e q ui vale nt). T he resc ue me dicat i o n is n ot 
all o we d t o be i n t he sa me dr u g class as t he o n g oi n g me dicati o n. F or e xa m ple, s u bjects will n ot be a ll o we d t o ta ke tra ma d ol as a resc ue me dicati o n if t he y are 
ta ki n g a n o pi oi d as c o nc o mita nt me dicati o n, or a n N S AI D as resc ue if t he y are usi n g a n N S AI D as c o nc o mita nt me dicati o n.  S u bjects ma y sta y o n c urre nt 
pai n me dicati o n as prescri be d or o ver t he c o u nter me dicati o n, b ut t his is n ot re q uire d fr o m Wee k 1 2  t hr o u gh c o m pleti o n of t he st u d y, Wee k  5 2.  
2 4.  At t he fi nal visit, s u bjects will be as ke d w hic h tre at me nt t he y t hi n k t he y recei ve d  an d w het her t he y w o ul d u n der g o  t he pr oce d ure a gai n if t heir k nee pai n 
ret ur ne d. 
Pa ge 9 4 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
1 7. 2.  I n vesti g at or’s A gree me nt 
P R O T O C O L N U M B E R:  
C N T X -4 9 7 5i -O A -3 0 4  
P R O T O C O L TI T L E:  
A Ra n d o mize d, D o u ble -b li n d, Place b o-co ntr olle d, 2 -I njecti o n 
5 2 -Wee k St u d y t o E val uate t he Efficac y a n d Safet y of I ntra-
artic ular  I njecti o ns of C N T X -4 9 7 5 -0 5  i n S u bjects wit h C hr o nic, 
M o derate -t o-se vere Oste oart hritis K nee Pai n  
P R O T O C O L  D A T E:  
Versi o n 3. 0, 1 2 Oct o ber 2 0 2 0  
I ha ve rea d t his pr ot oc ol a n d a gree t o c o n d uct t hi s cli nical trial as o utli ne d herei n. I will e ns ure 
t hat all s u b i n vesti gat ors a n d ot her st u d y staff me m bers ha ve rea d a n d u n dersta n d all as pects of 
t his pr ot oc ol. I a gree t o c o o perate f ull y wit h Ce ntre xi o n T hera pe utics C or p. a n d 
 
d uri n g t he  st u d y. I will a d here t o all F D A, I C H, a n d ot her a p plica ble re g ulati o ns a n d g ui deli nes 
re gar di n g cli nical trials o n a n I P d uri n g a n d after st u d y c o m pleti o n. 
 
 
 
Pri nte d Na me:  
  
 
 
 
  
 
 
Si g nat ure:  
  
 
 
  
 
 
Date:  
  
 
Pa ge 9 5 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
 
C N T X -4 9 7 5i -O A -3 0 4  
 
1 2 -Oct -2 0 2 0  
Versi o n 3. 0  
 
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
A P P E N DI C E S  
A.  St u d y S pecific Re q uire me nts  
B.  Re g ulati o ns a n d G o o d Cli nical Practice G ui deli nes  
C.  Se vere Aller gic Reacti o n –  A na p h yla xis / A na p h ylact oi d Reacti o n 
D.  C O VI D -1 9 Me m o t o St u d y Sites  
 
 
 
Pa ge 9 6 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6
A.
St u d y S pecific Re q uire me nts
E xa m ples of t he patie nt -re p orte d o utc o me scales t hat will be  use d  d uri n g t his st u d y  are attac he d 
t o t his a p pe n di x. T he f oll o wi n g is a n i n de x:  
•
A merica n C olle ge of R he u mat ol o g y ( A C R) D ia g n ostic C riteria
•
H os pital A n xiet y a n d De pressi o n Scale ( H A D S)
•
Fi br o m yal gia S y m pt o m Scale Sc ore ( F S S)
•
W O M A C Oste oart hritis I n de x Versi o n N R S 3. 1
•
K O O S K nee S ur ve y
•
S F - 3 6 Healt h S ur ve y
•
M O S Slee p Scale
•
E Q - 5 D- 5 L Healt h Stat us Q uesti o n naire
•
J oi nt Re place me nt Q uesti o n naire
•
Patie nt Gl o bal I m pressi o n of C ha n ge Assess me nt ( P GI C)
•
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire ( W P AI: S H P)
Pa ge 9 7 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
B.
Re g ul ati o ns a n d G o o d Cli nic al Pr actice G ui deli nes
1.
Re g ul ati o ns
Refer t o t he f oll o wi n g U nite d States C o de of Fe deral Re g ulati o ns ( C F R):  
B.
F D A Re g ulati o ns 2 1 C F R, Parts 5 0. 2 0 –  5 0. 2 7
S u b part B –  I nf or me d C o nse nt of H u ma n S u bjects
C.
F D A Re g ulati o ns 2 1 C F R, Parts 5 6. 1 0 7 –  5 6. 1 1 5
Part 5 6 –  I nstit uti o nal Re vie w B oar ds
S u b part B –  Or ga nizati o n a n d Pers o n nel
S u b part C –  I R B F u ncti o ns a n d O perati o ns
S u b part D –  Rec or ds a n d Re p orts
D.
F D A Re g ulati o ns 2 1 C F R, Parts 3 1 2. 5 0 –  3 1 2. 7 0
S u b part D –  Res p o nsi bilities of S p o ns ors a n d I n vesti gat or s
1.
G o o d Cli nic al Pr actice G ui deli nes
I C H G C P g ui deli nes ca n be f o u n d at t he f oll o wi n g U R L: 
htt p:// w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 6/ E 6 _ R 1 _ G
ui deli ne. p df  
htt p:// w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 6/ E 6 _ R 2 _ _
Ste p _ 4. p df  
Pa ge 9 8 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
C.
Se vere Aller gic Re acti o n –  A n a p h yl a xis/ A n a p h yl act oi d Re acti o n
•
•
Sa m ps o n et al. ( 2 0 0 6)
Pa ge 9 9 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Pa ge 1 0 0 of 1 3 3


Ce ntre xi o n T hera pe utics C or p.  
C o nfi de nti al  
C N T X -4 9 7 5i -O A -3 0 4  
1 2 -Oct -2 0 2 0
Versi o n 3. 0  
A D -M W -0 8. 0 4  1 5 -A pr -2 0 1 6  
 
 
 
 
  
 
 
 
  
 
  
 
Pa ge 1 0 1 of 1 3 3






C e ntr e xi o n T h er a p e utics  Pr ot oc ol CN T X - 4 9 7 5i- OA - 3 04  
H os pit al A n xi et y  & De pr essi o n  Sc al e 
  
S u bj ect N o:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
  S u bj ect I niti als:  _ _ _ _ _ _ _ _ _ _ _ _  
 D ay  
  M o nt h  
  Y e ar  
D at e  of C o m pl eti o n :  
Pl e as e si g n y o ur i niti als u p o n       
c o m pl eti n g t h e 
q u esti o n n air e o n t h e b ac k 
p a g e  
Pa ge 1 0 4 of 1 3 3
 
 


H os pital A n xiet y a n d 
De pressi o n Scale ( H A D S)  
Cli nicia ns are a wa re t hat e m oti o ns pla y a n i m p orta nt part i n m ost ill nesses. If y o ur cli nicia n k n o ws a b o ut t hese 
feeli n gs, he or s he will be a ble t o hel p y o u m ore.  
T his q uesti o n naire is desi g ne d t o hel p y o ur cli nicia n t o k n o w h o w y o u feel. Rea d eac h ite m bel o w a n d c hec k t he b o x 
w hic h c o mes cl osest t o h o w y o u ha ve bee n feeli n g i n t he past we e k.  
D o n’t ta ke t o o l o n g o ver y o ur re plies;  y o ur i m me diate reacti o n t o eac h ite m will pr o ba bl y be m ore acc urate t ha n a 
l o n g, t h o u g ht-o ut res p o nse.  
I feel as if I a m sl o w e d d o w n 
Nearl y all t he ti me  ☐ 
Ver y ofte n  ☐ 
S o meti mes  ☐ 
Ne ver  ☐ 
 I get a s ort of a n xi o us  feeli n g li ke " b utterflies " i n t he 
st o m ac h 
Ne ver  ☐ 
Occasi o nall y  ☐ 
Ofte n  ☐ 
Ver y ofte n  ☐ 
I h a ve l ost i nterest i n m y a p pe ar a nce 
Defi nitel y  ☐ 
Ofte n I d o n't ta ke as m uc h  car e as I s h o ul d  ☐ 
S o meti mes I d o n't ta ke as m uc h  care as I s h o ul d  ☐ 
I ta ke j ust as m uc h care as e ver ☐ 
I feel restless as if I h a ve t o be o n t he m o ve 
Defi nitel y  ☐ 
Q uite a l ot  ☐ 
N ot ver y m uc h  ☐ 
Ne ver  ☐ 
I l o o k f or w ar d wit h e nj o y me nt t o t hi n gs 
As m uc h as I e ver ha ve  ☐ 
S o me w hat less t ha n I use d t o ☐ 
M uc h less t ha n I use d t o  ☐ 
Rarel y  ☐ 
I get s u d de n feeli n gs of p a nic 
Ver y ofte n  ☐ 
Ofte n  ☐ 
N ot ver y ofte n  ☐ 
Ne ver  ☐ 
I c a n e nj o y a g o o d b o o k, r a di o or  
tele visi o n pr o gr a m 
Ofte n  ☐ 
S o meti mes  ☐ 
N ot ofte n  ☐ 
Ver y sel d o m  ☐ 
I feel te nse or " w o u n d u p " 
☐
M ost of t he ti me
☐
A l ot of t he ti me
☐
Fr o m ti me t o ti me, occasi o nall y
☐
Ne ver
I e nj o y t he t hi n gs I use d t o e nj o y 
☐
Defi nitel y
☐
N ot q uite s o m uc h
☐
O nl y a little
☐
Har dl y at all
I get a s ort of fri g hte ne d feeli n g as if 
s o met hi n g a wf ul is a b o ut t o h a p pe n 
☐
Ver y defi nitel y a n d fairl y b a dl y
☐
Yes, b ut n ot t o o ba dl y
☐
S o meti mes , b ut it d oes n’t w orr y me
☐
Ne ver
I c a n l a u g h a n d see t he f u n n y si de of t hi n gs 
☐
As m uc h as I al wa ys c o ul d
☐
N ot q uite s o m uc h n o w
☐
Defi nitel y n ot s o m uc h n o w
☐
Ne ver
W orr yi n g t h o u g hts g o t hr o u g h m y mi n d  
☐
A great deal of t he ti me
☐
A l ot of t he ti me
☐
N ot t o o ofte n
☐
Al m ost ne ver
I feel c heerf ul 
☐
Ne ver
☐
N ot ofte n
☐
S o meti mes
☐
M ost of t he ti me
I c a n sit at e ase a n d feel rel a xe d 
☐
Al wa ys
☐
Us uall y
☐
N ot ofte n
☐
Ne ver
H A D S  co p yri g ht  © R. P.  Snait h  an d  A. S. Zi g m o n d, 1 9 8 3,  1 9 9 2,  19 9 4.  
Rec or d  for m  ite ms ori gi nall y pu blis he d  in  Acta Ps yc hiatrica Sca n di na vica,  6 7 , 3 6 1 – 7 0 ,  
co p yri g ht  ©  Mu n ks gaar d  I nter nati o n al Pu blis hers  Lt d, Co p e n ha ge n,  19 8 3.  
T his  editi o n  first p u blis h e d  in  1 9 9 4  b y  nfer Nels o n Pu blis hi n g  Co m p a n y  Lt d,  n o w  GL  Assess m e nt  Li mited,   
1 st Fl o or  Va nta ge Lo n d o n,  Great West Roa d,  Bre ntf or d  TW 8  9A,  Unite d Ki n g d o m. 
G L  Assess me nt  is part of G L  E d ucati o n   w w w. gl -assess me nt.c o. u k 
T his  for m  ma y  not  b e  re pr o d u c e d  b y  an y  me a ns  wit h o ut first obt ai ni n g  p er missi o n  fr o m th e  pu blis h er. 
E- m ail: per missi o n s @ gl-assess me nt.c o. u k
All ri g hts  reser ve d incl u di n g  tra nslati o ns. 
Pa ge 1 0 5 of 1 3 3
 
 


C e ntr e xi o n T h er a p e utics  Pr ot oc ol CN T X - 4 9 7 5i- OA - 3 04  
Fi br o m y al gi a S y m pt o ms Sc al e 
  
S u bj ect N o:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
  S u bj ect I niti als:  _ _ _ _ _ _ _ _ _ _ _ _  
 D ay  
  M o nt h  
  Y e ar  
D at e  of C o m pl eti o n :  
Pl e as e si g n y o ur i niti als u p o n       
c o m pl eti n g t h e 
q u esti o n n air e o n t h e b ac k 
p a g e  
Pa ge 1 0 6 of 1 3 3
 
 




W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 1 of 6 
I N S T R U C TI O N S T O P A TI E N T S 
I n S e cti o n s A, B a n d C, q u e sti o n s will b e a s k e d i n t h e f oll o wi n g f or m at a n d y o u 
s h o ul d gi v e y o ur a n s w er s b y p utti n g a n “
 ” i n o n e of t h e b o x e s. 
E X A M P L E S : 
1. If y o u p ut y o ur “
 ”i n t h e b o x o n t h e f ar l eft a s s h o w n b el o w, t h e n y o u ar e
i n di c ati n g t h at y o u h a v e n o p ai n.
N o 
P ai n 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
P ai n 
2. If y o u p ut y o ur “   ”i n t h e b o x o n t h e f ar ri g ht a s s h o w n b el o w, t h e n y o u ar e
i n di c ati n g t h at y o u h a v e e xtr e m e p ai n.
N o 
P ai n 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
E xtr e m e 
P ai n 
3. Pl e a s e n ot e:
a) t h at t h e f urt h er t o t h e ri g ht y o u pl a c e y o ur “  ” t h e m or e p ai n y o u f e el.
b) t h at t h e f urt h er t o t h e l eft y o u pl a c e y o ur “   ” t h e l e s s p ai n y o u f e el.
c)
pl e a s e d o n ot pl a c e y o ur “   ”o ut si d e a n y of t h e b o x e s .
Y o u will b e a s k e d t o i n di c at e o n t hi s t y p e of s c al e t h e a m o u nt of p ai n, stiff n e s s 
or di s a bilit y y o u h a v e f elt d uri n g t h e l a st 4 8 h o ur s. 
T hi n k a b o ut y o ur _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) w h e n a n s w eri n g t h e q u e sti o n n air e. 
I n di c at e  t h e  s e v erit y  of  y o ur  p ai n  a n d  stiff n e s s  a n d  t h e  diffi c ult y  y o u  h a v e  i n 
d oi n g  d ail y  a cti viti e s  t h at  y o u  f e el ar e  c a u s e d  b y  t h e  art hriti s  i n  y o ur 
_ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) . 
Y o ur st u d y j oi nt h a s b e e n i d e ntifi e d f or y o u b y y o ur h e alt h c ar e pr of e s si o n al.   
If y o u ar e u n s ur e w hi c h j oi nt i s y o ur st u d y j oi nt, pl e a s e a s k b ef or e c o m pl eti n g 
t h e q u e sti o n n air e. 
C o p yri g ht © 1 9 9 6 Ni c h ol a s B ell a m y 
All Ri g ht s R e s er v e d 
 
 
Pa ge 1 0 8 of 1 3 3


W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 2 of 6 
S e cti o n A 
P AI N 
T hi n k a b o ut t h e p ai n y o u f elt i n y o ur _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) c a u s e d b y t h e art hriti s 
d uri n g t h e l a st 4 8 h o ur s . 
( Pl e a s e m ar k y o ur a n s w er s b y p utti n g a n “
” i n o n e of t h e b o x e s.) 
Q U E S TI O N: H o w m u c h p ai n h a v e y o u h a d  . . . 
1.  w h e n w al ki n g o n a fl at s urf a c e ?
N o
P ai n
0  
1  
2  
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
P ai n 
2.  w h e n g oi n g u p or d o w n st air s ?
N o
P ai n
0  
1  
2  
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
P ai n 
3. at ni g ht w hil e i n b e d ? (t h at i s - p ai n t h at  di st ur b s y o ur sl e e p)
N o
P ai n
0  
1  
2  
3  
4  
5  
6  
7  
8 
9  
1 0
E xtr e m e 
P ai n 
4.  w hil e sitti n g or l yi n g d o w n ?
N o
P ai n
0  
1  
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
P ai n 
5.  w hil e st a n di n g ?
N o
P ai n
0  
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
P ai n 
C o p yri g ht © 1 9 9 6 Ni c h ol a s B ell a m y 
All Ri g ht s R e s er v e d 
Pa ge 1 0 9 of 1 3 3


W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 3 of 6 
S e cti o n B  
S TI F F N E S S 
T hi n k a b o ut t h e stiff n e s s ( n ot p ai n) y o u f elt i n y o ur  _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) c a u s e d 
b y t h e art hriti s d uri n g t h e l a st 4 8 h o ur s .  
Stiff n e s s i s a s e n s ati o n of d e cr e a s e d e a s e i n m o vi n g y o ur j oi nt. 
( Pl e a s e m ar k y o ur a n s w er s b y p utti n g a n “
” i n o n e of t h e b o x e s.) 
6.  H o w s e v er e  h a s y o ur stiff n e s s b e e n aft er y o u fir st w o k e u p  i n t h e m or ni n g ?
N o 
Stiff n e s s 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Stiff n e s s 
7.  H o w s e v er e  h a s y o ur stiff n e s s b e e n aft er sitti n g or l yi n g d o w n or
w hil e r e sti n g l at er i n t h e d a y?
N o 
Stiff n e s s 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Stiff n e s s 
C o p yri g ht © 1 9 9 6 Ni c h ol a s B ell a m y 
All Ri g ht s R e s er v e d 
Pa ge 1 1 0 of 1 3 3


W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 4 of 6 
S e cti o n C 
DI F FI C U L T Y P E R F O R MI N G D AI L Y A C TI VI TI E S 
T hi n k a b o ut t h e diffi c ult y y o u h a d i n d oi n g t h e f oll o wi n g d ail y p h y si c al a cti viti e s c a u s e d 
b y t h e art hriti s i n y o ur _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) d uri n g t h e l a st 4 8 h o ur s . B y t hi s w e 
m e a n y o ur a bilit y t o m o v e ar o u n d a n d t a k e c ar e of y o ur s elf . 
( Pl e a s e m ar k y o ur a n s w er s b y p utti n g a n “
” i n o n e of t h e b o x e s.) 
Q U E S TI O N: H o w m u c h diffi c ult y h a v e y o u h a d  . . . 
8.  w h e n g oi n g d o w n t h e st air s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
9.  w h e n g oi n g u p t h e st air s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 0.  
w h e n g etti n g u p fr o m a sitti n g p o siti o n ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 1.  
w hil e st a n di n g ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 2.  
w h e n b e n di n g t o t h e fl o or ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 3.  
w h e n w al ki n g o n a fl at s urf a c e ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
C o p yri g ht © 1 9 9 6 Ni c h ol a s B ell a m y 
All Ri g ht s R e s er v e d 
Pa ge 1 1 1 of 1 3 3


W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 5 of 6 
DI F FI C U L T Y P E R F O R MI N G D AI L Y A C TI VI TI E S 
T hi n k a b o ut t h e diffi c ult y y o u h a d i n d oi n g t h e f oll o wi n g d ail y p h y si c al a cti viti e s c a u s e d 
b y t h e art hriti s i n y o ur _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) d uri n g t h e l a st 4 8 h o ur s . B y t hi s w e 
m e a n y o ur a bilit y t o m o v e ar o u n d a n d t a k e c ar e of y o ur s elf . 
( Pl e a s e m ar k y o ur a n s w er s b y p utti n g a n “
” i n o n e of t h e b o x e s.) 
Q U E S TI O N: H o w m u c h diffi c ult y h a v e y o u h a d  . . . 
1 4. g etti n g i n or o ut of a c ar, or g etti n g o n or off a b u s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 5.  w hil e g oi n g s h o p pi n g ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 6.  
w h e n p utti n g o n y o ur s o c k s or p a nt y h o s e or st o c ki n g s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 7.  
w h e n g etti n g o ut of b e d ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 8.  
w h e n t a ki n g off y o ur s o c k s or p a nt y h o s e or st o c ki n g s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
1 9.  
w hil e l yi n g i n b e d ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
C o p yri g ht © 1 9 9 6 Ni c h ol a s B ell a m y 
All Ri g ht s R e s er v e d 
Pa ge 1 1 2 of 1 3 3


W O M A C O st e o art hriti s I n d e x N R S 3. 1
W O M A C N R S 3. 1 – E n gli s h f or U S A – V 5  
P a g e 6 of 6 
DI F FI C U L T Y P E R F O R MI N G D AI L Y A C TI VI TI E S 
T hi n k a b o ut t h e diffi c ult y y o u h a d i n d oi n g t h e f oll o wi n g d ail y p h y si c al a cti viti e s c a u s e d 
b y t h e art hriti s i n y o ur _ _ _ _ _ _ _ _ _ _ _ _ ( st u d y j oi nt) d uri n g t h e l a st 4 8 h o ur s . B y t hi s w e 
m e a n y o ur a bilit y t o m o v e ar o u n d a n d t a k e c ar e of y o ur s elf . 
( Pl e a s e m ar k y o ur a n s w er s b y p utti n g a n “
” i n o n e of t h e b o x e s.) 
Q U E S TI O N: H o w m u c h diffi c ult y h a v e y o u h a d  . . . 
2 0.  w h e n g etti n g i n or o ut of t h e b at ht u b ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
2 1.  w hil e sitti n g ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
2 2.  
w h e n g etti n g o n or off t h e t oil et ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
2 3.  
w hil e d oi n g  h e a v y h o u s e h ol d c h or e s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
2 4.  
w hil e d oi n g li g ht h o u s e h ol d c h or e s ?
N o 
Diffi c ult y 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9  
1 0
E xtr e m e 
Diffi c ult y  
C o p yri g ht © 1 9 9 6 Ni c h o l a s B ell a m y 
All Ri g ht s R e s er v e d 
Pa ge 1 1 3 of 1 3 3


K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S), E n glis h versi o n L K 1. 0 
1 
K O O S K N E E S U R V E Y 
T o d a y’ s d at e: _ _ _ _ _/ _ _ _ _ _ _/ _ _ _ _ _ _ D at e of birt h: _ _ _ _ _/ _ _ _ _ _ _/ _ _ _ _ _ _  
N a m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I N S T R U C TI O N S: T hi s  s ur v e y  a s k s  f or  y o ur  vi e w  a b o ut  y o ur  k n e e.  T hi s 
i nf or m ati o n  will  h el p  u s  k e e p  tr a c k  of h o w  y o u  f e el  a b o ut  y o ur  k n e e  a n d  h o w 
w ell y o u ar e a bl e t o p erf or m y o ur u s u al a cti viti e s. 
A n s w er  e v er y  q u e sti o n  b y  ti c ki n g  t h e  a p pr o pri at e  b o x,  o nl y o n e   b o x  f or  e a c h 
q u e sti o n.  If  y o u  ar e  u n s ur e  a b o ut  h o w  t o a n s w er  a  q u e sti o n,  pl e a s e  gi v e  t h e 
b e st a n s w er y o u c a n. 
S y m pt o m s 
T h e s e  q u e sti o n s  s h o ul d  b e  a n s w er e d  t hi n ki n g  of  y o ur  k n e e  s y m pt o m s  d uri n g 
t h e l a st w e e k. 
S 1. D o y o u ha ve s welli n g i n y o ur k nee? 
Ne ver 
 
Rarel y 
 
S o meti mes 
 
Ofte n 
 
Al wa ys 
 
S 2. D o y o u feel gri n di n g, hear clic ki n g or  a n y ot her t y pe of n oise w he n y o ur k nee 
       m o ves? 
Ne ver 
 
Rarel y 
 
S o meti mes 
 
Ofte n 
 
Al wa ys 
 
S 3. D oes y o ur k nee catc h or ha n g u p w he n m o vi n g?  
Ne ver 
 
Rarel y 
 
S o meti mes 
 
Ofte n 
 
Al wa ys 
 
S 4. Ca n y o u strai g hte n y o ur k nee f ull y? 
Al wa ys 
 
Ofte n 
 
S o meti mes 
 
Rarel y 
 
Ne ver 
 
S 5. Ca n y o u be n d y o ur k nee f ull y?  
Al wa ys 
 
Ofte n 
 
S o meti mes 
 
Rarel y 
 
Ne ver 
 
Stiff n e s s  
T h e f oll o wi n g q u e sti o n s c o n c er n t h e a m o u nt of j oi nt stiff n e s s y o u h a v e 
e x p eri e n c e d d uri n g t h e  l a st w e e k i n y o ur k n e e. Stiff n e s s i s a s e n s ati o n of 
r e stri cti o n or sl o w n e s s i n t h e e a s e wit h w hi c h y o u m o v e y o ur k n e e j oi nt. 
S 6. H o w se vere is y o ur k nee j oi nt stiff ness after first wa ke ni n g i n t he m or ni n g? 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
S 7. H o w se vere is y o ur k nee stiff ness after sitti n g, l yi n g or resti n g  l ater i n t he d a y? 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
Pa ge 1 1 4 of 1 3 3


K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S), E n glis h versi o n L K 1. 0 
2 
P ai n 
P 1. H o w ofte n d o y o u e x perie nce k nee pai n? 
Ne ver 
 
M o nt hl y 
 
Wee kl y 
 
Dail y 
 
Al wa ys 
 
W h at  a m o u nt  of  k n e e  p ai n 
h a v e  y o u  e x p eri e n c e d  t h e l a st  w e e k  d uri n g  t h e 
f oll o wi n g a cti viti e s ? 
P 2. T wisti n g/ pi v oti n g o n y o ur k nee 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 3. Strai g hte ni n g k nee f ull y 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 4. Be n di n g k nee f ull y 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 5. Wal ki n g o n flat s urface 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 6. G oi n g u p or d o w n stairs 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 7. At ni g ht w hile i n be d 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 8. Sitti n g or l yi n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
P 9. Sta n di n g u pri g ht 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
F u n cti o n, d ail y li vi n g 
T h e f oll o wi n g q u e sti o n s c o n c er n y o ur p h y si c al f u n cti o n. B y t hi s w e m e a n y o ur 
a bilit y  t o  m o v e  ar o u n d  a n d  t o  l o o k  aft er  y o ur s elf.  F or  e a c h  of  t h e  f oll o wi n g 
a cti viti e s  pl e a s e  i n di c at e  t h e  d e gr e e  of diffi c ult y  y o u  h a v e  e x p eri e n c e d  i n  t h e 
l a st w e e k d u e t o y o ur k n e e. 
A 1. Desce n di n g stairs 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 2. Asce n di n g stairs 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
Pa ge 1 1 5 of 1 3 3


K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S), E n glis h versi o n L K 1. 0 
3 
F or  e a c h  of  t h e  f oll o wi n g  a cti viti e s  pl e a s e  i n di c at e  t h e  d e gr e e  of  diffi c ult y  y o u 
h a v e e x p eri e n c e d i n t h e l a st w e e k d u e t o y o ur k n e e. 
A 3. Risi n g fr o m sitti n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 4. Sta n di n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 5. Be n di n g t o fl o or/ pic k u p a n o bject 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 6. Wal ki n g o n flat s urface 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 7. Getti n g i n/ o ut of car 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 8. G oi n g s h o p pi n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 9. P utti n g o n s oc ks/st oc ki n gs 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 0. Risi n g fr o m be d 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 1. Ta ki n g off s oc ks/st oc ki n gs 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 2. L yi n g i n be d (t ur ni n g o ver, mai ntai ni n g k nee p ositi o n) 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 3. Getti n g i n/ o ut of bat h 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 4. Sitti n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 5. Getti n g o n/ off t oilet 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
Pa ge 1 1 6 of 1 3 3


K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S), E n glis h versi o n L K 1. 0 
4 
F or  e a c h  of  t h e  f oll o wi n g  a cti viti e s  pl e a s e  i n di c at e  t h e  d e gr e e  of  diffi c ult y  y o u 
h a v e e x p eri e n c e d i n t h e l a st w e e k d u e t o y o ur k n e e. 
A 1 6. Hea v y d o mestic d uties ( m o vi n g hea v y b o xes, scr u b bi n g fl o ors, etc) 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
A 1 7. Li g ht d o mestic d uties (c o o ki n g, d usti n g, etc) 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
F u n cti o n, s p ort s a n d r e cr e ati o n al a cti viti e s 
T h e f oll o wi n g q u e sti o n s c o n c er n y o ur p h y si c al f u n cti o n w h e n b ei n g a cti v e o n a 
hi g h er  l e v el.  T h e  q u e sti o n s  s h o ul d  b e a n s w er e d  t hi n ki n g  of  w h at  d e gr e e  of 
diffi c ult y y o u h a v e e x p eri e n c e d d uri n g t h e l a st w e e k d u e t o y o ur k n e e. 
S P 1. S q uatti n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
S P 2. R u n ni n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
S P 3. J u m pi n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
S P 4. T wisti n g/ pi v oti n g o n y o ur i nj ure d k nee 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
S P 5. K neeli n g 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
Q u alit y of Lif e 
Q 1. H o w ofte n are y o u a ware of y o ur k nee pr o ble m? 
Ne ver 
 
M o nt hl y 
 
Wee kl y 
 
Dail y 
 
C o nsta ntl y 
 
Q 2. Ha ve y o u m o difie d y o ur life st yle t o a v oi d p ote ntiall y da ma gi n g acti vities 
       t o y o ur k nee? 
N ot at all 
 
Mil dl y 
 
M o deratel y  
 
Se verel y 
 
T otall y 
 
Q 3. H o w m uc h are y o u tr o u ble d wit h lac k of c o nfi de nce i n y o ur k nee? 
N ot at all 
 
Mil dl y 
 
M o deratel y  
 
Se verel y 
 
E xtre mel y 
 
Q 4. I n ge neral, h o w m uc h diffic ult y d o y o u ha ve wit h y o ur k nee? 
N o ne 
 
Mil d 
 
M o derate 
 
Se vere 
 
E xtre me 
 
T h a n k y o u v er y m u c h f or c o m pl eti n g all t h e q u e sti o n s i n t hi s q u e sti o n n air e. 
Pa ge 1 1 7 of 1 3 3


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
Y o ur He alt h a n d Well- Bei n g 
T his s ur ve y as ks f or y o ur vie ws a b o ut y o u r he alt h.  T his i nf or m ati o n will hel p 
kee p tr ac k of h o w y o u feel a n d h o w well y o u  are a ble t o d o y o ur us u al acti vities. 
T h a n k y o u f or c o m pleti n g t his s urvey!  
F or e ac h of t he f oll o wi n g q uesti o ns, ple ase m ar k a n 
 i n t he o ne b o x t h at best 
descri bes y o ur a ns wer. 
1. I n ge ner al, w o ul d y o u s a y y o ur he alt h is:
E xcelle nt  
Ver y g o o d  
G o o d 
Fair 
P o or
1
2
3
4
5
2.  
C o m p are d t o o ne ye ar a g o , h o w w o ul d y o u r ate y o ur he alt h i n ge ner al
n o w ? 
M uc h better 
n o w t ha n o ne 
year a g o 
S o me w hat 
better  
n o w t ha n o ne 
year a g o 
A b o ut t he 
sa me as  
o ne year a g o 
S o me w hat 
w orse  
n o w t ha n o ne 
year a g o 
M uc h w orse 
n o w t ha n o ne 
year a g o 
1
2
3
4
5
Pa ge 1 1 8 of 1 3 3
S F- 3 6 Healt h S ur ve y


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
3. T he f oll o wi n g q uesti o ns are a b o ut acti vities y o u mi g ht d o d uri n g a t y pic al
d a y.  D oes y o ur he alt h n o w li mit y o u  i n t hese acti vities ?  If s o, h o w m uc h ?
Yes,  
li mite d  
a l ot 
Yes, 
li mite d  
a little 
N o, n ot 
li mite d  
at all 
a
Vi g or o us acti vities , s uc h as r u n ni n g, lifti n g  
hea v y o bjects, partici pati n g i n stre n u o us s p orts ...................... 
 1 ............. 
 2 ............. 
3
b
M o derate acti vities , s uc h as m o vi n g a ta ble, p us hi n g  
a vac u u m clea ner, b o wli n g, or pla yi n g g olf ............................ 
1 ............. 
 2 ............. 
3
c
Lifti n g or carr yi n g gr oceries .................................................... 
 1 ............. 
 2 ............. 
3
d
Cli m bi n g se veral  fli g hts of stairs ............................................. 
 1 ............. 
 2 ............. 
3
e
Cli m bi n g o ne  fli g ht of stairs .................................................... 
 1 ............. 
 2 ............. 
3
f
Be n di n g, k neeli n g, or st o o pi n g ................................................ 
 1 ............. 
 2 ............. 
3
g
Wal ki n g m ore t ha n a mile  ........................................................ 
 1 ............. 
 2 ............. 
3
h
Wal ki n g se veral h u n dre d yar ds  ............................................... 
 1 ............. 
 2 ............. 
3
i
Wal ki n g o ne h u n dre d yar ds  ..................................................... 
 1 ............. 
 2 ............. 
3
j
Bat hi n g or dressi n g y o urself .................................................... 
 1 ............. 
 2 ............. 
3
Pa ge 1 1 9 of 1 3 3


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
4.  
D uri n g t he p ast 4 wee ks , h o w m uc h of t he ti me h a ve y o u h a d a n y of t he
f oll o wi n g pr o ble ms wit h y o ur w or k or ot her re g ul ar d ail y acti vities as a
res ult of y o ur p h ysic al he alt h ?
All of  
t he ti me 
M ost of 
t he ti me 
S o me of  
t he ti me 
A little of 
t he ti me 
N o ne of 
t he ti me 
 
 
 
 
a 
C ut d o w n o n t he a m o u nt of   
ti me y o u s pe nt o n w or k or  
ot her acti vities ................................. 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
b 
Acc o m plis he d less  t ha n y o u  
w o ul d li ke ........................................ 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
  
c Were li mite d i n t he ki n d  of  
w or k or ot her acti vities .................... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
  
d Ha d diffic ult y  perf or mi n g t he  
w or k or ot her acti vities (f or  
e xa m ple, it t o o k e xtra eff ort) ........... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
5.  
D uri n g t he p ast 4 wee ks , h o w m uc h of t he ti me h a ve y o u h a d a n y of t he
f oll o wi n g pr o ble ms wit h y o ur w or k or ot her re g ul ar d ail y acti vities as a
res ult of a n y e m oti o n al  pr o ble ms  (s uc h as feeli n g de presse d or a n xi o us) ?
All of  
t he ti me 
M ost of 
t he ti me 
S o me of  
t he ti me 
A little of 
t he ti me 
N o ne of 
t he ti me 
 
 
 
 
a 
C ut d o w n o n t he a m o u nt of   
ti me y o u s pe nt o n w or k or  
ot her acti vities ................................. 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
b 
Acc o m plis he d less  t ha n y o u  
w o ul d li ke ........................................ 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
c 
Di d w or k or ot her acti vities  
less caref ull y t ha n us ual ................... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
5
Pa ge 1 2 0 of 1 3 3


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
6.  
D uri n g t he p ast 4 wee ks , t o w h at e xte nt h as y o ur p h ysic al he alt h or
e m oti o n al pr o ble ms i nterfere d wit h y o ur n or m al s oci al acti vities wit h
f a mil y, frie n ds, nei g h b ors, or gr o u ps ?
N ot at all  
Sli g htl y  
M o deratel y  
Q uite a bit  
E xtre mel y 
 
1
2
3
4
5
7.  
H o w m uc h b o dil y  p ai n h a ve y o u h a d d uri n g t he p ast 4 wee ks?
N o ne  
Ver y mil d  
Mil d  
M o derate  
Se vere  
Ver y se vere 
 
 
1
2
3
4
5
6
8.  
D uri n g t he p ast 4 wee ks , h o w m uc h di d p ai n i nterfere wit h y o ur n or m al
w or k (i ncl u di n g b ot h w or k o utsi de t he h o me a n d h o use w or k) ?
N ot at all  
A little bit  
M o deratel y  
Q uite a bit  
E xtre mel y 
 
 
1
2
3
4
5
Pa ge 1 2 1 of 1 3 3


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
9. T hese q uesti o ns are a b o ut h o w y o u feel a n d h o w t hi n gs h a ve bee n wit h y o u
d uri n g t he p ast 4 wee ks .  F or e ac h q uesti o n, ple ase gi ve t he o ne a ns wer t h at
c o mes cl osest t o t he w a y y o u h a ve bee n feeli n g.  H o w m uc h of t he ti me
d uri n g t he p ast 4 wee ks …
1 0.  
D uri n g t he p ast 4 wee ks , h o w m uc h of t he ti me h as y o ur p h ysic al he alt h or
e m oti o n al pr o ble ms  i nterfere d wit h y o ur s oci al acti vities (li ke visiti n g wit h
frie n ds, rel ati ves, etc.) ?
All of  
t he ti me 
M ost of  
t he ti me 
S o me of  
t he ti me 
A little of  
t he ti me 
N o ne of  
t he ti me 
1
2
3
4
5
All of  
t he ti me 
M ost of  
t he ti me 
S o me of 
t he ti me 
A little of t he 
ti me 
N o ne of 
t he ti me 
 
 
 
 
a  Di d y o u feel f ull of life? ..................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
5
b  Ha ve y o u bee n ver y ner v o us? ..........
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
5
c  Ha ve y o u felt s o d o w n i n t he  
d u m ps t hat n ot hi n g c o ul d  
c heer y o u u p? ...................................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
5
d Ha ve y o u felt cal m a n d   
peacef ul? ..........................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
5
e  Di d y o u ha ve a l ot of e ner g y? ..........
 1 ..............
 2 ..............
 3 ..............
 4 ..............
5
f Ha ve y o u felt d o w n hearte d  
a n d de presse d? .................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
5
g Di d y o u feel w or n o ut? ....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
5
h Ha ve y o u bee n ha p p y? .....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
5
i  Di d y o u feel tire d? ...........................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
5
Pa ge 1 2 2 of 1 3 3


S F- 3 6 v 2 ®  Healt h S ur ve y ©  1 9 9 2, 1 9 9 6, 2 0 0 0 Me dical O utc o mes Tr ust a n d Q ualit yMetric I nc or p orate d.  All ri g hts reser ve d. 
S F- 3 6 ®  is a re gistere d tra de mar k of Me dical O utc o mes Tr ust. 
( S F- 3 6 v 2®  Healt h S ur ve y Sta n dar d, U nite d States ( E n glis h)) 
1 1.  
H o w T R U E or F A L S E is e ac h  of t he f oll o wi n g st ate me nts f or y o u ?
Defi nitel y 
tr ue 
M ostl y  
tr ue 
D o n’t  
k n o w 
M ostl y  
false 
Defi nitel y 
false 
 
 
 
 
a I see m t o get sic k a little 
easier t ha n ot her pe o ple .................. 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
5
b
I a m as healt h y as  
a n y b o d y I k n o w .............................. 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
5
c
I e x pect m y healt h t o  
get w orse ......................................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
5
d
M y healt h is e xcelle nt ..................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
5
T h a n k y o u f or c o m pleti n g t hese q uesti o ns!
Pa ge 1 2 3 of 1 3 3






           E Q -5 D -5L H E AL T H Q U E S TI O N N AI R E  
1  
 U n d er e ac h h e a di n g, pl e as e c h e c k t h e O N E b ox t h at b est d escri b es y o ur h e alt h T O D A Y . 
M O BILI T Y  
 
I h a v e n o pr o bl e ms w al ki ng   
 
I h a v e sli g ht pr o bl e ms w al ki n g        
 
I h a v e m o d er at e pr o bl e ms w al ki n g         
 
I h a v e s e v er e pr o bl e ms w al ki n g        
 
I a m u n a bl e t o w al k         
S EL F -C A R E  
 
I h a v e n o pr o bl e ms w as hi n g  or dr essi n g m ys elf  
 
I h a v e sli g ht pr o bl e ms w as hi n g or dr essi n g m ys elf  
 
I h a v e m o d er at e pr o bl e ms w as hi n g or dr essi n g m ys elf  
 
I h a v e s e v er e pr o bl e ms w as hi n g or dr essi n g m ys elf  
 
I a m u n a bl e t o w as h  or dr ess m ys elf  
U S U AL A C TI VI TI E S ( e. g. w or k, st u d y, h o us e w or k, f a mil y or l eis ur e 
acti viti es)  
 
I h a v e n o pr o bl e ms d oi n g m y us u al acti viti es 
 
I h a v e sli g ht pr o bl e ms d oi n g m y us u al acti viti es 
 
I h a v e m o d er at e pr o bl e ms d oi n g m y us u al acti viti es 
 
I h a v e s e v er e pr o bl e ms d oi n g m y us u al acti viti es 
 
I a m u n a bl e t o d o m y us u al acti viti es  
P AI N / DI S C O M F O R T  
 
I h a v e n o p ai n or disc o mf ort 
 
I h a v e sli g ht p ai n or disc o mf ort 
 
I h a v e m o d er at e p ai n or disc o mf ort          
 
I h a v e s e v er e p ai n or disc o mf ort 
 
I h a v e extr e m e p ai n or disc o mf ort  
Pa ge 1 2 6 of 1 3 3


                               E Q -5 D -5L H E AL T H Q U E S TI O N N AI R E  
 
 
 
 
 
 
 
 
 
 
2  
 
 
A N XI E T Y / D E P R E S SI O N  
 
 
I a m n ot a nxi o us or d e pr ess e d 
 
 
I a m sli g htl y a nxi o us or d e pr ess e d 
 
 
I a m m o d er at el y a nxi o us or d e pr ess e d 
 
 
I a m s e v er el y a nxi o us or d e pr ess e d 
 
 
I a m extr e m el y a nxi o us or d e pr ess e d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                            
 
 
 
 
 
Pa ge 1 2 7 of 1 3 3


           E Q -5 D -5L H E AL T H Q U E S TI O N N AI R E  
3  
T h e w or st h e alt h 
y o u c a n i m a gi n e  
•
W e w o ul d lik e t o k n o w h o w g o o d or b a d y o ur h e alt h is T O D A Y.
•
T his sc al e is n u m b er e d fr o m 0 t o 1 0 0.
•
1 0 0 m e a ns t h e b est  h e alt h y o u c a n i m a gi n e.
0 m e a ns t h e w orst  h e alt h y o u c a n i m a gi n e.
•
M ar k a n X o n t h e sc al e t o i n dic at e h o w y o ur h e alt h is T O D A Y.
•
N o w, pl e as e writ e t h e n u m b er y o u m ar k e d o n t h e sc al e i n t h e b ox b el o w.
Y O U R H E A L T H T O D A Y  =  
1 0  
0  
2 0  
3 0  
4 0  
5 0  
6 0  
8 0  
7 0  
9 0  
1 0 0  
5  
1 5  
2 5  
3 5  
4 5  
5 5  
7 5  
6 5  
8 5  
9 5  
Pa ge 1 2 8 of 1 3 3
 




J OI N T R E PL A C E M E N T Q U E S TI O N N AI R E 
J OI N T R E PL A C E M E N T Q U E S TI O N N AI R E , V ersi o n 2. 0, 3 1-A u g -2 0 1 7  
Q U E S TI O N S T O B E A D MI NI S T E R E D A T ALL VI SI T S S U B S E Q U E N T T O B A S ELI N E VI SI T ( T R E A T M E N T VI SI T 1/ D A Y 1)  
Pa ge 1 3 0 of 1 3 3
 
 
  
 
 
 
 
 
 
 
 
 
 
  


P A TI E N T GL O B AL I M P R E S SI O N O F C H A N G E I N K N E E P AI N  
C o m p ar e d t o b ef or e st u d y tr e at m e nt, t h e p ai n fr o m m y k n e e ost e o art hritis  is: 
(c h ec k o nl y o n e r es p o ns e) 
□
v er y m uc h i m pr o v e d
□
m uc h i m pr o v e d
□
mi ni m all y i m pr o v e d
□
n o c h a n g e
□
mi ni m all y w ors e
□
m uc h w ors e
□
v er y m uc h w ors e
Pa ge 1 3 1 of 1 3 3


C e ntr e xi o n _ C N T X 4 9 7 5i -O A -3 0 4 _ W P AI: O A - Kn e e  V 2. 0 ( U S E n gli s h)  
1  
W or k Pr o d u cti vit y a n d A cti vit y I m p air m e nt Q u e sti o n n air e:  
O st e o art hriti s of t h e K n e e V 2. 0 ( W P AI: O A)  
T h e f oll o wi n g q u e sti o n s a s k a b o ut t h e eff e ct of y o ur o st e o art hriti s of t h e k n e e o n y o ur 
a bilit y t o w or k a n d p erf or m r e g ul ar a cti viti e s. Pl e a s e fill i n t h e  bl a n k s or cir cl e a n u m b er, 
a s i n di c at e d.  
1.
Ar e y o u c urr e ntl y e m pl o y e d ( d oi n g p ai d w or k ) ? _ _ _ _ _ N O _ _ _ Y E S
If N O, ti c k “ N O” a n d g o t o q u e sti o n 6.
T h e n e xt q u e sti o n s ar e a b o ut t h e p a st  s e v e n d a y s , n ot i n cl u di n g t o d a y. 
2.
D uri n g t h e p a st s e v e n d a y s, h o w m a n y h o ur s di d y o u mi s s fr o m w or k b e c a u s e of
pr o bl e m s a s s o ci at e d wit h y o ur o st e o art hriti s of t h e k n e e ? I n cl u d e h o ur s y o u
mi s s e d o n si c k d a y s, ti m e s y o u w e nt i n l at e, l eft e arl y, et c., b e c a u s e of y o ur
o st e o art hriti s of t h e k n e e. D o n ot i n cl u d e ti m e y o u mi s s e d t o p arti ci p at e i n t hi s
st u d y.
_ _ _ _ _ H O U R S
3.
D uri n g t h e p a st s e v e n d a y s, h o w m a n y h o ur s di d y o u mi s s fr o m w or k b e c a u s e of
a n y ot h er r e a s o n, s u c h a s h oli d a y s, ti m e off t o p arti ci p at e i n t hi s st u d y ?
_ _ _ _ _ H O U R S  
4.
D uri n g t h e p a st s e v e n d a y s, h o w m a n y h o ur s di d y o u a ct u all y w or k ?
_ _ _ _ _ H O U R S  (If “ 0”, g o t o q u e sti o n 6.)
Pa ge 1 3 2 of 1 3 3


C e ntr e xi o n _ C N T X 4 9 7 5i -O A -3 0 4 _ W P AI: O A - Kn e e  V 2. 0 ( U S E n gli s h)  
2  
5.
D uri n g t h e p a st s e v e n d a y s, h o w m u c h di d y o ur o st e o art hriti s of t h e k n e e aff e ct
y o ur pr o d u cti vit y w hil e y o u w er e w or ki n g ?
T hi n k a b o ut d a y s y o u w er e li mit e d i n t h e a m o u nt or ki n d of w or k y o u c o ul d d o,
d a y s y o u a c c o m pli s h e d l e s s t h a n y o u w o ul d li k e, or d a y s y o u c o ul d n ot d o y o ur
w or k a s c ar ef ull y a s u s u al. If o st e o art hriti s of t h e k n e e aff e ct e d y o ur w or k o nl y a
littl e, c h o o s e a l o w n u m b er. C h o o s e a hi g h n u m b er if o st e o art hriti s of t h e k n e e
aff e ct e d y o ur w or k a gr e at d e al.
C o n si d er o nl y h o w m u c h o st e o art hriti s of t h e k n e e  aff e ct e d 
pr o d u cti vit y w hil e y o u w er e w or ki n g . 
O st e o art hriti s 
of t h e k n e e h a d 
n o eff e ct o n m y 
w or k  
O st e o art hriti s of 
t h e k n e e 
c o m pl et el y 
pr e v e nt e d m e 
fr o m w or ki n g 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
CI R C L E A N U M B E R  
6.
D uri n g t h e p a st s e v e n d a y s, h o w m u c h di d y o ur o st e o art hriti s of t h e k n e e aff e ct
y o ur a bilit y t o d o y o ur r e g ul ar d ail y a cti viti e s, ot h er t h a n w or k at a j o b ?
B y r e g ul ar a cti viti e s, w e m e a n t h e u s u al a cti viti e s y o u d o, s u c h a s w or k ar o u n d t h e
h o u s e, s h o p pi n g, c hil d c ar e, e x er ci si n g, st u d yi n g, et c. T hi n k a b o ut ti m e s y o u w er e
li mit e d i n t h e a m o u nt or ki n d of a cti viti e s y o u c o ul d d o a n d ti m e s y o u a c c o m pli s h e d
l e s s t h a n y o u w o ul d li k e. If o st e o art hriti s of t h e k n e e aff e ct e d y o ur a cti viti e s o nl y a
littl e, c h o o s e a l o w n u m b er. C h o o s e a hi g h n u m b er if o st e o art hriti s of t h e k n e e
aff e ct e d y o ur a cti viti e s a gr e at d e al.
C o n si d er o nl y h o w m u c h o st e o art hriti s of t h e k n e e  aff e ct e d y o ur a bilit y 
t o d o y o ur r e g ul ar d ail y a cti viti e s, ot h er t h a n w or k at a j o b. 
O st e o art hriti s 
of t h e k n e e h a d 
n o eff e ct o n m y 
d ail y a cti viti e s  
O st e o art hriti s of 
t h e k n e e 
c o m pl et el y 
pr e v e nt e d m e 
fr o m d oi n g m y 
d ail y a cti viti e s  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
CI R C L E A N U M B E R  
Pa ge 1 3 3 of 1 3 3