Clinical trial NCT02740231
Conditions: Knee Osteoarthritis
Keywords: viscosupplement osteoarthritis knee intra-articular injection arthritis degenerative
Sponsor: Bone Therapeutics S.A
Start date: 2016-02-01; Completion date: 2018-04-27
Enrollment: 173 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Osteoarthritis (OA) is the most common joint disease affecting millions of people around the world, for which there is unfortunately no cure. Among existing therapies, viscosupplementation, i.e., the injection of hyaluronic acid into the joint, has an established place in the symptomatic treatment of knee OA.

The present Phase IIb/III aiming to assess the safety and efficacy of JTA-004 is organized in two phases. With results obtained in the first phase the best dose of JTA-004 is determined, and the efficacy of the selected dose will then be confirmed in the second phase.

Detailed description:

Arms: arm 1: Hylan G-F 20 arm 2: Sodium hyaluronate, plasma proteins and clonidine arm 3: Sodium hyaluronate, plasma proteins and clonidine arm 4: Sodium hyaluronate, plasma proteins and clonidine
Interventions: intervention 1: JTA-004 intra-articular injection intervention 2: Reference product intra-articular injection
Intervention descriptions: intervention 1: Each patient will undergo a single injection of JTA-004 into the knee joint intervention 2: Each patient will undergo a single injection of Reference product into the knee joint

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
JTA-KOA1 - Clinical Study Protocol 
JTA-KOA1-CSP 
V 04 
Author: EB 
Date: May 10, 2017 
Pg. 1/1 
 
 
CLINICAL STUDY PROTOCOL 
Study JTA-KOA1 
EudraCT number: 2015-002117-30 
 
Protocol Number: 000010/BT 
 
NTC Number: 0274023102740231 
 
Title 
A Two-stage 6-month, Multicentre, Randomised, Double-blind, Controlled Study on the 
Safety and Efficacy of a Single Intra-articular Administration of JTA-004 in Patients with 
Symptomatic Knee Osteoarthritis 
 
Sponsor 
Bone Therapeutics S.A. 
Rue Auguste Piccard, 37 
B-6041 Gosselies, Belgium 
 
 
 
Good Clinical Practice (GCP) Statement 
This study will be performed in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and all applicable Community and national 
legislation and regulatory requirements. 
 
 
 
All rights reserved. Unauthorised copying or use of this information is prohibited 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V  0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 /1 1 4  
 
 
C LI NI C A L S T U D Y P R O T O C O L 
St u d y J T A- K O A 1 
E u dr a C T n u m ber: 2 0 1 5- 0 0 2 1 1 7- 3 0 
 
Pr ot oc ol N u m ber: 0 0 0 0 1 0/ B T 
 
 
Title 
A T w o-sta ge 6- m o nt h, M ultice ntre, Ra n d o mise d, D o u ble- bli n d, C o ntr olle d St u d y o n t h e 
Safet y a n d Efficac y of a Si n gle I ntra-artic ul ar A d mi nistrati o n of J T A- 0 0 4 i n Patie nts wit h 
S y m pt o matic K nee Oste oart hritis 
 
S p o ns or 
B o ne T hera p e utics S. A. 
R ue A u g uste Piccar d, 3 7 
B- 6 0 4 1 G osselies, Bel gi u m 
 
 
 
G o o d Cli nic al Pr actice  ( GC P)  St ate m e nt  
T his st u dy will be perf or me d i n c o m pli a nce wit h G o o d Cli nic al Pr actice ( G C P), t h e 
De cl ar ati o n of Helsi nki ( wit h a me n d me nts), a n d all a p plic a ble C o m m u nity a n d n ati o n al 
le gisl ati o n a n d re g ul at ory re q uire me nts. 
 
 
 
All ri g hts reser v e d. U n a ut h orise d c o p yi n g or use of t his i nf or m ati o n is pr o hi bite d. 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 2 /1 1 4  
 
 
S P O N S O R SI G N A T O R Y A P P R O V A L  
 
E u dr a C T n u m ber : 2 0 1 5- 0 0 2 1 1 7- 3 0 
P r ot oc ol N u m ber : 0 0 0 0 1 0/ B T  
 
Title of t he pr ot oc ol :  
A t w o-sta ge 6- m o nt h, M ultice ntre, Ra n d o mise d, D o u ble- bli n d, C o ntr olle d St u d y o n t he Safet y 
a n d Efficac y of  Si n gle I ntra-artic ul ar A d mi nistrati o n of J T A- 0 0 4 i n Patie nts wit h S y m pt o matic 
K nee Oste o art hritis 
 
 
 
 
 
S p o ns or ’s re pres e ntati ve 
 
 
 
 
T h o mas LI E N A R D  S P R L re pres e nte d  
b y its per ma ne nt re prese ntati ve T h o mas LI E N A R D  
C hief E x ec uti ve Officer  
 
 
Na me a n d Title   
 
Date  
Si g nat ure  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 /1 1 4  
 
 
I N V E S TI G A T O R SI G N A T U R E A N D A G R E E M E N T WI T H T H E P R O T O C O L 
I, t he u n d ersi g ne d, 
A gree t o c o n d uct t his st u d y i n c o m plia nce wit h t his pr ot oc ol a n d t o ass u m e res p o nsi bilit y f or 
t he pr o per c o n d uct of t he st u d y at t his site. 
A gree t h at t he cli nical trial will be carrie d o ut i n acc or da n ce wit h a n y a n d all a p plica ble nati o nal 
a n d C o m m u nit y la ws, re g ulati o ns, g ui da nce, g ui deli nes, a n d pri nci ples re gar di n g: 
- Et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n patie nts 
- G o o d Cli nical Practice ( G C P) re gar di n g t he c o n d uct of cli nical trials a n d i n vesti gati o nal 
me dic i nal pr o d ucts f or h u ma n use 
- Cli nical safet y d ata ma n a ge m e nt, n otificati o n, a n d re p orti n g  
A gree:  
- T hat m y pri mar y res p o nsi bilit y is t o safe g u ar d t he ri g hts a n d well- bei n g of eac h patie nt 
partici pati n g i n t his st u d y, a n d t hat t he p atie nt’s ri g hts a n d well- bei n g m ust t a ke prece d e nce 
o ver t he g oals a n d re q uir e me nts of t he st u d y 
- T o e ns ure t he c o nfi de ntialit y a n d pr otecti o n of all i nf or mati o n o btai ne d fr o m a n d a b o ut t he 
patie nts 
- T o o btai n t he i nf or me d c o nse nt of eac h patie nt pri or t o perf or m a n y st u d y-relate d acti vi t y 
a n d e ns ure t h at:  
* Ver bal i nf or mati o n, a da pte d t o t he patie nt, has bee n pr o vi de d, a v oi di n g direct or i n direct 
pre ss ure, a n d t hat t he patie nt has u n derst o o d t he st u d y; 
* T he patie nt i nf or mati o n s heet a n d writte n i nf or me d c o nse nt f or m ( date d a n d n u m bere d 
versi o n a p pr o ve d b y t he Et hics C o m mittee) has bee n pr o vi de d; 
* T he patie nt h as bee n all o we d a reas o na bl e peri o d of reflecti o n ( o p p ort u nit y t o i n q uire 
a b o ut details of t he trial a n d t o deci de w het her or n ot t o partici pate i n t he trial) bef ore 
c o nse nti n g 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 /1 1 4  
 
 
- T o  kee p t he decisi o ns of t he E C s a n d preser ve t he writte n pr o of of t he i nf or me d c o nse nt of 
t he patie nts or t heir a ut h orise d le gal re prese nt ati ve 
- T o e ns ure t hat n o h u ma n bi ol o gical st u d y sa m ple is retai ne d o n site or else w here wit h o ut 
t he a p pr o val of t h e S p o ns or a n d t he e x press writte n c o nse nt of t he patie nt 
- T o perf or m n o ot her bi ol o gical assa ys o n t he h u ma n bi ol o gical st u d y s a m ple t ha n t h ose 
descri be d i n t he pr ot o c ol or its a me n d me nt(s) 
- T o pr o m ptl y re p ort a n y u na ntici pate d pr o ble ms i n researc h c o vere d u n der t his a gree me nt 
t hat i n v ol ve a n y ris k t o t he patie nts 
- T o e ns ure pr o per st u d y i nf or mati o n tra nsfer a n d st u d y data c ollecti o n i n a clear, le gi ble 
wa y a n d i n c o nf or mit y wit h t he s o urce d oc u me nts ( patie nt file)  
- T o e ns ure a de q uat e res o urces t o s uccessf ull y c o m plete t he st u d y wit h re gar d t o dea dli nes, 
q ualifie d pers o n nel a n d material 
I ac k n o wle d ge 
- T hat I h a ve bee n i nf or me d t hat certai n Re g ulat or y A ut h orities re q uire t he S p o ns or t o o btai n 
a n d s u p pl y, as n ecessar y, details a b o ut t he I n vesti gat or’s o w ners hi p i nterest i n t he S p o ns or 
or t he i n v esti gati o nal me dici nal pr o d uct, a n d m ore ge n erall y a b o ut his/ her fi na nci al ties 
wit h t he S p o ns or. T he S p o ns or will use a n d discl ose t he i nf or mati o n s olel y f or t he p ur p os e 
of c o m pl yi n g wit h r e g ulat or y re q uire me nts. 
 
Pri nci pal I n v esti gat or 
 
 
 
 
Na me a n d Title   
 
Date  
Si g nat ure  












C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 0 /1 1 4  
 
 
T A B L E O F C O N T E N T S 
1   
IN T R O D U C TI O N  ............................................................................................................. 2 3  
1. 1  
Oste oart hritis  ............................................................................................................ 2 3  
1. 1. 1  I nci de nce of K nee Oste oart hritis ..................................................................... 2 3  
1. 1. 2  Aeti ol o g y of Oste oart hritis  .............................................................................. 2 3  
1. 1. 3  Pat h o p h ysi ol o g y of Oste oart hritis  ................................................................... 2 4  
1. 2  
Treat me nt O pti o ns f or Oste oart hritis ........................................................................ 2 5  
1. 2. 1  Visc os u p ple me ntati o n  ..................................................................................... 2 5  
2   
B A C K G R O U N D O F T H E S T U D Y  .................................................................................. 2 7  
2. 1  
Ge neral Descri pti o n of J T A -0 0 4  .............................................................................. 2 7  
2. 2  
N o n -cli nical Data ..................................................................................................... 2 7  
2. 2. 1  A nti -i nfla m mat or y pr o perties of J T A-0 0 4  ...................................................... 2 7  
2. 2. 2  Effects of J T A -0 0 4 o n c h o n dr oc yte meta b olis m a n d e xtracell ular matri x 
s y nt hesis i n vitr o .......................................................................................................... 2 8  
2. 2. 3  Effects of J T A -0 0 4 o n t he visc osit y of s y n o vial fl ui d of a pat h ol o gical rat k nee
  
2 8  
2. 3  
Cli nical Data  ............................................................................................................. 2 9  
2. 4  
Assess me nt of A ntici pate d Be nefits a n d Ris ks  ........................................................ 2 9  
3   
IN V E S TI G A TI O N A L P L A N  ............................................................................................ 3 1  
3. 1  
Ge neral St u d y Desi g n  ............................................................................................... 3 1  
3. 2  
St u d y O bj ecti ve  ........................................................................................................ 3 2  
3. 2. 1  Pri mar y E n d p oi nt  ............................................................................................ 3 2  
3. 2. 2  Sec o n dar y E n d p oi nts  ....................................................................................... 3 2  
3. 2. 3  
 ..................................................................................... 3 2  
3. 2. 4  Safet y E n d p oi nts  ............................................................................................. 3 3  
3. 3  
Mai n St u d y Pr oce d ures  ............................................................................................ 3 3  
3. 3. 1  Patie nt I nf or mati o n a n d I nf or me d C o nse nt  ..................................................... 3 3  
3. 3. 2  Ra n d o misati o n a n d Bli n di n g Pr oce d ures  ........................................................ 3 5  
Ra n d o misati o n a n d Bli n de d Treat me nt All ocati o n ..................................................... 3 5  
Treat me nt Pre parati o n, Patie nt Treat me nt a n d Bli n di n g of t he St u d y ........................ 3 6  
3. 3. 3  Pr oce d ures per Treat me nt Gr o u p  .................................................................... 3 7  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 1 /1 1 4  
 
 
3. 4  
Patie nt E val uati o n ..................................................................................................... 3 8  
3. 4. 1  Cli nical E val uati o n  .......................................................................................... 3 8  
3. 4. 2  Bi ol o gical E val uati o n  ...................................................................................... 3 8  
3. 4. 3  Ra di ol o gical E val uati o n  .................................................................................. 3 9  
3. 5  
St u d y P o p ulati o n a n d Selecti o n  ................................................................................ 3 9  
3. 5. 1  Eli gi bilit y  ......................................................................................................... 3 9  
3. 5. 2  I ncl usi o n Criteria ............................................................................................. 3 9  
3. 5. 3  E xcl usi o n Criteria  ............................................................................................ 4 0  
3. 7  
Ge neral O ver vie w of Visits a n d Pr oce d ures  ............................................................ 4 3  
4   
D E T AI L E D S C H E D U L E O F  VI SI T S A N D P R O C E D U R E S  .......................................... 4 5  
4. 1  
Scree ni n g Peri o d ( Visit # 1)  ...................................................................................... 4 5  
4. 2  
Ra n d o misati o n/ Baseli ne/ Treat me nt Visit ( Visit # 2)  ................................................ 4 5  
4. 3  
F oll o w -u p Visit # 3 ( Wee k 2 ± 1 wee k)  .................................................................... 4 6  
4. 4  
F oll o w -u p Visit # 4 ( M o nt h 3 ± 3 wee ks)  ................................................................. 4 7  
4. 5  
F oll o w -u p Visit # 5 ( M o nt h 6 ± 4 wee k s) ................................................................. 4 7  
5   
R A TI O N A L E F O R T H E S T U D Y D E SI G N  ..................................................................... 4 8  
5. 1  
St u d y Rati o nale  ........................................................................................................ 4 8  
5. 2  
T y pes of Oste oart hritis  ............................................................................................. 4 8  
5. 3  
Cli nical a n d Bi ol o gical E val uati o n T o ols  ................................................................. 4 8  
5. 3. 1  Cli nical E val uati o n  .......................................................................................... 4 8  
5. 3. 2  Bi ol o gical E val uati o n  ...................................................................................... 5 0  
5. 4  
Rati o nale f or C h oice of Refere nce Gr o u p  ................................................................ 5 1  
6   
IN V E S TI G A TI O N A L M E DI CI N A L P R O D U C T A N D R E F E R E N C E T R E A T M E N T  .. 5 2  
6. 1  
Treat me nts A d mi nistere d  ......................................................................................... 5 2  
6. 1. 1  I n vesti gati o nal Me dici nal Pr o d ucts ................................................................. 5 2  
6. 1. 2  Refere nce  ......................................................................................................... 5 2  
6. 2  
Treat me nt wit h I n vesti gati o nal me dici nal pr o d ucts a n d refere nce  ........................... 5 2  
6. 2. 1  Rec o nstit uti o n Pr oce d ure  ................................................................................ 5 2  
6. 2. 2  I nj ecti o n Pr oce d ure.......................................................................................... 5 2  
6. 2. 3  P ost -i nj ecti o n Pr oce d ures ................................................................................ 5 4  
6. 2. 4  C o nc o mita nt Me dicati o ns ................................................................................ 5 4  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 2 /1 1 4  
 
 
6. 3  
St u d y F oll o w -u p  ....................................................................................................... 5 5  
6. 4  
Pac ka gi n g a n d La belli n g  .......................................................................................... 5 5  
6. 5  
St ora ge  ...................................................................................................................... 5 5  
6. 6  
S u m mar y of I n vesti gati o nal me dici nal pr o d ucts a n d Refere nce  .............................. 5 5  
6. 7  
Trac ki n g, Tracea bilit y a n d Acc o u nta bilit y of I n vesti gati o nal me dici nal pr o d ucts a n d 
refere nce............................................................................................................................. 5 6  
7   
S A F E T Y A S S E S S M E N T S  ................................................................................................ 5 8  
7. 1  
O ver vie w of Safet y Para meters a n d E n d p oi nts  ........................................................ 5 8  
7. 1. 1  Me dical Hist or y a n d De m o gra p hics  ................................................................ 5 8  
7. 1. 2  Vital Si g ns  ....................................................................................................... 5 9  
7. 1. 3  P h ysical E xa mi nati o n  ...................................................................................... 5 9  
7. 1. 4  La b orat or y Safet y Meas ure me nts  .................................................................... 5 9  
7. 2  
Ot her Safet y Meas ure me nts  ..................................................................................... 6 0  
7. 2. 1  Pre g na nc y T est  ................................................................................................ 6 0  
7. 2. 2  A d diti o nal Safet y E xa mi nati o ns a n d Pr oce d ures  ............................................ 6 1  
8   
S A F E T Y D E FI NI TI O N S A N D R E P O R TI N G R E Q UI R E M E N T S  .................................. 6 2  
8. 1  
Defi niti o ns  ................................................................................................................ 6 2  
8. 1. 1  A d verse E ve nt ( A E)  ........................................................................................ 6 2  
8. 1. 2  Seri o us A d verse E ve nt ( S A E)  ......................................................................... 6 2  
8. 1. 3  Se verit y a n d Seri o us ness  ................................................................................. 6 4  
8. 1. 4  Ca usal  Relati o ns hi p t o war ds t he I n vesti gati o nal Me dici nal Pr o d uct  .............. 6 5  
8. 1. 5  O utc o me of A d verse E ve nts  ............................................................................ 6 5  
8. 1. 6  A d verse Dr u g Reacti o n ( A D R)  ....................................................................... 6 6  
8. 1. 7  Seri o us A d verse Reacti o n ( S A R)  .................................................................... 6 6  
8. 2  
I de ntif yi n g A d verse E ve nts ...................................................................................... 6 6  
8. 3  
List of F oreseea ble A d verse E ve nts a n d A ntici pate d A d verse Dr u g Effects  ........... 6 7  
8. 4  
Re p orti n g of Safet y Iss ues  ........................................................................................ 6 8  
8. 4. 1  Re p orti n g E ve nts t o t he S S O b y t he Pri nci pal I n vesti gat or  ............................ 6 8  
8. 4. 2  Re p orti n g E ve nts t o E Cs a n d A ge ncies b y t he S S O  ........................................ 7 0  
8. 4. 3  Seri o us A d verse E ve nt St o p pi n g R ule  ............................................................ 7 0  
8. 4. 4  Safet y Data M o nit ori n g  ................................................................................... 7 0  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 3 /1 1 4  
 
 
8. 4. 5  Data Safet y M o nit ori n g B oar d  ........................................................................ 7 0  
8. 5  
Ma na ge me nt of Safet y Iss u es  ................................................................................... 7 1  
8. 5. 1  Pr oce d ure i n Case of Pre g na nc y  ...................................................................... 7 1  
8. 5. 2  E mer ge nc y Pr oce d ures  .................................................................................... 7 1  
8. 6  
L o n g -T er m Safet y Re p orti n g S yste m  ....................................................................... 7 2  
9   
P R E M A T U R E R E M O V A L F R O M T H E S T U D Y  ........................................................... 7 3  
9. 1  
Reas o ns f or Patie nt Pre mat ure Disc o nti n uati o n  ....................................................... 7 3  
9. 2  
Pr oce d ure f or Patie nt Pre mat ure Disc o nti n uati o n  .................................................... 7 4  
9. 3  
Re place me nt of Patie nts  ........................................................................................... 7 4  
9. 4  
Pre mat ure Ter mi nati o n of t he Cli nical Trial  ............................................................ 7 5  
1 0   
S T A TI S TI C A L C O N SI D E R A TI O N S A N D M E T H O D S O F A N A L Y SI S  ...................... 7 6  
1 0. 1  A nal ysis P o p ulati o ns  ............................................................................................... 7 6  
1 0. 2  St u d y o bj ecti ves  ...................................................................................................... 7 6  
1 0. 3  Pri mar y E n d p oi nt  .................................................................................................... 7 7  
1 0. 4  Sec o n dar y E n d p oi nts  .............................................................................................. 7 7  
1 0. 5  
 7 7  
1 0. 6  Safet y  ...................................................................................................................... 7 8  
1 0. 7  Statistical A nal ysis  .................................................................................................. 7 8  
1 0. 7. 1  Patie nts Dis p ositi o ns  ..................................................................................... 7 8  
1 0. 7. 2  Pr ot oc ol De viati o ns  ....................................................................................... 7 9  
1 0. 7. 3  De m o gra p hics a n d ot her Baseli ne C haracteristics  ........................................ 7 9  
1 0. 7. 4  Me dical Hist or y, C o nc o mita nt Me dicati o ns .................................................. 7 9  
1 0. 7. 5  Pri mar y E n d p oi nt  .......................................................................................... 8 0  
1 0. 7. 6  Sec o n dar y 
 E n d p oi nts .......................................................... 8 0  
1 0. 7. 7  Safet y A nal ysis  .............................................................................................. 8 1  
1 0. 8  Ra n d o misati o n  ........................................................................................................ 8 2  
1 0. 9  Sa m ple Size Esti mati o n  .......................................................................................... 8 2  
1 0. 1 0  Met h o ds t o Be Use d t o Ha n dle Missi n g Val ues  ................................................... 8 3  
1 0. 1 1  M ulti plicit y  ........................................................................................................... 8 3  
1 0. 1 2  
 8 3  
1 0. 1 3  I n de pe n de nt D at a M o nit ori n g C o m mittee ....................................................... 8 5  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 1 4 /1 1 4  
 
 
1 0. 1 3. 1  Me m bers  ...................................................................................................... 8 5  
1 0. 1 3. 2  Res p o nsi bilities  ............................................................................................ 8 5  
1 0. 1 3. 3  St u dy D at a t o be se nt t o t he I D M C .............................................................. 8 5  
1 0. 1 3. 4  U n bli n di n g Pr oce d ure  ................................................................................. 8 6  
1 0. 1 3. 5  Res ults  ......................................................................................................... 8 6  
1 1   
S T U D Y M A N A G E M E N T  ................................................................................................ 8 7  
1 1. 1  S o urce D oc u me nts/ Data .......................................................................................... 8 7  
1 1. 2  M o nit ori n g  .............................................................................................................. 8 8  
1 1. 3  S o urce D oc u me nts/ Data Verificati o n  ..................................................................... 9 0  
1 1. 4  C o m pleti o n of Case Re p ort F or ms, Si g ni n g a n d Fili n g  .......................................... 9 1  
1 1. 5  Data Ma na ge me nt  ................................................................................................... 9 1  
1 1. 6  A u dits a n d I ns pecti o ns  ............................................................................................ 9 2  
1 1. 7  Access t o S o urce Data  ............................................................................................ 9 3  
1 1. 8  Trai ni n g of Staff  ...................................................................................................... 9 3  
1 1. 9  C ha n ges t o t he Pr ot oc ol  .......................................................................................... 9 3  
1 2   
A D MI NI S T R A TI V E, L E G A L A N D E T HI C A L A S P E C T S  ............................................ 9 5  
1 2. 1  Et hical Pri nci ples a n d C o n d uct of t he Trial  ............................................................ 9 5  
1 2. 2  Healt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o nal Re vie w B oar d
  
9 7  
1 2. 3  Patie nt Data Pr ot ecti o n a n d C o nfi de ntialit y ............................................................ 9 8  
1 2. 4  I ns ura nce ................................................................................................................. 9 9  
1 2. 5  Fi na ncial As pects  .................................................................................................. 1 0 0  
1 2. 6  Arc hi vi n g at t he E n d of t he St u d y  ......................................................................... 1 0 0  
1 3   
R E P O R TI N G A N D P U B LI C A TI O N S P O LI C Y  ............................................................ 1 0 2  
1 3. 1  Cli nical St u d y Re p ort  ............................................................................................ 1 0 2  
1 3. 2  P u blicati o ns a n d P osters  ....................................................................................... 1 0 2  
1 4   
R E F E R E N C E S  ................................................................................................................ 1 0 5  
1 5   
A N N E X E S  ....................................................................................................................... 1 0 9  
1 5. 1  A N N E X 1  : W O M A C
®  V A 3. 1 Q U E S TI O N N AI R E  ............................................ 1 0 9  
1 5. 2  A N N E X 2: P AI N VI S U A L A N A L O G U E S C A L E  .............................................. 1 1 0  
1 5. 3  
 . 1 1 1  


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1 5. 4  
 1 1 2  
1 5. 5  A N N E X 5: R A DI O L O GI C A L E V A L U A TI O N  .................................................. 1 1 3  
 
 
 
 


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LI S T O F T A B L E S 
T a ble 1: Detaile d Sc he d ule of Visits a n d Pr oce d ures – D o u ble- bli n d p has e .......................... 4 4  
T a ble 2: A d mi nistrati o n of t he I n vesti gati o nal me dici nal pr o d uct .......................................... 5 4  
T a ble 3: I d e ntit y of J T A- 0 0 4 I n vesti gati o nal me dici nal pr o d ucts a n d Refere nce................... 5 6 
T a ble 4:  O ver vie w of Safet y Para met ers a n d Ti m e P oi nts ..................................................... 5 8 
T a ble 5: O ver vie w of C ollecte d V ol u mes f or Bl o o d A nal ys es ............................................... 6 0  
T a ble 6: Classificati o n of A d verse E ve nts .............................................................................. 6 4  
T a ble 7: O bser vati o n Peri o d f or t he Occ urre nce of A E a n d S A E ........................................... 6 7  
T a ble 8: S u m mar y of F oreseea ble A d v erse E ve nts ................................................................. 6 8  
T a ble 9: T he Kell gre n- La wre n ce Gra di n g S yst e m of Oste oart hritis .................................... 1 1 4  
  


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LI S T O F A B B R E VI A TI O N S 
A C R   
A merica n C olle ge of R he u mat ol o g y  
A E   
A d verse E v e nt  
B MI   
B o d y Mass I n d e x  
b p m   
Beats p er mi n ute  
C E   
C o nf or mité E ur o pée n n e  
C O M P   
Cartila ge Oli g o m eric Matri x Pr otei n  
e C R F  
electr o nic Cas e Re p ort F or m  
D C F   
Data Clarificati o n F or m  
D M P   
Data Ma na ge me nt Pla n  
E C(s)   
Et hics C o m mittee(s)  
F A S   
F ull A nal ysis Set  
G   
Ga u ge  
G C P   
G o o d Cli nical Practice  
G M P   
G o o d Ma n ufact uri n g Practice  
H A   
H yal ur o nic Aci d  
H Cl   
H y dr oc hl ori de  
I A  
I ntr a-artic ular  
I B  
I n v esti gat or’s Br oc h ure 
I C F  
I nf or me d C o nse nt F or m 
I S F  
I n v esti gat or Site File 
I U D  
I ntr a uteri ne de vice 
I W R S  
I nteracti ve We b Res p o nse S yste m 
L O C F  
M CI D  
Last O bs er vati o n Carrie d F or war d  
Mi ni mal Cli nicall y I m p orta nt Differe nce  
Me d D R A   
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M W   
M olec ular wei g ht  
N S AI Ds   
N o nster oi dal A nti -I nfla m mat or y Dr u gs 


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O A   
Oste oart hritis  
P P   
Per Pr ot oc ol  
S A   
Safet y A nal ysis  
S A E   
Seri o us A d verse E v e nt  
S A F   
Safet y Set  
S A P   
Statistical A nal ysis Pla n  
S A R   
Seri o us A d verse Reacti o n  
S D   
Sta n dar d De viati o n  
S D V   
S o urce Data Verifi cati o n  
S P M   
St u d y Pr oce d ure Ma n u al  
S S O   
St u d y Safet y Officer  
S O Ps   
Sta n dar d O perati n g Pr oce d ures  
T M F   
Trial Master File  
V A S   
Vis ual A nal o g ue Scale  
W H O   
W orl d Healt h Or ga nisati o n  
W O C F   
W orst O bser vati o n Carri e d F or war d  
W O M A C
®  
Wester n O ntari o Mc Mast er U ni versit y Sc ore  
 
 
 


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D E FI NI TI O N S O F T E R M S 
 C ase  Re p ort F o r m (e C R F): a pri nte d, o ptical or electr o nic d o c u me nt desi g ne d t o rec or d 
all of t he pr ot oc ol-re q uir e d i nf or mati o n t o be re p orte d t o t he S p o ns or o n eac h trial s u bject 
 C o m plete d P atie nt:  a patie nt w h o c o m plete d all sc he d ule d visits u p t o last sc he d ule d visit 
(i ncl usi ve) 
 C o ntr act Rese arc h Or g a nis ati o n ( M o nit or ): a pers o n or a n or ga nisati o n c o ntracte d b y 
t he S p o ns or t o perf or m o ne or m ore of t he S p o ns or's tri al-relat e d d uties a n d f u ncti o ns 
 C o or di n ati n g I n vesti g at or:  I n v esti gat or w h o is a p p oi nte d b y t he S p o ns or t o c o or di nate 
w or k i n a m ultice ntre cli nical st u d y  
 Disc o nti n ue d or wit h dr a w n p atie nt:  a patie nt 
w h o has bee n e nr olle d, scree ne d, 
ra n d o mise d, or treate d b ut has wit h dra w n fr o m t he st u d y bef ore c o m pleti o n of t he last 
sc he d ule d visit 
 D o u b le- bli n di n g: d o u ble- bli n di n g is a pr oce d ure i n w hic h t he patie nt, t he I n vesti gat or, t h e 
m o ni t or, a n d data a nal yst are ke pt u n a ware of t he treat me nt assi g n me nts 
 
D at a S afet y 
M o nit ori n g B o ar d  ( DS M B): A n i n de pe n de nt d ata m o nit ori n g c o m mittee 
esta blis he d b y t he S p o ns or t o assess at i nter vals t he pr o gress of a cli nical trial, t he safet y 
data, a n d t he critical efficac y e n d p oi nts, a n d t o rec o m me n d t o t he S p o ns or w het her t o 
c o nti n ue, m o dif y or st o p t he trial  
 E n d p oi nt(s):  i n dicat or(s) use d f or assessi n g t h e pri mar y h y p ot hesis of a st u d y 
 Eli gi ble p atie nt : scree ne d patie nt ( ha vi n g si g n e d a n d date d t he i nf or me d c o nse nt f or m) 
w h o is c o nsi dere d eli gi bl e acc or di n g t o selecti o n criteria  
 E nr olle d p atie nt : patie nt w h o has date d a n d si g n e d t he I nf or m e d C o nse nt F or m  
 E t hics C o m mittee ( E C): A re vie w p a nel t hat is res p o nsi ble f or e ns uri n g t he pr otecti o n of 
t he ri g hts, s afet y, a n d well- bei n g of h u m a n s u bjects i n v ol ve d i n a cli nical trial a n d is 
a de q uatel y c o nstit ute d t o pr o vi de ass ura n ce of t hat pr otecti o n 
 G o o d Cli nic al Pr a ctice ( G C P):  set of i nter nati o nall y rec o g nize d et hical a n d scie ntific 
re q uire me nts a n d sta n dar ds as re gar ds t o t he desi g n, c o n d u ct, perf or ma nce, m o nit ori n g, 
a u diti n g, rec or di n g, a nal ys es, a n d re p orti n g of cli nical trials, t hat pr o vi des ass ura nce t hat 


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t he data a n d re p ort e d res ults are cre di ble a n d acc urate, a n d t h at t he ri g hts, safet y, well- bei n g, 
a n d c o nfi de ntialit y of trial patie nts are pr otecte d 
 I nf or me d c o nse nt: pr ocess b y w hic h a patie nt v ol u ntaril y c o nfir ms his/ her willi n g n ess t o 
partici pate i n a partic ular trial, after ha vi n g bee n i nf or me d of all as pects of t he trial t hat are 
rele va nt t o t he patie nt's decisi o n t o partici pate. I nf or me d c o nse nt is d oc u me nte d b y mea ns 
of a writte n, si g ne d a n d d ate d i nf or me d c o nse nt f or m 
 I nvesti g ati o n Site:  a n y p u blic or pri vate e ntit y or h os pital facilit y w here cli nical trial a n d 
trial-relate d acti vities are c o n d ucte d 
 
I n vesti g ati o n al Me dici n al Pr o d uct (I M P): a p har mace utical f or m of a n acti ve s u bsta nce 
or Place b o  bei n g teste d or use d as a refere n ce i n a cli nical trial  
 In vesti g at or:  a pers o n res p o nsi ble f or t he c o n d uct of t he cli nical trial at a trial site. If a trial 
is c o n d ucte d b y a t ea m of i n di vi d uals at a tri al site, t he I n vesti gat or is t he res p o nsi ble lea der 
of t he tea m a n d ma y b e calle d t he pri nci pal i n vesti gat or. 
 I nvesti g at or’s Br o c h ure (I B):  c o m pilati o n of t he cli nical a n d n o n-cli nical data o n t he 
i n vesti gati o nal me dici nal pr o d uct w hic h are rele va nt t o t he st u d y of t he pr o d uct i n h u ma n 
s u bjects 
 J T A- 0 0 4:  rec o nstit ute d J T A- 0 0 4 fi nis he d pr o d uct t o be a d mi nistere d ( 2 ml or 4 ml) t o 
oste oart hritic patie nts a n d c o m bi ni n g hi g h m olec ular wei g ht h yal ur o ni c aci d a n d t w o acti ve 
me dici nal s u bsta nces 
 Le g all y a ut h orize d re prese nt ati ve:  i n di vi d ual or j u dicial or ot her b o d y a ut h orize d u n der 
a p plica ble la w t o c o nse nt, o n be half of a pr os pecti ve patie nt, t o t he patie nt's partici pati o n i n 
t he cli nical trial 
 M o nit or:  W hile I C H G C P uses t he ter m " M o nit or" i nstea d of Cli nical Researc h Ass ociate 
( C R A), t he t w o ter ms are c o nsi dere d t o b e s y n o n y m o us. A M o nit or is a p ers o n e m pl o ye d 
b y a S p o ns or, or b y a C o ntract Researc h Or ga nizati o n ( M o nit or) acti n g o n a S p o ns or’s 
be half, w h o m o nit ors t he pr o gress of a cli nical tri al a n d e ns ures t h at is c o n d u cte d, rec or de d, 
a n d re p orte d i n acc or da nce wit h t h e pr ot oc ol, writte n pr oce d ures, a n d t he a p plica ble 
re g ulat or y re q uire me nts.  


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 P ati e nt:  a n i n di vi d ual w h o partici pates i n a cli nical trial, eit her as a reci pie nt of t h e 
i n vesti gati o nal me dici nal pr o d uct or a me m b er of t he refere n ce gr o u p 
 R a n d o mis ati o n:  pr ocess of assi g ni n g p atie nts t o t he i n vesti gati o nal me dici nal pr o d uct or 
refere nce gr o u ps usi n g a n esta blis he d rec o g nize d statistical met h o d ol o g y t o deter mi ne t he 
assi g n me nt i n or der t o re d uce bias 
 Re fere nce (tre at me nt): a n i n v esti gati o nal or mar kete d pr o d uct (e. g., acti ve c o ntr ol), 
place b o, use d i n t he refere nce i n a cli nical trial  
 S cree ne d p atie nt:  p atie nt w h o has date d a n d si g ne d t he i nf or me d c o nse nt f or m (e nr olle d 
patie nt) a n d w h o has p erf or me d t he c hec ki n g of t he selecti o n criteria 
 S cree ni n g f ail ure:  scree ne d patie nt b ut w h o is n ot eli gi ble f or t he st u d y after c h ec ki n g t he 
selecti o n criteri a 
 
S eri o us A d verse E ve nt ( S A E ): a n y u nt o war d me dical occ urre nce or effect i n a patie nt or 
cli nical trial patie nt a d mi nistere d a me dici n al pr o d uct, w hic h d oes n ot n ecessaril y h a ve a 
ca usal relati o ns hi p wit h t his treat me nt, a n d t hat, at a n y d ose, res ults i n deat h, is life-
t hreate ni n g, re q uir es 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, 
res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y, or is a c o n ge nital a n o mal y or birt h 
defect.  
 
Seri o us A d verse Re a cti o n ( S A R ): a n y u nt o war d a n d u ni nte n d e d res p o nses t o a n 
i n vesti gati o nal me dici nal pr o d uct rel ate d t o a n y d ose a d mi nistere d ( ha vi n g a reas o na ble 
ca usal relati o ns hi p t o t he pr o d uct), a n d t hat res ults i n deat h, is life-t hreat e ni n g, re q uires 
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, res ults i n persiste nt or 
si g nifica nt disa bilit y or i nca pacit y, or is a c o n ge nital a n o mal y or birt h defect.  
 S o urce d at a:  all i nf or mati o n i n ori gi nal rec or ds, certifie d c o pies of ori gi nal rec or ds of 
cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical trial, necessar y f or t h e 
rec o nstr ucti o n a n d e val u ati o n of t he trial 
 S o urce d oc u me nt:  pri nt e d, o ptical or electr o nic d oc u me nt c o ntai ni n g s o urce data 
 S p o ns or:  i n di vi d ual, c o m pa n y, i nstit uti o n or or ga nizati o n w hic h ta kes res p o nsi bilit y f or t he 
i nitiati o n, ma na ge me nt a n d/ or fi na nci n g of a cli nical trial 


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 St or a ge:  mai nte na nce of t he i n vesti gati o nal me dici nal pr o d uct u n der a p pr o priate c o ntr olle d 
c o n diti o ns u ntil a d mi nistrati o n  
 S t u d y Pr ot oc ol: d oc u m e nt t hat states t he rati o nale, o bjecti ves, d esi g n a n d pr o p ose d 
a nal ysis, met h o d ol o g y, m o nit ori n g, c o n d uct a n d rec or d- kee pi n g of t he cli nical trial 
 S t u d y Re p ort: d oc u me nt descri bi n g t he desi g n, e x ec uti o n, statistical a nal ysis a n d res ults 
of a trial 
 St u d y S afet y Officer ( S S O) : i n di vi d ual desi g nate d t o perf or m t he h a n dli n g, n otificati o n, 
an d re p orti n g of safet y iss ues 
 
S us pecte d U ne x pecte d S eri o us A d verse Re a cti o n ( S U S A R):  seri o us a d verse reacti o n, t he 
nat ure, s e verit y, s p ecificit y, or o utc o me of w hic h is n ot c o nsiste nt wit h a p plica ble pr o d uct 
i nf or mati o n (e. g., t he I n v esti gat or’s Br oc h ure) 
 T re ate d p atie nt:  p atie nt t o w h o m a treat me nt has bee n a d mi nistere d 


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1  
I N T R O D U C TI O N 
1. 1  
Oste o art hritis 
T he m ost c o m m o n t y p e of art hritis is oste oart hritis ( O A) als o k n o w n as de ge nerati ve j oi nt 
disease. O A is a c hr o nic, pr o gressi ve m usc ul os keletal dis or der c haract erize d b y f ocal areas of 
fi brillati o n, fiss ures, ulcerati o n a n d f ull t hic k ness l oss of artic ul ar cartila ge wit hi n s y n o vi al 
j oi nts, ass ociate d wit h h y p ertr o p h y of b o ne ( oste o p h ytes a n d s u b c h o n dral b o ne s cler osis) a n d 
t hic ke ni n g of t he ca ps ul e. O A ca n affect a n y j oi nt, b ut is m ost c o m m o n a n d m ore p ai nf ul i n 
wei g ht- b eari n g j oi nts s uc h as t h e k nees a n d hi ps, b ut ca n als o affect t he h a n d, t he s pi ne, a n d 
m ore rarel y t he wrist, el b o w, a n d s h o ul der j oi nts ( Ma ne k a n d La n e, 2 0 0 0). Cli nicall y, t he 
c o n diti o n is c haracterize d b y j oi nt pai n, te n der ness, li mitati o n of m o ve me nt, cre pit us ( grati n g, 
crac ki n g or p o p pi n g s o u n ds i n t he j oi nt), a n d stiff ness after i m m o bilit y a n d li mitati o n of 
m o ve me nt 
wit h occasi o nal eff usi o n a n d v aria ble de grees of l ocal i nfla m mati o n. T he 
pat h ol o gical c ha n ge, w he n se vere, res ults i n ra di ol o gical c h a n ges (l oss of j oi nt s pace, 
s u bc h o n dral scler osis, c ysts a n d oste o p h ytes) ( Ma ne k a n d La n e, 2 0 0 0). 
1. 1. 1  I nci de nce of K nee Oste o art hritis 
W orl d wi de, O A is t he m ost c o m m o n j oi nt dis or der. T he i nci de n ce of O A i ncreas es wit h a ge. 
Me n are affecte d m ore oft e n t ha n w o me n a m o n g t h ose a ge d bel o w 4 5 years, w hereas w o me n 
are affect e d m ore fre q u e ntl y a m o n g t h ose a ge d a b o ve 4 5 years ( Peterss o n et al., 2 0 0 2). I n 
de vel o pe d c o u ntries, t he pre vale nce of s y m pt o matic k nee O A is a p pr o xi matel y 1 0 % i n me n a n d 
1 3 % i n w o me n a m o n g a d ults 6 0 years of a ge or ol d er ( Z h a n g a n d J or da n, 2 0 1 0). T he pre vale nce 
of O A is e x pecte d t o i ncrease i n t h e c o mi n g years as ris k fact ors, s uc h as a n a gi n g p o p ulati o n 
a n d o besit y, b ec o me m ore pre val e nt. 
1. 1. 2  Aeti ol o gy of Oste o art hritis 
T he de vel o p me nt of O A i n v ol ves m ulti ple s yst e mic a n d l ocal fact ors. S yst e mic fact ors i n cl u de 
a d va nce d a ge, fe male ge n der, a n d fa mil y hist or y. Ge netic fact ors are als o t h o u g ht t o pla y a r ole 
i n t he de vel o p me nt of O A, a n d differe nt ge n es ma y be i m plicate d i n differe nt t y pes of art hritis. 
L ocal fact ors c o m prise o ver wei g ht a n d o besit y, j oi nt i nj ur y, re petiti ve us e of j oi nts at w or k, 
partici pati o n i n certai n s p orts, j oi nt la xit y, a b n or mal a nat o mic ali g n m e nt, m uscle wea k ness a n d 


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atr o p h y ( Fels o n et al., 2 0 0 0; Z ha n g a n d J or da n, 2 0 1 0 ). A m o n g all t hese fact ors, o b esit y a n d 
j oi nt i nj ur y a p p ear t o be t he str o n gest ris k fact ors t hat ha ve t he p ote ntial f or s u bsta ntial i m pact 
o n a p o p ulati o n le vel.  
1. 1. 3  P at h o p hysi ol o gy of Oste o art hritis 
O A ca n be cate g orize d i nt o t w o mai n t y pes  of O A, w hic h ha ve differi n g ca uses: pri mar y 
(i di o pat hic) O A or sec o n dar y O A. Pri mar y O A is t he m ost c o m m o n t y p e, has n o i de ntifia bl e 
ca use a n d ma y be l ocalize d (i n v ol vi n g o nl y o ne or t w o sites) or ge neralize d (affecti n g at least 
t hree sites) ( Laj e u nesse e t al., 2 0 0 3). Sec o n d ar y O A is ca us e d b y a n u n derl yi n g c o n diti o n s uc h 
as a j oi nt i nj ur y, acc u m ulati o n of calci u m i nsi de t he j oi nt, r he u mat oi d or ot her art hritis, 
meta b olic or e n d ocri ne dis or ders, or c o n ge nital fact ors.  
O A has pre vi o usl y bee n c o nsi dere d as a diseas e res ulti n g fr o m wear a n d tear of t he j oi nts; 
h o we ver, it ca n be m ore e x actl y des cri be d as a dis or der res ult i n g fr o m se veral bi oc he mical, 
bi o mec ha nical, i nfla m mat or y a n d i m m u n ol o gic fact ors ( Laje u nesse et al., 2 0 0 3).  
In healt h y cartila ge, t here is a c o nti n ual pr ocess of nat ural brea ki n g d o w n a n d re pair of t he 
cartila ge e xtracell ular matri x i n j oi nts. T his pr ocess bec o mes disr u pte d i n O A, lea di n g t o a n 
a b n or mal re p air res p o ns e. T he s m o ot h s urface of t he cartila ge be gi ns t o deteri orate a n d t o 
bec o me w or n ca usi n g fri cti o n bet wee n t he b o nes. If t he cartila ge wears d o w n c o m pletel y, t he 
res ult will be b o n e t o b o ne c o ntact. As pieces of cartila ge brea k off, t he b o nes t hic ke n a n d 
br oa de n, ca usi n g i nfla m mati o n. T his i nfla m mati o n ma y sti m ulate ne w b o n e o ut gr o wt hs calle d 
oste o p h ytes t o f or m ar o u n d t he j oi nts. As t he b o nes t hic ke n a n d br oa d e n, j oi nts bec o me stiff, 
pai nf ul, a n d ma y be diffic ult t o m o ve. Fl ui d ma y als o b uil d u p i n t he j oi nts. 
T he reas o n t his n or mal re pair pr ocess is disr u pte d is n ot k n o w n b ut c olla ge n ol ytic e nz y mes are 
t h o u g ht t o c o ntri b ute t o t he brea k d o w n of cartila ge. C yt o ki nes a n d gr o wt h fact ors are t h o u g ht 
t o pla y a r ole i n t he pat h o p h ysi ol o g y of t he O A. I nterle u ki n- 1 a n d T u m o ur Ne cr osis Fact or-  
ma y f u ncti o n t o acti vate e nz y mes i n v ol ve d i n pr ot e ol ytic di gesti o n of cartila ge ( Pelletier et al.,  
1 9 9 3). Gr o wt h fact ors s uc h as Tiss ue Gr o wt h Fact or- β a n d I ns uli n Gr o wt h Fact or- 1 ma y pl a y 
a r ole i n t he b o d y's att e m pts t o re pair cartila ge t hr o u g h cartila ge s y nt hesis (Ia n n o ne a n d 
La p a d ula, 2 0 0 3). 


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1. 2  
Tre at me nt O pti o ns f or Oste o art hritis 
T he re is c urre ntl y n o c ure f or O A. Treat me nt f or O A f oc us es o n relie vi n g a n d c o ntr olli n g pai n 
a n d s y m pt o ms, pre ve nti n g dise ase pr o gressi o n, mi ni mizi n g disa bilit y, a n d i m pr o vi n g q u alit y of 
life. Ma na ge me nt of O A i ncl u des varie d tec h ni q ues a n d pri nci ples, b ot h n o n- p har mac ol o gi c 
a n d p har mac ol o gi c i n nat ure.  
M ost treat me nts c o nsist of a c o m bi nati o n of t he f oll o wi n g met h o ds: e d ucati o n, wei g ht l oss, 
e x ercise, j oi nt pr otecti o n, p h ysical a n d occ u pati o n al t hera p y. A lar ge n u m ber of dr u gs are als o 
prescri be d f or patie nts wit h O A, t y picall y use d t o re d uce t he i nfla m mati o n, w hic h i n t ur n 
decreases pai n a n d stiff ness. T hese dr u gs i ncl u de aceta mi n o p he n a n d n o n-ster oi dal a nti-
i nfla m mat or y dr u gs ( N S AI Ds), C O X- 2 i n hi bit ors, t o pical a n al gesics, narc otic a nal gesics, 
g l uc osa mi ne a n d c h o n dr oiti n, tr a ma d ol a n d i ntra-artic ular (I A) c ortic oster oi ds ( Ma ne k a n d 
La n e, 2 0 0 0). Alt h o u g h effecti ve i n re d uci n g s y m pt o ms, N S AI Ds are ofte n ass ociate d wit h si de 
effects s o meti mes descri be d as c ostl y f or s oci et y. T he pri mar y s afet y c o ncer n wit h N S AI Ds is 
t he i ncrease i n gastr oi nt esti nal pr o ble ms, i ncl u di n g ulcerati o n, h ae m orr h a ge, a n d p erf orati o n 
( R ot h, 2 0 1 1). C o m pare d t o tra diti o nal N S AI Ds, C O X- 2 i n hi bit ors clai m t o be m ore selecti ve i n 
t heir m o de of acti o n, wit h re d uce d gastr oi ntesti nal c o m plicati o ns. H o we ver, a n i ncrease d ris k 
of car di o vasc ular c o m plicati o ns has rece ntl y b ee n attri b ute d t o vari o us N S AI Ds i ncl u di n g 
C O X- 2 i n hi bit ors ( Mc Getti ga n a n d He nr y, 2 0 0 6). I A ster oi ds are effecti ve b ut us uall y h a ve 
q uite s h ort d urati o n of effect ( G o d wi n a n d Da wes, 2 0 0 4). 
I n s e vere cas es, w he n t h e t hera pies a b o ve d o no t w or k, s ur ger y ma y b e c o nsi dere d as a last-
res ort eff ort t o ma na ge O A s y m pt o ms. S ur gical i nter ve nti o ns i ncl u de t otal j oi nt art hr o plast y 
a n d j oi nt la va ge a n d d e bri de me nt. T here is n o e vi de nce d e m o nstrati n g t hat la va ge or 
de bri de me nt is m ore effecti ve i n relie vi n g pai n or i m pr o vi n g f u ncti o n t ha n n o n-s ur gical 
treat me nt ( M osele y et al.,  2 0 0 2). Art hr o plast y h as si g nifica ntl y re d uce d k nee pai n a n d i ncreas e d 
f u ncti o nalit y i n patie nts w h o were se verel y i nca pacitate d bef ore s ur ger y ( P e n dlet o n et al., 
2 0 0 0). Pr ost hesis l o ose ni n g a n d i nfecti o n are a m o n g t he c o m plicati o ns t hat ca n occ ur. 
1. 2. 1  Visc os u p ple me nt ati o n 
Alt h o u g h t here are se veral n o n -s ur gical treat me nts a vaila ble f or t he treat me nt of k nee O A, t heir 
l o n g-ter m use a n d t heir s afet y ha v e n ot bee n s yste maticall y m o nit ore d. Vis c os u p ple me ntati o n 
has bee n use d i n t he treat me nt of s y m pt o ms ass oci ate d wit h k nee O A wit h a fa v o ura ble s afet y 


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pr ofile ( Pa g na n o a n d Westric h, 2 0 0 5). Visc os u p ple me ntati o n is a n I A t hera pe utic tec h ni q ue f or 
t he treat me nt of k n ee O A base d o n t he p h ysi ol o gic i m p orta n ce of h yal ur o nic aci d (H A ) i n 
sy n o vial j oi nts. Its t hera p e utic g oal is t o a d dress t he ca use of pai n a n d t o i m pr o ve m o bilit y of 
t he j oi nt b y re placi n g t h e l o w elast o visc o us oste oart hritic s y n o vial fl ui d wit h hi g h elast o visc o us 
s ol uti o ns of H A or its deri vati ves. 
T here are se v eral differe nt stre n gt hs of visc os u p ple me nts of wi del y differe nt m olec ular wei g hts. 
T his differe nce of m olec ular wei g ht ( M W) is t h o u g ht t o b e of i m p orta nce wit h res pect t o t he 
v ol u me/a m o u nt a n d n u m ber of i njecti o ns, t he resi d ue ti me i n t he j oi nt a n d bi ol o gic effects 
( H ua n g et al., 2 0 1 0).  
B ase d o n m a n y a nal ys es, visc os u p ple me ntati o n is a n effecti ve alter nati ve treat me nt f or k n e e 
O A wit h be neficial effects o n pai n, f u ncti o n a n d patie nt gl o bal ass ess me nt. M ore o ver, it was 
s h o w n t hat visc os u p ple me nts ha ve m ore pr ol o n ge d effects t ha n I A c ortic oster oi ds ( Bella m y et 
al.,  2 0 0 9).  
 
 


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2  
B A C K G R O U N D O F T H E S T U D Y  
2. 1  
G e ner al Descri pti o n of J T A- 0 0 4 
JT A- 0 0 4 is a si n gle a d mi nistrati o n e n ha nce d visc os u p ple me nt de vel o pe d f or t he treat me nt of 
k nee O A. It is c o m p os e d of t hree acti ve s u bsta nces: 
H yal ur o nic aci d ( H A ), 
 
. H A is a nat ural p ol ysacc hari de 
( gl yc os a mi n o gl yca n). T h e nat ur all y occ urri n g H A, as f o u n d s y n o vial fl ui d f or e x a m ple, s h o w 
hi g hl y elast o visc o us pr o perties a n d ha ve pr otecti ve, l u bricati n g, s h oc k a bs or bi n g, a n d str uct ure-
sta bilizi n g effects. Si nce t he elasticit y a n d visc osit y of s y n o vial fl ui d are directl y pr o p orti o nal 
t o t he c o nte nt a n d i nte grit y of H A, a n I A i njecti o n of H A  re prese nts a rati o nal a p pr oac h f or t he 
ma na ge me nt of k nee O A. I A i njecti o n of J T A- 0 0 4 is t heref ore i nte n d e d t o re pr o d uce t h e nat ural 
co m p ositi o n of s y n o vial fl ui d, a n d t h us, t o i m pr o ve pai n a n d j oi nt f u ncti o n.  
N -( 2, 6- dic hl or o p he n yl)- 4, 5- di h y dr o- 1H -i mi daz ol- 2-a mi ne has k n o w n a ntal gic a n d a nti-
i nfla m mat or y pr o perties ( S u n et al., 2 0 1 3, R o mer o- Sa n d o val et al., 2 0 0 7, Z ha n g et al., 2 0 1 1; 
see secti o n 2. 2 N o n-cli ni cal Data) a n d h u ma n plas ma pr o vi de gelificati o n pr o perties. T hese t w o 
acti ve s u bsta nces are e x pecte d t o e n h a nce t he J T A- 0 0 4 acti o n. 
F or f urt h er i nf or mati o n c o ncer ni n g t he des cri pti o n of J T A- 0 0 4 , please refer t o t he I n vesti gat or’s 
Br oc h ure (I B). 
2. 2  
N o n -cli nic al D at a 
2. 2. 1  A nti-i nfl a m m at ory pr o perties of J T A- 0 0 4 
T he a nti-i nfla m mat or y pr o perties of J T A - 0 0 4 were s h o w n 
 
 i n t hree i n de pe n de nt e x peri me nts. 
 
 
 


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2. 3  
Cli n ic al D at a 
J T A- 0 0 4 has n ot yet b ee n a d mi nistere d t o h u m a ns. H o we v er, cli nical e val uati o n of si milar 
pr o d ucts ca n b e f o u n d i n t he I B. 
2. 4  
Asse ss me nt of A ntici p ate d Be nefits a n d Ris ks 
Base d o n t he e x perie nce fr o m ot her H A - b ase d pre p arati o ns, reas o na bl y f oreseea ble ris ks li n ke d 
t o t he pr o d uct a n d t h e a d mi nistrati o n pr oce d ure ca n b e i de ntifie d. I n p artic ular, a ntici pat e d 
a d verse dr u g effects are s u m marize d i n Secti o n 8 of t his pr ot oc ol. M ost of t hese effects are mil d 
t o m o derate i n nat ur e, tr a nsie nt a n d ca n be a v oi de d or li mite d b y si m ple be dsi de pr oce d ures 
(e. g., a p pl yi n g ice o n t he i njecti o n site t o li mit l ocal reacti o ns).  
Risks li nke d t o M a n uf act uri n g 
J T A- 0 0 4 is ma n ufact ure d acc or di n g t o t he G o o d Ma n ufact uri n g Practis e ( E u drale x V ol 4, 
a n ne x es 1 a n d 1 3). T he w h ole ma n ufact uri n g pr ocess is als o e n vir o n me ntall y c o ntr olle d. T he 
fi nis he d pr o d uct is c o ntr olle d f or sterilit y a n d i de ntit y. 
Risks li nke d t o t he A d mi nistr ati o n Pr oce d ure  
Reas o na bl y f oreseea ble ris ks li n ke d t o t he a d mi nistrati o n pr oce d ure (i.e., i ntra-artic ular 
i njecti o n) ca n b e i de ntifie d. Mis uses or use err ors, s uc h as periartic ular i njecti o n, ma y o cc ur 
a n d are n ot differe nt fr o m t he o nes e x pecte d wit h c o m merci all y a vaila bl e H A pre p arati o ns. 
T heir occ urre nce, h o we ver, is e x pecte d t o be ver y l o w si nce t he pr o d uct will o nl y be 
a d mi nistere d b y trai ne d a n d e x perie nce d I n d e pe n d e nt P h ysicia n. 
 
 


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Risks li nke d t o t he I nvesti g ati o n al Me dici n al Pr o d uct 
J T A- 0 0 4 c o ntai ns t hree acti ve s u bsta nces: t he h yal ur o ni c aci d, t he h u m a n plas ma a n d a 2 
a dre n orece pt or a g o nist 1. M ost of t he re p orte d H A-relate d  a d v erse effects, s uc h as p ai n at t he 
i njecti o n site a n d l ocal j oi nt s welli n g, are mil d t o m o derat e i n n at ure, tra nsie nt a n d ca n be 
av oi de d or li mite d b y si m ple be dsi de pr oce d ures (e. g., a p pl yi n g ice o n t he i njecti o n site t o li mit 
l ocal reacti o ns). H y perse nsiti vit y t o H A has bee n re p orte d; t heref ore p atie nts wit h k n o w n 
h y perse nsiti vit y t o H A will be e x cl u de d fr o m t he st u d y at Scree ni n g.  
Gi ve n t he p har mac ol o gical effects of 
2 a dre n orece pt or a g o nists, it is p ossi ble t hat 
a d mi nistrati o n of a n y of t he teste d J T A- 0 0 4 stre n gt hs c o ul d i n d uce tra nsie nt h y p ote nsi ve 
epis o de. “I nstr ucti o ns f or Use” will t heref ore i ncl u de pr otecti ve meas ures s uc h as m o nit ori n g 
t he patie nt at t he I n vesti gati o n Site f or 4 5 mi n ut es p ost-i njecti o n. Precli nical t o xicit y st u dies 
ha ve s h o w n t hat J T A- 0 0 4, u p t o 1 0 ti mes t he h u ma n i njecte d d ose, d oes n ot ca use a n y t o xicit y, 
b ut o nl y tra nsi e nt mil d t o m o derate effects t hat disa p peare d 6 h o urs after i njecti o n. T hese effects 
were n ot c o nsi d ere d as a d verse effects d ue t o t heir nat ure ( Le wis et al., 2 0 0 2).  
R esi d ual ris ks ha ve t o be f urt her esti mate d d uri n g t he st u d y. 
P atie nt Be nefit 
D ur i n g t his trial, patie nts ca n recei ve eit her J T A- 0 0 4 or t he c o m merciall y a v aila ble 
visc os u p ple me nt, S y n visc- O ne ® . T here is e vi de nce t hat o ne si n gle I A i nj ecti o n of S y n visc-
O ne ®  re d uces j oi nt pai n a n d i m pr o ves f u ncti o n i n patie nts wit h k nee O A o ver a peri o d of at 
least 6 m o nt hs ( C he v alier et al., 2 0 1 0 ). J T A- 0 0 4 is a H A -bas e d pre parati o n e x pecte d t o act b y 
t he sa me mec ha nis m as t he c urre ntl y a vaila bl e visc os u p ple me nts. H o we v er, c o m pare d t o ot her 
H A - base d pre parati o ns, J T A- 0 0 4 c o ntai ns acti ve s u bsta nces wit h gelificati o n pr o perties w hic h 
ha s s h o w n t o sta bilize H A a n d a ntal gic a n d a nti-i nfla m mat or y pr o p erties. T he cli nical be nefits 
ex pecte d fr o m J T A- 0 0 4  si n gle I A i njecti o n are t heref ore a pr ol o n ge d relief of O A s y m pt o ms. 
In c o ncl usi o n, wit h t he d ata c ollecte d t o date, t he a ntici pate d be n efits-ris ks bala nce of J T A- 0 0 4 
is fa v o ura ble. A m ore precise esti mate of t his bal a nce will be o btai n e d after cli nical trials. 
                                                 
1 t he al p ha- 2 a dre ner gic rece pt or a g o nist 2, 6- Dic hl or o- N- 2-i mi d az oli di n yli de ne be nze na mi n e h y dr oc hl ori d e 




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3. 2  
St u d y O bjecti ve 
T he o bjecti ve of t his st u d y is t o assess t he s afet y a n d efficac y of J T A- 0 0 4 si n gle I A 
a d mi nistrati o n i n patie nts s ufferi n g fr o m s y m pt o matic O A of t he k nee at t he e n d of t he st u d y 
peri o d (at M o nt h 6).  
T his st u d y is a pr os pecti ve, ra n d o mize d, d o u b le- bli n d c o ntr olle d t w o-sta ge P hase II/ P has e III 
trial i ncl u di n g 3 test a n d 1 refere nce pr o d ucts t o select t he best test pr o d uct a n d de m o nstrate its 
s u peri orit y c o m pare d t o t he refere n ce treat me nt. 
 
 
 
 
 
3. 2. 1  Pri m ary E n d p oi nt  
T he pri mar y e n d p oi nt is t he Wester n O nt ari o a n d Mc Master U ni versities ( W O M A C ®  V A 3. 1 
pai n s u bscale (s u bscale A): t he i n di vi d ual c ha n ges i n W O M A C ®  V A 3. 1 pai n s u bscale sc ore 
bet wee n b aseli ne a n d M o nt h 6 will be calc ulate d a n d c o m pare d t o t he refere nce gr o u p. 
3. 2. 2  Sec o n d ary E n d p oi nts 
T he sec o n d ar y efficac y e n d p oi nts are: 
- W O M A C
®  V A 3. 1 pai n s u bscale ( W O M A C ®  s u bs cale A) at M o nt h 3 
- W O M A C ®  V A 3. 1 t otal sc ore o ver ti me 
3. 2. 3  Ex pl or at ory E n d p oi nts 
 
  
 
 
  
 
 
 
  
 
 
 


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3. 2. 4  S afety E n d p oi nts 
Fr o m t he treat me nt visit t o t he e n d of t he st u d y peri o d at M o nt h 6, patie nts will be s yste maticall y 
assesse d f or t he p ote ntial occ urre nce of a n y a d verse e ve nts ( A Es) a n d seri o us a d verse e v e nts 
( S A E), relate d or n ot t o t he pr o d uct or t he pr oce d ure, usi n g patie nt o pe n q uesti o n naire, p h ysical 
e x a mi nati o n (i ncl u di n g vital si g ns), a n d la b orat or y meas ure me nts.  
T he  fi nal St u d y Re p ort will t heref ore b e esta blis he d at M o nt h 6. 
3. 3  
M ai n St u d y Pr oce d ures 
3. 3. 1  P atie nt I nf or m ati o n a n d I nf or me d C o nse nt 
Bef ore a n y st u d y-relat e d pr oce d ure, t he Pri nci pal I n vesti gat or ( or a me m ber of t he i n vesti gati n g 
tea m, desi g nat e d b y t h e Pri nci pal I n vesti gat or) 
will gi ve detaile d a n d c o m pre he nsi ve 
i nf or mati o n re gar di n g all as pects of t he trial t o t he patie nt ( or his/ her le gall y a ut h orize d 
re pres e ntati ve), i ncl u di n g n ota bl y t he f oll o wi n g p oi nts: 
• P ur p ose, o bjecti ves, a n d nat ure of t he tri al (i ncl u di n g all perf or me d pr oce d ures) 
• C o n diti o ns u n der w hic h t he i n vesti gati o n are c o n d ucte d 
• C o nse q ue nces a n d si g nifi ca nce of t he i n vesti gati o n 
• E x pecte d be nefits a n d i n c o n ve nie nces a n d ris ks 
• T reat me nts a n d pr o ba bilit y f or ra n d o m assi g n me nt t o eac h treat me nt 
• Tests perf or m e d 
• Ri g ht t o recei ve t he c o nfir me d res ults of t he tests perf or me d, clearl y e x plai ne d 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 4 /1 1 4  
 
 
• Ri g hts of t he patie nt t o p h ysical, 
me ntal, a n d s ocial i nte grit y, di g nit y, pri vac y, 
c o nfi de ntialit y, a n d pr ot ecti o n of his pers o nal data a n d me dical rec or ds, i n acc or da n ce wit h 
t he Decl arati o n of Helsi n ki o n Et hical Pri nci ples f or Me dical R esearc h i n v ol vi n g H u ma n 
Patie nts, a d o pte d b y t h e Ge neral Asse m bl y of t he W orl d Me dical Ass ociati o n ( 1 9 9 6), wit h 
a me n d me nts, a n d a n y ot her a p plica ble C o m m u nit y a n d nati o nal la ws, re g ulati o ns, 
g ui da nce, g ui deli nes, a n d pri nci ples  
• Me dical c o nfi d e ntialit y - Rec or di n g a n d pr otecti o n of patie nt data 
• Ac cess a n d s cr uti n y of p ers o nal data a n d i nf or mati o n d uri n g i ns pecti o n b y t he A ge ncies 
a n d a n y ot her pr o perl y a ut h orise d pers o ns, pr o vi de d t hat s uc h i nf or mati o n is treate d as 
strictl y c o nfi d e ntial a n d is n ot ma de p u blicl y a v aila ble 
• R i g ht t o ref use t o partici pate or wit h dra w fr o m t he cli nical trial, at a n y ti me, wit h o ut a n y 
res ulti n g detri me nt, p e nalt y or l oss of be n efits t o w hic h t he patie nt is ot her wise e ntitle d, 
n ota bl y i n ter ms of me di cal care, f oll o w- u p, a n d p atie nt- p h ysi cia n rel ati o ns hi p 
• Pr o visi o n ma de f or i ns ur a nce or i n d e m nit y t o c o v er t he lia bilit y of b ot h t h e S p o ns or a n d 
Pri nci pal I n vesti gat or (i ncl u di n g all me m bers of t h e his/ her tea m a n d a n y ot her partici pa nts 
t o t he trial) 
T his detaile d i nf or mati o n will be gi ve n i n b ot h oral a n d writte n f or ms ( Patie nt I nf or mati o n 
Letter a n d I C F), i n a p pr o priate a n d clear ma n ner, w or de d i n t he patie nt’s m ot her t o n g ue, usi n g 
n o n -tec h nical a n d practical la n g u a ge a n d ter ms t hat are easil y u n derst o o d b y t he p atie nt ( or 
his/ her le gal l y a ut h orize d re pres e ntati ve). T he i nf or mati o n pr o vi de d will n ot i ncl u de a n y t er m 
or se nte nce t hat a p p ears t o wai ve a n y of t he patie nt's le gal ri g hts, or a p pears t o release t he 
I n v esti gat or, I nstit uti o n/I n v esti gati o n Site, S p o ns or, S p o ns or’s re prese nt ati ves, a n d/ or t he 
M o nit or fr o m lia bilit y f or ne gli ge nce. 
T he patie nt ( or his/ her le gall y a ut h orize d re prese ntati ve) will t he n be pr o vi de d a m ple ti me a n d 
o p p ort u nit y t o i n q uire a b o ut details a n d as k a n y q u esti o ns a b o ut t he trial t o t he Pri nci pal 
I n v esti gat or ( or t h e pers o n w h o c o n d ucts t he i nf or me d c o nse nt pr ocess), a n d t o deci de w het her 
or n ot t o partici pate i n t he trial. All q uesti o ns a b o ut t he trial will be a ns were d t o t he satisfacti o n 
of t he patie nt ( or his/ her l e gall y a ut h orize d re prese ntati ve). 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 5 /1 1 4  
 
 
If t he patie nt ( or his/ her le gall y a ut h orize d re prese ntati ve) a grees t o partici pate, he/s he will be 
i n vite d t o date a n d si g n t he I C F. O ne ori gi nal c o p y of t he I C F si g ne d b y t h e patie nt ( or his/ her 
le gall y a ut h orize d re prese ntati ve) a n d b y t h e Pri nci pal I n vesti gat or ( or t he p ers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt pr ocess) will be gi v e n t o t he patie nt ( or his/ her le gal l y 
a ut h orize d re pres e ntati ve). T he ot her ori gi nal c o p y d ul y si g ne d will be ke pt i n t he I n v esti gat or 
Site File (I S F) at t he I n vesti gati o n Site. 
T he  Pri nci pal I n vesti gat or will t he n c o m plete a n d si g n t he e C R F, t here b y attesti n g a n d 
rec or di n g t hat si g ne d I C F has bee n o btai ne d fr o m t he patie nt.  
As s o o n as t he I C F has b ee n si g ne d b y t h e p atie nt a n d t he Pri nci p al I n vesti gat or, t he “ Patie nt 
Car d” will be c o m plete d a n d gi v e n t o t he patie nt. 
N ote: T he S p o ns or h as pre pare d a te m plate of t he I C F w hic h e m b o dies t he I C H G C P re q uire d 
ele me nts a n d a n y l ocal rele va nt re g ulati o ns t o be discl ose d f or t he c o nse nt t o be le gall y 
effecti ve. T he Pri nci p al I n vesti gat or h as t he fi nal res p o nsi bilit y f or t h e fi nal prese ntati o n of t he 
IC F. T h e fi n al versi o n of t he pr ot oc ol a n d t he Patie nt I nf or mati o n S heet a n d I C F will pre vi o usl y 
be n otifie d t o t he rele va nt A ge ncies a n d s u b mitte d t o a n d a p pr o ve d a n d/ or pr o vi de d a fa v o ura ble 
o pi ni o n i n writi n g b y t h e rele va nt E Cs b ef ore t he b e gi n ni n g of t he tri al. T hese d oc u me nts (a n d 
t he I B) m a y als o nee d t o be s u bse q ue ntl y re vise d d uri n g t h e c o urse of t he i n vesti gati o n, 
w he ne ver i m p orta nt ne w i nf or mati o n t hat ma y b e rele va nt t o t he patie nts' safet y a n d/ or re-
e val uati o n of t he ris k/ be nefit rati o bec o mes a vail a ble. I n t his case, a n y c h a n ge, u p date, a n d/ or 
a me n d me nts t o t hese d oc u me nts will first be n otifie d t o t he rele va nt A ge n ci es a n d s u b mitte d t o 
a n d a p pr o ve d b y t he E Cs pri or t o a n y s u b missi o n t o t he patie nts (a n d all c o ncer ne d Pri nci pal 
I n v esti gat ors a n d I n v esti gati n g Sites) e x ce pt w he n it is necessar y t o eli mi nate a p pare nt 
i m me diate hazar ds t o p atie nts. T he I n v esti gat or ma y n ot perf or m a pr oce d ure o n a p atie nt 
wit h o ut  ne w si g ne d I C F if t he pr oce d ure was n ot me nti o ne d i n t he ori gi nal I C F. 
3. 3. 2  R a n d o mis ati o n  a n d Bli n di n g Pr oce d ures 
R a n d o mis ati o n a n d Bli n de d Tre at me nt All oc ati o n  
Patie nts will be ra n d o mise d i n a 1: 1: 1: 1 rati o t o J T A- 0 0 4 gr o u ps or Refere nce gr o u p   
 
acc or di n g t o a ra n d o misati o n sc he me t hr o u g h I nteracti ve 
We b Res p o nse S yste m 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 6 /1 1 4  
 
 
(I W R S). T he I W R S will o nl y be accessi ble t hr o u g h a sec ure we bsite t o a ut h orise d users wit h 
vali d l o gi n a n d pass w or d.  
O nce t he eli gi bilit y a n d p artici pati o n of t he patie nt has bee n c o nfir me d: 
- T he I W R S will deter mi ne t he treat me nt gr o u p of t he patie nt a n d all ocate a treat me nt 
n u m ber t o t he patie nt i n or der t o ass o ciate a s pecific treat me nt (I M P or Refere n ce) t o a 
s pecific patie nt. 
- A n otificati o n of t he treat me nt n u m ber wit h o ut refere n ce t o t he nat ure of t he treat me nt 
( bli n de d n otificati o n) 
will be se nt t o t he Pri nci pal I n vesti gat or a n d S p o ns or’s 
re pres e ntati ve.  
- A n otificati o n of t he treat me nt n u m ber wit h t h e nat ure of t he treat me nt ( u n bli n de d 
n otificati o n) will be se nt t o t he S p o ns or’s Pr o d ucti o n Ma na ger i n or der t o l a bel t he 
treat me nt wit h t he treat me nt n u m ber b ut als o t o t he l ocal P har macist a n d t he I n d e pe n d e nt 
P h ysicia n. 
Tre at me nt Pre p ar ati o n, P atie nt Tre at me nt a n d Bli n di n g of t he St u dy  
N ot later t ha n t he da y bef ore t he tr eat me nt Visit # 2, t he kit c o ntai ni n g t he treat me nt (I M P or 
refere nce pr o d uct) la belle d wit h t he treat me nt n u m ber will be s hi p pe d t o t he H os pital P har mac y. 
T he I M P will be rec o nstit ute d b y t he p har macist of t he h os pital at t he re q uest of t he I n d e pe n de nt 
P h ysicia n. T he refere n ce pr o d uct d oes n ot nee d rec o nstit uti o n b ut t he I n d e pe n de nt P h ysi cia n 
m ust  als o re q uir e t he pre parati o n b y t h e l ocal. Bef ore t h e i njecti o n ti me, t he St u d y N urs e will 
pic k u p t he rec o nstit ute d I M P or t he r efere nce pr o d uct at t he H os pital P har mac y a n d bri n g it, 
i nt o a bli n di n g tra nsfer b o x, t o t he I n d e pe n de nt P h ysicia n. 
Alt h o u g h s hi p pi n g p ac k a ge s will be i de ntical, J T A- 0 0 4 a n d refere nce pr o d ucts will n ot be 
pr o vi de d i n t he sa me pri mar y p ac k a gi n g. 
T he st u d y will be c o n d ucte d d o u ble- bli n d wit h refere nce t o t he e v al uati o n of trial res ults. 
- T he I n vesti gat ors will be bli n d t o treat me nt assi g n me nts wit h res pect t o t he patie nt 
e val uati o n. T he y will recr uit, i ncl u de a n d ass ess p atie nts d uri n g t he w h ole st u d y f oll o w- u p 
peri o d, b ut will n ot treat t he patie nts. I n vesti gat ors will t heref ore n ot be a ware of treat me nt 
assi g n me nt. 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 7 /1 1 4  
 
 
- Patie nts will be bli n d t o treat me nt assi g n me nt, as t he f o ur patie nt gr o u ps will u n der g o t he 
sa me i ntra-artic ular i njecti o n ( perf or me d b y t he I n de pe n de nt P h ysicia n). As t he a p peara n ce 
of t he res us pe n de d J T A- 0 0 4 is differe nt fr o m t he refere nce, a p pr o priate m eas ures m ust be 
ta ke n t o e ns ure t hat t he patie nt is u na ble t o see t he i njecte d treat me nt d uri n g t he i njecti o n 
pr oce d ure. T he i njecti o n pr oce d ure will be i de ntical i n all patie nts. 
- O nl y t he I n de pe n d e nt P h ysicia n a n d t he l ocal P har macist will n ot be bli n d t o treat me nt 
assi g n me nts, as t he y will perf or m t he rec o nstit uti o n or t he i ntra-artic ular a d mi nistrati o n of 
t he I M P.  
U n bli n di n g is restri cte d t o e mer ge n c y sit uati o ns a n d s h o ul d o nl y b e use d u n der circ u msta nces 
i n w hic h k n o wle d ge of t he treat me nt gi ve n d uri n g t he trial is necessar y f or t he pr o per treat me nt 
a n d me dical care of t he p atie nt. I n t he case of me dical e mer ge n c y, dec o di n g will be d o ne f or a 
patie nt b y c h o osi n g t h e “ U n bli n di n g” o pti o n of t he I W R S t hat all o ws t he user t o lear n t he n at ure 
of t he treat me nt ta ke n b y a patie nt i n. U n der n or mal circ u msta nces, t his o pti o n is o nl y a v aila ble 
t o Pri nci pal I n v esti gat ors/ C o-I n vesti gat ors. I n a d diti o n, t he date of u n bli n di n g m ust be rec or de d 
i n t he a p pr o priate pl ace i n t he e C R F a n d si g ne d b y t he Pri nci pal I n vesti gat or. 
3. 3. 3  Pr oce d ures per Tre at m e nt Gr o u p 
Patie nts will u n der g o d uri n g Baseli ne/ Treat me nt visit ( Visit # 2) a si n gl e 2 ml or 4 ml I A 
a d mi nistrati o n of J T A- 0 0 4 or 6 ml of refere n ce treat me nt i nt o t he k nee j oi nt. T he rec o m me n de d 
nee dle siz e is a 2 1- ga u ge nee dle ( or alter nati vel y a 1 9- ga u ge nee dle) b ut t he c h oice of t he nee dle 
size is at t he I n d e pe n d e nt P h ysicia n’s discreti o n. T he size of t h e nee dle m ust be rec or de d i n t he 
a p pr o priate pl ace i n t he e C R F. 
Af ter a d mi nistrati o n, t he patie nt will be as ke d t o re mai n at t he I n vesti gati o n Site f or 4 5 mi n utes. 
F or m or e i nf or mati o n re gar di n g t he a d mi nistrati o n pr oce d ure of i n v esti gati o nal m e dici nal 
pr o d ucts, please refer t o Secti o n 6 of t h is pr ot oc ol. 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 8 /1 1 4  
 
 
3. 4  
P ati e nt E v al u ati o n 
3. 4. 1  Cli nic al Ev al u ati o n 
I n or der t o a v oi d bias, (self-re p orte d) cli nical e val uati o n s h o ul d be t he first pr oce d ure d uri n g a 
st u d y visit bef ore disc ussi n g wit h t h e Pri nci pal I n vesti gat or or t he St u d y N urse/ C o or di nat or. 
T he patie nt m ust c o m plete t he q uesti o n naires al o ne wit h o ut a n y o utsi de i nter ve nti o n ( Br ya nt 
a n d Fer na n des, 2 0 1 1). 
T he f oll o wi n g cli nical assess me nts will be e val uat e d: 
- W O M A C
®  V A 3. 1 (see d etails i n secti o n 5. 3. 1 a n d A n ne x 1) : at eac h f oll o w- u p visit fr o m 
t he baseli ne/treat me nt visit t o t he e n d of t he st u d y f oll o w u p at M o nt h 6, patie nts will be 
assesse d usi n g t he W O M A C ® I n d e x f or k nee O A  se verit y a n d s y m pt o ms. T o t his e n d, eac h 
I n v esti gati n g Site will recei ve vali date d W O M A C®  I n d e x es i n t he la n g ua ge of t he patie nt 
a n d t he W O M A C ®  I n de x User G ui de i n E n glis h. 
 
 
 
.  
- 
 
 
 
 
3. 4. 2  Bi ol o gic al Ev al u ati o n 
At baseli ne/treat me nt , a n d 3 a n d 6 m o nt hs after treat me nt, t he effects of t he i n vesti gati o nal 
me dici nal pr o d uct s o n k nee O A  se v erit y will als o be e x pl ore d 
 
 
 
T his met h o d ma y be t h us a n o p p ort u nit y t o gat her  m ore i nf or mati o n o n  t he 
m o de of acti o n  a n d efficac y of J T A-0 0 4 .  


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 3 9 /1 1 4  
 
 
3. 4. 3  R a di ol o gic al Ev al u ati o n 
T he Pri nci pal I n vesti gat or or t he ra di ol o gist m ust gra d e t he se v erit y of O A acc or di n g t o 
Kell gre n- La wre nce Ra di o gra p hic Sc ore. F or t he p ur p ose of t his st u d y, ra di o gra p hic assess me nt 
is o nl y re q uire d o n t he tar get k nee 
 
 
 
 
 
3. 5  
S t u d y P o p ul ati o n a n d Selecti o n 
3. 5. 1  Eli gi bility 
Pri or t o patie nt i n cl usi o n a n d ra n d o misati o n, a Scree ni n g peri o d is pla n ne d t o all o w v erificati o n 
of patie nt eli gi bilit y.  
 
 
 
 
 
 
 
 
T he re is a ra n d o m ge n der distri b uti o n i n t his st u d y. T he patie nts will n ot be selecte d acc or di n g 
t o t heir ge n der b ut acc or di n g t o i ncl usi o n a n d e x cl usi o n criteria as set o ut i n t his pr ot oc ol. Si nce 
t here are n o k n o w n or e x pecte d ge n der differe nces i n efficac y, a n d/ or safet y pr ofile of t he st u d y 
pr o d ucts, n o s u b gr o u p a n al ysis wit h ge n der as a v aria ble is pla n ne d.  
O nc e ra n d o mise d (all ocati o n t o eit her J T A- 0 0 4  or refere nce gr o u p), patie nts will recei ve 
a p p oi nt me nt f or t he si n gl e I A i njecti o n.  
3. 5. 2  I ncl usi o n Criteri a 
All patie nts m ust satisf y  A L L t he f oll o wi n g criteria at st u d y e ntr y: 
- Male/fe male a ge d bet wee n 5 0 t o 7 9 years. 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 0 /1 1 4  
 
 
- A m b ulat or y (a ble t o wal k u nassiste d, t he use of a cr utc h or a wal ki n g stic k is all o we d) 
- Dia g n os e d 
wit h pri mar y k nee 
O A, f ulfilli n g t he f oll o wi n g 
A merica n C olle ge of 
R he u mat ol o g y ( A C R) criteria at t he tar get k nee:  
 Pai n ≥ 4 0 m m o n a 0- 1 0 0 m m V A S d uri n g t he 3 da ys prece di n g t h e d ate of t he 
Scree ni n g Visit (see A n ne x 2) 
 M or ni n g stiff n ess n ot e x cee di n g 3 0 mi n utes  
 Kell gre n- La wre nce gra d e II or III (c o nfir me d b y X-ra y wit hi n t he last 6 m o nt hs) 
- I ns ufficie nt/faile d res p o nse t o a nal gesics a n d/ or N S AI D  
- Willi n g a n d a ble t o a bstai n fr o m p h ysical t hera p y of t he k nee a n d k nee braces f or t he e ntire 
d urati o n of st u d y 
- Ca pa ble t o u n dersta n d a n d c o m pl y wit h st u d y re q uire me nts a n d t o pr o vi de a writte n, date d, 
a n d si g n e d i nf or me d c o ns e nt pri or t o a n y st u d y pr oce d ure f or p artici pati o n i n t he st u d y a n d 
tra ns missi o n of pers o nal "a n o n y mize d" d ata 
3. 5. 3  Excl usi o n Criteri a 
T he f oll o wi n g criteria s h o ul d be c hec k e d at t he ti me of st u d y e ntr y. If A N Y e xcl usi o n criteri o n 
a p plies, t he p atie nt m ust n ot be i ncl u de d i n t he st u d y: 
C urre nt sy m pt o ms a n d/ or si g ns rel ate d t o t he dise ase u n der st u dy 
- Is olat e d s y m pt o matic fe m or o patellar O A of t he t ar get k nee 
- Hist or y of tr a u ma or s ur ger y or art hr osc o p y at t he tar get k nee wit hi n 6 m o nt hs bef ore 
i ncl usi o n  
- C o nc o mita nt i nfla m mat or y dise ase or ot h er c o n diti o n affecti n g t he j oi nts (e. g., r he u mat oi d 
art hritis, se ptic art hritis, i nfla m mat or y j oi nt disease, meta b olic b o n e dis ease, ps ori asis, 
g o ut, micr ocr ystalli ne art hr o pat hies/c h o n dr ocalci n osis, Pa get’s disease) 
- A n y m usc ul os kel etal c o n diti o n (s uc h as hi p oste oart hritis, a m p utati o n, ne ur ol o gic dis or der ) 
t hat w o ul d i m pe de meas ure me nt of efficac y at tar get k n ee 
- Tar get k nee pr ost hesis pl a n ne d wit hi n 1 2 m o nt hs after t he Scree ni n g Visit  
C urre nt or previ o us di a g n oses, si g ns a n d/ or sy m pt o ms 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 1 /1 1 4  
 
 
- U nc o ntr olle d dia betes mellit us, e n d-sta ge h e patic or re nal diseas e d oc u me nte d i n t he 
patie nt’s file  
- C urre nt ( or wit hi n t he last 5 years pri or t o e nteri n g t he st u d y) hist or y of s oli d or 
hae mat ol o gical ne o plasia or b o ne marr o w tra ns pla ntati o n (e x ce pt f or basal cell carci n o ma 
a n d c o m pletel y e x cise d s q ua m o us cell carci n o ma) 
- Ot her se v ere ac ute or c hr o nic me dical or ps yc hiatric c o n diti o ns or pre- dis p ositi o ns or 
la b orat or y a b n or malities, as j u d ge d b y t he I n vesti gat or 
- C urre nt or past hist or y of c oa g ulati o n dis or ders, as j u d ge d b y t he I n vesti gat or  
- H y p erse nsiti vit y t o a n y c o m p o ne nts of H A- bas e d i njecti o n pr o d ucts 
- Hist or y of h y perse nsiti vit y t o h u ma n bi ol o gi cal material i ncl u di n g bl o o d a n d bl o o d deri ve d 
pr o d ucts, p ote ntial e x ci pie nts a n d resi d ues fr o m ma n ufact uri n g pr ocess, d oc u me nte d 
cli nicall y or b y l a b orat or y tests 
- H y p erse nsiti vit y t o a via n pr otei ns 
- Lif e e x pecta nc y less t h a n 6 m o nt hs 
 
C urre nt or previ o us tre at me nt 
- Partici pati o n i n a n ot her cli nical st u d y wit hi n 6 m o nt hs pri or t o Scree ni n g  
- Patie nts pre vi o usl y treate d wit h J T A- 0 0 4 
- Treat me nt: 
 Wit hi n 6 m o nt hs pri or t o Scree ni n g: i ntra-artic ular h yal ur o ni c aci d i njecti o n at t he tar get 
k nee 
 Wit hi n 2 m o nt hs pri or t o Scree ni n g: i ntra-artic ular gl uc oc ortic oi ds at t he tar get k n ee 
- C urre nt c he m o-, ra di o- or i m m u n o-ca ncer-t hera p y or i m m u n os u p pressi ve t hera p y 
- C urre nt a nti- h y p erte nsi v e me dicati o n t he effects of w hic h are k n o w n t o be p ote ntiate d b y 
a si n gle d os e of cl o ni di ne  
- C urre nt ( or wit hi n 6 m o nt hs pri or t o Scree ni n g) illicit dr u g a b us e 
S afety as pects c o n cer ni n g fe m ale s u bjects of c hil d be ari n g p ote nti al 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 2 /1 1 4  
 
 
- Fe males w h o are pre g n a nt, lactati n g or w o m a n wit h c hil d beari n g p ote ntial (last me nstr ual 
blee di n g less t ha n 1 2 m o nt hs a g o) u n willi n g t o us e me dicall y acce pta ble c o ntrace pti o n, or 
w o me n 
wit h c hil d beari n g p ot e ntial u n willi n g t o perf or m a pre g n a nc y test bef or e 
a d mi nistrati o n of st u d y tr eat me nt.  
Ot her excl usi o n criteri a 
- B o d y Mass I n d e x ( B MI) of 3 5 k g/ m 2 or greater 
 
 


C O N FI D E N TI A L 
 
J T A - K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 3 /1 1 4  
 
 
3. 7  
Ge ner al O ver vie w of Visits a n d Pr oce d ures 
A n o ver vie w of t he st u d y assess me nts a n d pr oce d ures is gi ve n i n Ta ble 1 bel o w. St u d y 
pr oce d ures are descri be d f or J T A- 0 0 4 pr o d ucts a n d refere nce. 




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 5 /1 1 4  
 
 
4  
D E T AI L E D S C H E D U L E O F VI SI T S A N D P R O C E D U R E S 
B ef ore a n y st u d y-rel ate d pr oce d ure, t he Pri nci p al I n v esti gat or ( or a me m b er of his/ her tea m) 
will gi ve, b ot h i n oral a n d writte n, detaile d a n d c o m pre he nsi ve i nf or mati o n re gar di n g all as pects 
of t he trial t o t he patie nt (i ncl u di n g t he Patie nt I nf or mati o n S heet a n d I C F). After si g ni n g t he 
I C F, t he patie nt will be gi ve n a u ni q ue Patie nt I de ntificati o n N u m ber. 
4. 1  
S cree ni n g Peri o d ( Visit # 1)  
Visit # 1 will i ncl u de t he f oll o wi n g pr oce d ures t o be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 2  
R a n d o mis ati o n/ B aseli ne/ Tre at me nt Visit ( Visit # 2) 
Baseli ne/ Treat me nt ( Da y 0) Visit # 2 
 
y.  Bef ore ra n d o misati o n, t he i n vesti gat or or t he st u d y n urse will call t he patie nt t o 
c o nfir m his/ her p artici pati o n t o t he st u d y. Pr o m ptl y after p atie nt partici p ati o n c o nfir me d, t he 
patie nt will be gi ve n a u ni q ue Ra n d o misati o n N u m ber a n d will be all ocate d t o o ne of t he f o ur 
st u d y ar ms (J T A- 0 0 4 5 0 2ml  or 4 ml, J T A- 0 0 4 1 0 0 2 ml, or Refere n ce) t hr o u g h I W R S platf or m. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 6 /1 1 4  
 
 
D uri n g Visit # 2, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D ur i n g t he w h ol e st u d y f oll o w- u p after I A of J T A or refere n ce pr o d uct, patie nts m ust n ot 
recei v e a n y I A tr eat me nt i n t he tar get k nee (eit her h yal ur o nic aci d or c ortic oi ds i njecti o n). If 
s uch I A i njecti o n is perf or me d, reas o ns m ust be d oc u me nte d i n t he c o nc o mita nt me dicati o ns 
secti o n a n d t he patie nt m ust be wit h dra w n fr o m st u d y. T he “ Earl y Ter mi nati o n F or m” m ust be 
co m plete d i n s uc h cas e. 
4. 3  
F oll o w- u p Visit # 3 ( Wee k 2   
) 
D ur i n g t his visit, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 7 /1 1 4  
 
 
 
 
 
 
 
 
4. 4  
F oll o w- u p Visit # 4 ( M o nt h 3   
) 
D ur i n g t his visit, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 5  
F oll o w- u p Visit # 5 ( M o nt h 6   
) 
D ur i n g t his visit, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 8 /1 1 4  
 
 
5  
R A TI O N A L E F O R T H E S T U D Y D E SI G N 
5. 1  
S t u d y R ati o n ale 
B o ne T h era p e utics S. A. has de vel o pe d a n e n h a nce d H A -base d visc os u p ple me nt (J T A- 0 0 4 ) 
wit h sta bilisi n g effects o n t he j oi nt mec ha nical i nte grit y. C o m pare d t o ot her H A - base d 
pre parati o ns, t he n o v elt y of J T A- 0 0 4 lies i n its c o m p ositi o n a n d f or m ulati o n e x pecte d t o e xte n d 
its acti o n, as J T A- 0 0 4 i ncl u des acti ve s u bsta nces6 wit h gelificati o n pr o perti es a n d a ntal gic a n d 
a nti-i nfla m mat or y pr o perties. Si n gle i njecti o n of J T A-0 0 4  is t heref ore i nte n de d t o pr o vi de 
pr ol o n ge d  relief of O A s y m pt o ms. 
T he o verall g o al of J T A- K O A 1 is t o deter mi ne J T A- 0 0 4 safet y, select t he b est stre n gt h i n ter ms 
of e fficac y a n d c o m pare it t o a n a p pr o ve d visc os u p ple me nt. 
5. 2  
T y pes of Oste o art hritis 
K nee O A is classifie d i n f o ur s e verit y gra des, fr o m d o u btf ul t o se v ere, acc or di n g t o t he 
Kell gre n- La wre nce gra di n g s yste m. T his cate g orical scale i nc or p orates i m p orta nt ra di o gra p hic 
feat ur es of O A (see A n ne x 5). 
In or der t o ha ve a st u d y p o p ulati o n as h o m o ge n o us as p ossi ble a n d t o a v oi d patie nts wit h 
d o u btf ul a n d se vere O A, t he st u d y will o nl y i n cl u de patie nts wit h Gra de II a n d Gra de III 
s y m pt o matic k nee O A. 
5. 3  
Cli n ic al a n d Bi ol o gic al E v al u ati o n T o ols 
5. 3. 1  Cl i nic al Ev al u ati o n 
T he us ual t o ol t o assess pai n is t he V A S. T his t o ol all o ws relia ble assess me nt of s y m pt o ms 
( Brei vic k et al., 2 0 0 8). A V A S is a meas ure me nt i nstr u me nt de dicate d t o t he e val uati o n of 
c haracteristics, attit u des or s y m pt o ms t h at is beli e ve d t o ra n ge acr oss a c o nti n u u m of val ues 
a n d ca n n ot easil y be directl y meas ure d (e. g., pai n or ge neral healt h stat us i n t his partic ular 
st u d y). I n V A S, t he s y m pt o m t hat a patie nt feels ra n ges acr oss a c o nti n u u m fr o m n o s y m pt o m 
                                                 
6   H u ma n plas ma a n d t h e al p ha- 2 a dre ner gic rece pt or a g o nist 2, 6- Dic hl or o- N- 2-i mi d az oli di n yli de ne be nze na mi ne 
h y dr oc hl ori de  


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 4 9 /1 1 4  
 
 
( 0 m m) t o e xtre me s y m pt o m ( 1 0 0 m m) o n a h oriz o ntal li ne of 1 0 0 m m i n le n gt h. T he patie nt 
mar ks o n t he li ne t he p oi nt t hat he/s he feels, re prese nts his/ her p erce pti o n of his/ her c urre nt 
stat us of s y m pt o m. T he V A S sc ore is deter mi ne d b y meas uri n g i n milli metres fr o m t he left 
ha n d e n d of t he li ne t o t h e p oi nt t hat t he patie nt mar ks (see A n ne x 2). 
W O M A C ®  
Cli nical e val uati o n of t he k nee is us uall y p erf or me d usi n g d e dicate d o pe n q uesti o n naires a n d/ or 
sc ores, w hi c h ha v e b ee n de vel o pe d a n d est a blis he d i n or der t o ass ess k nee pai n, k nee stiff ness, 
a n d/ or k nee f u ncti o n ( p h ysical disa bilit y) i n patie nts wit h pri mar y O A, b ut als o f or ot her k nee 
diseases. T hes e i ncl u de t he Le q ues n e a n d W O M A C ®  Sc ores. 
P atie nts will be assesse d usi n g t he W O M A C ®  I n d e x. T he W O M A C®  Oste oart hritis I n d e x is a 
tri- di me nsi o nal, self-a d mi nistere d, patie nt‐ce ntre d healt h stat us q uesti o n naire f or k nee disease 
se verit y a n d oste o necr osis s y m pt o ms (see A n ne x 1). 
Alt h o u g h t he Le q ues ne s c ore is fre q ue ntl y us e d a n d cite d i n t he literat ure, it prese nts a n u m ber 
of li mitati o ns a n d pitfalls re gar di n g its use i n cli nical practice. I n dee d, it has de m o nstrate d its 
usef ul ness a n d effi cac y as a n o utc o me f u ncti o nal meas ure after hi p s ur ger y o nl y ( Le q ues n e et 
al.,  2 0 0 3; St uc ki et al., 1 9 9 8). B y c o ntrast, t he W O M A C®  I n de x, w hic h all o ws a t h or o u g h 
e val uati o n of pai n, stiff ness, a n d f u ncti o n (t hr o u g h 3 s u bscales wit h a t otal of 2 4 q uesti o ns), has 
bee n wi del y v ali date d a n d use d: it has bee n st a n dar dise d a n d teste d f or relia bilit y, v ali dit y, a n d 
res p o nsi ve ness i n p atie nts wit h k nee O A i n vari o us cli nical setti n gs, i ncl u di n g b ot h m e dical 
( p har mac ol o gi cal) a n d s ur gical ma na ge me nt (t otal hi p re place me nt) of patie nts ( Bella m y, 2 0 0 2; 
Bella m y, 2 0 0 5; Bella m y et al., 1 9 8 8). 
M ore o ver, a n d c o ntr aril y t o t he ot her k nee sc ores, t he W O M A C
®  I n de x is a vaila ble n ot o nl y i n 
L i kert scal e f or mat b ut als o i n V A S f or mat. I n dee d, V A S has b ee n s u g geste d t o be m ore 
re pr o d uci ble a n d se nsiti ve c o m pare d t o Li k ert scales ( Geric h et al., 2 0 0 7). 
As f or pri mar y e n d p oi nt, t he W O M A C ®  I n de x pai n s u bscale will be use d. 
H o w e ver, t he W O M A C ®  I n de x t otal sc ore, stiff ness a n d f u ncti o n s u bscales will be use d as 
sec o n dar y e n d p oi nts. 
T he  mi ni mal cli nicall y i m p orta nt differe nce ( M CI D) re pres e nt t he s mallest differe n ce i n s c ore 
i n t he d o mai n of i nterest w hic h patie nts percei ve as be neficial a n d w hic h w o ul d ma n date, i n t he 
a bse nce of tr o u bles o me si de effects a n d e x cessi ve c ost, a c ha n ge i n t he patie nt’s ma na ge me nt 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 0 /1 1 4  
 
 
( Beat o n et al., 2 0 0 2). F or t he 
W O M A C®  I n de x pai n s u bscale, t he M CI D, e x presse d i n a 
perce nt a ge of t he b aseli ne is defi ne d i n t he literat ure as a differe nce of 2 0 % or 1 0 m m of t he 
baseli ne ( E hri c h et al., 2 0 0 0; Bella m y et al, 2 0 0 5). 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 1 /1 1 4  
 
 
5. 4  
R ati o n ale f or C h oice of Refere nce Gr o u p 
Acti ve c o m parat ors s h o ul d be c h ose n wit h care. A n e x a m ple of a s uita ble acti ve c o m parat or 
w o ul d be a wi del y us e d t hera p y w h ose efficac y i n t he rele va nt i n dicati o n has bee n clearl y 
esta blis he d a n d q ua ntifie d i n well desi g ne d a n d well d oc u me nte d s u peri orit y trial(s) a n d w hic h 
ca n be relia bl y e x pecte d t o e x hi bit si milar efficac y i n t he c o nte m plate d acti ve c o ntr ol trial (I C H 
E 9 ). O pti mall y, t his is de m o nstrate d b y fi n di n g t hat t he acti ve treat me nt i nte n de d f or use as t he 
acti ve c o ntr ol w as relia bl y f o u n d  s u p eri or t o place b o.  
F or t he se reas o ns, a m o n g t he se veral c o m merciall y a vaila ble H A pre p arati o ns, S y n visc- o n e®  
was selecte d as refere n ce i n t his cli nical trial. I n d ee d, S y n visc- O ne ®  is a n a p pr o ve d a n d well-
esta blis he d treat me nt of k nee O A i n E ur o p e a n d U S A. T hree cli nical tri als ha ve s h o w n t hat 
S y n visc- O ne ®  is s afe a n d effecti ve b y pr o vi di n g st atisticall y si g nifica nt a n d cli nicall y rele va nt 
pai n relief i n p atie nts s ufferi n g fr o m k nee O A. T he first st u d y ( C o nr ozier et al., 2 0 0 9) 
de m o nstrate d t hat a si n gl e 6 ml i ntra-artic ular i njecti o n of S y n visc- O ne ®  is as safe a n d effecti ve 
t hat m ulti ple i njecti o n ( 2 ml, t hree ti me, o ne wee k a p art) i n pr o vi di n g staticall y si g nifica nt, 
cli nicall y rele va nt pai n relief, as meas ure d b y W O M A C ®  A pai n sc ores at 2 4 wee ks. A c ha n ge 
fro m baseli ne at 2 4 wee ks of ˗ 3 4. 9 m m ( c orres p o n di n g t o a mea n perce nta ge c ha n ge i n pai n 
fr o m baseli ne of 5 4. 7 %). T he sec o n d st u d y ( C he valier et al., 2 0 1 0), a c o ntr olle d ra n d o mise d, 
m ultice nter, d o u ble- bli n d st u d y, c o m pares a si n gl e ( 6 ml) I A i njecti o n of S y n visc- O ne ® t o a 
place b o ( P B S). T his st u d y de m o nstrate d t hat a si n gle 6 ml i ntra-artic ular i njecti o n of S y n visc-
O ne ®  pr o vi des staticall y si g nifica nt, cli nicall y rele va nt pai n relief, as meas ure d b y W O M A C®  
A pai n sc ores o ver 2 6 wee ks, wit h a m o dest differe nce c o m p are d wit h place b o (˗ 3, 0 m m, S E M 
1, 5 2, p = 0. 0 4 7). A n esti mate d c ha n ge fr o m baseli ne o ver 2 6 wee ks of ˗ 2 1 m m (c orres p o n di n g 
t o a mea n p erce nta ge c h a n ge i n pai n fr o m bas eli ne of 3 6 %) is o bser ve d f or S y n visc- O ne ®  
vers us a n esti mate d c ha n ge fr o m baseli ne of ˗ 1 7, 2 5 m m (c orres p o n di n g t o a m ea n perce nta ge 
c ha n ge i n pai n fr o m baseli ne of 2 9 %) o bser ve d f or place b o de m o nstrati n g t hat S y n visc- O ne ®  
is relia bl y s u peri or t o place b o. T he last st u d y ( Drieser et al., 2 0 1 5) c o m pare d a hi g h m olec ular 
wei g ht h yal ur o n a n ( Ost e nil ® Pl us) t o S y n visc- O ne ® . I n t his ra n d o mise d, d o u ble- bli n d st u d y, a n 
esti mate d c ha n ge fr o m baseli ne after 2 6 wee ks of ˗ 3 4. 3 m m (c orres p o n di n g t o a mea n 
perce nt a ge c ha n ge i n pai n fr o m baseli ne of 5 8. 9 %) is o bser ve d f or Oste nil ® Pl us vers us a n 
esti mate d c ha n ge fr o m b aseli ne of ˗ 3 6. 2 m m (c orres p o n di n g t o a mea n perce nta ge c h a n ge i n 
pai n fr o m bas eli ne of 6 2. 5 %) o bser ve d f or S y n visc- O ne ®  d e m o nstrati n g t hat b ot h treat me nts 
pr o vi de statisticall y si g nifica nt a n d cli nicall y rele va nt pai n relief. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 2 /1 1 4  
 
 
6  
I N V E S TI G A TI O N A L   
M E DI CI N A L   
P R O D U C T  
A N D  
R E F E R E N C E 
T R E A T M E N T 
6. 1  
T re at me nts A d mi nistere d 
6. 1. 1  I nvesti g ati o n al Me dici n al Pr o d ucts 
T he i n vesti gati o nal me di ci nal pr o d ucts ( 3 differe nt stre n gt hs: J T A- 0 0 4 5 0 ( 2 ml), J T A- 0 0 4 5 0 
( 4 ml) a n d J T A- 0 0 4 1 0 0 ( 2 ml)) will be pr o vi de d 
 
 
 
  
 
 
 
 
6. 1. 2  Refere nce 
T he refere n ce treat me nt, S y n visc - O ne® , is a sterile visc oelastic s ol uti o n pr o vi de d i n a rea d y-t o-
use s yri n ge. T he si x millilitre s ol uti o n c o ntai ns 4 8 m g s o di u m h yal ur o nate. 
6. 2  
T re at me nt wit h I n vesti g ati o n al me dici n al pr o d ucts a n d refere nce 
6. 2. 1  Rec o nstit uti o n Pr oce d ure 
 
T he refere n ce pr o d uct is pr o vi de d i n a rea d y- t o- use s yri n ge 
a n d d oes n ot nee d rec o nstit uti o n. 
6. 2. 2  I njecti o n Pr oce d ur e 
 
 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 3 /1 1 4  
 
 
 
 
 
 
. T he 
i njecti o n is acc o m plis he d foll o wi n g p u nct ure t hr o u g h t he s ki n a n d i nt o t he j oi nt s pace. If 
resista nce is e nc o u nt ere d, re directi o n of t he nee dle ma y b e necessar y. T he use of l oc al 
a naest hesia wit h li d ocai ne pri or t o  t he I A i njecti o n is at t he discreti o n of t he I n d e pe n de nt 
P h ysicia n .  
T he i njecti o ns will be perf or me d b y a n I n d e pe n de nt P h ysi cia n  w h o are ver y well e x perie nce d 
wit h t his t y pe of a d mi nistrati o n  t o li mit t he ris k of periartic ular a d mi nistrati o n . Pr o d uct s s h o ul d 
be i njecte d i n t he s y n o vi al s pace o nl y a n d n ot i nt o bl o o d vessels, e xtra -artic ularl y, or i n t h e 
s y n o vial tiss ue or ca ps ul e. If t he w h ole v ol u me  of I n vesti gati o n Me dici nal Pr o d uct ca n n ot be 
i njecte d, t he reas o n m ust be d oc u me nte d i n t he eC R F . 
T he pr o d ucts are i nte n de d f or si n gle use a n d strict ase ptic a d mi nistrati o n tec h ni q ue m ust be 
f oll o we d. F or t he refere n ce, t he s yri n ge c o ntai ni n g t he H A s ol uti o n s h o ul d be use d i m me diatel y 
 i n or der t o g u ara nt ee d t he sterilit y of t he 
pr o d uct .  
If eff usi o n is f o u n d i n t he k nee u p o n nee dle place me nt i n t he j oi nt s pace, it m ust be re m o ve d 
bef ore li d ocai ne a n d J T A -0 0 4  or refere n ce pr o d uct is i njecte d. 
 
 
 
 
 
 
 
 
T he a d mi nistrati o n pr oce d ure is s u m marise d i n t he Ta ble 2  bel o w:  




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 5 /1 1 4  
 
 
A n y me di cati o n will be rec or de d i n t he e C R F. 
6. 3  
St u d y F oll o w- u p  
Safet y a n d efficac y e n d p oi nts will be deter mi ne d i n all patie nts at eac h sc he d ule d visit o ver t he 
w h ole f oll o w- u p peri o d. 
6. 4  
P ac k a gi n g a n d L a belli n g  
La b el te xt will be pre pare d t o meet t he re q uire me nts of t he E ur o pea n Directi ve ( 2 0 0 3/ 9 4/ E C ) 
a n d t he l ocal re g ul ati o n, a n d t o mai ntai n t he d o u ble- bli n d. All pr o d ucts will be la belle d “ F or 
I n v esti gati o nal Use O nl y.”  
Re gar di n g t he pac k a gi n g a n d la belli n g of i n v esti gati o nal me dici nal pr o d uct, a st u d y pr oce d ure 
ma n ua l ( S P M) f or t he Pri nci pal I n vesti gat or i ncl u di n g ste p-b y -ste p i nstr ucti o ns a n d detaile d 
descri pti o ns will be pr o vi de d t o eac h I n vesti gat or bef ore t he b e gi n ni n g of t he cli nical trial . 
C o m plete i nf or mati o n a n d trai ni n g of t he partici pati n g healt hcare pr ofessi o nals will als o be 
c o n d ucte d d uri n g t he Site I nitiati o n Visit.  
P lease refer t o t he S P M  f or t he Pri nci pal I n vesti gat or f or m ore d etails. 
6. 5  
S t or a ge 
J T A- 0 0 4 pr o d ucts are ma n ufact ur e d b y B o ne T hera pe utics S. A., G osselies, Bel gi u m.   
 
 
 
O pe ne d or da ma ge d pac ka ges or via ls s h o ul d n ot be use d. 
S y n visc- O ne ® , ma n ufact ure d b y Ge nz y m e C or p orati o n, Ne w J erse y, U S A are pr o vi de d i n a 
s yri n ge ( n o- nee dl e c o- pac ke d wit h it) a n d s h o ul d be st ore d bel o w 3 0 ° C a n d pr otecte d fr o m 
s u nli g ht a n d freezi n g. O pe ne d or da m a ge d pac ka ges or s yri n ges s h o ul d n ot be use d. 
6. 6  
S u m m ar y of I n vesti g ati o n al me dici n al pr o d ucts a n d Refere nce 
A descri pti o n of i n vesti gati o nal me di ci nal pr o d ucts a n d refere nce is s u m marise d i n Ta ble 3 
be l o w:  




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 7 /1 1 4  
 
 
T his trac ki n g s yste m w o ul d e ns ure t hat i n vesti gati o nal me dici nal pr o d ucts a n d refere nce are 
trac ke d a n d trace d d uri n g fr o m t he or der t o patie nt a d mi nistrati o n, eac h ste p bei n g 
s yste maticall y c ollecte d, verifie d, a n d rec or de d usi n g s pecific F or ms a n d Recei pts. 
T he p har macist of t he h os pital m ust e ns ure t hat t he i n vesti gati o nal me dici nal pr o d ucts a n d 
refere nce are ke pt u n d er sec ure c o n diti o ns, wit h access li mite d t o t h ose a ut h orise d b y t he 
I n v esti gat or.  
Pr o d ucts acci d e ntall y d a ma ge d d uri n g s hi p me nt or at a n I n vesti gati o n Site s h o ul d be acc o u nte d 
f or a n d d oc u me nte d. It s h o ul d be n ote d t hat all e m pt y vials of J T A- 0 0 4 a n d s yri n ges of refere nce 
will  be ke pt a n d st ore d at eac h I n v esti gati o n Site u ntil M o nit or verificati o n visits a n d ret ur ne d 
t o t he S p o ns or f or destr ucti o n o nce t he acc o u nt a bilit y is perf or me d. Dis p osal of hazar d o us 
material, i.e., s yri n ges a n d nee dles, m ust be c o nf or m t o a p plica ble la ws a n d re g ulati o ns. T he 
pr o d ucts m ust n ot be use d o utsi de t he trial. 
W he n t he st u d y is c o m pl ete d, all u n use d pr o d ucts at eac h I n vesti gati o n Site will be ret ur ne d t o 
t he S p o ns or f or destr ucti o n. 
Fi nall y, d ata a n d rec or ds re q uire d f or f ull tracea bilit y will be ke pt b y t he S p o ns or a n d 
I n v esti gat or f or a mi ni m u m of 2 0 years after cli nical use. 
 




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 5 9 /1 1 4  
 
 
7. 1. 2  Vit al Si g ns 
Vital si g ns 
 will be meas ure d   
.  
 
 
 
 
Res ults of meas ure me nts s h o ul d o nl y  b e re p orte d as A E if, i n t he I n v esti gat or’s o pi ni o n, it is 
o utsi de of “e x pecte d v al ues or variati o ns”. T he y m ust be c o nsi dere d as S A E if t he y f ulfil t h e 
S A E defi niti o n. 
7. 1. 3  P hysic al Ex a mi n ati o n 
 
 
 
 
 
  
 
. 
7. 1. 4  L a b or at ory S afety Me as ure me nts 
A n y s a m ple testi n g will be d o ne i n li ne wit h t he c o nse nt of t he i n di vi d ual patie nt.  
 
 
 
 
 
 
 
 




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 1 /1 1 4  
 
 
T h ese i nf or mati o n will b e rec or de d o n t he Me dical Hist or y pa ge of t he e C R F. 
7. 2. 2  A d diti o n al S afety Ex a mi n ati o ns a n d Pr oce d ures 
If a n y u n clear cli nical e ve nt, i ncl u di n g s y m pt o ms, si g ns, or ot her o bser vati o ns or a b n or malities, 
s h o ul d occ ur, t he I n v esti gat or, or a n y ot her p h ysici a n i n c har ge, ma y p erf or m a d diti o nal cli nical 
e x a mi nati o ns a n d pr oce d ures ( ot her t ha n o utli ne d i n t his pr ot oc ol), i ncl u di n g a n y cli nical, 
la b orat or y, i ma gi n g a n d/ or tec h nical testi n g, i n or der t o clarif y a n d esta blis h t he aeti ol o g y a nd 
dia g n osis of t his cli nical e ve nt.  


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 2 /1 1 4  
 
 
8  
S A F E T Y D E FI NI TI O N S A N D R E P O R TI N G R E Q UI R E M E N T S 
8. 1  
De fi niti o ns 
8. 1. 1  A dverse Eve nt ( A E)  
A n a d verse e v e nt ( A E) is defi ne d as a n y u nt o w ar d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject w h o has bee n a d mi nistere d a p h ar mace utical pr o d uct a n d/ or a n y 
i n vesti gati o nal me dici nal pr o d uct a n d w hic h d oes n ot necessaril y h a ve a ca usal rel ati o ns hi p 
wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v o ura bl e a n d u ni nte n d e d si g ns (i ncl u di n g 
a n y a b n o r mal la b orat or y fi n di n gs), s y m pt o ms, or disease te m p orall y ass o ciate d wit h t he use of 
a me dici nal pr o d uct, wit h o ut a n y j u d g me nt a b o ut ca usalit y. A d verse e ve nts will be gra de d wit h 
res pect t o i nte nsit y a n d cl assifie d as eit her s eri o us or n o n-seri o us acc or din g t o t he W orl d Healt h 
Or ga nisati o n Classificati o n . 
All di sease si g ns a n d s y m pt o ms e x perie nce d b y t he patie nt will be rec or de d o n t he e C R F fr o m 
t he ti me of t he patie nt si g ns t he I C F u ntil c o m pleti o n of t he fi nal st u d y visit. 
If cli nicall y si g nifica nt w orse ni n g of t he patie nts' p h ysical c o n diti o n is n ote d, t he c ha n ges will 
be d oc u me nte d as A E o n t he A E Pa ge of t he e C R F. Cli nical si g nifica n ce is defi ne d as a n y 
variati o n i n si g ns, s y m pt o ms, or testi n g t hat has me dical rele va nce a n d ma y res ult i n a n 
alterati o n i n me dical care.  
8. 1. 2  Seri o us A dverse Eve nt ( S A E) 
A n S A E is defi ne d as a n y A E or S A R t hat, i n t he vie w of t he i n v esti gat or or s p o ns or, res ults i n 
a n y of t he f oll o wi n g o utc o mes (I C H E 2a): 
 De at h 
 L if e-t hreate ni n g A E  
 In p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
 Persiste nt or si g nifi ca nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal 
life f u ncti o ns 
 C o n ge nital a n o mal y/ birt h defect 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 3 /1 1 4  
 
 
Me dical a n d scie ntific j u d ge m e nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g 
is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat m a y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalisati o n b ut ma y je o par dise t he patie nt or ma y 
re q uire i nter ve nti o n t o pr e ve nt o ne of t he ot h er o utc o mes liste d i n t he defi niti o n a b o ve. 
N otes  
Lif e-t hreate ni n g mea ns t hat t he patie nt is at i m me diate ris k of deat h at t he ti me of t he e v e nt; it 
d oes n ot refer t o a n e ve nt, w hic h h y p ot h eticall y mi g ht ha ve ca use d deat h if it was m or e se v ere 
or ha d c o nti n ue d u ntreate d. T he ter m "life-t hreat e ni n g" d oes n ot i m pl y a p ossi ble f ut ure c o urse 
w hic h mi g ht or mi g ht n ot ha ve h a p pe ne d, b ut was pre ve nte d d ue t o a de q uat e p h ysicia n's acti o n. 
F or e x a m ple, a si m ple bacterial w o u n d i nfecti o n ca n p ote ntiall y lea d t o ga n gre ne, se psis, a n d 
e ve nt uall y deat h; w hile s e psis is us uall y re gar de d as a S A E beca use of k n o w n hi g h m ortalit y, 
t he pri mar y w o u n d i nfecti o n itself is us uall y n ot re gar de d as a S A E. I n a nal o g y, a ne wl y 
dia g n ose d mali g na nt dise ase is us uall y re gar de d as a S A E beca use mali g n a nt diseases us uall y 
ha ve a hi g h m ortalit y rat e a n d are t heref ore life-t hreate ni n g. 
Pla n ne d h os pitalizati o n f or a pre-e xisti n g c o n diti o n, or a pr oce d ure re q uire d b y t he pr ot oc ol, 
wit h o ut seri o us deteri orati o n i n healt h, is n ot c o nsi dere d a s eri o us a d v erse e ve nt. 
C o n ge nital a n o mal y mea ns a n y p h ysi ol o gical or p h ysical d efect o bser ve d i n a c hil d b or n fr o m 
a m ot her w h o partici pate d i n t he c urre nt st u d y a n d w h o beca me pre g n a nt d uri n g t h e c o urse of 
t his st u d y. 




C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 5 /1 1 4  
 
 
8. 1. 4  C a us al Rel ati o ns hi p t o w ar ds t he I nvesti g ati o n al Me dici n al Pr o d uct 
I n practice, det er mi nati o n of t he ca usal relati o ns hi p bet wee n a n A E a n d t he i n vesti gati o nal 
me dici nal pr o d uct m ust be ma de b y t he I n v esti gat or b y a ns weri n g t h e f oll o wi n g q uesti o ns:  
“ D o y o u c o nsi der t hat t here is a reas o na bl e p ossi bilit y t hat t he e ve nt ma y h a ve bee n ca use d b y 
t he i n vesti gati o nal me dici nal pr o d uct? ”  
acc or di n g t o t he f oll o wi n g defi niti o ns: 
 Yes: t he relati o ns hi p of t he A E a n d t he use of t he pr o d uct ca n b e defi nitel y esta blis he d. 
 P ossi ble: t here is n o clear relati o ns hi p bet wee n t h e A E a n d t he us e of t he st u d y pr o d uct ; 
h o we ver, o ne ca n n ot defi nitel y c o n cl u de t hat t here is n o relati o ns hi p. 
 N o: t here is n o rel ati o ns hi p bet wee n t he A E a n d t he use of t he i n vesti gati o nal me dici nal 
pr o d uct. T his ma y i ncl u d e b ut is n ot li mite d t o t he i nci de nt bei n g a n e x pect e d o utc o me of 
a pre vi o usl y e xisti n g or c o nc urre nt diseas e, c o n c o mita nt me dicati o n or pr oce d ure t he 
patie nt e x perie nce d. 
 U n k n o w n: t he relati o ns hi p of t he A E a n d t he use of t he pr o d uct is n ot assessa ble 
T he ca usalit y assess me nt gi ve n b y t he I n vesti gat or s h o ul d n ot be d o w n gra de d b y t he S p o ns or. 
If t he S p o ns or disa grees wit h t he I n vesti gat or’s ca usalit y assess me nt, b ot h, t he o pi ni o n of t he 
I n v esti gat or a n d t he S p o ns or s h o ul d be pr o vi de d wit h t he re p ort. 
8. 1. 5  O utc o me of A dverse Eve nts 
T he I n v esti gat or will be as ke d t o i n dicate t he o utc o me of t he A E usi n g t he f oll o wi n g cate g ories: 
Res ol ve d wit h o ut se q uelae, Res ol ve d wit h se q u elae, Deat h, or O n g oi n g. T he I n vesti gat or 
s h o ul d use me dical j u d g me nt t o c o m pare t h e re p orte d A E t o si milar t y pe e ve nts o bs er ve d i n 
cli nical practice. 
Bel o w are t he a p plica ble g ui deli nes f or o utc o me assess me nt: 
 Res ol ve d wit h o ut se q uelae: t he A E has res ol ve d wit h o ut resi d ual s y m pt o ms 
 Res ol ve d wit h se q uelae: t he A E has res ol v e d, h o we ver, resi d ual c o ns e q ue nces will persist 
 Deat h: t he A E e n d e d wit h deat h 
 O n g oi n g: t he A E is n ot r es ol ve d yet 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 6 /1 1 4  
 
 
If t he o utc o me of a n A E is n ot a vaila ble at t he ti me of t he i nitial re p ort or at st u d y e xit 
( pre mat ure or n ot), f oll o w- u p will pr ocee d u ntil o utc o me is k n o w n. All c ollecte d data will be 
rec or de d i n s o urce d oc u me nts. 
8. 1. 6  A dverse Dr u g R e acti o n ( A D R) 
A d verse Dr u g Reacti o n ( A D R): a n y u nt o w ar d a n d u ni nte n de d res p o nse t o a n i n vesti gati o nal 
me dici nal pr o d uct relat e d t o a n y d ose a d mi nistere d ( ha vi n g a reas o na ble ca usal relati o ns hi p t o 
t he pr o d uct, t he ter m “reas o na bl e ca usal relati o ns hi p” mea ni n g t hat t here is e vi de nce or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p). 
U ne x pecte d A D R: a n a d verse reacti o n w h ose nat ure, se verit y, s p ecificit y, or o utc o me is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or m ati o n (e. g., I n vesti gat or’s Br oc h ure) 
8. 1. 7  Seri o us A dverse Re acti o n ( S A R) 
Seri o us A d verse R eacti o n ( S A R): a n y u nt o war d a n d u ni nte n de d res p o ns es t o a n i n vesti gati o nal 
me dici nal pr o d uct relat e d t o a n y d ose a d mi nistere d ( ha vi n g a reas o na ble ca usal relati o ns hi p t o 
t he pr o d uct, t he ter m “reas o na bl e ca usal relati o ns hi p” mea ni n g t hat t here is e vi de nce or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p), a n d t hat res ults i n deat h, is life-t hreate ni n g, re q uires 
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, res ults i n persiste nt or 
si g nifica nt disa bilit y or i nca pacit y, or is a c o n ge nital a n o mal y or birt h defect. 
8. 2  
I de ntif yi n g A d verse E ve nts 
T he occ urre nce of A E/ S A E (relate d or n ot t o pr o d uct or st u d y pr oce d ure) will be assesse d b y 
n o n - directi ve q uesti o ni n g of t he patie nt fr o m Visit # 1, a n d eac h ot her visit searc hi n g f or a n y 
c ha n ges i n healt h stat us (e. g., " Ha ve a n y a d verse e ve nts, seri o us a d v erse e v e nts occ urre d si nc e 
t he last visit?") (see Ta bl e 7 bel o w). 
 
 






C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 6 9 /1 1 4  
 
 
All re p orta ble e ve nts m ust be n otifie d b y t he I n vesti gat or t o t he St u d y Safet y Officer ( S S O).  
S A Es will be d oc u me nte d o n t he S A E Re p ort c o ntai ni n g a detaile d writte n descri pti o n of t he 
e ve nt. 
S A E Re p orts F or ms s h o ul d be c o m plete d, si g n e d a n d se nt b y t he I n vesti gat or n ot later t ha n  
wit hi n 2 4 h o urs of e ve nt occ urre nce or a w are ness t o t he S S O b y e- mail 
w h o will i nf or m t he S p o ns or of t he 
safet y e v e nt occ urre n ce. 
Briefl y, t he S A E Re p ort F or m will i ncl u de t he f oll o wi n g i nf or mati o n a n d differe ntiate d 
assess me nt:  
 
Patie nt I de ntifi cati o n N u m ber 
 
I n v esti gati o n site a n d c o u ntr y 
 
E ve nt: or ga n s yste m 
 
S A E stat us a n d descri pti o n 
 
Date of e v e nt o nset a n d e ve nt res ol uti o n 
 
O utc o me (rec o ver y wit h or wit h o ut se q uelae, o n g oi n g, deat h) 
 
Ac ti o n ta ke n ( n o ne, pati e nt disc o nti n uati o n a n d wit h dra wal fr o m t he st u d y, c ha n ge i n 
c o nc o mita nt 
me dicati o n(s) a n d/ or ne w 
me dicati o n(s), i n patie nt h os pitalisati o n or 
pr ol o n gati o n of e xisti n g i n patie nt h os pitalisati o n, n o n- dr u g t hera p y gi ve n, ot her) 
 
Criteria f or seri o us ness ( deat h, life-t hreate ni n g, me dical or s ur gical i nter ve nti o n t o 
pre ve nt life-t hreate ni n g ill ness or i nj ur y or p er ma ne nt i m pair me nt t o a b o d y str u ct ure, 
per ma ne nt i m pair me nt of a b o d y str uct ure or a b o d y f u ncti o n, ne w or pr ol o n ge d 
h os pitalisati o n, c o n ge nit al a b n or malit y or birt h defect), a n d se verit y ( mil d, m o derate, 
se vere) 
 
Assess me nt of rel ati o ns hi p t o t he i n vesti gati o nal me dici nal pr o d uct (e val uate d as yes, 
p ossi bl y, n o) 
 
Assess me nt of relati o ns hi p t o pr oce d ures, i ncl u di n g t he treat me nt i njecti o n a n d bl o o d 
sa m pli n g (e v al uate d as yes, p ossi bl y, n o) 


C O N FI D E N TI A L 
 
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Date: Ma y 1 0 , 2 0 1 7  
P g. 7 0 /1 1 4  
 
 
8. 4. 2  Re p orti n g Eve nts t o E Cs a n d A ge ncies by t h e S S O 
T he S S O is res p o nsi ble f or re p orti n g S A Es recei ve d fr o m I n v esti gat ors t o t he E Cs a n d 
A ge ncies, w hile bli n di n g will be preser ve d f or b ot h Pri nci pal I n vesti gat ors a n d S p o ns or u nless 
it is c o nsi dere d necessar y i n t he i nterest of res earc h patie nt safet y.  
A n y S A E w hic h i n dicates a n i m mi ne nt ris k of deat h, seri o us i nj ur y, or seri o us ill ness a n d t hat 
re q uires pr o m pt re me dial acti o n f or ot her patie nts, users or ot her pers o ns or a ne w fi n di n g are 
t o be rec or de d a n d re p orte d i m me diatel y, b ut n ot l ater t h a n 7 c ale n d ar d a ys  after a ware n ess 
b y t he S S O.  
A n y ot her re p ort a ble e ve nt as des cri be d a b o ve is t o be rec or de d a n d re p orte d i m me diatel y, b ut 
n ot l ater t h a n 1 5 c ale n d ar d a ys  f oll o wi n g t he dat e of a ware n ess b y t he S S O. T he re p ort m ust 
be pr o vi de d t o all A ge n cies rele va nt t o all states i n w hic h t he trial is ta ki n g place.  
8. 4. 3  Seri o us A dverse Eve nt St o p pi n g R ule 
I n case of S A E occ urs, w hic h ha ve n ot bee n i de ntifie d i n nat ure, se verit y or fre q ue n c y i n t his 
pr ot oc ol or i n t he I B a n d, w hic h are t h o u g ht t o be p ossi bl y relate d t o i n vesti gati o nal me dici nal 
pr o d uct s  a n d are c o nsi dere d t o be a healt h ris k f or all partici pati n g patie nts, B o ne T hera pe utics 
S. A. ma y deci de i n c o ns ultati o n wit h t he I n vesti gat ors t o p ost p o ne treat me nt of ne wl y i ncl u de d 
patie nts u ntil t he I n vesti gat ors a n d B o ne T hera p e utics S. A. ha ve t h or o u g hl y i n vesti gate d t h e 
e ve nt(s) a n d c o ncl u de t h at c o nti n uati o n of t he trial is j ustifie d. 
8. 4. 4  S afety D at a M o nit ori n g 
T he occ urre nce of A Es a n d S A Es will be m o nit ore d d uri n g t h e w h ole st u d y peri o d o n a n 
o n g oi n g basis b y t h e S S O a n d t he S p o ns or. T he S p o ns or will als o recei ve fr o m t he S S O a 
re g ular d etaile d u p date d listi n g of all A Es a n d S A Es.  
8. 4. 5   
D at a S afety M o nit ori n g B o ar d 
A Data Safet y M o nit ori n g B o ar d ( D S M B) will be esta blis he d t o assess t he safet y a n d efficac y 
data e n d p oi nts at i nter vals. T his b oar d will rec o m me n d t o t he S p o ns or w het her t o c o nti n ue, 
m o dif y or st o p t he trial. F urt her i nf or mati o n c o ncer ni n g t h e D S M B ca n be f o u n d i n t he S A P.  


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8. 5  
M a n a ge me nt of S afet y Iss ues  
8. 5. 1  Pr oce d ure i n C ase of Pre g n a ncy 
All pre g n a ncies occ urri n g d uri n g t he trial (i ncl u di n g b ot h patie nt pre g na nc y a n d patie nt’s 
part ner pre g n a nc y) will b e s yste maticall y re p orte d wit hi n 2 4 h o urs of di a g n osis t o t he S S O a n d 
M o nit or (a Pre g n a nc y F or m 
will be i m me diatel y c o m plete d, 
wit h s u bse q ue nt ur ge nt 
n otificati o n). 
If t here is a pre g na nc y d uri n g t he st u d y peri o d, t h e patie nt m ust be f oll o we d a n d t he o utc o me 
of pre g na nc y m ust be re p orte d t o t he S S O a n d M o nit or. F oll o w- u p s hall be c o n d ucte d t o o btai n 
o utc o me i nf or mati o n o n all pr os pecti ve re p orts. 
A n y pre g na n c y will be ha n dl e d as a n S A E re gar dless t he relati o ns hi p bet wee n t he treat me nt 
a n d t he e ve nt. A n y c o m plicati o n arisi n g d uri n g pre g n a nc y will be rec or de d as a n A E/ A D E a n d 
will c o nstit ute a S A E if it f ulfils a n y of t he s pecifie d criteria f or a S A E. 
At t he e n d of t he pre g na n c y, w het her t hat is f ull-ter m or pre mat ure, i nf or mati o n o n t he stat us 
of t he m ot her a n d c hil d will be f or war de d t o S S O. 
If t he o utc o me of pre g n a nc y is: 
 Ele cti ve a b orti o ns wit h o ut c o m plicati o ns, t he y will be rec or de d, d oc u me nte d a n d 
re p orte d t o t he S S O a n d M o nit or, b ut t he y s h o ul d n ot be ha n dle d as A E; 
 A n y s p o nta ne o us 
miscarria ges or a b orti o ns f or 
me dical reas o ns, or c o n ge nital 
a b n or malities or birt h defects, will be rec or de d, d oc u me nte d, re p orte d, a n d ha n dle d as 
S A E a n d f ull details will be re q uest e d. 
8. 5. 2  E mer ge ncy Pr oce d ures 
I n case of S A E or a n y ot her safet y e v e nt or me dical c o ncer n, t he f oll o wi n g c o ntact will be 
a vaila ble ( 2 4/ 7 c o ver) f or c o nti n u o us s u p p ort a n d assista nce ( S S O): 
E m er ge ncy a n d S afety Eve nts P h o ne N u m ber: 
 
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat pr oce d ures a n d e x pertise are a vaila ble t o c o pe 
wit h me dical e m er ge n cies d uri n g t he st u d y. Eac h patie nt will recei ve a “ Patie nt Car d” wit h t h e 


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na me a n d s ur na me a n d t he Patie nt I de ntificati o n N u m ber, Title a n d E u dra C T N u m ber of t he 
st u d y, t y pe of tr eat me nt recei ve d a n d Na me of t he S p o ns or. T his car d will als o rec or d t he n a me, 
s ur na me, f ull a d dress, a n d p h o ne n u m ber of t he I n vesti gat or, t h e a d dress a n d p h o ne n u m ber of 
t he E mer ge n c y R o o m of t he I n v esti gati o n Site, a n d t he E mer ge nc y a n d S afet y E ve nts P h o ne 
N u m ber ( 2 4/ 7 c o ver). T he ai m of t his car d is t o i nf or m a n y p h ysicia n h a vi n g t o deal wit h a 
patie nt i n a n e mer ge nc y sit uati o n t hat t he patie nt is i n v ol ve d i n a cli nical trial a n d t hat he/s he 
ca n c o ntact t he I n vesti gat or f or m ore rele va nt i nf or mati o n. Patie nts will be i nstr ucte d t o carr y 
t his car d ar o u n d at a n y ti me d uri n g t he st u d y. 
F or a n y ot her q uesti o ns or st u d y i nf or mati o n, t he f oll o wi n g c o ntact will be a vaila ble ( office 
h o urs) f or c o nti n u o us s u p p ort a n d assista nce: 
H otli ne - P h o ne N u m ber:
 
H ot li ne - E- m ail:
  
8. 6  
L o n g- Ter m S afet y Re p orti n g S yste m  
Fi nall y, d uri n g t he c o urse of t h e trial, t h e S p o ns or pla ns t o d esi g n, de v el o p, a n d s u b mit t o t he 
rele va nt C As, a det aile d strate g y f or l o n g-ter m patie nt f oll o w- u p, u n der P har mac o vi gila nce 
Pla n i n li ne wit h t he I C H T o pic E 2 E. 


C O N FI D E N TI A L 
 
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9  
P R E M A T U R E R E M O V A L F R O M T H E S T U D Y 
9. 1  
Re as o ns f or P atie nt  Pre m at ure Disc o nti n u ati o n 
N otificati o n of patie nt st u d y disc o nti n uati o n (a n d reas o ns f or disc o nti n uati o n) will be 
c o m m u nicate d t o t he M o nit or a n d/ or t he S p o ns or b y t he I n vesti gat or as s o o n as p ossi ble. T he 
I n v esti gat or will d oc u me nt t he circ u msta nces f or pre mat ure disc o nti n uati o n i n t he patie nt's 
e C R F as f oll o ws: 
 Vi ol ati o n of eli gi bility criteri a 
Patie nts will be wit h dra w n if i nc orrectl y i ncl u de d (i.e., n ot i n c o m plia nce wit h o ne or m ore 
eli gi bilit y criteria). T he I n vesti gat or ma y c o nt act t he M o nit or i n or der t o disc uss t he p ote ntial 
c o nti n uati o n of wr o n gl y i ncl u de d patie nts if j u d ge d t hat it is i n t he i nterest of t he patie nt t o 
c o nti n ue t he st u d y. 
I n a n y case, a n d es peci all y if t he patie nt is wit h dra w n f or safet y reas o ns, t he e x pla nati o n f or 
t his disc o nti n uati o n d ue t o vi olati o n of eli gi bilit y criteria s h o ul d be d oc u me nte d i n t he e C R F. 
 A dverse Eve nts / Seri o us A dverse Eve nts 
A n y patie nts ma y be wit h dra w n fr o m t he st u d y at t he I n v esti gat or’s discreti o n i n case of a safet y 
c o ncer n. H o we ver, patie nts ca n b e wit h dra w n fr o m t he st u d y f or A E/ S A E (i ncl u di n g n ota bl y 
cli nical a n d/ or la b orat or y e ve nts) o nl y if t he I n vesti gat or has cl earl y d eter mi ne d t hat t he 
patie nt’s wit h dra wal w o ul d re d uce safet y ris ks. I n t his case, t he A E Pa ge i n t he e C R F m ust be 
c o m plete d, e x plai ni n g t he rati o nale f or wit h dra wal. I n a d diti o n, t he I n vesti gat or s h o ul d e ns ure 
t hat a de q uate me di cal care a n d ma na ge me nt will be pr o vi de d t o t he patie nt. 
 Wit h dr a w n c o nse nt 
Partici pati o n i n t he st u d y is strictl y v ol u ntar y. A patie nt has t he ri g ht t o wit h dra w fr o m t he st u d y 
at a n y ti me, a n d f or a n y reas o n, wit h o ut prej u dice t o f urt her treat me nt, care, a n d p atie nt-
p h ysicia n relati o ns hi p. U n der t hese circ u msta nces, a n a de q u ate sta n dar d of care will al wa ys be 
a d o pte d b y t he I n v esti gat or. T he reas o n(s) f or wit h dra wi n g c o nse nt will als o be re vie we d wit h 
t he patie nt a n d d o c u me nte d i n s o urce d oc u me ntati o n a n d t he e C R F. Partic ularl y, t he p atie nt 
m ust be caref ull y q u esti o ne d f or t he p ossi ble occ urre nce of a n y A E/ S A E. 


C O N FI D E N TI A L 
 
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 L ac k of c o m pli a nce t o t he pr ot oc ol 
T he I n v esti gat or or t he S p o ns or ca n ter mi nate t he st u d y at a n y ti me f or n o n-c o m plia nt patie nts. 
 L ost t o f oll o w- u p  
Eff orts m ust be ma de t o re-c o nt act patie nts w h o d o n ot ret ur n f or sc h e d ule d visits i n or der t o, 
at mi ni m u m, deter mi ne healt h stat us a n d t he p ote ntial occ urre n ce of A E/ S A E. All eff orts t o re-
c o ntact patie nt s will be d oc u me nte d i n t he s o urce d oc u me ntati o n a n d t he e C R F. 
 L ac k of effic acy 
Earl y disc o nti n uati o n f or lac k of efficac y will n ot be c o nsi dere d as a n A E b ut as a treat me nt 
fail ure. T h e reas o n of t he lac k of efficac y will be d oc u m e nte d i n t he e C R F a n d s o urce 
d oc u me nts.  
 Ot h er re as o ns 
If n o a b o ve- me nti o ne d reas o ns are a p plica ble i n case of earl y disc o nti n uati o n, t he ot her 
reas o n(s) will be clearl y d oc u me nte d a n d e x plai ne d i n t he e C R F a n d s o urce d oc u me nts. 
9. 2  
Pr o ce d ure f or P ati e nt Pre m at ure Disc o nti n u ati o n 
I n cas e of pre mat ure disc o nti n uati o n a n d w he n e ver p ossi ble, I n v esti gat ors will as k patie nts t o 
pe rf or m Visit # 5 ( E xit Visit) as t he Pre mat ure Disc o nti n uati o n Visit. At t he e n d of t he E xit 
V isit, t he I n v esti gat or will declare pre mat ure disc o nti n uati o n i n t he e C R F. If st u d y p artici pati o n 
is ter mi nate d d ue t o a n A E p ossi bl y relate d t o t h e st u d y treat me nt or trial-relate d pr oce d ures, 
t he patie nt will h o we ver be f oll o we d b y a d diti o nal e x a mi nati o ns acc or di n g t o t he me dical 
j u d g me nt of t h e I n v esti gat or u ntil t he A E is res ol ve d or t he I n vesti gat or dee ms f urt her 
o bse r vati o ns or e x a mi nati o ns t o be n o l o n ger me di call y i n di cate d. All c ollecte d data s h o ul d be 
rec or de d i n t he s o urce d o c u me nts a n d e C R F. 
9. 3  
Re pl ace me nt of P atie nts 
As e val uati o n of t he patie nt n u m ber t o be ra n d o mise d i n t he st u d y ta kes i nt o acc o u nt a 
perce nt a ge of disc o nti n u e d patie nts, patie nts wit h dra w n fr o m t he st u d y will n ot be re place d. 


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9. 4  
Pre m at ure Ter mi n ati o n of t he Cli nic al Tri al 
O ve rall, t he st u d y ca n be pre mat urel y i nterr u pt e d i n certai n circ u msta n ces. T he S p o ns or has t he 
ri g ht t o st o p or i nterr u pt t he st u d y f or t he f oll o wi n g reas o ns: 
- Safet y iss u es 
- F oll o wi n g a decisi o n of t he S p o ns or 
- F oll o wi n g a decisi o n of t he A ge nci es or t he E C s 
F or t he first t hree o pti o ns, t he E Cs a n d A ge ncies m ust be i nf or me d. 
 
 


C O N FI D E N TI A L 
 
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1 0  S T A TI S TI C A L C O N SI D E R A TI O N S A N D M E T H O D S O F A N A L Y SI S 
 
 
 
 
 
1 0. 1  A n al ysis P o p ul ati o ns 
F o ur tr eat me nt gr o u ps i ncl u di n g t he refere nce a n d J T A- 0 0 4 gr o u ps will be st u die d a n d 
co m pare d. C o m paris o ns wit h res pect t o refere nce will be perf or me d i n a s u peri orit y d esi g n.  
Patie nt p o p ulati o ns are d efi ne d as f oll o w e d: 
- T he  safet y s et ( S A F) will i ncl u de all treate d p atie nts. 
- T he F ull A nal ysis Set ( F A S) will i ncl u de all ra n d o mise d a n d treate d patie nts.  
- T he Per- Pr ot oc ol ( P P) set will i ncl u de all  patie nts of t he F A S wit h o ut a n y maj or pr ot oc ol 
de viati o n. 
De m o gra p hics, b aseli ne c haracteristics a n d efficac y varia bl es will be a nal ys e d usi n g t h e F A S. 
T hese a n al ys es will be perf or me d as ra n d o mise d a n d treate d. 
T he F A S will be c o nsi dere d as pri mar y c o h ort f or t he selecti o n of t he b est J T A- 0 0 4 pr o d uct 
a n d f or t he s u peri orit y a n al ysis. Pri mar y criteri o n a n d c orres p o n di n g v aria bles will be a n al ys e d 
i n t he F A S a n d i n t he P P.  
All safet y varia bl es will be a nal yse d o n a n as- treate d basis usi n g t he S A F. 
1 0. 2  St u d y O bjecti ves 
Pri mar y st u d y o bj ecti ves are (i) t he selecti o n of t he best J T A - 0 0 4 stre n gt h a n d (ii) t he 
s u peri orit y assess me nt of t he b est J T A- 0 0 4 stre n gt h efficac y t o t he refere nce. T he y will be 
deter mi ne d as f oll o w: 


C O N FI D E N TI A L 
 
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- F or selecti o n of best J T A- 0 0 4 stre n gt h,  b y c o m p ari n g t he differe nt J T A- 0 0 4 gr o u ps t o eac h 
ot her wit h res pect t o t he W O M A C ®  V A 3. 1 pai n s u bscale sc ore ( mea n differe nces b et wee n 
baseli ne a n d M o nt h 3) base d o n t he p oi nt esti mates a n d t he 9 0 % c o nfi de nce i nter vals, 
- F or s u peri orit y assess me nt, b y c o m pari n g t he b est J T A- 0 0 4  stren gt h a n d refere n ce o n t he 
mea n differe nces i n W O M A C ®  V A 3. 1 pai n s u bscale sc ore bet wee n b aseli n e a n d M o nt h 6. 
1 0. 3  P ri m ar y E n d p oi nt 
T he pri mar y e n d p oi nt is t he c ha n ge bet w ee n b aseli ne a n d M o nt h 6 of t he Wester n O ntari o a n d 
Mc Master U ni versities ( W O M A C
®  V A 3. 1 pai n s u bscale (s u bscale A)). 
T he  W O M A C®  I n de x pai n s u bscale is a sta n dar dise d a n d v ali date d met h o d ol o g y f or ass essi n g 
pa i n ass ociate d wit h O A  a n d is ofte n use d as a pri mar y e n d p oi nt i n st u dies f or treat me nt of t his 
disea se ( Bella m y et al., 1 9 8 8). 
1 0. 4  S ec o n d ar y E n d p oi nts 
T he sec o n d ar y efficac y e n d p oi nts are: 
- W O M A C ®  V A 3. 1 pai n s u bscale ( W O M A C®  s u bs cale A) at M o nt h 3 
- W O M A C ®  V A 3. 1 t otal sc ore o ver ti me 
1 0. 5  E x pl or at or y E n d p oi nts 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 


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1 0. 6  S afet y 
Fr o m i ncl usi o n (si g ni n g of I C F) t o t he e n d of t he st u d y f oll o w u p at M o nt h 6, patie nts will be 
s yste maticall y assesse d f or t he p ote ntial occ urre nce of a n y (seri o us) pr o d uct or pr oce d ure 
relate d a d v erse e ve nts usi n g patie nt o pe n q uesti o n naire, p h ysical e x a mi nati o n a n d la b orat or y 
meas ure me nts.  
Safet y will be assesse d usi n g t he f oll o wi n g varia bles: 
- A E  a n d S A E 
- Vital si g ns a n d p h ysical e x a mi nati o n 
- La b orat or y a nal yses 
- C o nc o mita nt me dicati o ns 
T he fi nal St u d y Re p ort, i ncl u di n g assess me nt of b ot h safet y a n d efficac y e n d p oi nts, will be 
esta blis he d at M o nt h 6. 
1 0. 7  S t atistic al A n al ysis 
C o nti n u o us varia bles will be des cri be d usi n g t he n u m ber of o bser ve d val u es, mea n, sta n dar d 
de viati o n ( S D), me dia n, first q uartile, t hir d q uartile, mi ni m u m a n d ma xi m u m val ues. 
Cate g orical data will be prese nte d usi n g c o u nts ( n u m ber a n d n u m ber of n o n- missi n g data) a n d 
perce nt a ges. 
All tests will be c o n d ucte d at a 5 % t w o-si de d al p ha le vel of si g nifica n ce u nless ot her wise state d.  
1 0. 7. 1  P atie nts Dis p ositi o ns 
All e nr olle d patie nt s will be acc o u nte d f or. All p ost-i ncl usi o n disc o nti n uati o ns will be 
s u m marise d b y ti me of, a n d reas o n f or, disc o nti n uati o n. T he n u m ber of patie nts scree n e d a n d 
n ot i ncl u de d will be pres e nte d wit h t he mai n reas o n f or t heir n o n-i ncl usi o n. 
P atie nt dis p ositi o n will be base d o n t he scree ne d p o p ulati o n a n d ta b ulate d f or t he f oll o wi n g 
cate g ories: 
- T otal n u m ber of patie nts e nr olle d 


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P g. 7 9 /1 1 4  
 
 
- N u m ber ( perce nt a ge) of patie nts c o m pleti n g t he st u d y 
- N u m ber ( perce nt a ge) of patie nts pre mat urel y disc o nti n u e d fr o m st u d y 
- Pri mar y reas o n f or pre mat ure disc o nti n uati o n 
- N u m ber of patie nts i n t he S A F 
- N u m ber of patie nts i n t he F A S 
- N u m ber of patie nts i n t he P P  
F or eac h p o p ulati o n, r eas o ns f or e x cl usi o n fr o m t he p o p ulati o n will be ca ref ull y descri be d. 
1 0. 7. 2  Pr ot oc ol  Devi ati o ns 
Patie nts prese nti n g maj or de viati o n will be e x cl u de d fr o m t he P P. Maj or pr ot oc ol de viati o ns 
will be as f oll o ws:  
- Vi olati o n of i ncl usi o n/e xcl usi o n criteria  
- 
Missi n g W O M A C
®  s u bscale A score at baseli ne a n d/ or at M o nt h 6  
M aj or a n d mi n or pr ot oc ol vi olati o n will be precisel y defi ne d. Fre q u e nc y a n d perce nta ges of 
patie nts wit h pr ot oc ol de viati o ns will be ta b ulate d.  
1 0. 7. 3  De m o gr a p hics a n d ot her B aseli ne C h ar acteristics 
Descri pti ve statistics of de m o gra p hics, a n d ot her baseli ne c haracteristics as well as me dical 
hist or y will be prese nte d f or all i ncl u de d patie nts. I n a d diti o n, a s u m mar y of de m o gra p hic a n d 
baseli ne c haracteristics will be prese nte d b y I n v esti gati o n Site.  
1 0. 7. 4  Me dic al Hist ory, C o nc o mit a nt Me dic ati o ns 
Pre vi o us a n d c o nc o mita nt me dicati o ns will be s u m marise d f or all e nr olle d patie nt s. 
Fre q u e nc y of m e dicati o n will be s u m marise d usi n g des cri pti ve statistics:  
- fre q ue n c y of patie nts wit h at least o ne pre vi o us me dicati o n  
- fre q ue n c y of patie nts wit h at least o ne c o n c o mita nt me dicati o n 


C O N FI D E N TI A L 
 
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V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 8 0 /1 1 4  
 
 
Fre q u e nc y will be gi ve n b y preferre d ter m acc or di n g t o t he W H O Dr u g Di cti o nar y ( W H O D D) 
use d f or dr u gs c o di n g. E ac h fre q u e nc y t a ble will be s orte d b y d esce n di n g fre q ue n c y of A T C 
ter m a n d t he n wit hi n eac h A T C b y des ce n di n g fre q ue nc y of W H O Dr u g na me (all treat me nt 
gr o u ps). 
Me dical hist or y will be s u m marise d f or all i ncl u de d patie nts, a n d fre q u e nc y of 
pat h ol o gies will be s u m m arise d usi n g descri pti ve statistics. Fre q u e ncies will be gi v e n b y s yste m 
or ga n a n d preferre d t er m acc or di n g t o t he M e d D R A Dicti o nar y.  
1 0. 7. 5  Pri m ary E n d p oi nt 
T he mea n c ha n ge i n t he W O M A C ®  V A 3. 1 p ai n s u bscale s c ore of J T A- 0 0 4-treate d patie nts 
bet wee n bas eli ne a n d M o nt h 6 will be c o m pare d t o t he mea n c ha n ge i n t he W O M A C ®  V A 3. 1 
pai n s u bscale sc ore of t h e refere n ce-treat e d patie nts bet wee n bas eli ne a n d M o nt h 6. 
T he  f oll o wi n g h y p ot h esis is state d t o s h o w s u peri orit y of J T A -0 0 4 t o R efere nce : 
H 0: 
T he differe nce i n t he m ea n c h a n ge fr o m baseli n e at M o nt h 6 bet wee n J T A- 0 0 4 a n d 
R efere n ce is s u peri or or e q ual t o 0.  
H 1:  T he differe nce i n t he m ea n c h a n ge fr o m baseli n e at M o nt h 6 bet wee n J T A- 0 0 4 a n d 
R efere n ce is i nferi or t o 0.  
T his h y p ot hesis is e x presse d mat he maticall y b y: 
H 0: Mea n J T A-0 0 4 - Mea n R efer e nce ≥ 0 vers us  
H 1: Me a n J T A-0 0 4 - Mea n R efer e nce < 0 
1 0. 7. 6  Sec o n d ary 
 E n d p oi nts 
F o r t he a nal ysis of t he sec o n dar y e n d p oi nts,  
- W O M A C
®  V A 3. 1 pai n s u bscale ( W O M A C ®  s u bs cale A) at M o nt h 3 
- W O M A C ®  V A 3. 1 t otal sc ore o ver ti me 
g r o u ps will be c o m pare d usi n g a para metric or n o n- para m etric A N C O V A (acc or di n g t o t he 
n or malit y of dat a a n d t h e h o m o ge neit y of t he varia nces) wit h t he f oll o wi n g fact ors: baseli ne 
val ue a n d gr o u p. Re p eate d meas ures a n al yses will be perf or me d o n l o n git u di nal data. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 8 1 /1 1 4  
 
 
I n eac h gr o u p se p arat el y, t he e v ol uti o n of eac h para meter b et wee n bas eli ne a n d eac h ti me p oi nt 
will be descri be d usi n g t he n u m ber of o bser ve d v al ues, mea n, sta n dar d de viati o n ( S D) 9 5 %-
c o nfi de nce i nter vals.   
 
 
Cate g orical data will be prese nte d usi n g c o u nts ( n u m ber a n d n u m ber of n o n- missi n g data) a n d 
perce nt a ges. 
1 0. 7. 7  S afety A n alysis 
All safet y a nal yses will be c o n d ucte d o n t h e S A F a nd ta b ulate d b y treat me nt gr o u p. 
A E/ S A E 
A E/ S A E will be c o de d usi n g t he Me d D R A. F or eac h A E re p orte d, t he n u m ber a n d p erce nt a ge 
of patie nts will be ta b ulate d base d o n s yste m or ga n class a n d preferre d ter m. Si milar ta b ulati o ns 
will be perf or m e d b y se verit y, relati o ns hi p t o t he st u d y pr o d uct/ pr oce d ure, acti o n ta ke n a n d 
o utc o me. T he n u m ber a n d perce nt a ge of patie nts w h o e x perie nce d a n A E as defi ne d i n t he pre-
defi ne d s u bsets of e ve nts will als o be ta b ulate d. 
T h e fre q ue n c y of A E/ S A E will be c o m pare d bet w ee n t he gr o u ps usi n g c hi-s q uare or Fis her’s 
e x act tests (as a p pr o pri ate). 
A n a nal ysis of f oll o wi n g para meters will als o be p erf or me d: 
- Treat me nt-e mer ge nt ( S) A E ( occ urri n g or w orse ni n g after treat me nt)  
- ( S) A E lea di n g t o pre m at ure wit h dra wal 
Ot her safet y v aria bl es 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
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V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 8 2 /1 1 4  
 
 
Sta n dar d s u m mar y st atistics of la b orat or y v al ues a n d s hift ta bles pres e nti n g i n ci de nce of 
la b orat or y a b n or malities will als o be pr o vi de d b y treat me nt gr o u p. T he fre q ue n c y of 
n or mal/a b n or mal e x a mi nati o n will be ta b ulate d f or eac h ti me p oi nt a n d eac h treat me nt gr o u p. 
Detaile d statistical met h o d ol o g y f or t h e safet y a nal ys es will be pr o vi de d i n t he S A P. 
1 0. 8  R a n d o mis ati o n 
Patie nts will be ra n d o mise d i n o ne of t he t hree J T A- 0 0 4 gr o u ps or i n t he refere nce gr o u p 
acc or di n g t o a 1: 1: 1 : 1 rati o usi n g I W R S. 
1 0. 9  S a m ple Size Esti m ati o n  
T he sa m ple siz e calc ulati o n f or t he s u peri or it y trial f or t he pri mar y e n d p oi nt – c ha n ge i n 
W O M A C ®  V A 3. 1 pai n s u bscale fr o m bas eli ne t o M o nt h 6 - is base d t he f oll o wi n g ass u m pti o ns:  
- T he  mea n pai n differe nce of patie nts treat e d wit h t he J T A- 0 0 4 a n d t h ose treate d wit h t he 
refere nce treat me nt is ass u me d t o be - 7 m m (i.e. t he mea n J T A- 0 0 4 treat me nt is 7 m m 
better t ha n t he refere nce). T he a bs ol ute mea n differe nce is set t o 7 m m w hic h is bel o w t he 
acce pte d M CI D of t he W O M A C ®  V A 3. 1 pai n s u bscale, w hic h is 1 0 m m ( E hric h et al., 
2 0 0 0; Bella m y et al., 2 0 0 1); 
- T he  sta n dar d de viati o n of t he mea n pai n differe n ce bet wee n t he t w o treat m e nts, esti mate d 
fr o m t he B orrás- Ver dera et al., 2 0 1 2 a n d Pa vel ka a n d Ue b el hart., 2 0 1 1 data, are i n t he 
ra n ge of 4. 7 t o 6. 6 m m f or sa m ple sizes bet wee n 4 8 a n d 2 4, res pecti vel y. T o e ns ure 
ma xi mal p o wer, a sta n dar d de viati o n val ue of 1 0. 5 was use d f or sa m ple size esti mati o n.); 
U n der t he sce n ari o of a mea n bet w ee n gr o u p differe nce of - 7 m m (i.e., J T A- 0 0 4 is better t ha n 
co ntr ol b y a mea n of 7 m m)  wit h a sta n dar d de viati o n of 1 0. 5 m m, t hirt y-se ve n ( 3 7) pa tie nts 
per gr o u p are re q uir e d f or a nal ysis, reac hi n g a p o wer of 8 0 % t o test f or s u peri orit y, k ee pi n g t he 
t y pe I err or at 0. 0 5 (t w o-si de d). T his w o ul d all o w c ollecti n g e n o u g h efficac y dat a per gr o u p 
w hile a v oi di n g e x p osi n g t o o ma n y patie nts. 
T h e le vel of dr o p- o ut is esti mate d t o 1 0 %. T h us 4 1 patie nts per gr o u p ha v e t o be i ncl u de d. 
As recr uit me nt will c o nti n ue i n all 4 treat me nt gr o u ps u ntil t he fi nal a n al ysis, t he ma xi m u m 
t otal n u m ber of i ncl u de d patie nts will be 1 6 4 ( 4 x 4 1). 


C O N FI D E N TI A L 
 
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V 0 4   
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P g. 8 3 /1 1 4  
 
 
1 0. 1 0  Met h o ds t o Be Use d t o H a n dle Missi n g V al ues 
T he f oll o wi n g i m p utati o n will be ma de i n case of missi n g data: 
- 
Missi n g data d ue t o treat me nt-relate d A E lea di n g t o st u d y wit h dra wal will be ha n dle d 
usi n g  t he 
W orst O bser vati o n Carrie d F or war d ( W O C F) met h o d: t he patie nt’s w orst 
o bser vati o n fr o m sc he d ul e d or u nsc he d ule d visits will be use d t o re place his/ her missi n g 
val ues after st u d y wit h dra wal. 
- 
Missi n g data d ue t o a n y reas o n ot her t ha n treat me nt-relate d A E lea di n g t o st u d y 
wit h dra wal will be ha n dl e d usi n g t he Last O bser vati o n Carrie d F or war d ( L O C F) met h o d: 
t he patie nt’s last o bser ve d val ue fr o m sc he d ule d or u nsc he d ule d visit will be use d t o 
re place his/ her missi n g v al ues after st u d y wit h dra wal. 
- 
Missi n g data i n -bet w ee n t w o a djace nt n o n -missi n g val ues will be ha n dle d usi n g t he mea n -
i n-bet wee n met h o d: t he mea n of t he t w o ( bef ore a n d after) a djace nt val ues will be use d t o 
re place his/ her missi n g v al ue. 
- 
If t here are m ore t ha n o n e missi n g val ues i n -b et w ee n, t he L O C F a p pr oac h will be use d: 
t he patie nt’s last o bser ve d val ue fr o m sc he d ule d or u nsc he d ule d visit will be use d t o 
re place his/ her missi n g v al ues. 
1 0. 1 1  M ulti plicit y 
T his is a 2-sta ge desi g n wit h a n i nteri m a nal ysis. I n or der t o g uara ntee t h e e x peri me nt- wise 
err or pr o ba bilit y of 5 %, t he p- val ues of t he test will be a dj uste d acc or di n g t o t he D u n nett met h o d 
( K oe ni g et al., 2 0 0 8;). Wit h t w o gr o u ps i n t he fi nal s u peri orit y a n al ysis t he c o nfi de nce i nter vals 
will be calc ulate d usi n g t he D u n nett-c orrecte d t- v al ue, w hic h is 1. 9 9 i nstea d of t he u na dj uste d 
t- val ue of 1. 9 6. 
T he m ulti plicit y f or t he sec o n dar y e n d p oi nts will be c o ntr olle d usi n g H oc h ber g’s ste p- u p-
met h o d ( H oc h ber, 1 9 8 8). 
 
 
 


C O N FI D E N TI A L 
 
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C O N FI D E N TI A L 
 
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1 0. 1 3  I nde pe n de nt D at a M o nit ori n g C o m mittee 
1 0. 1 3. 1 Me m bers 
T he I D M C will c o nsist of 2 pers o ns w h o are n ot i n v ol ve d i n a n y ki n d i n t he st u d y. O ne pers o n 
will be a statisticia n a n d o ne pers o n will be a R he u mat ol o gist. 
1 0. 1 3. 2 Res p o nsi bilities 
T he me m bers of t he I D M C are res p o nsi ble f or t he data a nal ysis a n d me dical i nter pretati o n 
c o ncer ni n g cli nical rele va nce a n d t o xicit y of t he i nteri m a nal ysis. T he y will s u m marize t he 
res ults a n d gi ve a writte n re p ort t o t he s p o ns or. 
1 0. 1 3. 3 St u dy D at a t o be se nt t o t he I D M C 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
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A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
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1 0. 1 3. 4 U n bli n di n g Pr oce d ure 
T o e ns ure t he o verall bli n di n g of t he st u d y, t he treat me nt of patie nts i ncl u de d i n t he i nteri m 
a nal ysis will be u n bli n de d b y t he I n d e pe n de nt D ata M o nit ori n g C o m mittee (I D M C, see 7. 5. 1). 
T he statisticia n of t he I D M C will recei v e t he seale d e n vel o pe c o ntai ni n g t he c o m plete 
ra n d o mizati o n list. Arri val has t o be c o nfir me d i n writi n g (c o nfir m ati o n b y e- m ail will be 
acce pta ble). He will e xtract t he me dicati o n n u m bers i ncl u de d i n t he i nteri m a nal ysis a n d 
perf or m t he statistical a nal ysis as d escri be d a b o ve. 
T he I D M C will n ot discl ose a n y i nf or mati o n re gar di n g t he c o nte nts of t he ra n d o mizati o n list t o 
t he s p o ns or. 
1 0. 1 3. 5 Res ults 
T he res ults of t he i nteri m a nal ysis will be se nt t o t he S p o ns or. 
 
 


C O N FI D E N TI A L 
 
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1 1  S T U D Y M A N A G E M E N T 
1 1. 1  S o urce D oc u me nts/ D at a 
Eac h I n vesti gati o n S ite will mai ntai n a n d arc hi ve all a p pr o priate m e dical a n d researc h rec or ds 
relate d t o t he tri al, i n c o m plia nce wit h I C H E 6 G C P Secti o n 4. 9, a n d re g ulat or y a n d i nstit uti o nal 
re q uire me nts f or t he pr ot ecti o n of patie nt c o nfi de ntialit y.  
S o urce data are all i nf or mati o n, certifie d c o pi es of ori gi n al rec or ds of cli nical fi n di n gs, 
o bser vati o ns, or ot her acti vities i n a cli nical trial n ecessar y f or t h e rec o nstr ucti o n a n d e val uati o n 
of t he trial. 
S o urce d oc u m e nts are pri nte d, o ptical or electr o nic d oc u me nt c o nt ai ni n g s o urce d ata. T he y ma y 
i ncl u de, b ut are n ot li mite d t o, patie nt's me dical rec or ds, h os pital c harts if a n y, cli nic al a n d 
office c harts if a n y, t he I n vesti gat or's patie nt st u d y files, p har mac y dis pe nsi n g rec or ds, rec or de d 
data fr o m a ut o mate d i nstr u me nts, as well as t he res ults of dia g n ostic tests, s uc h as ra di o gra p hs, 
la b orat or y a n d uri ne pre g na nc y tests w he n a p plica ble. 
T he  f oll o wi n g i nf or mati o n s h o ul d be e ntere d i nt o t he patie nt's me dical rec or ds: 
- 
Patie nt na me, s ur na me a n d date of birt h 
- 
Patie nt's c o ntact i nf or mati o n 
- 
Me dical c hart (e. g., h os pital s o urce d oc u m e nt trac ki n g n u m ber), if a n y 
- 
A state me nt t hat I C F was o btai ne d wit h t he dat e of I C F c ollecti o n a n d a d oc u me ntati o n 
o n t he pers o n w h o c o n d u cte d t he I nf or me d C o nse nt Pr ocess 
- 
Dates of i nitial scree ni n g a n d all patie nt visits 
- 
T he patie nt i de ntificati o n n u m ber  
- 
T he st u d y title a n d/ or t he pr ot oc ol n u m ber a n d t he na me of t he S p o ns or 
- 
Me dical/s ur gical rele va nt hist or y a n d p h ysical e xa mi nati o n  
- 
Res ults of bl o o d press ure, heart rate, res pir at or y rate a n d b o d y te m perat ure 
- 
Res ults of uri ne pre g na n c y t est ( o nl y f or fe male wit h c hil d beari n g p ote ntial) 
- 
Res ults of ra di o gra p hs w he n a p plica ble 


C O N FI D E N TI A L 
 
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La b orat or y res ults n otes/re p orts 
- 
All c o nc o mita nt me dicati o ns a n d c o nc urre nt pr oce d ures  
- 
Occ urre nce a n d stat us of a n y A E a n d S A E 
- 
T he date t he patie nt e xite d t he st u d y, wit h a n ote as t o w het her t he patie nt c o m plete d 
t he st u d y or t he reas o n f or disc o nti n uati o n 
T he q uesti o n naires are t o be c o m plete d directl y b y t he patie nt. T he ori gi nal pa ges, c o nsi dere d 
as s o urce d ata, will be ke pt a n d file d o n site (i n t he I S F). 
All data ca pt ur e d f or t his st u d y are t o be rec or de d i n t he patie nt’s n otes first a n d t he n e ntere d i n 
t he e C R F.  
1 1. 2  M o nit ori n g 
Bef ore st u d y i nitiati o n, t he C R A will visit t he I n vesti gati n g Sites t o e v al u ate t he feasi bilit y of 
partici pati n g t o t he st u d y (e. g., patie nt recr uit me nt, staff a vaila bilit y, facilities, e q ui p me nt). 
D uri n g t he St u d y I nitiati o n Visit, t he C R A will i nitiate t he Pri nci pal I n v esti gat or a n d t he site 
staff i n or der t o tr ai n t he PI a n d t he site staff o n t h e St u d y Pr ot oc ol a n d trial-relate d pr oce d ures, 
a n d verif y g o o d u n dersta n di n g of G C P (e. g., I n vesti gat or's res p o nsi bilities) a n d a n y ot her 
a p plica ble C o m m u nit y a n d nati o nal le gal a n d re g ul at or y re q uire me nts, n ota bl y as re gar ds 
sta n dar ds of q ualit y a n d safet y f or t he pr oc ure me nt (i ncl u di n g patie nt selecti o n a n d i ncl usi o n), 
testi n g, distri b uti o n, a d mi nistrati o n, a n d tracea bilit y of h u ma n tiss ues a n d cells, as well as 
n otificati o n a n d re p orti n g of a n y S A E a n d/ or Seri o us A d verse Safet y/ Q ualit y E ve nts. 
Ver y s h ortl y after t he first patie nt i ncl usi o n, a n o n-site m o nit ori n g visit will ta ke place i n or der 
t o verif y t he a d here nce t o t he pr ot oc ol a n d st u d y pr oce d ures, a n d t h us a v oi di n g a n y n o n-
c o m plia nce i n t he f ut ure i ncl usi o ns, if a p plica ble. 
D uri n g t he c o urse of t he st u d y, o n-site m o nit ori n g visits a n d re g ul ar c o ntacts wit h t he 
I n v esti gati o n Sites will be c o n d uct e d b y t he M o nit or i n or der t o pr o vi de d etaile d i nf or mati o n 
a n d s u p p ort t he I n vesti gat or(s), a n d t o assess t hat t he st u d y is perf or me d i n c o m plia nce a n d 
acc or da nce t o t he pr ot o c ol, I C H- G C P, a n d all a p plica ble re gi o nal a n d nati o nal re g ulat or y 
req uire me nts (s ee t he refere nce d oc u me nts i n Secti o n 1 2 ). 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 8 9 /1 1 4  
 
 
F or i nsta nce, t he f oll o wi n g as p ects will be cl osel y verifie d: 
- 
Pr oc ure me nt of si g ne d a n d date d I C F 
- 
Patie nt ri g hts, i ncl u di n g pr otecti o n of pri vac y a n d c o nfi de ntialit y of pers o nal data a n d 
me dical rec or ds, well bei n g, a n d safet y 
- 
Patie nt recr uit me nt, eli gi bilit y, sel ecti o n, a n d i ncl usi o n 
- 
St u d y pr oce d ures, i ncl u di n g la b orat or y tests, i n vesti gati o n-relate d pr oce d ures a n d 
i ma gi n g pr oce d ures, if a n y 
- 
I n v esti gati o nal 
me dici nal pr o d uct recei pt, verificati o n, a n d fi nal deli v er y b y t he 
P har macist 
- 
I n v esti gati o nal me dici nal pr o d uct recei pt a n d verificati o n b y t he I n vesti gat or 
- 
I n v esti gati o nal me dici nal pr o d uct acc o u nta bilit y a n d tracea bilit y 
- 
S A E n otificati o n a n d re p orti n g 
- 
E mer ge nc y a n d pre g n a nc y pr oce d ures 
- 
Data ge n erati o n a n d c ollecti o n pr ocess es 
- 
Acc urac y of data c ollecte d a n d rec or de d i n t he e C R F 
- 
Facilities a n d S ite staff 
- 
I S F (a n d ot her o n-site s o urce d oc u m e ntati o n) 
A n y d etecte d n o n -c o m pli a nce wit h t he pr ot oc ol, G C P or a n y ot her a p plica ble C o m m u nit y a n d 
nati o nal le gal a n d re g ulat or y re q uir e me nts will be f ull y d o c u me nte d b y t he M o nit or wit h t he 
e x pla nati o n pr o vi de d b y t he I n v esti gat or o n a d e viati o n l o g a n d a N ote t o Fil e, w he n a p plica ble. 
T his l o g will i ncl u de t he patie nt i de ntificati o n n u m ber, t he date of de viati o n occ urre d a n d a 
s u m mar y of t he d e viati o n. All pr ot oc ol de viati o ns t hat ha ve o cc urre d d uri n g t he st u d y s h o ul d 
be  classifie d as mi n or or maj or. A patie nt wit h a maj or de viati o n is n ot i ncl u de d i n t he P P. 
D ur i n g t he m o nit ori n g visits, t he I n vesti gat or a n d cli nical st u d y staff s h o ul d be a vaila ble f or 
q ue sti o ns, verificati o n of data fr o m t he s o urce d oc u me ntati o n, a n d p ossi ble c orrecti o ns t o t he 
e C R F. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
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A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 9 0 /1 1 4  
 
 
F oll o wi n g eac h m o nit ori n g visit, a f oll o w- u p letter will be se nt t o t he I n vesti gat or detaili n g a n y 
acti o n re q uir e d b y eit her t he site staff or t he M o nit or. A n y acti o n m ust, w here ver p ossi ble, b e 
a d dresse d i m me diatel y or b y t he ne xt sc he d ule d m o nit ori n g visit. 
T he M o nit or will c o nti n u o usl y b e reac ha ble a n d a vaila ble bet wee n visits if t he I n vesti gat or(s), 
or ot he r st u d y staff at t he site, nee ds a d diti o nal i nf or mati o n a n d/ or a d vice. 
T he st u d y site ma y als o b e patie nt t o q ualit y ass ura nce a u dit b y t h e S p o ns or as well as i ns p ecti o n 
b y a p pr o priate Re g ul at or y A ge ncies. 
I n v esti gat ors s hall pr o vi de a c urric ul u m vitae or e q ui vale nt. T he c urric ul u m vitae s hall gi ve 
na me, date/ place of birt h, a d dress, a n d place of w or k, a n d s hall s h o w t he trai ni n g, a p p oi nt me nts, 
a n d a n y ot her i nf or m ati o n t hat will c o nfir m t he s uita bilit y of t he cli nical I n v esti gat or t o be 
res p o nsi ble f or t he cli nical trial. All I n vesti gat ors or ot her res p o nsi ble pe o ple s h o ul d be liste d 
t o get her o n t he “ Site Si g n at ure a n d Dele gati o n l o g ”. T his l o g, ke pt u p t o d ate i n t he I n v esti gat or 
S ite File, will rec or d e x a m ples of eac h i n di vi d ual's ha n d writi n g, si g n at ure/i nitials a n d j o b title 
as well as t he tas ks t he I n vesti gat or h as dele gate d t o his staff ( wit h date of dele gati o n). T he 
In v esti gat or m ust si g n t his l o g t o i n dicate his/ her a ut h orisati o n. 
1 1. 3  S o urce D oc u me nts/ D at a Verific ati o n 
T o e ns ure t hat d ata i n t he e C R F are acc urate a n d c o m plete, a n d i n acc or da nce wit h p atie nt 
s o urce d o c u me nts a n d ot her s o urce d ata (e. g., la b orat or y res ults re p orts), 1 0 0 % of s o urce data 
verificati o n ( S D V) will be perf or m e d b y t he M o nit or o n all data a n d e C R F i ncl u di n g b ut n ot 
li mite d t o S A E F or ms a n d pre g n a nc y-relate d d o c u me nts, c o nsisti n g i n a c o m paris o n of t he 
s o urce d oc u me ntati o n data wit h t he e C R F a n d ot her rec or ds rele va nt t o t he st u d y. T his will 
re q uire dir ect access t o all ori gi nal rec or ds f or eac h patie nt. 
F or t he patie nt q uesti o n n aires, 1 0 0 % S D V will be perf or me d b y t he M o nit or o n site. F oll o wi n g 
t his S D V, a n y err ors ( dis cre pa n cies) greater t ha n 3 m m n otice d o n a V A S d uri n g i n de pe n d e nt 
verificati o n b y/ o n be h alf of t he S p o ns or (e. g., a u dits) m ust tri g ger a p pr o priat e c orrecti ve acti o ns 
t o e ns ure e x act ness of all V A S val ues i n t he st u d y. 
T he pr ocess of o btai ni n g i nf or me d c o nse nt a n d t he prese nce o n file of t he si g ne d a n d date d I C F 
will be verifie d f or all patie nts scree ne d, w het her or n ot t he y were eli gi ble. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 9 1 /1 1 4  
 
 
T he bac k-tr a nscri pti o n of data fr o m t he e C R F i nt o s o urce d oc u me nts is n ot all o we d, i ncl u di n g 
w he n discre p a ncies/ o missi o ns are detecte d b y S D V. 
As s o me data will be directl y e nt ere d i nt o t he e C R F, t he e C R F will be c o nsi dere d as s o urce 
d oc u me nt f or t hese d ata. T he “ L o cati o n of S o urce Data” list will be c o m plete d c o nfir mi n g t he 
l ocati o n of t he s o urce dat a. 
1 1. 4  C o m pleti o n of C ase Re p ort F o r ms, Si g ni n g a n d Fili n g 
T he patie nts will b e m o nit ore d t hr o u g h o ut t he c o urse of t h e st u d y a n d all res ults of e val uati o ns 
will be rec or de d i n t he e C R F. T he e C R F will be c o m plete d f or eac h patie nt s cree n e d i n t he tri al. 
F or scree ni n g fail ure p atie nts, o nl y t he d e m o gra p hic data, t he i ncl usi o n a n d e x cl usi o n criteria 
a n d t he reas o n of t he scree ni n g fail ure m ust be k e pt. T he y will be c o m plete d as s o o n as p ossi ble 
after t he p atie nt visit. 
Us uall y t he I n v esti gat or e nters all re c or di n gs i n t he e C R F, b ut t he rec or di n g of data i n t he e C R F 
ma y b e dele gate d b y t he I n v esti gat or t o a desi g nat e d re prese ntati ve (s h o ul d be d oc u me nte d o n 
t he “ Site Si g nat ur e a n d Dele gati o n Lo g ”). T he i nf or mati o n rec or de d b y t h e I n vesti gat or i n t he 
e C R F s h o ul d prefera bl y be i n E n glis h. T he e C R F m ust be si g ne d a n d date d b y t he I n vesti gat or 
w h o ta kes res p o nsi bilit y f or t he p u nct ualit y, c o m plete ness, c o nsiste nc y, acc urac y a n d l e gi bilit y 
of t he data re p orte d t o t he S p o ns or i n t he e C R F. T he e C R F a n d relate d s o urce data will be ma de 
a vaila ble b y t he I n v esti gat or f or dat a verifi cati o n at eac h s c he d ule d m o nit ori n g visit. 
T he  c o m plete d ori gi nal e C R Fs are t he s ole pr o pert y of t he S p o ns or a n d s h o ul d n ot be ma de 
a vaila ble i n a n y f or m t o t hir d parties, e x ce pt f or a ut h oris e d re prese ntati ves of a p pr o priate 
A ge ncies, wit h o ut writte n per missi o n fr o m t he S p o ns or. C o m plete d e C R F a n d S A E/ Pre g na n c y-
relate d d oc u m e nts will be c ollecte d b y t he M o nit or d uri n g m o nit ori n g visits f or a nal ysis a n d 
fili n g. All ori gi n al e C R F s h o ul d be k e pt i n t h e S p o ns or’s file. A c o p y of all t hese d oc u m e nts 
will be st ore d i n t he I n vesti gat or's arc hi ves after c o m pleti o n or disc o nti n uati o n of t he trial f or 
d urati o n of 2 0  years acc or di n g t o S p o ns or’s S O Ps, a n d a p plica ble la ws. 
1 1. 5  D at a M a n a ge me nt 
T he st u d y Data Ma n a ge me nt Pla n ( D M P) will descri be met h o ds use d t o c ollect, c hec k, a n d 
pr ocess cli nical data, as well as t he pr oce d ure t o f oll o w f or d ata base l oc k. T he D M P will be 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
J T A-K O A 1 -C S P   
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A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 9 2 /1 1 4  
 
 
de vel o pe d b y t he C R O a n d t he S p o ns or a n d a p pr o ve d b y t he S p o ns or. It will als o list t he r oles 
a n d res p o nsi bilities of t he pers o n nel ( wit h t h e c orres p o n di n g f u ncti o ns) i n v ol ve d i n d ata 
ma na ge me nt pr o cess. 
T he data bas e l oc k will be p ossi ble after a p pr o val b y at least 2 a ut h orise d re prese ntati ves of t he 
S p o ns or. 
1 1. 6  A u d its a n d I ns pecti o ns 
A ut h orise d re prese nt ati ves of t he S p o ns or, M o nit or, A ge n cies, a n d/ or E Cs ma y visit t he site at 
an y ti me d uri n g or after t he st u d y t o p erf or m a u dits a n d/ or i ns pecti o ns, i ncl u di n g S D V. T he 
p ur p ose of s u c h a u dit or i ns pecti o n is t o s yst e maticall y a n d i n de pe n de ntl y e x a mi ne all 
i n vesti gati o n-relate d pr oce d ures a n d d o c u me nts a n d t o det er mi ne w het her t hese data a n d 
pr oce d ures were c o n d ucte d, c ollecte d, rec or de d, a nal ys e d, a n d re p orte d acc uratel y a n d i n 
acc or da nce wit h t he a p pr o ve d St u d y Pr ot oc ol , G C P, a n d all a p plica ble C o m m u nit y a n d n ati o nal 
le gal a n d re g ul at or y re q uire me nts (see ref ere n ce d oc u me nts i n Secti o n 1 2). 
T he  I n vesti gat or m ust i m me diatel y i nf or m t he S p o ns or a n d/ or t he M o nit or if c o ntacte d b y a n 
A ge nc y a n d/ or E C a b o ut a n i ns pecti o n at his/ her site. 
T he  pres e nce of t h e M o nit or o n site is ma n dat or y i n case of visit/a u dit ( at least f or t he S D V 
a u dit a n d de briefi n g wit h t he I n vesti gat or) b y a n y a ut h orise d re pres e ntati ve of t he S p o ns or . 
Ne vert hel ess, w he n j ustifie d, t he 
M o nit or ma y be re pres e nte d b y a n ot her re prese nt ati ve 
i n v ol ve d i n t he st u d y. 
D uri n g t h ese a u dits a n d i ns pecti o ns, pr otecti o n of t he patie nt ri g hts a n d pri vac y, a n d 
c o nfi de ntialit y of t he p atie nt pers o n nel data a n d me dical rec or ds, will be strictl y res p ecte d, a n d 
patie nts will be i nf or me d t hat a ut h orise d re prese ntati ves fr o m t he S p o ns or, A ge n cies a n d/ or 
E C s ma y wis h t o i ns pect t heir me dical rec or ds. 
A n y res ults a n d i nf or mati o n arisi n g fr o m t he i ns p ecti o ns b y t he A ge n cies a n d/ or E Cs will b e 
i m me diatel y c o m m u nicat e d b y t h e I n vesti gat or t o t he S p o ns or or its re pres e ntati ve(s). 
T he  I n vesti gat or s h o ul d ta ke all t he c orrecti ve acti o ns f or a n y iss ue or pr o ble m i de ntifie d a n d 
raise d d uri n g a u dit/i ns pecti o ns. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
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A ut h or: E B   
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1 1. 7  Access t o S o urce D at a 
A ut h orise d re prese ntati v es of t he S p o ns or, A ge n cies a n d/ or E Cs will be all o we d t o ha ve f ull 
a n d direct access t o t he vari o us rec or ds rel ati n g t o t he trial t o verif y a d h ere nce t o t he St u d y 
Pr ot oc ol, G C P, a n d a n y a p plica ble C o m m u nit y a n d nati o nal le gislati o n a n d re g ulat or y 
re q uire me nts, a n d t he c o m plete ness, c o nsiste nc y, le gi bilit y a n d acc urac y of t he data bei n g 
re p orte d. 
1 1. 8  T r ai ni n g of St aff 
I n a d diti o n, t he I n vesti gat or will mai ntai n rec or ds of all i n di vi d uals i n v ol ve d i n t he st u d y 
c o n d uct ( me dical, n ursi n g, a n d ot her staff). T he I n v esti gat or will e ns ure t hat a p pr o priate 
i nf or mati o n rele va nt t o t he st u d y is gi ve n t o t he st u d y staff, a n d t hat a n y ne w i nf or m ati o n of 
rele va n ce t o t he efficac y of t he st u d y will be pr o vi de d t o t he staff i n v ol ve d. T he I n vesti gat or 
m ust i nf or m t he M o nit or, i n a ti mel y ma n ner, of a n y c h a n ge i n t he st u d y site staff. 
1 1. 9  C h a n ges t o t he Pr ot oc ol 
T he I n vesti gat or ca n n ot i m ple me nt a n y d e viati o n fr o m or c ha n ges t o t he St u d y Pr ot oc ol wit h o ut 
pri or 
a p pr o val 
b y t he 
S p o ns or 
a n d 
pri or 
s u b missi o n, re vie w 
a n d 
d oc u me nte d 
a p pr o val/fa v o ura ble o pi ni o n fr o m t he C As a n d E C s (e x ce pt w he n necessar y t o eli mi nate 
i m me diate hazar ds t o st u d y p atie nts, or w he n c ha n ges i n v ol ve o nl y l o gisti cal or a d mi nistrati ve 
as pects of t he st u d y, e. g., c ha n ges i n M o nit ors or p h o ne n u m bers). A n y de viati o n fr o m t he 
St u d y Pr ot oc ol will be i d e ntifie d, re vi e we d, a n d re p orte d b y t h e M o nit or wit h a n e x pla nati o n 
pr o vi de d b y t he I n vesti gat or o n t he pr ot oc ol d e viati o n L o g, a n d a “ N ote t o File” w he n 
a p plica ble. 
If it is necess ar y f or t he St u d y Pr ot oc ol t o be a me n de d, t he a me n d m e nt or a ne w versi o n of t he 
S t u d y Pr ot oc ol will be s u b mitte d t o a n d a p pr o ve d b y t he A Cs a n d E C s bef ore i m ple me ntati o n.  
If a pr ot oc ol a m e n d me nt re q uires a c h a n ge t o a partic ular site's I C F, t he C R A, 
M o nit or, 
S p o ns or, a n d site's C A will be n otifie d. A p pr o val of t he re vis e d I C F b y t he C R A, M o nit or, 
S p o ns or, a n d c o ncer ne d C As a n d E Cs, if a p plica ble, is re q uire d bef ore t he re vise d f or m is use d. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
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V 0 4   
A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 9 4 /1 1 4  
 
 
T he M o nit or ( u n der t he s u per visi o n of t he S p o ns or) will distri b ute a me n d me nts a n d ne w 
versi o ns of t he St u d y Pr ot oc ol t o eac h I n vesti gat or  f or re vi e w a n d a p pr o val, a n d t o t he site staff. 
T he  distri b uti o n of t hese d oc u me nts t o t he A ge n cies a n d E Cs will be ha n dle d acc or di n g t o l ocal 
practice. 
A me n d me nts t o t he trial are re gar de d as “s u bsta ntial” if t he y are li kel y t o ha ve a si g nifica nt 
i m pact o n: 
- 
T he safet y, p h ysic al healt h, a n d me ntal i nte grit y of t he patie nt s; 
- 
T he scie ntific val u e of t h e trial; 
- 
T he c o n d uct or m a na ge m e nt of t he trial; 
- 
T he q ualit y a n d/ or safet y of a n y i n vesti gati o nal me dici nal pr o d uct use d i n t he trial. 
If a n y ne w e ve nt occ urs or a n y i nf or mati o n bec o mes a vaila ble re gar di n g eit her t he c o n d uct of 
t he trial or t he d e vel o p me nt of t he i n v esti gati o nal me dici nal pr o d ucts, w hic h ma y i m pact s afet y 
of t he p atie nts or e val uati o n of t he ris k- be nefit rati o f or t h e cli nical trial, t he S p o ns or will 
i m me diatel y i nf or m t he I n vesti gat ors, a n d a p pr o priate safet y meas ures will be ta ke n t o pr otect 
pa tie nts a gai nst a n y i m me diate hazar d. T he S S O  ( u n der t he s u per visi o n of t he S p o ns or) will 
als o i m me diatel y i nf or m A ge ncies a n d E Cs of t hese e ve nts a n d/ or data, a n d t he meas ures will 
be ta ke n. 


C O N FI D E N TI A L 
 
J T A -K O A 1 - Cli nic al St u d y Pr ot oc ol  
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A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
P g. 9 5 /1 1 4  
 
 
1 2  A D MI NI S T R A TI V E, L E G A L A N D E T HI C A L A S P E C T S 
1 2. 1  E t hic al Pri nci ples a n d C o n d uct of t he Tri al 
T he trial will be c o n d uct e d i n acc or da nce wit h all a p plica ble C o m m u nit y a n d nati o nal la ws, 
re g ulati o ns, g ui d a nce, g ui deli nes, a n d pri nci ples re gar di n g: 
- 
Pr otecti o n of t he ri g hts, safet y, pri vac y, a n d well- bei n g of h u ma n s u bjects 
- 
Et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects 
- 
G o o d 
Cli nical Practice ( G C P) re gar di n g t he c o n d uct of cli nical trials a n d 
i n vesti gati o nal me dici nal pr o d ucts f or h u ma n use 
- 
Cli nical safet y data ma na g e me nt, n otificati o n, a n d re p orti n g wit hi n t he c o nte xt of 
cli nical trials 
- 
G o o d 
Ma n ufact uri n g 
Practice a n d q ualit y re q uire me nts f or 
ma n ufact ure of 
i n vesti gati o nal me dici nal pr o d ucts f or h u ma n use 
- 
Sta n dar d O perati n g Pr oce d ures ( S O Ps) of t he rele va nt i nstit uti o ns 
T his i ncl u des n ota bl y t he f oll o wi n g refere nce d oc u me nts: 
- 
W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki o n Et hical Pri nci ples f or Me dical 
Researc h i n v ol vi n g H u m a n Patie nts ( wit h a me n d me nts) 
- 
C harter of F u n da me nt al Ri g hts of t he E ur o pea n U ni o n ( 2 0 1 2 / C3 2 6/ 0 2) 
- 
Directi ve 9 5/ 4 6/ E C of t h e E ur o p ea n Parlia me nt a n d of t he C o u ncil of 2 4 Oct o ber 1 9 9 5 
o n t he pr otecti o n of i n di vi d uals wit h re gar d t o t h e pr ocessi n g of p ers o nal data a n d o n 
t he free m o ve me nt of s uc h data 
- 
Sta n dar ds f or Pri vac y of I n di vi d uall y I d e ntifia ble Healt h I nf or mati o n - 4 5 C F R Parts 
1 6 0 a n d 1 6 4 (J a n uar y 2 5 , 2 0 1 3, Pri vac y R ul e, U nit e d States De part me nt of Healt h a n d 
H u ma n Ser vices) 
- 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6, P u blic La w 1 0 4- 9 1 
( A u g ust, 2 1, 1 9 9 6, 1 0 4t h C o n gress, U nite d States of A merica) 
- 
I C H T o pic E 6 ( R 1) - G ui deli ne f or G o o d Cli nical Practice - ( Se pte m ber 1 9 9 7, 
E ur o pea n Me dici nes A ge nc y, C P M P/I C H/ 1 3 5/ 9 5) 


C O N FI D E N TI A L 
 
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I C H T o pic E 8 - Ge neral C o nsi derati o ns f or Cli nical Trials - ( Marc h 1 9 9 8, E ur o pea n 
Me dici nes A ge n c y, C P M P/I C H/ 2 9 1/ 9 5) 
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I C H T o pic E 9 – N ote f or g ui da nce o n statistical pri nci ples f or cli nical trials ( Marc h 
1 9 9 8, E ur o pea n M e dici ne A ge nc y, C P M P/I C H/ 3 6 3/ 9 6) 
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Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 
o n t he a p pr o xi mati o n of t he la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he 
Me m ber States relati n g t o t he i m ple me ntati o n of g o o d cli nical practice i n t he c o n d u ct 
of cli nical trials o n me dici nal pr o d ucts f or h u ma n use 
- 
C o m missi o n Directi ve 2 0 0 5/ 2 8/ E C of 8 A pril 2 0 0 5 la yi n g d o w n pri nci ples a n d 
detaile d g ui deli nes f or g o o d cli nical practice as re gar ds i n vesti gati o nal me dici nal 
pr o d ucts f or h u ma n us e, as well as t he re q uire me nts f or a ut h oris ati o n of t he 
ma n ufact uri n g or i m p ort ati o n of s uc h pr o d ucts 
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I C H T o pic E 2 A - Cli nical Safet y Data M a na ge m e nt : Defi niti o ns a n d Sta n dar ds f or 
E x pe dite d  
Re p orti n g 
- 
( N o ve m ber 
1 9 9 4, 
E ur o pea n  
Me dici nes  
A ge nc y, 
C P M P/I C H/ 3 7 7/ 9 5) 
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Detaile d G ui da nce o n t he C ollecti o n, Verificati o n a n d Prese ntati o n of A d verse 
Reacti o n Re p orts arisi n g fr o m Cli nical Tri als o n Me dici nal Pr o d ucts f or H u ma n Use - 
E ur o pea n C o m missi o n (J u ne 2 0 1 1 , E N T R/ C T 3) 
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Detaile d G ui da n ce o n t he E ur o p ea n d ata base of S us pecte d U ne x pect e d Seri o us 
A d verse R eacti o ns ( E u dra vi gila n ce, Cli nical Tri al M o d ule) - E ur o pea n C o m missi o n 
( A pril 2 0 0 4, E N T R/ C T 4) 
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C o m missi o n Directi ve 2 0 0 3/ 9 4/ E C of 8 Oct o ber 2 0 0 3 la yi n g d o w n t he pri nci ples a n d 
g ui deli nes of g o o d ma n ufact uri n g practice i n res pect of me dici nal pr o d ucts f or h u ma n 
use a n d i n vesti gati o nal me dici nal pr o d ucts f or h u ma n use 
- 
E ur o pea n U ni o n G ui deli nes t o G o o d Ma n ufact uri n g Practice - Me dici n al Pr o d ucts f or 
H u ma n a n d Vet eri nar y Use - I n v esti gati o nal M e dici nal Pr o d ucts ( R ules G o ver ni n g 
Pr o d ucts i n t he E ur o pea n U ni o n, E u drale x V ol u me 4, A n ne x e 1 3, 0 3 Fe br uar y 2 0 1 0, 
E N T R/ F/ 2/ A M/a n D ( 2 0 1 0) 3 3 7 4) 
- 
G ui deli ne o n t he Re q uire me nts t o t he C he mical a n d P har mace utical 
Q ualit y 
D oc u me ntati o n c o n cer ni n g I n vesti gati o nal Me di ci nal Pr o d ucts i n Cli nical Trials - 


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C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use ( C H M P) E ur o pea n Me dici nes 
A ge nc y ( 3 1 Marc h 2 0 0 6, C H M P/ Q W P/ 1 8 5 4 0 1/ 2 0 0 4) 
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G ui da nce o n I n vesti gati o nal 
Me dici nal Pr o d ucts (I M Ps) a n d ‘ n o n i n vesti gati o nal 
me dici nal pr o d ucts’ ( NI M Ps) - E ur o pea n C o m missi o n ( 1 8 Marc h 2 0 1 1, E u drale x 
V ol u me   
1 0   
-   
Cli nical   
Trials,   
N otice   
t o   
A p plica nts, 
S A N C O/ C/ 8/ S F/c g/a. 5. 0 0 1( 2 0 1 1) 3 3 2 8 5 5) 
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A n d a n y ot her a p plica ble a n d rele va nt nati o nal la ws a n d re g ulati o ns  
1 2. 2  He alt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w B o ar d 
Bef ore t he be gi n ni n g of t he trial: 
- 
T he Cli nical Trial A p plicati o n ( C T A) will be s u b mitte d t o a n d a p pr o ve d/a ut h orize d b y 
t he C As 
- 
T he rele va nt E Cs will a p pr o ve a n d/ or pr o vi de fa v o ura ble o pi ni o n o n t he cli nical trial, 
base d o n a c o m pre he nsi ve file, i ncl u di n g (as re q uire d) t he St u d y Pr ot oc ol ( wit h 
a me n d me nts), writte n Patie nt I nf or m ati o n S heet a n d I nf or me d C o nse nt F or m (I C F), 
ot her writte n i nf or mati o n t o be pr o vi de d t o patie nts (s uc h as t he Patie nt St u d y Car d), 
patie nt recr uit me nt pr oce d ures, I n vesti gat or's Br oc h ure, a v aila ble safet y i nf or mati o n, 
i nf or mati o n a b o ut pa y me nts a n d c o m pe nsati o n a v aila ble t o patie nts, t he I n vesti gat ors 
c urre nt c urri c ul u m vitae a n d/ or ot her d o c u me ntati o n e vi de nci n g q u alificati o ns, a list 
of i n v ol ve d E Cs a n d att e n dees, a n d a n y ot her d oc u me nts t hat t he E Cs ma y n ee d t o 
f ulfil its res p o nsi bilities, t he s uita bilit y of t he I n v esti gat or(s), facilities, a n d t he 
met h o ds a n d material t o be use d i n o btai ni n g a n d d oc u me nti n g i nf or m e d c o nse nt of 
t he trial s u bject. 
- 
T he a b o ve- me nti o ne d d o c u me nts ma y als o n ee d t o be s u bse q ue ntl y re vise d d uri n g t he 
c o urse of t he trial, f or i nsta nce w he ne v er i m p orta nt ne w i nf or mati o n t h at ma y b e 
rele va nt t o t he patie nts' s afet y a n d/ or re-e v al uati o n of t he ris k/ be nefit rati o bec o mes 
a vaila ble. I n t his cas e, a n y c h a n ge, u p dat e, a n d/ or a me n d me nts t o t hese d oc u me nts will 
al wa ys be first s u b mitte d t o a n d a p pr o ve d b y t he C As a n d E Cs pri or t o a n y s u b missi o n 
t o t he patie nts (a n d all c o ncer ne d I n vesti gat ors a n d I n v esti gati n g Sites).  


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T he S p o ns or has pre pare d a te m plate of t he I C F, w hic h e m b o dies t he I C H G C P 
re q uire d el e me nts a n d i n cl u des a n y l ocal re g ulati o ns t o be discl ose d f or t he c o nse nt t o 
be le gall y effecti ve. 
T he  I n v esti gat or a n d I n vesti gati n g Site will n ot i nitiate n or a p pl y a n y st u d y pr oce d ure or deli ver 
I M P or refere n ce u ntil a p pr o vals ha ve bee n o btai ne d fr o m t he C As a n d E Cs. C o pies of a n y 
c orres p o n d e nce bet w ee n t he I n vesti gat or a n d t he C As a n d/ or E Cs will be gi ve n t o t he M o nit or 
or t he  S p o ns or. 
T he I n v esti gat or will i m me diatel y n otif y t he St u d y Safet y Officer a n d/ or t h e S p o ns or a b o ut t he 
occ urre nce of a n y S A E a n d ot her rele va nt Seri o us A d verse Safet y/ Q u alit y E ve nts, i n or der t o 
all o w pr o per n otificati o n a n d re p orti n g of t hese e ve nts t o t he C As, E Cs, a n d t he ot her 
I n v esti gat ors i n v ol ve d i n t he trial. Detaile d descri pti o n of Safet y Data N otificati o n, Re p orti n g, 
a n d Ma na ge m e nt pr oce d ures is pr o vi de d i n Secti o n 8 ). 
T he S p o ns or ( wit h or wit h o ut t he s u p p ort fr o m t he M o nit or) is res p o nsi ble f or s u b mitti n g t o t he 
C As a n d E Cs a n y a me n d me nt t o t he St u d y Pr ot oc ol, a n d a n y c ha n ges t o t he Patie nt I nf or mati o n 
S heet a n d I nf or me d 
C o nse nt a n d/ or I n v esti gat or’s 
Br oc h ure, f or a p pr o val pri or t o 
i m ple me ntati o n. 
T he I n vesti gat or will pre pare a n d s u b mit ( wit h or wit h o ut t he s u p p ort fr o m t he M o nit or) a n n ual 
rep orts t o t he C As a n d E Cs, a n d acc or di n g t o l ocal re g ul ati o ns a n d g ui d eli nes. T he I n vesti gat or 
( wit h s u p p ort fr o m t he St u d y Safet y Officer) m ust als o pr o vi de t he C As a n d E Cs wit h a n y 
re p orts of S A Es fr o m t he st u d y site, as dictate d b y t he C As a n d E Cs re q uire me nts. 
T he C As a n d E Cs will b e n otifie d b y t he S p o ns or a b o ut t he e n d of t he trial wit hi n 9 0 da ys. If 
t he trial is ter mi nate d earlier, t he C As will be n otifie d wit hi n 1 5 da ys. A re p ort s u m marisi n g 
t he st u d y res ults will be se nt t o t he C As wit hi n o ne year after t he e n d of t he trial. 
1 2. 3  P ati e nt D at a Pr otecti o n a n d C o nfi de nti alit y 
T he c o nfi de ntialit y of data a n d rec or ds t hat c o ul d i de ntif y patie nts will be pr otecte d i n or der t o 
res pect pri vac y a n d c o nfi de ntialit y r ules, i n a cc or da nce wit h all a p plica ble C o m m u nit y a n d 
nati o nal le gislati o n a n d re g ul at or y re q uire me nts (see t he refere n ce d o c u me nts i n Secti o n 1 2. 1 ). 
A re p ort of t h e res ults of t he st u d y ma y b e p u blis he d or se nt t o t he a p pr o pri ate A ge n cies i n a n y 
me m ber state i n w hic h t h e st u d y dr u g ma y ulti matel y b e mar k ete d, b ut t he patie nt's n a me will 


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n ot be discl ose d i n t hese d oc u me nts. T he patie nt's na me ma y be discl ose d t o t he S p o ns or ( or 
a n y a ut h orise d re prese nt ati ve, i ncl u di n g t he M o nit or) or t he A ge nci es, d uri n g i ns pecti o ns of 
trial rec or ds a n d d ata. A p pr o priate preca uti o ns will al wa ys be ta ke n t o m ai ntai n c o nfi de ntialit y 
of me dical r ec or ds a n d p ers o nal i nf or mati o n. 
B y t he wa y of t he I C F, writte n a ut h orisati o n will be o btai ne d fr o m eac h p atie nt pri or t o e ntr y 
i nt o t he st u d y, i n acc or da nce wit h a p plica ble C o m m u nit y a n d nati o nal le gislati o n a n d re g ulat or y 
re q uire me nts (see t he refere nce d oc u me nts i n Secti o n 1 2). T he patie nts will be i nf or me d t hat 
t he res ults will be ke pt a n d a nal ys e d i n a c o m p uter b ut t hat n ot hi n g a part fr o m w hat has bee n 
rec or de d i n t he e C R F will be re gistere d. T he y will als o be i nf or me d t hat t heir data will o nl y be 
availa ble t o t he a b o v e- m e nti o ne d e ntities. 
T he  writte n I C F will e x plai n t hat st u d y d ata will b e st ore d i n a c o m p uter data base, mai ntai ni n g 
c o nfi de ntialit y i n acc or da nce wit h all a p plica ble C o m m u nit y a n d nati o nal le gislati o n a n d 
re g ulat or y re q uire me nts. T he patie nt‘s na mes will n ot be rec or de d i n t his data base. T he writte n 
I C F will als o e x plai n t hat, f or dat a verifi cati o n p ur p oses, a ut h orise d re prese ntati ves of t he 
S p o ns or ( or a n y a ut h orise d re pres e ntati ve, i ncl u di n g t h e M o nit or), A ge n cies, a n d/ or E Cs ma y 
re q uire direct access t o parts of t he h os pital or practice rec or ds rele va nt t o t he st u d y, i ncl u di n g 
patie nts' me dical hist or y. 
Fi nall y, i n or der t o e ns ure tr acea bilit y of i n vesti gati o nal m e dici nal pr o d ucts a n d refere n ce , 
t o get her wit h t he re q uire me nts re gar di n g pr otecti o n of pri vac y a n d c o nfi de ntialit y of p ers o nal 
data a n d me dical rec or ds, a u ni q ue i de ntificati o n c o de ( Patie nt I de ntificati o n N u m ber) will be 
all ocate d d uri n g t he scree ni n g of t he patie nt. T he li n k bet wee n t he i de ntit y of t he patie nt a n d 
t he i de ntificati o n c o de will be pr otecte d a n d k e pt strictl y c o nfi de ntial. T his i nf or mati o n will be 
k n o w n a n d rec or de d o nly  b y t he I n vesti gat or a n d will be ke pt a n d rec or de d i n restricte d access 
files: t he I S F at t he I n v esti gati o n Site.  
1 2. 4  I ns ur a nce 
T he S p o ns or’s lia bilities i n c o n necti o n wit h t he st u d y will be c o vere d b y a n i ns ura nce p olic y, 
i ncl u di n g a n y e ve nt, d a ma ge, i nj ur y, or deat h of t he patie nt, occ urri n g d uri n g t he c o urse of t he 
st u d y a n d bei n g or n ot, directl y or i n directl y, li n ke d t o t he st u d y, a n d i n acc or da n ce wit h a n y 


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a p plica ble C o m m u nit y a n d nati o nal le gislati o n a n d re g ulat or y re q uire m e nts. Details o n t he 
e xisti n g patie nts i ns ura nce are gi v e n i n t he Patie nt I nf or mati o n S heet. 
T he S p o ns or i ns ura nce will als o c o ver all i n di vi d uals partici pati n g t o a n d/ or i nter ve ni n g i n t he 
st u d y, i n de pe n de ntl y fr o m t he nat ure of t he e xisti n g li n k bet wee n t he S p o ns or, t he partici pa nt, 
a n d t he patie nt. 
1 2. 5  F i n a nci al As pects 
Fi na ncial d etails re gar di n g efficac y of t he st u d y will be s pecifie d i n a n “I n v esti gati o nal Site 
A gree me nt ” si g n e d b y t h e S p o ns or a n d t he Pri nci pal I n v esti gat or bef ore t h e start of t he st u d y 
(eac h p art y will recei ve a n ori gi nal si g ne d c o p y). 
T he I n vesti gat or at eac h site m ust c o m pl y wit h all t he ter ms, c o n diti o ns, a n d o bli gati o ns of t he 
“I n vesti gati o nal Site A gree me nt”. 
1 2. 6  Ar c hi vi n g at t he E n d of t he St u d y 
After t he cl ose- o ut visit at eac h site, a c o p y of t h e f oll o wi n g d oc u me ntati o n ( n o n-e x ha usti ve 
list) will be st ore d i n t he I n v esti gat or's arc hi ves f or a peri o d of 2 0 years acc or di n g t o E ur o pea n 
dire cti ves, nati o nal la ws a n d S p o ns or’s S O Ps. Arc hi vi n g res p o nsi bilities ca n n ot be tra nsferre d 
t o t he S p o ns or. 
- I n v esti gat or's Trial Mast er Site File wit h t he fi nal Pr ot oc ol a n d c urre nt I n v esti gat or 
Br oc h ure 
- C o p y of c o m plet e d e C R Fs, S A E, a n d Pre g n a nc y F or ms 
- Si g ne d I C Fs 
- Patie nt scree ni n g a n d E nr ol me nt L o g a n d Patie nt I d e ntificati o n C o de List 
- S o urce d oc u me ntati o n 
- All re g ulat or y d o c u me nts re q uire d b y I C H- G C P a n d a n y ot h er a p plica bl e C o m m u nit y 
a n d/ or nati o nal la ws a n d re g ulati o ns 
All st u d y-rel ate d d oc u me ntati o n m ust be st ore d i n a sec ure ma n ner a n d m ust re mai n a vaila ble 
u p o n re q uest fr o m t he S p o ns or or a n y A ge ncies a n d/ or E Cs. 


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Bef ore or at t he e n d of t he arc hi vi n g peri o d, t he S p o ns or ca n re q uest a n e xte nsi o n of t he st ora ge 
of all materi als, or p art of t he m, f or a f urt her peri o d. A n a p pr o priate a gree me nt will be dra w n 
u p acc or di n gl y. If a n e xte nsi o n of t he st ora ge is n ot re q uire d, it is t h e res p o nsi bilit y of t h e 
I n v esti gat or t o d eci de t o destr o y or kee p t hese st u d y-relat e d materials after t his arc hi vi n g 
peri o d. It is t he res p o nsi bilit y of t he S p o ns or t o i nf or m t he sites w he n arc hi vi n g is n o l o n ger 
nee de d. 


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1 3  R E P O R TI N G A N D P U B LI C A TI O N S P O LI C Y 
1 3. 1  Cli n ic al St u d y Re p ort 
W he n all c o m plete d e C R Fs a n d Dat a Clarificati o n F or ms ( D C Fs) ha ve b ee n c ollecte d, a n d d ata 
ha ve bee n a n al ys e d, a draft of t he Cli nical St u d y Re p ort will be pr o d uce d a n d will be se nt t o 
t he C o or di nati n g I n vesti gat or a n d all Pri nci pal I n vesti gat ors f or re vie w. If a re vie wer d oes n ot 
agree wit h all or part of t he Cli nical St u d y Re p ort, his/ her c o m me nts s hall be rec or de d a n d 
c o m m u nicate d t o t he ot her Pri nci pal I n vesti gat ors. W he n a gree me nt o n t he c o nte nts has bee n 
reac h e d, t he re p ort will be si g ne d b y t he S p o ns or a n d C o or di nati n g I n v esti gat or. 
T he Cli nical St u d y Re p ort will i ncl u de t he "I n di vi d ual Patie nt Data Listi n g" ( 1 6. 4 of C S R 
acc or di n g t o t he I C H). T he res ults will be ta b ulate d, e val uate d, a n d iss ue d as a c o m plete fi nal 
Cli nical St u d y Re p ort acc or di n g t o t he I C H- E 3 “ N ote f or g ui d a nce o n str uct ure a n d c o nte nt of 
cli nical st u d y re p orts”. T his re p ort will be writte n i n E n glis h. 
I n acc or da n ce wit h a p plica ble re q uire m e nts, t he S p o ns or will se n d t he Cli nical St u d y Re p ort t o 
b ot h t he A ge ncies a n d E Cs wit hi n o ne year after t he e n d of t he tri al.  
1 3. 2  P u blic ati o ns a n d P osters 
A n y a n d all S p o ns or c o nfi de ntial i nf or mati o n, i ncl u di n g b ut n ot li mite d t o scie ntific, tec h ni cal, 
cli nical, me dical a n d/ or re g ulat or y i nf or mati o n, d oc u me nts, data a n d d at a bases, b asic a n d/ or 
cli nical researc h res ults, pr o d uct i nf or mati o n a n d met h o ds, materials, pate nts a n d pate nt 
a p plicati o ns, k n o wle d ge, k n o w- h o w, i deas, c o n ce pts, desi g n, al g orit h ms, tra de secrets, researc h 
a n d de vel o p me nt acti vities, pr ojects, a n d pla ns, strate gic orie nt ati o ns, s ociet y str u ct ure, 
or ga nisati o n a n d c olla b orati o ns, c o ntracts a n d a gree me nts, b usi ness, fi na nci al a n d/ or mar keti n g 
pla ns a n d i nf or mati o n, w het her i n oral, writte n (i ncl u di n g b ut n ot li mite d t o writte n d oc u me nts, 
me m ora n d u m, 
mi n utes, c orres p o n de nce, re p orts), gra p hic (i ncl u di n g b ut n ot li mite d t o 
dra wi n gs, fi g ures, sc h e ma or ot her material) or c o m p uter-rea da ble f or m, will re mai n t he s ole 
pr o pert y of t he S p o ns or. 
A n y a n d all st u d y d ata, data bases, res ults, materials, a nal ysis, i nf or mati o n, d oc u me nts, a n d 
re p orts (i ncl u di n g b ut n ot li mite d t o e C R Fs), c ollecte d, ge nerate d, create d, writte n, a n d/ or 
ot her wise o btai ne d d uri n g ( or i n c o n n ecti o n wit h) t he st u d y u n d er t he St u d y Pr ot oc ol (e x ce pt 


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f or st u d y patie nt’s me di cal rec or ds), w het h er i n oral, writte n (i ncl u di n g b ut n ot li mite d t o 
d oc u me nts, me m ora n d u m, mi n utes, re p orts, c orres p o n de n ce), gra p hic (i ncl u di n g b ut n ot 
li mite d t o dra wi n gs, fi g ures, sc he m a or ot her material) or c o m p uter-rea da ble f or m, will bec o me 
t he pr o pert y of t he S p o ns or. 
T he  I n vesti gat or will retai n a n y i nf or mati o n or data of a n y ki n d p ertai ni n g t o t he st u d y, 
i ncl u di n g b ut n ot li mite d t o st u d y res ults fr o m i n di vi d ual St u d y Sites, as well as a n y S p o ns or 
C o nfi de ntial I nf or m ati o n f or t he p ur p ose of t he st u d y, w het her i n a n y a n d all i nta n gi ble a n d/ or 
ta n gi ble e x pressi o ns, i n a n y me dia, i n strict c o nfi de nce, a n d s hall n ot directl y or i n directl y 
p u blis h, c o m m u nicate, disse mi nate, dis pla y, d eli ver, distri b ute, re pr o d uce, discl ose, or 
ot her wise ma ke a vaila ble s uc h i nf or mati o n a n d/ or data t o a n y t hir d part y pri or writte n a p pr o val 
fr o m t he S p o ns or. 
P u blicati o n, c o m m u nicati o n (i ncl u di n g b ut n ot li mite d t o a bstracts a n d p osters), discl os ur e, 
releas e, or disse mi nati o n of a n y i nf or mati o n or data of a n y ki n d pertai ni n g t o t he St u d y, 
i ncl u di n g st u d y res ults fr o m i n di vi d ual st u d y sites, is h o we ver p ossi ble i n m ut ual a gree me nt 
bet wee n t he I n vesti gat ors a n d t he S p o ns or, pr o vi d e d t hat:  
- 
A n y pr o p ose d c o m m u nicati o n (i ncl u di n g, b ut n ot li mite d t o a bstracts a n d p osters) or 
p u blicati o n will be s u b mitte d t o t he S p o ns or pri or t o a n y s u b missi o n; a n d 
- 
A n y pr o p ose d c o m m u nicati o n or p u blicati o n 
will reflect t he c olla b orati o n a n d 
res pecti ve r oles of t he I n v esti gat ors, I n vesti gati o n Sites, a n d t he S p o ns or' p ers o n nel; a n d 
- 
T he S p o ns or s hall be gi ve n t hirt y ( 3 0) da ys t o re vie w c o m m u nicati o ns (a bstracts a n d 
p osters), a n d si xt y ( 6 0) d a ys t o r e vie w p u blicati o ns; a n d 
- 
I n t he e ve nt t hat t he S p o ns or d oes n ot o bject t o t he pr o p ose d c o m m u nicati o n or 
p u blicati o n wit hi n t hirt y ( 3 0) da ys or si xt y ( 6 0) d a ys of its recei pt, as t he case ma y be, 
it will be dee me d t o ha ve bee n a p pr o ve d; a n d 
- 
I n t he e ve nt t hat t he S p o ns or o bjects t o t he pr o p ose d c o m m u nicati o n or p u blicati o n f or 
reas o ns rel ati n g t o t he pate nta bilit y of a n i n ve nti o n or t he pr otecti o n of a n y ot her f or ms 
of i ntellect ual pr o pert y ri g hts t hat w o ul d be discl ose d b y s u c h pr o p ose d c o m m u nicati o n 
or p u blicati o n, t he n s u b missi o n of t he c o m m u nicati o n or p u blicati o n will be dela ye d f or 
a ma xi m u m of si x ( 6) m o nt hs t o e na ble t he S p o ns or t o pr otect its ri g h ts; a n d 


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I n t he e v e nt t hat t he S p o ns or reas o na bl y o bjects t o t he pr o p ose d c o m m u nicati o n or 
p u blicati o n as c o nflicti n g wit h or c o m pr o misi n g t he S p o ns or's i ntellect ual pr o pert y 
ri g hts or i nterests, t he pr o p ose d c o m m u nicati o n or p u blicati o n s hall be m o difie d i n or der 
t o f ull y a d dress t he S p o ns or's c o n cer ns a n d re q uests of m o dificati o ns (i ncl u di n g, b ut n ot 
li mite d t o deleti o n of a n y S p o ns or C o nfi de ntial I nf or mati o n fr o m t he pr o p ose d 
c o m m u nicati o n or p u blicati o n), a n d s uc h m o difie d c o m m u nicati o n or p u blicati o n ma y 
n ot be s u b mitte d, p u blis he d, discl ose d, or disse mi nate d u ntil t he S p o ns or has c o nfir me d 
its a gree me nt i n writi n g; a n d 
- 
A n y o bj ecti o n/re q uest e d m o dificati o n ma de b y t he S p o ns or c o ncer ni n g a pr o p ose d 
c o m m u nicati o n or p u blicati o n s hall be wit h i m ple me nte d d ue re gar ds of t he i m p orta nce 
of sc ie ntific disse mi nati o n of t he st u d y res ults. 
 


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1 4  R E F E R E N C E S 
- Att ur M, Kras n o k uts k y- Sa m uels S, Sa m uels J, A bra ms o n S B. Pr o g n ostic bi o mar kers i n 
oste oart hritis. C urr O pi n R he u mat ol. 2 0 1 3; 2 5: 1 3 6- 4 4. 
- A xelra d T. W, Ei n h or n T. A. Use of Cli nical Assess me nt T o ols i n t he E val uati o n of Fract ure 
He ali n g. I nj ur y. I nt. J. Care I nj ure d 4 2 ( 2 0 1 1) 3 0 1- 3 0 5. 
- Beat o n D E, B oers M, Wells G A. Ma n y faces of t he mi ni mal cli nicall y i m p orta nt differe nce 
( M CI D): a literat ure re vi e w a n d directi o ns f or f ut ure researc h. C urr O pi n R he u mat ol. 2 0 0 2 
Mar; 1 4( 2): 1 0 9- 1 4. Re vie w. 
- Bella m y N. W O M A C: a 2 0- year e x peri me ntal re vie w of a patie nt-ce ntere d self-re p orte d 
healt h stat us q uesti o n nair e. J R he u mat ol. 2 0 0 2; 2 9: 2 4 7 3- 2 4 7 6. 
- Bella m y N. T he W O M A C K nee a n d Hi p Oste o art hritis I n dices: de v el o p me nt, vali dati o n, 
gl o balizati o n a n d i nfl ue nce o n t he de vel o p me nt of t he A U S C A N Ha n d Oste oart hritis 
I n dices. Cli n E x p R he u mat ol. 2 0 0 5; 2 3: S 1 4 8- 1 5 3. 
- Bella m y N, B uc h a na n 
W W, G ol ds mit h C H, Ca m p bell J, Stitt L W. Vali dati o n st u d y of 
W O M A C: a healt h stat us i nstr u me nt f or meas uri n g cli nicall y i m p orta nt patie nt rele va nt 
o utc o mes t o a ntir he u m atic dr u g t hera p y i n patie nts wit h oste oart hritis of t he hi p or k nee. J 
R he u mat ol. 1 9 8 8; 1 5: 1 8 3 3- 1 8 4 0. 
- Bella m y N, Ca m p bell J, Welc h V, Gee T L, B o ur ne R, Wells G A. Visc os u p ple me nts f or t he 
treat me nt of oste oart hritis of t he k nee. C oc hra n e Data base of S yste matic Re vie ws. 2 0 0 9, 
Iss u e 1. 
- Bella m y N, Carr A, D o u ga d os M, S hea B, Wells G. T o war ds a defi niti o n of " differe n ce" i n 
oste oart hritis. J R he u mat ol. 2 0 0 1 Fe b; 2 8( 2): 4 2 7- 3 0. Re vie w 
- B orrás- Ver dera A, Calce d o- Ber nal V, Oje da- Le ve nfel d J, Cla vel- Sai nz C. Efficac y a n d 
safet y of a si n gle i ntra-artic ular i njecti o n of 2 % h yal ur o nic aci d pl us ma n nit ol i n k nee 
oste oart hritis o ver a 6- m o nt h peri o d. Re v Es p Cir Ort o p Tra u mat ol. 2 0 1 2; 5 6: 2 7 4- 8 0. 
- Brei vi k H, B orc h gre vi n k P C, Alle n S M, R ossela n d L, Brei vi k Hals E K, K varstei n G, 
St u b ha u g A. Assess m e nt of pai n. Br. J. A naest h. 2 0 0 8; 1 0 1: 1 7- 2 4. 
- Br ya nt D , F er na n d es N . Meas uri n g patie nt o utc o mes: a pri mer. I nj ur y. 2 0 1 1; 4 2: 2 3 2- 2 3 5.  
- C he valier X, J er osc h J, G o u pille P, va n Dij k N, L u yt e n F P, Sc ott D L, Baille ul F, Pa vel ka K. 
Si n gle, i ntra-artic ular tr eat me nt wit h 6 ml h yla n G- F 2 0 i n patie nts wit h s y m pt o matic 
pri mar y ost e oart hritis of t he k nee: a ra n d o mise d, 
m ultice ntre, d o u ble- bli n d, place b o 
c o ntr olle d trial. A n n R he u m Dis. 2 0 1 0 J a n; 6 9( 1): 1 1 3- 9  


C O N FI D E N TI A L 
 
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Date: Ma y 1 0 , 2 0 1 7  
P g. 1 0 6 /1 1 4  
 
 
- Drieser R. L., A v o uac B., Bar di n T. Efficac y of o ne i ntra -artic ular  i njecti o n of 2 % nat ural 
s o di u m h yal ur o nate is n o n i nferi or t o c he micall y cr ossli n ke d h yla n G -F 2 0 i n t he treat me nt 
of pai nf ull ti bi ofe m oral oste oart hritis. P oster at t he W orl d C o n gress o n Oste o p or osis, 2 0 1 5.  
- E hric h E W, Da vies G M, Wats o n DJ, B ol o g nes e J A, Sei de n ber g B C, Bell a m y N. Mi ni mal 
perce pti ble cli nical i m pr o ve me nt wit h t he 
Wester n O ntari o a n d Mc Master U ni versities 
oste oart hritis i n de x q uesti o n naire a n d gl o bal assess me nts i n patie nts wit h oste oart hritis. J 
R he u mat ol. 2 0 0 0 N o v; 2 7( 1 1): 2 6 3 5- 4 1. 
- Fels o n D T , La wre n ce R C, Die p pe P A, et al. Oste o art hritis: Ne w i nsi g hts. Part 1: T he disease 
a n d its ris k fact ors. A n n I nter n Me d. 2 0 0 0; 1 3 3: 6 3 5 -6 4 6.   
- Geric h J. Vis ual a nal o g u e scal es f or m o de-i n d e pe n de nt meas ure me nt i n s elf-a d mi nistere d 
q uesti o n naires. Be ha v Res Met h o ds. 2 0 0 7; 3 9: 9 8 5- 9 2. 
- G o d wi n M, Da wes M. I ntra-artic ul ar ster oi d i njecti o ns f or pai nf ul k nees. S yste matic re vie w 
wit h meta-a nal ysis. Ca n Fa m P h ysi cia n. 2 0 0 4; 5 0: 2 4 1 – 2 4 8. 
- Ha ys R D, M orales L S. T he R A N D- 3 6 meas ure of healt h-relat e d q ualit y of life. A n n Me d 
2 0 0 1; 3 3( 5): 3 5 0- 7 
- H oc h ber, Y. A s har per B o nferr o ni pr oce d ure f or m ulti ple tests of si g nifica nce. Bi o metrica  
1 9 8 8;  7 5 : 8 0 0 -2  
- H ua n g T L, Hs u H C, Ya n g K C, Ya o C H, Li n F H. Effect of differe nt m olec ular wei g ht 
h yal ur o n a ns o n oste o art hritis-relate d pr otei n pr o d u cti o n i n fi br o blast-li ke s y n o vi oc ytes fr o m 
patie nts wit h ti bia platea u fract ur e. J Tra u ma. 2 0 1 0; 6 8: 1 4 6- 5 2.  
- Ia n n o ne F, La pa d ula G. T he pat h o p h ysi ol o g y of oste oart hritis. A gi n g Cli n E x p Res. 2 0 0 3; 
1 5: 3 6 4- 7 2.  
- J ac ks o n D W, E va ns N A, T h o mas B M.  Acc urac y of nee dle place me nt i nt o t he i ntra-artic ular 
s pace of t h e k nee. J B o ne J oi nt S ur g A m. 2 0 0 2 ; 8 4- A : 1 5 2 2- 7 
- K oe ni g F, Bra n nat h W, Bretz F, P osc h M. A da pti ve D u n nett tests f or treat me nt sele cti o n. 
Statist. Me d. 2 0 0 8; 2 7: 1 6 1 2- 1 6 2 5 
- K ote v o gl u N, I yi b oz k urt P C, Hiz O, T o ktas H, K ura n B. A pr os pecti ve ra n d o mise d c o ntr olle d 
cli nical trial c o m pari n g t he efficac y of differe nt m olec ular wei g ht h yal ur o na n s ol uti o ns i n t he 
treat me nt of k nee oste oart hritis. R he u mat ol I nt. 2 0 0 6 Fe b; 2 6( 4): 3 2 5– 3 0.  
- Laj e u nesse D, Re b o ul P. S u bc h o n dral b o ne i n oste oart hritis: A bi ol o gic li n k wit h artic ular 
cartila ge lea di n g t o a b n or mal re m o deli n g. C urr O pi n R he u mat ol. 2 0 0 3; 1 5: 6 2 8- 6 3 3.  
- Le q u es ne 
M G, 
M a he u E. Cli nical a n d ra di ol o gical e val uati o n of hi p, k nee a n d ha n d 
oste oart hritis. A gi n g Cli n E x p Res. 2 0 0 3; 1 5: 3 8 0- 3 9 0. 
- Le wis R W, Billi n gt o n R, De br y u n e E, Ga mer A, La n g B, Car pa ni ni F. Rec o g niti o n of 
a d verse a n d n o na d v erse effects i n t o xicit y st u dies. T o xic ol Pat h ol. 2 0 0 2; 3 0: 6 6- 7 4. 


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A ut h or: E B   
Date: Ma y 1 0 , 2 0 1 7  
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- Ma ne k NJ, La ne N E. Oste oart hritis: C urre nt c o n ce pts i n dia g n osis a n d ma na ge me nt. A m 
F a m P hysici a n.  2 0 0 0; 1 5: 1 7 9 5- 1 8 0 4. 
- Mc Getti ga n P, He nr y D.  Car di o vasc ular ris k a n d i n hi biti o n of c ycl o o x y ge n ase: a s yst e matic 
re vie w of t h e o bser vati o nal st u dies of sel ecti ve a n d n o nsel ecti v e i n hi bit ors of 
c ycl o o x y ge nas e 2. J A M A. 2 0 0 6; 2 9 6: 1 6 3 3- 4 4. 
- M o bas heri A a n d He nr oti n Y. Bi o mar kers of Oste oart hritis: A Re vie w of Rece nt Researc h 
Pr o gress o n S ol u ble Bi oc he mical 
Mar kers, P u blis he d Pate nts a n d Areas f or F ut ure 
De vel o p me nt. Rece nt Pate nts o n Bi o mar kers. 2 0 1 1; 1: 2 5 - 4 3. 
- M osele y J B, O' Malle y K, Peterse n NJ, et al. A c o ntr olle d trial of art hr osc o pic s ur ger y f or 
oste oart hritis of t he k nee. N E n gl J Me d. 2 0 0 2; 3 4 7: 8 1 – 8 8.  
- Pa g na n o M, Westric h G. S uccessf ul n o n o perati ve ma na ge me nt of c hr o nic oste oart hritis pai n 
of t he k nee: safet y a n d efficac y of retreat me nt wit h i ntra-artic ular h yal ur o na ns. Oste oart hritis 
Cartila ge. 2 0 0 5; 1 3: 7 5 1- 6 1.  
- Pa vel ka K , Ue b el hart D ., Efficac y e val u ati o n of hi g hl y p urifi e d i ntra-arti c ular h yal ur o nic 
aci d ( Si n o vial ®) vs h yla n G- F 2 0 ( S y n vis c ®) i n t he treat me nt of s y m pt o matic k nee 
oste oart hritis. A d o u ble- bli n d, c o ntr olle d, ra n d o mize d, parallel- gr o u p n o n-i nferi orit y st u d y. 
Oste oart hritis Cartila ge.  2 0 1 1 N o v; 1 9( 1 1): 1 2 9 4- 3 0 0. 
- Pelletier J P, Di Battista J A, R o u g hle y P, Mc C oll u m R, Martel- Pelletier J. C yt o ki n es a n d 
i nfla m mati o n i n cartila ge de gra dati o n. R he u m Dis Cli n N ort h A m. 1 9 9 3; 1 9: 5 4 5 – 6 8. 
- Pe n dlet o n A, Ar de n N, D o u ga d os M, et al. E U L A R rec o m me n dati o ns f or t he ma na ge me nt 
of k nee oste o art hritis: Re p ort of a tas k f orce of t he Sta n di n g C o m mittee f or I nter n ati o nal 
Cli nical St u dies I n cl u d i n g T hera p e utic Trials. A n n R he u m Dis . 2 0 0 0; 5 9: 9 3 6– 9 4 4.  
- Peterss o n I F, J ac o bss o n L T. Oste oart hritis of t h e peri p heral j oi nts. Best Pract Res Cli n 
R he u mat ol. 2 0 0 2; 1 6: 7 4 1- 7 6 0. 
- Ra ma n R, D utt a A, Da y N, S har ma H K, S ha w CJ, J o h ns o n G V. Efficac y of H yla n G -F 2 0 
a n d S o di u m H yal ur o nat e i n t he treat me nt of oste oart hritis of t he k n ee — a pr os pecti ve 
ran d o mize d cli nical trial. K nee. 2 0 0 8 A u g; 1 5( 4): 3 1 8 – 2 4.  
- R ot h S H. N o nster oi dal a nti-i nfla m mat or y dr u g gastr o pat h y: ne w a ve n u es f or safet y. Cli n 
I nter v A gi n g. 2 0 1 1; 6: 1 2 5 – 1 3 1. 
- R o mer o- Sa n d o val A, Eis e nac h J C. Cl o ni di ne re d uces h y perse nsiti vit y a n d alters t he bala nce 
of pr o- a n d a nti-i nfla m m at or y le u k oc yt es after l ocal i njecti o n at t he site of i nfla m mat or y 
ne uritis.  Brai n Be h a v I m m u n. 2 0 0 7 J ul; 2 1( 5): 5 6 9- 8 0. 


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- Sa msa G, E del ma n D, R ot h ma n M L, Willia ms G R, Li ps c o m b J, Matc har D. Deter mi ni n g 
cli nicall y i m p orta nt differe n ces i n healt h stat us 
meas ures: a ge n eral a p pr oac h wit h 
ill ustrati o n t o t he Healt h Utilities I n de x Mar k II. P har mac o ec o n o mics, 1 9 9 9; 1 5: 1 4 1- 5 5. 
- Sc he pers T , Kie b o o m B C , Besse ms G H , V o gels L M , va n Li es h o ut E M , Pat ka P. S u btalar 
vers us tri ple art hr o desis after i ntra-artic ular cal ca neal fract ures. Strate gies Tra u ma Li m b 
Rec o nstr.  2 0 1 0 A u g; 5 ( 2): 9 7- 1 0 3. E p u b 2 0 1 0 Mar 2 3. 
- S hearer D, M ors he d S. C o m m o n ge neric meas ures of healt h relate d q ualit y of life i n i nj ure d 
patie nts. I nj ur y, I nt. J. Care I nj ure d 4 2. 2 0 1 1: 2 4 1 – 2 4 7 
- St uc ki G, Sa n g ha O, St uc ki S, Mic hel B A, T y n d all A, Dic k W, T heiler R. C o m paris o n of 
t he W O M A C ( Wester n O ntari o a n d Mc Master U ni versities) oste oart hritis i n de x a n d a self-
re p ort f or mat of t he s elf-a d mi nistere d Le q ues n e- Al g of u ncti o nal i n de x i n patie nts wit h k nee 
a n d hi p oste oart hritis. Oste oart hritis Cartila ge. 1 9 9 8; 6: 7 9- 8 6. 
- S u n R, Z ha o W, Ha o Q, Tia n H, Tia n J, Li L, Jia W, Ya n g K. I ntra-artic ul ar cl o ni di ne f or 
p ost- o perati ve a n al gesia f oll o wi n g art hr os c o pic k n ee s ur ger y: a s yst e matic r e vie w a n d meta-
a nal ysis. K nee S ur g S p orts Tra u mat ol Art hr osc. 2 0 1 4 Se p; 2 2( 9): 2 0 7 6- 8 4. 
- Z ha n g Y, J or da n J M. E pi de mi ol o g y of oste o art hritis. Cli n Geriatr Me d. 2 0 1 0; 2 6: 3 5 5- 3 6 9. 


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1 5  A N N E X E S 
1 5. 1  
A N N E X 1 : W O M A C ®  V A 3. 1 Q U E S TI O N N AI R E 
See t he d oc u me nts att ac he d. 
 
 
 




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C O N FI D E N TI A L 
 
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1 5. 5  A N N E X 5 : R A DI O L O GI C A L E V A L U A TI O N 
 
 
 
 
 
 
 
 
 
 
 
 
T he Kell gre n- La wre n ce Gra di n g S yst e m c o nsists of Gra d e 0, Gra de I, Gra de II, Gra de III a n d 
Gra de I V. T his cat e g orical scale i nc or p orates i m p orta nt ra di o gra p hi c feat ures of O A: 
- 
J oi nt s pace narr o wi n g: b o ne is visi ble o n X-ra ys b ut t he artic ular cartila ge t hat c o vers it 
is n ot. A n or mal j oi nt t heref ore a p p ears t o ha ve a s pace bet wee n t he b o nes. A n y decreas e 
i n s pace i m plies a re d u cti o n i n cartila ge c o v er. 
- 
Oste o p h yt es: s mall b o n y pr ojecti o ns t hat f or m ar o u n d j oi nt 
mar gi ns. T he y are 
res p o nsi ble f or li miti n g ra n ge of m oti o n a n d ca n ca use pai n. 
- 
Scler osis: t his mea ns ‘ har de ni n g’ a n d is a si g n of oste oart hritis, see n as i ncrease d w hite 
areas i n t he b o n e at t he j oi nt mar gi ns.