Prospective Multicenter Non-interventional Study in Patients With Knee or Hip Osteoarthritis Having a Theraflex® Treatment to Evaluate Changes in Pain, Functions in Daily Living, and Quality of Life for an Observation Period up to 64 Weeks
Conditions: Osteoarthritis
Sponsor: Bayer

 
D oc u me nt T y pe:  
St u d y Pr ot oc ol  
Offici al Title:  
Pr os pecti ve m ultice nter n o n -i nter ve nti o nal st u d y i n patie nts wit h 
k nee or hi p oste oart hritis ha vi n g a T herafle x  treat me nt t o e val uate 
c ha n ges i n pai n, f u ncti o ns i n dail y li vi n g, a n d q ualit y of  life f or a n 
o bser vati o n peri o d u p t o 6 4 wee ks.  
N C T N u m ber:  
N C T 0 3 3 3 0 2 8 8  
D oc u me nt D ate:  
0 4 Jul  2 0 1 8  
 
 
 

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B A Y E R  
 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L  
 
Title:  
Pr os pecti ve m ultice nter n o n -i nter ve nti o nal st u d y i n patie nts wit h 
k nee or hi p oste oart hritis ha vi n g a T herafle x ®  treat me nt t o 
e val uate c ha n ges i n pai n, f u ncti o ns i n dail y li vi n g, a n d q ualit y of 
life f or a n o bser vati o n peri o d u p t o 6 4 wee ks. 
Dr u g:  
T herafle x ®  ( Gl uc osa mi ne h y dr oc hl ori de 5 0 0 m g a n d 
C h o n dr oiti n s o di u m s ulfate 4 0 0 m g)  
S p o ns or’s  na me  a n d a d dress: 
A/ O B A Y E R  
3r d R y bi ns ka ya str., 1 8, bl d. 2 1 0 7 1 1 3, M osc o w, R ussia n 
Fe derati o n  
St u d y  I de ntifier 
I M P A C T n u m ber  1 9 6 4 9 
Versi o n / Date:  
3 . 0 / 4 J ul 2 0 1 8 
De vel o p me nt P hase:  
P hase I V, N o n-i nter ve nti o nal st u d y 
 
By  si g ni n g t his d oc u me nt, t hese pers o ns a gree  t o c o n d uct t he st u dy i n acc or d a nce t o t his 
Pr ot oc ol 
 
 
Res p o nsi bilit y f or st u d y c o n d ucti n g:    
 
Cli nical Researc h St u d y Ma na ger  
Si g nat ure:  
Date:  
Res p o nsi bilit y f or me dic al as pects:  
 
Me dical Affairs C o ns u mer Healt h  
Tea m Lea der  
Si g nat ure:  
Date:  
Res p o nsi bilit y f or pr o d uct s afet y:  
 
P har mac o vi gila nce C o u ntr y Hea d  
Si g nat ure:  
Date:  
Res p o nsi ble s t u d y st atistici a n: 
, Statistics,  
Ba yer U S, L L C  
Si g nat ure:  
Date:  
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T his material is Ba yer pr o pert y. T his is c o nfi de ntial i nf or mati o n w hic h ma y be use d o nl y be 
Ba yer. It ca n n ot be tra nsf erre d, e ve n p artiall y, t o a n y t hir d si de wit h o ut a pre vi o us writte n 
a gree m e nt of Ba y er  
 
 
P P D
P P D
P P D
P P D

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1.  
T a ble of c o nte nts  
О г л а в ле н ие  
1.  T a ble of c o nte nts  ................................................................................................................ 2 
2.  List of a b bre vi ati o ns .......................................................................................................... 4 
3.  Res p o nsi ble p arties  ............................................................................................................ 6 
3. 1  
St u d y i nitiat or a n d f u n der/ M A H ...................................................................................... 6 
4.  S y n o psis  .............................................................................................................................. 7 
5.  A m e n d m e nts  .................................................................................................................... 1 0 
6.  Milest o nes  ......................................................................................................................... 1 1 
7.  R ati o n ale a n d b ac k gr o u n d .............................................................................................. 1 1 
8.  Rese arc h q uesti o ns a n d o bjecti ves  ................................................................................. 1 2 
8. 1  
Pri mar y o bjecti ve  ........................................................................................................... 1 2 
8. 2  
Sec o n dar y o bjecti ves ...................................................................................................... 1 3  
9.  Rese a rc h m et h o ds ............................................................................................................ 1 3 
9. 1  
St u d y desi g n ................................................................................................................... 1 3  
9. 1. 1  
Pri mar y e n d p oi nt(s) .................................................................................................... 1 5  
9. 1. 2  
Se c o n dar y e n d p oi nt(s) ................................................................................................ 1 5  
9. 1. 3  
Stre n gt hs of st u d y desi g n ............................................................................................ 1 5  
9. 2  
Setti n g  ............................................................................................................................ 1 5 
9. 2. 1  
Eli gi bilit y  .................................................................................................................... 1 5 
9. 2. 2  
I n cl usi o n criteria  ......................................................................................................... 1 6 
9. 2. 3  
E xcl usi o n criteria  ........................................................................................................ 1 6 
9. 2. 4  
Wit h dra wal  .................................................................................................................. 1 6 
9. 2. 5  
Re place me n t ................................................................................................................ 1 6 
9. 2. 6  
Re prese ntati ve n ess  ...................................................................................................... 1 6 
9. 2. 7  
Visits  ........................................................................................................................... 1 6 
9. 3  
Varia bles  ........................................................................................................................ 2 1 
9. 3. 1  
Varia bles t o det er mi ne t h e pri mar y e n d p oi nt(s) ......................................................... 2 1  
9. 3. 2  
Varia bles t o det er mi ne t h e sec o n dar y e n d p oi nt(s) ...................................................... 2 1  
9. 3. 3  
Detaile d descri pti o n of varia bles c ollecte d  ................................................................. 2 1 
9. 4  
Data s o urces  ................................................................................................................... 2 6 
9. 5  
St u d y size ....................................................................................................................... 2 6  
9. 6  
Data ma na g e me nt  ........................................................................................................... 2 6 
9. 7  
Data a n al y sis .................................................................................................................. 2 7 
9. 7. 1  
Statistical c o nsi derati o ns  ............................................................................................. 2 7 
9. 8  
Q ualit y c o ntr ol ............................................................................................................... 2 7  
9. 8. 1  
Data q ualit y  ................................................................................................................. 2 7 
9. 8. 2  
Q ualit y re vie w ............................................................................................................. 2 8 
9. 9  
Li mitati o ns of t he resear c h met h o ds  .............................................................................. 2 9 
1 0.  Pr otecti o n of h u m a n s u bjects  ......................................................................................... 2 9 
1 0. 1  Et hical c o n d uct of t he st u d y ........................................................................................... 2 9  
1 0. 2  Re g ulat or y a ut h orit y a p pr o vals/a ut h orizati o ns .............................................................. 2 9  
1 0. 3  I n d e pe n de nt et hics c o m mittee (I E C) or i nstit uti o nal re vie w b o ar d (I R B) ..................... 2 9 
1 0. 4  A u dit a n d I ns pecti o n ...................................................................................................... 3 0  

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1 1.  P atie nt i nf or m ati o n a n d c o nse nt .................................................................................... 3 0 
1 1. 1  Patie nt i ns ura nce  ............................................................................................................ 3 0 
1 1. 2  C o nfi de ntialit y ................................................................................................................ 3 0 
1 2.  M a n a ge m e nt a n d re p orti n g of a d verse e ve nts/ a d verse re acti o ns  ................................ 3 1 
1 2. 1  Defi niti o ns  ...................................................................................................................... 3 1 
1 2. 2  C ollecti o n  ....................................................................................................................... 3 3 
1 2. 3  Ma na ge me nt  a nd r e p orti n g ............................................................................................. 3 3  
1 2. 4  E val uati o n ...................................................................................................................... 3 4  
1 3.  Pl a ns f or disse mi n ati n g a n d c o m m u nic ati n g st u d y res ults  ......................................... 3 4 
1 4.  Refere nces  ........................................................................................................................ 3 5 
A n ne x 1: List of st a n d -al o ne d oc u me nts  .............................................................................. 3 7 
A n ne x 2: A d diti o n al i nf or m ati o n .......................................................................................... 3 8  
A n ne x 3: Descri pti o n of a m e n d m e nts  ................................................................................... 3 9 
A n ne x 4: Si g n at ure p a ges ...................................................................................................... 4 2  
 
 
 
 

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2.  
List of a b bre vi ati o ns 
A E  
A d verse E v e nt  
A T C  
A nat o mical T hera pe utic C he mical ( Classificati o n S yste m)  
C F R  
C o de of Fe d er al Re g ulati o ns 
C h  
C h o n dr oiti n S ulfate 
C R F  
Case Re p ort F or m  
C R O  
C o ntract Researc h Or g a nizati o n  
D M P  
Data Ma na g e me nt Pla n  
E C  
E ur o pea n C o m missi o n 
E D C  
Electr o nic D ata Ca pt ure  
E F PI A  
E ur o pea n Fe d erati o n of P har mace utical I n d ustries a n d Ass ociati o ns 
E M A  
E ur o pea n Me dici ne A ge nc y 
E N Ce P P   
 E ur o pea n N et w or k of C e nters i n P har mac oe pi d e mi ol o g y a n d   
P har mac o vi gila nce  
E U  
E ur o pea n U ni o n 
E U L A R   
E ur o pea n L ea g ue A gai nst R he u matis m 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
G C P  
G o o d Cli nical Practice  
Gl  
Gl uc osa mi ne 
G P P  
G o o d P u bl icati o n Practice 
G V P  
G o o d P har mac o vi gila nce Practice 
H E O R  
Healt h Ec o n o mics a n d O utc o mes Researc h  
H O O S  
Hi p i nj ur y a n d Oste oart hritis O utc o me Sc ore 
H O O S -P S  
H O O S - p h ysical s h ort f or m 
I C D 
I nter nati o nal Classificati o n of Diseases 
I C H 
I nter nati o nal C o nfere nce of Har m o nizati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I N N 
I nter nati o nal N o n pr o prietar y Na me 
I R B 
I nstit uti o nal Re vie w B oar d 
I T 
I nf or mati o n Tec h n ol o g y  
 
K O O S  
K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore 
K O O S -P S  
K O O S - p h ysical s h ort f or m 
M A H  
Mar keti n g A ut h orizati o n H ol der  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
M R P  
Me dical Re vie w Pla n  
N/ A  
N ot A p plica ble 
NI S  
N o n -i nter ve nti o nal St u d y 
N N H  
N u m ber Nee de d t o H ar m 
O A  
Oste oart hritis  
O S  
O bser vati o nal St u d y 
P A S  
P ost- A ut h orizati o n St u d y 
P A S S  
P ost- A ut h orizati o n Safet y St u d y 

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P B R E R  
Peri o dic be nefit -ris k e val uati o n re p ort 
P R O  
Patie nt Re p orte d O utc o m e 
P S U R  
Peri o dic Safet y U p dat e Re p ort  
Q P P V  
Q ualifie d Pers o n Res p o nsi ble F or P har mac o vi gila nce 
Q R P  
Q ualit y Re vie w Pla n  
S A E  
Seri o us A d verse E v e nt 
S A P  
Stat istical A nal ysis Pla n 
S T R O B E   
Stre n gt he ni n g t he Re p orti n g of O bser vati o nal St u dies i n E pi de mi ol o g y 
W H O D D   
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.  
Res p o nsi ble p arties  
3. 1  
St u d y i niti at or a n d fu n der /M A H  
R ole:  
A ut h or  
Na me:  
, Cli nical Researc h M a na ger,  
Me dical Aff airs C o ns u mer Healt h  
E -mail:  
 
 
 
R ole:  
St u d y I nitiat or  
Na me:  
, Cate g or y ma na ger H C P,  
, R ussia 
E -mail:  
 
 
 
R ole:  
St u d y c o n d uct res p o nsi ble  
Na me:  
, Cli nical Researc h M a na ger 
E -mail:  
 
 
 
R ole:  
St u d y safet y lea d  
Na me:  
, P V C o u ntr y Hea d 
E -mail:  
 
 
 
R ole:  
St u d y me dical e x pert  
Na me:  
, Me dical Affairs C o ns u mer Healt h Tea m Lea der 
E -mail:  
 
 
 
R ole : 
St u d y statisticia n  
Na me:  
, Statistics, Ba yer U S, L L C 
E -mail:  
 
C o ntact details of t he res p o nsi ble parties A/ O Ba y er  are a v aila ble u p o n re q uest.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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4.  
S y n o psis 
 
Acr o n y m /Title  
Pr os pecti ve m ultice nter n o n -i nter ve nti o nal st u d y i n patie nts 
wit h k nee or hi p oste oart hritis ha vi n g a T herafle x ®  treat me nt t o 
e val uate c ha n ges i n pai n, f u ncti o ns i n dail y li vi n g, a n d q ualit y 
of life f or a n o bser vati o n peri o d u p t o  6 4 wee ks  
Pr ot oc ol versi o n i de ntifier  
3 . 0 
D ate of l ast v ersi o n of 
pr ot oc ol 
4 -J ul-2 0 1 8  
I M P A C T st u d y n u m ber 
1 9 6 4 9  
Dr u g  
T herafle x ®  ( BA Y  8 7 4 0 1 7 )  
St u d y t y pe /St u d y p h ase 
P hase I V, n o n-i nter v e nti o nal st u d y 
A ut h or  
, Cli nical Researc h M a na ger 
Me dical Affairs C o ns u mer Healt h  
 
R ati o n ale a n d b ac k gr o u n d  
T his l o n g -ter m pr os pecti ve o bser vati o nal st u d y i n s u bjects wit h 
k nee  or  hi p  O A,  w h o  recei ve T h erafle x ® ,  will  all o w  t o  o btai n 
val ua ble i nf or mati o n  i n res pect of d y na mic s of pai n s y n dr o me, 
f u ncti o ns of li vi n g, q u alit y of life a n d s atisfacti o n of p atie nt as 
well  as  of  act u al  dr u g  utilizati o n  b y  patie nts  wit h  O A f or  a n 
o bser vati o n peri o d u p t o 6 4 wee ks. 
 
Si nce  i n  R ussia  at  t he  prese nt  ti me  t here  are  n o  a p pr o ve d 
sta n dar ds  of  R e g ulat or y  A ut h orities  f or  t he  ma na ge me nt  of 
patie nts wit h O A, we e x p ect t hat t his st u d y will hel p t o e val uate 
t he a p pr oac h of d o ct ors t o t he treat me nt of O A a n d t o u n dersta n d 
t he r ole of T herafl e x ®  i n t heir rec o m me n d ati o ns. 
 
Rese arc h q uesti o n a n d 
o bjecti ves  
T he pri mar y o bjecti ve of t he st u d y is: 
•  T o e val uate c ha n ges i n p ai n, f u ncti o ns i n dail y li vi n g, 
a n d  O A relate d q ualit y of life f or a n o bser v ati o n peri o d 
u p t o 6 4 wee ks  
T he sec o n d ar y o bjecti ves i n t his st u d y are: 
•  T o assess dr u g utilizati o n wit h T herafle x ®  f or a n 
o bser vati o n peri o d u p t o 6 4 wee ks peri o d 
•  T o assess patie nts satisfacti o n wit h T herafle x ®  
treat me nt f or a n o bser v ati o n peri o d u p t o 6 4 wee ks  
•  Descri pti o n of t he use of a nal gesics f or O A f or a n 
o bser vati o n peri o d u p t o 6 4 wee ks  
P P D

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•  Descri pti o n of patie nt c h aract eristics ( A ge, B MI, 
Wei g ht, A nal gesics i nta k e)  
 
St u d y desi g n  
O p e n-la bel, m ultice nter , si n gle c o u ntr y, n o n-i nter ve nti o nal 
pr os pecti ve st u d y i n a c o h ort of patie nts wit h Hi p or K nee O A 
sta ge I t o III w h o starte d a treat me nt wit h T herafle x ®  wit h 
e val uati o n of healt h stat us b y p h ysical e xa mi nati o n a n d 
vali date d patie nt a n d p h ysicia n’s q uesti o n naires f or a n 
o bser vati o n peri o d u p t o 6 4 wee ks 
P o p ul ati o n 
Male a n d fe male patie nts fr o m 4 5 t o 7 5 years  of a ge wit h hi p or 
k nee oste oart hritis sta ge I t o III. A p pr o xi matel y 1 1 0 0 s u bjects 
are pla n n e d t o e nr olle d  i n t he st u d y i n a b o ut 6 0 st u d y ce nters i n 
R ussia.  
 
V ari a bl es 
Varia bles t o det er mi ne t h e pri mar y e n d p oi nt(s) 
• 
C ha n ges i n pai n, ot her s y m pt o ms, f u ncti o ns a n d k nee 
relate d q ualit y of life ass esse d b y K O O S i n patie nts 
wit h k nee O A 
• 
C ha n ges i n pai n, ot hers s y m pt o ms, f u ncti o ns a n d hi p 
relate d q ualit y of life ass esse d b y H O O S i n patie nts 
wit h hi p O A  
Varia bles t o det er mi ne t h e sec o n dar y e n d p oi nt(s): 
• 
Dr u g utilizati o n of T herafle x ®  t hera p y as re p ort e d b y 
t he patie nt t o t heir p h ysicia n 
• 
Patie nt satisfacti o n meas ure d wit h a Li kert res p o nse 
scale (fr o m 5 – ver y s atisfie d  t o 1-ver y dissatisfie d )  
• 
T y pe, fre q u e nc y a n d le n gt h of pai n killer f or t he 
s y m pt o matic treat me nt of hi p O R k nee O A f or a n 
o bser vati o n peri o d u p t o 6 4 wee ks  
• 
Ot her me dicati o n/ p h ysical t hera p y f or O A relate d pai n 
( dr u gs, d urati o n of use, d ose, fre q u e nc y) 
 
D at a s o urces  
T he i n vesti gat o r c ollects hist oric data ( de m o gra p hic a n d 
cli nical c haracteristics) fr o m me dical rec or ds if a v aila ble. 
Li ke wise, t he i n vesti gat or c ollects treat me nt relate d data d uri n g 
visits t hat ta ke place i n r o uti ne practice. E ac h p atie nt is 
i de ntifie d b y a u ni q ue ce ntral patie nt i de ntificati o n c o de, w hic h 
is o nl y use d f or st u d y p ur p oses. F or t he d urati o n of t he st u d y 
a n d after war ds, o nl y t he patie nt’s treati n g p h ysici a n or 
a ut h orize d site pers o n nel is a ble t o i de ntif y t he patie nt base d o n 
t he patie nt i de ntificati o n c o de.  

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St u d y size  
It is pla n ne d t o e nr oll a p pr o xi matel y 1 1 0 0 patie nts i nt o t he 
st u d y.  
D at a a n al ysis 
All varia bles will be a n al yze d i n a n e x pl orat or y m a n ner wit h 
a p pr o priate d escri pti ve st atistical met h o ds: cate g orical 
varia bles b y fre q ue n c y ta bles (a bs ol ute a n d relati v e 
fre q ue n cies) a n d c o nti n u o us varia bles b y sa m ple statistics (i.e. 
mea n, sta n dar d d e viati o n, mi ni m u m, me dia n, q uartil es a n d 
ma xi m u m).  
Statistical a nal yses will be perf or me d usi n g vali date d statistical 
s oft ware (e. g. S A S, S A S I nstit ute I nc.). 
Milest o nes  
Pla n ne d start of data c ollecti o n – Oct, 2 0 1 7 
F P F V  – O ct 2 0 1 7;  
L P L V  – Fe b 2 0 2 0;  
e n d of st u d y – Ma y 2 0 2 0  
 
 

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5.  
A m e n d m e nts  
T a ble 1 : A m e n d m e nts 
A m e n d m e nt 
N u m ber  
Re as o n f or A me n d me nt  
Ne w versi o n 
n u m ber  
Effecti v e 
D ate  
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
C orrecti o n of e x cl usi o n criteria was c o n d ucte d, 
si nce it beca me o b vi o us t hat wit h i nitial e xcl usi o n 
criteria sl o w patie nt recr uit me nt is pre dicta ble  
T he a p pr o ac h f or c o m pleti n g t he q uesti o n naire 
was clarifi e d i n cas e t he patie nt has m ulti ple j oi nt 
O A or bilater al K nee/ Hi p O A.  
Re q uire me nts f or c ollecti o n of vital si g ns a n d 
data of p h ysical e xa mi nati o n we re clarifie d. 
I nf or mati o n a b o ut t he I n de pe n de nt Et hics 
C o m mittee res p o nsi ble f or pr ot oc ol relat e d 
d oc u me ntati o n re vie w a n d a p pr o val was u p d ate d 
T he n u m ber of p atie nts is re d uce d fr o m 1 5 0 0 
patie nts t o 1 1 0 0 patie nts. 
 
Ori gi nall y pla n ne d t o c o n d uct a n o bser v a ti o nal 
st u d y of t he T herafle x pr o d uct  i n 8 0 st u d y 
ce nters of M os c o w, St. Peters b ur g a n d Yar osl a vl 
re gi o ns. I n c o n n ecti o n wit h t he a d diti o nal 
a d mi nistrati ve barrier o n t he part of t he M osc o w 
Healt h Care De part me nt, i nstea d of 4 0 ce nt ers 
pla n ne d f or o p e ni n g i n t he M osc o w re gi o n, t he 
n u m ber of st u d y ce nters i n M osc o w has dr o p pe d 
t o 2 0. T h us, t he t otal n u m ber of st u d y ce nters will 
n ot e xcee d 6 0, w hic h is 7 5 % of t he pla n ne d 
n u m ber of cli nical ce nters. I n pr o p orti o n wit h 
re d uce d n u m b er of st u d y ce nters, t he n u m ber of 
patie nts i n t he st u d y is als o re d uce d b y 2 5 %, 
w hic h i n n u merical ter ms a p pr o xi matel y 
c orres p o n ds t o 1 1 0 0 pati e nts.  
I n or der t o calc ulate t h e i n dicat or of “p atie nts l ost 
t o f oll o w-u p s u bjects”, w as ma de a si m ple 
a nal ysis of t he V 2 fre q ue nc y o n t he gr o u p of t he 
first 1 0 % of s u bjects i ncl u de d i nt o t he st u d y. T he 
a nal ysis was carrie d o ut after 3 - 6 m o nt hs fr o m t he 
date of patie nts r ecr uit me nt, w hic h c orres p o n ds t o 
all o wa ble ti me- wi n d o w f or t he sec o n d visit . As a 
res ult of t his a nal yses, “p atie nts  l ost t o f oll o w- u p” 
i n de x is a b o ut 7 %, w hic h is si g nifica ntl y l o wer 
t ha n i nitiall y ass u me d fi g ure f or t his i n dicat or (I n 
t he St u d y Ris k Re gister t his ris k fact or w as 
re gistere d as 2 0 % a n d a b o ve). T his a d diti o nall y 
ma kes p ossi ble t o re d uce t he st u d y p o p ulati o n t o 
2, 0 
 
 
 
 
 
 
 
 
 
 
 
 
3. 0 
1 7- N o v - 2 0 1 7 
 
 
 
 
 
 
 
 
 
 
 
 
4-J ul- 2 0 1 8 

Pa ge 1 1  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
1 1 0 0 s u bjects wit h o ut ne gati ve effect o n t he 
res ult of t he w h ole st u d y.  
Si nce t he a nal ysis of all varia bles i n t he st u d y will 
be carrie d o ut usi n g a p pr o priate met h o ds of 
descri pti ve statistics, a decreas e i n t he n u m ber of 
patie nts ca n n ot ha ve a ne gati ve i m p act o n t he 
re pres e ntati ve ness. 
I nitiall y It was pla n n e d t o ha ve i nteri m a nal ysis 
after all s u bjects ha ve c o m plete d V 2. Wit h t his 
a me n d me nt t he starti n g p oi nt is c ha n gi n g – 
I nteri m a nal ysis  will be c o n d ucte d after 5 0 % of 
s u bjects (first 5 5 0 e nr olle d) ha ve c o m plet e d V 2 i n 
or der t o assess t he c ha n g es after t h e first c o urs e at 
t he half of t he st u d y p o p ulati o n.. 
6.  
Milest o nes  
Defi niti o ns:  
•  Start of st u d y: 
F P F V  
•  Start of data c ollecti o n:  date of first dat a e ntr y i n data base  
•  E n d of data c ollecti o n:  date of last data e ntr y i n data base   
•  E n d of st u d y:  
date of clea n data b ase  
•  O bser vati o n peri o d:  
ti me- wi n d o w f or data c ollecti o n  
•  Fi nal re p ort:   
fi nal re p ort of st u d y res ults 1 2 m o nt hs after clea n data base  
7.  
R ati o n ale  a n d b ac k gr o u n d  
 
I n t he rec o m me n dati o ns of T he Oste oart hritis Researc h S ociet y I nter n ati o nal ( O A R SI) a n d T he 
E ur o pea n L ea g ue A gai nst R he u matis m ( E U L A R), all t hera pe utic a g e nts f or Oste oart hritis ( O A ) 
treat me nt  are  classifi e d  t o  n o n-p har mac ol o gical,  p har mac ol o gical  a n d  i n vasi ve  treat me nts, 
w hic h ca n ha ve n ot o nl y s y m pt o m -m o dif yi n g, b ut als o str uct ure -m o dif yi n g effects o n t he b asis 
of t heir a bilit y t o p ositi vel y i nfl ue nce disease pr o gressi o n ( Z ha n g W. et al., 2 0 0 8). Str uct ure-
m o dif yi n g  me dicati o ns  f or  O A  treat me nt  are  t h ose  w h ose  acti o ns  are  base d  o n  a n a b olic 
pr ocesses acti vati o n i n cartila ge matri x, s u p pressi o n of l ys os o mal e nz y mes a n d sti m ulati o n of 
c h o n dr oc yte  f u n cti o ns  (Jer osc h  J.,  2 0 1 1).  Sl o w -acti n g  dr u gs  ( gl uc os a mi ne,  c h o n dr oiti n, 
h y al ur o nic aci d, diacerei n, u nsa p o nifia ble matters of a v oca d o a n d s o ya) e x ert a d ela ye d effect 
t hat  lasts be y o n d disc o nti n uati o n.  T hese  t hera pe utic  a ge nts  p ossess  n ot  o nl y  s y m pt o matic 
effects, b ut  als o,  pr o b a bl y,  ma y  retar d  t he  O A  pr o gressi o n,  ha vi n g  a n  i nfl ue nce  o n  se veral 
pat h o ge nesis li n ks of t he disease ( Z h a n g W. et al., 2 0 0 8). 
 
T he de m o nstrate d efficac y of gl uc osa mi ne ( Gl) a n d c h o n dr oiti n s ulfate  ( Ch) i n f or m of m o n o-
me dicati o n  i n  se veral  s t u dies  create d  t he  necess ar y  prere q uisites  f or  c o m bi ne d  t hera p y  ( Qi u 
G X.,et al., 2 0 0 5, Ze g els B., 2 0 1 3). It w as s h o w n i n a n e x peri me nt al m o del, t hat c o m bi nati o n of 
c h o n dr oiti n s ulfate a n d gl uc osa mi ne i ncreas e d c h o n dr oc yte pr o d ucti o n of gl yc osa mi n o gl yca ns 
b y 9 6, 9 % vers us 3 2 % i n case of a n a d mi nistrati o n of c h o n dr oiti n s ulfate or gl uc osa mi ne al o ne 
( Li p piel o L. et al., 1 9 9 9). T he G AI T trial st u d yi n g t he i m pact of gl uc osa mi ne ( 5 0 0 m g 3 ti mes 
dail y) a n d c h o n dr oiti n s ulfate ( 4 0 0 m g 3 ti mes dail y) o n t he j oi nt s pace narr o wi n g pr o gressi o n 

Pa ge 1 2  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
i n  g o nart hr osis  ha ve s h o w n hi g her  p ote ntial  of  cli nical  effect  pre d o mi na ntl y  i n  t he  II 
ra di ol o gical  sta ge  ( K ell gre n/ La wr e nce)  i n  c o m p aris o n  wit h  t he  III  o ne  i n  t he  s u b gr o u p  of 
patie nts  wit h  m o derate -t o-se ver e  k nee  pai n  ( Cle g g  D O.  et  al.,  2 0 0 6).  M ore o ver,  t he  a ut h ors 
f oc use d atte nti o n  o n  g o o d  safet y  pr ofile  of  t he  t hera p y  t hat  w as  c o m para ble  wit h  place b o 
a d mi nistrati o n ( Sa witz ke, 2 0 1 0). Acc or di n g t o La pa ne K L. et al., a b o ut a h alf ( 4 7 %) of p atie nts 
o ver 4 9 years wit h ra di o gra p hic k ne e O A us e a d diti o nal me dici nes a n d a b o ut a q uarter ( 2 4 %) 
c o m bi ne d  a d diti o nal  a n d  c o n ve nti o nal  ( pre d o mi na ntl y  N S AI Ds)  me dicati o ns.  T he  m ost 
p o p ular a d diti o nal me dici nes wer e gl uc osa mi ne  a n d c h o n dr oiti n: m ore  t ha n 5 5 % use d t hes e 
pr o d ucts al o ne or i n c o m bi nati o n ( La pa ne K L. et al., 2 0 1 2). I n vesti gat ors of t he U ni versit y of 
Q uee nsla n d ( A ustr alia), ha ve f o u n d o ut w hile q uesti o ni n g of patie nt of 2 7 -9 5 years ol d wit h 
k nee a n d hi p j oi nts O A, t hat f or t he p ur p ose of pai n relief a n d j oi nt f u ncti o n i m pr o ve me nt  m ost 
fre q ue ntl y  us e d  me di cati o ns  are  t h ose  c o ntai ni n g G L   a n d  C h ( 5 1 %  of  males  a n d  6 0 %  of 
fe males) ( N g N T. et al., 2 0 1 2). 
 
U p t o 3 0 % of O A p atie nts o ver 5 5 y ears i n U K d o n’t recei ve a n a d e q uate t hera p y of c hr o ni c 
pai n s y n dr o me ( Mc Ali n d o n  T E. et al., 1 9 9 2). C hr o nic pai n i n O A lea ds t o s h orte ni n g of patie nt 
life d urati o n b y a n a vera g e of 1 0 – 1 2 years ( N uesc h, Die p pe, & Reic he m bac h, 2 0 1 1..) C hr o nic 
disa bilit y i n O A lea ds t o a n 2. 4 ti mes i ncrease i n  m ortalit y ( hazar d rati o 3. 9 1) b ut i n ass o ciati o n 
wit h m ulti -m or bi dit y i n 4 ti mes ( hazar d rati o 3. 9 1) c o m pare d wit h ge neral p o p ulati o n ( La n di 
F. et al., 2 0 1 0). 
 
R ussia n Mi nistr y of Healt h rec o m me n ds t o use o nl y N S AI Ds (“ T he Sta n dar d of Pri mar y Healt h 
Care i n G o nart hr osis a n d Si milar Cli nical C o n diti o ns”, 2 0 1 2).  H o we ver, i n R ussia a variet y of 
me dici nal pr o d u cts fr o m c h o n dr o pr otect ors cat e g or y are wi del y rec o m me n de d b y p h ysici a ns 
a n d t he m aj orit y of lea di n g scie ntific e x perts c o nsi der t his treat me nt as effecti ve as a part of t he 
c o m ple x t her a p y. T his f act was reflecte d i n t h e rece ntl y p u blis he d “ Rec o m me n dati o ns f or t he 
Treat me nt of Patie nts wit h Oste oart hr osis wit h C o m or bi dit y i n Cli nical Practice of G Ps”, 2 0 1 5. 
T his  d oc u me nt,  pre par e d  b y  R ussia n  Scie ntific  S ociet y  of  G Ps  a n d  Ass ociati o n  of  R ussia n 
R he u mat ol o gist, c o m pile d b y 1 0 0 mai n R ussia n e x perts fr o m differe nt re gi o ns, affir ms, t h at a 
c o m ple x O A t hera p y s h o ul d i ncl u de s y m pt o matic sl o w acti n g dr u gs a n d t he best cli nical res ults 
w o ul d be o btai ne d wit h t he c o m bi nati o n of Gl a n d Ch. 
 
T h us,  t he  l o n g-t er m  pr os pecti ve  o bser vati o nal  st u d y  i n  s u bjects  wit h  k nee  or  hi p  O A,  w h o 
recei v e T herafle x® , will all o w t o o btai n val ua ble i nf or mati o n  i n res pect of  d y na mics of pai n 
s y n dr o me, f u ncti o ns of li vi n g, q ualit y of life a n d s atisfacti o n of patie nt as w ell as of act ual dr u g 
utilizati o n b y patie nts wit h O A f or a n o bs er vati o n peri o d u p t o 6 4 wee ks. 
 
Use of G l a n d C h is wi des prea d a m o n g O A patie nts w orl d wi de, h o we ver si nce i n R ussia at t he 
prese nt ti me t h ere are n o sta n dar ds a p pr o ve d b y  Re g ulat or y A ut h orities f or t he ma na g e me nt of 
patie nts wit h O A, we e x p ect t hat t his st u d y will hel p t o e val uate t he a p pr o ac h of d oct ors t o t he 
treat me nt of O A a n d t o u n dersta n d t he r ole of T h erafl e x ®  wit hi n t he t hera pe utic al g orit h m i n 
t he c o nte xt of r o uti ne cli nical practice. 
 
 
8.  
Rese arc h q uesti o ns a n d o bjecti ves  
8. 1  
Pri m ar y o bjecti ve  
 
T he pri mar y o bjecti ve of t he st u d y is: 

Pa ge 1 3  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
•  T o e val uate c ha n ges i n p ai n, f u ncti o ns i n dail y li vi n g, a n d  O A rel ate d q ua lit y of life 
f or a n o bser vati o n peri o d u p t o 6 4 wee ks  
8. 2  
Sec o n d ar y o bjecti ve s 
 
T he sec o n d ar y o bjecti ves  i n t his st u d y are: 
•  T o assess dr u g utilizati o n wit h T herafle x ®  f or a n o bser vati o n peri o d u p t o 6 4 wee ks   
•  T o assess patie nts  satisfacti o n wit h T herafle x ®  treat me nt f or a n o bser vati o n peri o d u p 
t o 6 4 wee ks  
•  Descri pti o n of t he use of a nal gesics f or O A f or a n o bser vati o n peri o d u p t o 6 4 wee ks 
•  D escri pti o n  of patie nt c h aract eristics  ( A ge, B MI, Wei g ht, A nal gesics i nta k e  at 
baseli ne ) 
9.  
Rese arc h m et h o ds  
9. 1  
St u d y desi g n  
T his is a c o m pa n y s p o ns ore d, si n gle c o u ntr y, o pe n- la bel m ultice nter n o n-i nter ve nti o nal 
pr os pecti ve st u d y i n a c o h ort of patie nts  wit h Hi p or K nee O A sta ge I t o I II w h o starte d a 
treat me nt wit h T her afle x ®  wit h e val uati o n of healt h stat us b y p h ysical e xa mi nati o n a n d 
vali date d patie nt a n d p h ysicia n’s q uesti o n naires f or a n o bser v ati o n peri o d u p t o 6 4 wee ks. 
T here are u p t o 4 st u d y visits pla n ne d: w it hi n t w o wee ks after starti n g t he T herafl e x ®  treat me nt 
s u bjects will be i ncl u de d i nt o t he st u d y i n t he i nitial st u d y visit if t he y meet all i ncl usi o n criteria 
a n d n o ne of t he e xcl usi o n criteria. T he i nitial visit is f oll o we d b y t w o f oll o w-u p visits a n d fi nal 
e n d of o bser v ati o n visit f or a n o bser v ati o n peri o d  u p t o  6 4 wee ks . If patie nt s witc hes t o a n ot her 
Gl a n d C h bra n d t he o bser vati o n of t he patie nt is ter mi nate d. 
D uri n g all  visits data  ge nerate d  d uri n g t he n or m al  cli nical  practice  will  be  c ollecte d  b y  t he 
i n vestigat or.  I n  a d diti o n  t he  patie nt  re p orte d  o ut c o me  assessi n g  K nee  or  Hi p  oste oart hritis 
o utc o me  will  be  c ol lecte d  at  t he  ti me  of  t he  visit  as  well  as  a  si m ple  patie nt  satisfacti o n 
q uesti o n naire. 
F or K n ee O A t he K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S) will be use d.  F or Hi p 
O A  t he  Hi p  Oste oart hritis  O utc o me  Sc ore  ( H O O S)  will  be  use d  ( See  secti o n  9. 3. 3. 8) ).T o 
re d uce t he n u m ber of q u esti o ns a n d t he b ur d e n of t he patie nt, t he p h ysical s h ort f or m of b ot h 
patie nt  re p orte d  o utc o mes  ( P R O ) ( K O O S-P S ,  H O O S-P S)  c o ntai ni n g  re d uce d  n u m ber of 
q uesti o ns re places  t h e  t w o  s u bscales  f u n cti o ns  “ dail y  li vi n g”  a n d  “f u ncti o ns,  s p orts  a n d 
recr eati o nal acti vities” 
 
 

Pa ge 1 4  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
Fi g ure 1: St u d y O ver vie w  
 
 
 

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I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
9. 1. 1  
Pri m ar y e n d p oi nt(s)  
T he Pri mar y e n d p oi nts ar e: 
•  C ha n ges i n pai n, ot her s y m pt o ms, f u ncti o ns a n d k nee rel ate d q ualit y of life assesse d 
b y K O O S i n patie nts wit h k nee O A fr o m t he first assess me nt t hr o u g h o ut t he 
o bser vati o n peri o d 
•  C ha n ges i n pai n, ot hers s y m pt o ms, f u ncti o ns a n d hi p relate d q ualit y of life assesse d b y 
H O O S i n patie nts wit h hi p O A  fr o m t he first assess me nt t hr o u g h o ut t he o bser vati o n 
peri o d 
9. 1. 2  
Sec o n d ar y e n d p oi nt(s)  
T he sec o n d ar y e n d p oi nt(s) is/are: 
•  Dr u g utilizati o n of T her afle x ®  t hera p y as re p ort e d b y t he patie nt t o t heir p h ysicia n 
•  Patie nt satisfacti o n meas ure d wit h a Li kert res p o nse scale (fr o m 1-v er y dissatisfie d t o 
5 – ver y satisfie d)   
•  T y pe, fre q u e nc y a n d le n gt h of pai n killer f or t he s y m pt o matic treat me nt of hi p O R 
k nee O A f or a n o bs er vati o n peri o d u p t o 6 4 wee ks 
•  Ot her me dica l/ p h ysical t hera p y f or O A relate d p ai n ( dr u gs/t y pe of t hera p y, d urati o n of 
use, d ose, fr e q ue nc y) 
9. 1. 3  
Stre n gt hs of st u d y desi g n  
T he n o n-i nter ve nti o nal st u d y desi g n was c h ose n t o all o w e val uati o n ( or assess me nt) of 
c urre nt cli nical practices. I n c o ntrast t o cli nical st u dies, t he desi g n of n o n- i nter ve nti o nal 
st u dies ( NI S) d oes n ot i ncl u de ra n d o mizati o n a n d " bli n di n g", a n d selecti o n of patie nts d oes 
n ot de pe n d o n t he strict criteria of i ncl usi o n/e xcl usi o n. T here are als o li mitati o n s t o t his 
desi g n (e. g. n o p ossi bilit y f or c o m paris o n), b ut f or t he p ur p ose of t h e o bjecti ves i n t his st u d y 
t his met h o d ol o g y s hall pr o vi de s ufficie nt data. 
N o n -i nter ve nti o nal st u dies are a val ua bl e i nstr u me nt as t he y all o w a n al ysis sa m ples of 
patie nts wit h o ut s pecial selecti o n d uri n g r o uti ne cli nical practice.  
A pr os pecti ve n o n- i nter v e nti o nal st u d y, i n c o ntrast t o a retr os pecti ve o n e, ma kes it p ossi ble t o 
pla n i n a d va nce t he desi g n, pr oce d ure of gat h eri n g a n d pr ocessi n g of d ata, w hic h c o nsi dera bl y 
i ncreas es vali dit y of t he r es ults.  
9. 2  
Setti n g  
9. 2. 1  
Eli gi bilit y  
Male a n d f e male patie nts fr o m 4 5 t o 7 5 of a ge wit h hi p or k nee oste oart hritis sta ge I t o III. 
A p pr o xi matel y 1 1 0 0 s u bjects ar e pla n ne d t o be i n cl u de d i n t he st u d y i n a b o ut 6 0 st u d y ce nters 
i n R ussia.  
 
 

Pa ge 1 6  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
9. 2. 2  
I ncl usi o n criteri a 
I n cl usi o n criteria: 
• 
Patie nts 4 5 t o 7 5 years wit h Hi p or K nee O A sta g e I t o III  
• 
Patie nt starte d c urr e nt treat me nt wit h T herafl e x ®  n ot m ore t ha n 2 wee ks  pri or t o 
i ncl usi o n i nt o t he st u d y 
• 
Pers o nall y si g ne d a n d date d i nf or me d c o nse nt. 
9. 2. 3  
E xcl usi o n criteri a  
E xcl usi o n criteria:  
• Patie nts partici pati n g i n a n i n vesti gati o nal pr o gra m wit h i nter ve nti o ns o utsi de of 
r o uti ne cli nical practice 
• Patie nts wit h Hi p or K nee O A sta ge 0 or sta ge I V  
• C o ntrai n dicati o ns f or use of T herafle x ®  i n acc or da nce wit h a p pr o v e d la bel( k n o w n 
h y perse nsiti vit y , se vere c hr o nic re n al fail ure) 
• Fe males w h o ar e pre g n a nt o r breastfee di n g  
• Patie nts w h o c o m plete d a treat me nt wi t h T herafle x ®  or t he ot her S y m pt o matic  
Sl o w- Acti n g dr u g i n Osteо art hritis ( S Y S A D O A)  less t ha n 5 m o nt hs bef ore start 
of t he c urr e nt treat me nt  
• Patie nts w h o c o m plete d i ntra -artic ul ar c ortic oster oi ds treat me nt i n t he last 3 
m o nt hs bef ore e nr oll me nt  . 
• Patie nts w h o c o m plete d h yal ur o nic i njecti o ns a n d/ or platelet -ric h plas ma ( P R P) 
t hera p y of t he l o w er li m bs i n t he last 6 m o nt hs.  
9. 2. 4  
Wit h dr a w al 
I n t his o bser vati o nal st u d y, wit h dra wal fr o m t he st u d y is i n de pe n de nt of t he u n derl yi n g t hera p y 
a n d will n ot affect t he p atie nt’s me dical care. Eac h patie nt ca n ref use t o f urt her p artici pate or 
ma y wit h dra w fr o m t he st u d y at a n y ti me a n d wit h o ut gi vi n g a reas o n. If a patie nt wa nts t o 
ter mi nate t he st u d y partici pati o n, n o f urt her dat a will be c ollecte d. H o w e ver, t he patient will be 
as ke d w h et her s h e / he a gr ees t hat t he d ata c ollecte d s o far ca n be use d. I n case t he p atie nt d oes 
n ot a gree, t h ese data will n ot be use d f or a n y patie nt le vel a nal ysis of st u d y data. T his i ncl u des 
safet y dat a wit h t he e xce pti o n t hat data alrea d y ca pt ure d i n t he c o m pa n y’s safet y dat a base will 
be  ke pt.  H o w e ver,  data  w hic h  ar e  rel e va nt  f or  pri mar y  o utc o mes  mi g ht  be  dis pla ye d  o n  a n 
a g gre gat e d le v el t o assess a p ote ntial bias. I n case a patie nt w o ul d li ke t o wit h dra w t he c o nse nt 
gi ve n earlier, s/ he s h o ul d i nf or m his/ her d oct or a n d t he site s h o ul d d oc u me nt t he wit h dra wal i n 
t he Case Re p ort F or m as well as i n t he patie nt me dical rec or ds .  
9. 2. 5  
Re pl ace m e nt  
Patie nts will n ot be re place d aft er dr o p o ut. 
9. 2. 6  
Re prese nt ati ve ness  
T he patie nts i ncl u de d i n t he st u d y s h o ul d be select e d o nl y base d o n eli gi bilit y acc or di n g t o 
i ncl usi o n criteria. N o f urt her selecti o n s h o ul d be a p plie d. I n v esti gat ors will be as ke d t o 
sa m ple c o nsec uti ve p atie nts w he ne ver p ossi ble t o re d uce s electi o n bias. 
9. 2. 7  
Visits  
T he i n vesti gat or d oc u me nts a n i nit ial visit, f oll o w- u p visits a n d t he e n d of o bser vati o n/fi nal 
visit f or eac h patie nt i n t he case re p ort f or m ( C R F). F oll o w- u p visits occ ur d uri n g r o uti ne 
practice, t h e st u d y pr ot oc ol d oes n ot defi ne e x act referral dates f or t h ose visits. T he e n d of 

Pa ge 1 7  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
o bser vati o n/fi nal visit is t o be d oc u me nte d f or a p eri o d u p t o 6 4 wee ks after start of t he i nitial 
treat me nt. 
T he o bser vati o n peri o d f or eac h p atie nt is u p t o 6 4 wee ks . If patie nt s witc hes t o a n ot her Gl 
a n d C h bra n d t he o bser vati o n of t he patie nt is ter mi nate d. 
9. 2. 7. 1  
Pri or t o i ncl usi o n  
A s u bject  ca n  o nl y  b e  i ncl u de d  i n  t he  st u d y  aft er  he/s h e  has  p urc h ase d  t he  pr o d u ct  i n  a 
p har mac y.  H o w e ver p ote ntial patie nt w h o li ke t o partici pate i n t he st u d y s h o ul d be i ncl u de d as 
earl y as p ossi ble b ut n ot l ater t ha n 2 wee ks after t he y starte d t he treat me nt i nt o t he st u d y t o gai n 
data i n t he be gi n ni n g of t he T her afle x ®  treat me nt.   
Patie nt ca n be ma de a war e a b o ut t he st u d y eit her b y t he treati n g p h ysicia n O R b y a p har macist 
w h e n a patie nt is p ur c hasi n g T herafle x ® . 
P hysici a n  
At t he ti me t he p h ysicia n deci des t o gi ve a rec o m me n dati o n f or Gl + C h treat me nt t o a patie nt 
dia g n ose d  wit h  hi p  O R  k nee  O A  a n d  o nce  a  patie nt  is  f o u n d  t o  b e  p ote ntiall y  eli gi ble  f or 
i ncl usi o n,  t he  i n vesti gat or  will  i nf or m  t he  p atie nt  a b o ut  t he  st u d y  t o get her  wit h  t he 
rec o m me n dati o n of t h e tr eat me nt. 
T he i n vesti gat or m ust e x plai n t o t he patie nts t hat he/s he will  ma ke t he fi nal c h oice o n t he Gl + C h 
pr o d uct a vaila ble o n t h e mar ket. 
P h ar m acy 
P har mac y ma y als o b e a p pr oac he d f or t he recr uit me nt of p ote ntial st u d y partici pa nts. At t he 
ti me p oi nt a s u bject is p urc hasi n g T herafle x ®  t he p har macist ma y i nf or m t he s u bject a b o ut t he 
p ote ntial st u d y a n d if t here is i nterest b y t he patie nt, t he p har macist w o ul d ma ke a referral t o 
a n i n vesti gat or near b y partici pati n g i n t he st u d y. 
9. 2. 7. 2  
Visit 1: E nr oll me nt /I niti al visit 
Visit 1 is t he first Visit at t he p h ysicia n after t he s u bject b o u g ht t he pr o d u ct i n a p h ar mac y a n d 
starte d treat me nt wit h T herafl e x ® . Visit 1 m ust be wit hi n t he first 2 wee ks after start of treat me nt 
wit h T herafle x ® . 
A patie nt w h o has n ot bee n i nf or me d a b o ut t he st u d y pri or t o t he rec o m me n dati o n of Gl + C h 
b ut is c urre ntl y o n T herafle x ®  treat me nt wit hi n n o m ore t ha n f or 2 wee ks a n d meets all i ncl usi o n 
a n d n o ne of t he e xcl usi o n criteria ca n als o be i n cl u de d i n t he st u d y. 
D uri n g t he visit t he i n vesti gat or gi ves  t he n ecessar y e x pla nati o ns a b o ut t h e NI S, as ks t he p atie nt 
t o rea d t he i nf or mati o n f or t he st u d y patie nts a n d t h e i nf or me d c o nse nt f or m. If t he p atie nt gi ves 
t he c o nse nt t o partici pate i n t he st u d y, t he i nf or me d c o nse nt is si g ne d b ot h b y t he patie nt a n d 
t he i n vesti gat or.  
D uri n g t he visit t he i n vesti gat or c o n d u cts all e xa mi nati o ns acc or di n g t o t h e l ocal r o uti ne cli nical 
practice.  I n  a d diti o n  t he  i n vesti gat or  pr o vi des  t o  t he  s u bject  t he  P R O  q u esti o n naire  a n d  t he 
o verall satisfacti o n q uesti o n f or c o m pleti o n f or Visit 1. If t he patie nt has m ulti ple j oi nt O A or 
d o u ble- si de d ( bilateral) K nee/ Hi p O A, o nl y o ne «tar get » j oi nt t o be select e d f or t he e val uati o n, 
w here the  patie nt  e x peri e nces  t he  m ost  se vere  pai n at  t he  ti me  of  e nr oll me nt.  Filli n g  i n  a 
q uesti o n naire, t he p atie nt nee ds t o ass o ciate his/ her res p o nses wit h t he "tar get" j oi nt o nl y d uri n g 
t he e ntire f oll o w- u p p eri o d. 
 
 
F oll o wi n g i nf or mati o n will be ca pt ure d i n t he C R F: 

Pa ge 1 8  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
•  Date of visit  
o  da y, m o nt h, year 
•  Date of i nf or m e d c o nse nt 
•  Ra di ol o gical Dia g n osis of O A of Hi p or K nee acc or di n g t o t he Kell gre n a n d La wre n ce 
Criteria *  
•  Patie nt de m o gra p hic data 
•  Ge n der  
•  Date of birt h  
•  Race / et h nicit y  
•  P h ysical E xa mi nati o n  
•  Wei g ht ( k g) 
•  Hei g ht (c m) ( V 1 o nl y) 
•  Vital Si g ns  
o  Bl o o d Press ure 
o  B o d y Te m perat ur e (a xill ar y te m perat ure)  
o  Heart r ate   
•  Lifest yle  
•  Alc o h ol a n d t o bacc o use 
•  Re vie w of T herafle x ®  dr u g  utilizati o n  
o  Start / E n d of treat me nt  
o  D ose/fre q u e nc y of treat m e nt  
•  K O O S or H O O S Q u esti o n naire ( P R O)  
• 
Patie nt satisfacti o n wit h T herafl e x ® 
•  Me dical hist or y   
•  C o nc o mita nt disease(s)  
•  C o nc o mita nt me dicati o n  
•  C o nc o mita nt n o n- me dicati o n t hera pies (e. g. p h ysi ot hera p y , s ur g er y)  
•  A d verse e ve nts  
All  ex a mi n ati o ns  are  p erf or me d  acc or di n g  t o  t he  l oc al  r o uti ne  i nstit uti o n al  pr actice  as  
i n dic ate d by t he atte n di n g p hysici a n. P R O s h o ul d be c o m plete d at t he ti me of t he visit at t he 
p hysici a n by t he p atie nt. 
9. 2. 7. 3  
F oll o w- u p Visits I & II  
F oll o w- u p visit will be t he first visit at t he p h ysicia n d uri n g t he ti me fra me w ee k 1 6- 2 4 ( F oll o w-
u p I), wee k 3 6- 4 4 ( F oll o w-u p II), after start of treat me nt wit h T herafle x ® . If patie nt s witc h es t o 
a n ot her S y m pt o matic  Sl o w - Acti n g dr u g i n Oste оart hritis ( S Y S A D O A), t he o bser vati o n of t he 
patie nt is ter mi nate d.  
D uri n g  t he  f oll o w -u p  visit  t he  i n vesti gat or  c o n d ucts  all  e x a mi nati o ns  acc or di n g  t o  t he  l ocal 
r o uti ne  cli nical  pr actice.  I n  a d diti o n  t he  i n v esti gat or  pr o vi des  t o  t he  s u bject  t he  P R O 

Pa ge 1 9  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
q uesti o n naire a n d t he o v erall satisfacti o n q uesti o n f or c o m pleti o n.  T he pat ie nt nee ds t o assess 
t he o utc o me of j oi nt treat me nt, w hic h was selecte d as t he “tar g et” at t he first visit. 
F oll o wi n g i nf or mati o n will be ca pt ure d i n t he C R F: 
•  Date of visit  
o  da y, m o nt h, year 
•  P h ysical E xa mi nati o n  
•  Wei g ht  ( k g) 
•  Vital Si g ns  
o  Bl o o d Press ure  
o  B o d y Te m perat ur e (a xill ar y te m perat ure)  
o  Heart r ate   
•  Re vie w of T herafle x ® dr u g utilizati o n  
o  Start / E n d of treat me nt  
o  D ose/fre q u e nc y of treat m e nt  
•  K O O S or H O O S Q u esti o n naire ( P R O)  
•  Patie nt satisfacti o n wit h T herafl e x ®  
•  C o nc o mita nt me dicati o n  
•  C o nc o mita nt disease(s)  
•  C o nc o mita nt n o n- me dicati o n t hera pies (e. g. p h ysi ot hera p y, s ur ger y)  
•  A d verse e ve nts  
All  ex a mi n ati o ns  are  p erf or me d  acc or di n g  t o  t he  l oc al  r o uti ne  i nstit uti o n al  pr actice  as  
i n dic ate d by t he atte n di n g p hysici a n. P R O s h o ul d be c o m plete d at t he ti me of t he visit at t he 
p hysici a n by t he p atie nt. 
9. 2. 7. 4  
Fi n al Visit / E n d of O bser v ati o n  
Fi nal  Visit  /  E n d  of  O bser vati o n  will  be  t he  first  visit  at  t he  p h ysicia n ’s  office after  a n 
o bser vati o n peri o d u p t o 6 4 wee ks  after start of treat me nt wit h T herafle x ® . F i nal visit s h o ul d be 
perf or me d d uri n g t he ti me fra m e wee k 5 6- 6 4 
D uri n g t he visit t he i n vesti gat or c o n d u cts all e xa mi nati o ns acc or di n g t o t h e l ocal r o uti ne cli nical 
practice.  I n  a d diti o n  t he  i n vesti gat or  pr o vi des  t o  t he  s u bject  t he  P R O  q u esti o n naire  a n d  t he 
o verall satisfacti o n q uesti o n f or c o m pleti o n. T he patie nt nee ds t o assess t he o utc o me of j oi nt 
treat me nt, w hic h w as  sel ecte d as t he t ar get at t he first visit. 
F oll o wi n g i nf or mati o n will be ca pt ure d i n t he C R F: 
•  Date of visit  
o  da y, m o nt h, year 
•  P h ysical E xa mi nati o n  
•  Wei g ht ( k g)  
•  Vital Si g ns  
o  Bl o o d Press ure 
o  B o d y Te m perat ur e (a xill ar y te m perat ure)  
o  Heart r ate   
•  Re vie w of T herafle x ®  dr u g  utilizati o n  

Pa ge 2 0  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
o  Start / E n d of treat me nt  
o  D ose/fre q u e nc y of treat m e nt  
•  K O O S or H O O S Q u es ti o n naire ( P R O) 
•  Patie nt satisfacti o n wit h T herafl e x ®  
•  C o nc o mita nt disease(s)  
•  C o nc o mita nt n o n- me dicati o n t hera pies (e. g. p h ysi ot hera p y, s ur g er y)  
•  A d verse e ve nts  
All ex a mi n ati o ns are p erf or me d acc or di n g t o t he l oc al r o uti ne cli nic al pr actice as i n dic ate d b y 
t he atte n di n g p hysici a n. P R O s h o ul d be c o m plete d at t he ti me of t he visit at t he p hysici a n by 
t he p atie nt. 
Pre mat ure e n d of t her a p y d oes n ot a ut o maticall y i m pl y e n d of d oc u me ntati o n: t he patie nt 
s h o ul d be f oll o we d u p u ntil t he e n d of t he o bser vati o n peri o d ( 6 4 wee ks) or u ntil n o l o n ger 
p ossi ble.  
Ta ble 2: Ta b ulate d o v er vie w o n varia bles c ollecte d d uri n g t he st u d y 
 
Pri or t o 
i ncl usi o n t o 
t he st u d y 
Visit 1  
I n cl usi o n i nt o t he 
st u d y 
Visit 2 & 3  
F oll o w- u p 
visit  
Visit 4  
Fi nal Visit / E n d 
of O bser v ati o n 
 
 
First Visit after 
starti n g treat me nt 
wit h T herafle x ®  
[ n ot m ore t ha n 2 
wee ks]  
Wee k 1 6 -2 4  
Wee k 3 6 - 4 4 
after start of 
treat me nt wit h 
T herafl e x ®  
Wee k 5 6 - 6 4 
after start of 
treat me nt wit h 
T herafl e x ®  
Assess me nt of 
i ncl usi o n / 
e xcl usi o n criteria  
 
X 
 
 
I nf or mati o n a b o ut 
t he st u d y  
X 
 
 
 
Writte n I nf or m e d 
C o nse nt  
 
X 
 
 
Patie nt 
de m o gra p hic dat a  
 
X 
 
 
P h ysical 
E xa mi nati o n *  
 
X 
X 
X 
Hei g ht / Wei g ht * *  
 
X  
X  
X  
Vital si g ns  
 
X  
X  
X  
O A Sta gi n g  
acc or di n g t o 
Kell gre n & 
La wre n ce *  
 
X 
 
 
Lifest yle  
 
X 
 
 
C o nc o mita nt 
t hera pies  ot her 
t ha n dr u g 
 
X 
X 
X 
Me dical hist or y  
/c o nc o mita nt 
diseases  
 
X 
X 
X 

Pa ge 2 1  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
C o nc o mita nt 
me dicati o n  
 
X 
X 
X 
A d verse e ve nts  
 
X  
X  
X  
Re vie w of 
T herafl e x ®  dr u g  
utilizati o n  
 
X 
X 
X 
K O O S or H O O S 
Q uesti o n naire 
( P R O) 
 
X 
X 
X 
Patie nt 
satisfacti o n 
( P R O) 
 
X 
X 
X 
* perf or me d i n acc or d a n ce wit h l oc al pr actice 
* * Hei g ht at V isit 1 o nly  
9. 3  
V ari a bles  
T he i n vesti gat or c ollects hist oric data ( de m o gra p hic a n d cli nical c h aracteristics) fr o m me dical 
rec or ds if a vaila ble, or else b y i nter vie wi n g t he patie nt. Li ke wise, t he i n vesti gat or c ollects 
treat me nt relat e d data d uri n g i nitial visit a n d f oll o w- u p visits. T he i n vesti gat or d oc u me nts t he 
st u d y-rele va nt dat a f or eac h patie nt i n t he cas e re p ort f or m ( C R F). T h e C R F is a vaila ble u p o n 
re q uest (see Ta ble 3 , A n ne x 1). 
9. 3. 1  
V ari a bles t o deter mi ne t he pri m ar y e n d p oi nt(s)  
T he varia bl e(s) f or pri mar y o bjecti ve(s) is/are:  
•  C ha n ges i n pai n, ot her s y m pt o ms, f u ncti o ns a n d k nee relate d q ualit y of life assess e d 
K O O S i n patie nts wit h k nee O A  fr o m t he first assess me nt t hr o u g h o ut t he o bser vati o n 
peri o d 
•  C ha n ges i n pai n, ot hers s y m pt o ms, f u ncti o ns a n d hi p relate d q ualit y of life assesse d b y  
H O O S i n patie nts wit h hi p O A  fr o m t he first assess me nt t hr o u g h o ut t he o bser vati o n 
peri o d 
9. 3. 2  
V ari a bles t o deter mi ne t he sec o n d ar y e n d p oi nt(s)  
T he o utc o me varia ble(s) f or sec o n d ar y o bjecti ve(s) is/are: 
•  Dr u g utilizati o n of T her afle x ®  t hera p y as re p ort e d b y t he patie nt t o t heir p h ysicia n 
•  Patie nt satisfacti o n meas ure d wit h a Li kert res p o nse scale ( fr o m 1-v er y dissatisfie d t o 
5 – ver y satisfie d )  
•  T y pe, fre q u e nc y a n d le n gt h of pai n killer f or t he s y m pt o matic treat me nt of hi p O R 
k nee O A f or a n o bs er vati o n peri o d u p t o 6 4 wee ks  
•  Ot her me dical/ p h ysical t hera p y  f or O A relate d p ai n ( dr u gs, d urati o n of use, d ose, 
fre q ue n c y) 
9. 3. 3  
Det aile d descri pti o n of v ari a bles c ollecte d  
9. 3. 3. 1  
D ate of Visit  
• 
Date ( D a y, M o nt h, Year ) of visit  
9. 3. 3. 2  
P atie nt d e m o gr a p h ic d at a 
F or de m o gr a p hic/ s oci o- d e m o gra p hic ass ess me nt, t he f oll o wi n g data will be rec or d e d:  
• 
Year of birt h  

Pa ge 2 3  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
9. 3. 3. 8  
K O O S or H O O S q uesti o n n aire ( P R O)  
De pe n di n g o n t he dia g n osis ( k nee vs. hi p O A), o n e of t he t w o f oll o w i n g q u esti o n naires will 
be use d. 
K nee i nj ury a n d Oste o art hritis O utc o me Sc ore ( K O O S) 
T he K O O S q uesti o n nair e s h o ul d be c o m plete d d uri n g t he visit at t he p h ysicia n b y t he patie nt. 
K O O S c o nsists of 5 s u bscales; Pai n, ot her S y m pt o ms, F u ncti o n i n dail y li vi n g ( A D L), 
F u ncti o n i n s p ort a n d recreati o n ( S p ort/ Rec) a n d k nee rel ate d Q ualit y of life ( Q O L). T he 
pre vi o us wee k is t he ti me peri o d c o nsi dere d w he n a ns weri n g t he q u esti o ns. Sta n dar dize d 
a ns wer o pti o ns ar e gi ve n ( 5 Li kert b o xes) a n d eac h q uesti o n is assi g ne d a sc ore fr o m 0 t o 4.  
K O O S has bee n v ali date d i n patie nts wit h mil d t o m o derate O A ( Kell gre n a n d La wre nce 
gra des I -III) of t hee k nee he nce a si milar p o p ulati o ns as o bser ve d i n t he st u d y ( Ta n ner, 2 0 0 7). 
K O O S is patie nt -a d mi nistere d, t he f or mat is user frie n dl y, a n d ta kes a b o ut 1 0 mi n utes t o 
c o m plete.  
T he ori gi nal K O O S Q uesti o n naire c o ntai ns a t otal of 4 2 q uesti o ns. T o re d uce t he n u m ber of 
q uesti o ns t o 2 7 t he K O O S- p h ysical s h ort f or m ( K O O S- P S) c o ntai ni n g 7 Q uesti o ns o n 
f u ncti o n re places t he t w o s u bscales f u ncti o ns, dail y li vi n g  wit h 1 7 q uesti o ns ( A 1-A 1 7) a n d 
f u ncti o ns, s p orts a n d recr eati o nal acti vities wit h 5 q uesti o ns ( S P 1-S P 5 ). 
T he pr o p ose d q u esti o n naire f or t he p atie nt wit h k nee O A w o ul d c o ntai n f oll o wi n g ele me nts 
t heref or e: 
•  S y m pt o ms: 5 q uesti o ns ( S 1- S 5) fr o m K O O S  
•  Stiff ness: 2 Q uesti o ns ( S 6- S 7) fr o m K O O S  
•  Pai n: 9 Q uesti o ns ( P 1- P 9) fr o m K O O S  
•  F u ncti o n: 7 q uesti o ns fr o m K O O S- P S  
•  Q ualit y of life: 4 Q uesti o ns ( Q 1 -Q 4) fr o m K O O S  
Li n k f or f urt her i nf or mati o n: htt p:// w w w. k o os. n u/i n de x. ht ml  
 
Hi p dis a bility a n d Oste o art hritis O utc o me Sc ore ( H O O S) 
 
T he H O O S q uesti o n nair e s h o ul d be c o m plete d  d uri n g t he visit at t he p h ysicia n b y t he patie nt. 
 
H O O S c o nsists of 5 s u bscales; Pai n, ot her S y m pt o ms, F u ncti o n i n dail y li vi n g ( A D L), 
F u ncti o n i n s p ort a n d recreati o n ( S p ort/ Rec) a n d hi p relate d Q ualit y of life ( Q O L). T h e last 
wee k is ta ke n i nt o  c o nsi d erati o n w he n a ns weri n g t he q uesti o ns. Sta n dar dize d a ns wer o pti o ns 
are gi ve n ( 5 Li kert b o xes) a n d eac h q uesti o n gets a sc ore fr o m 0 t o 4.  
 
Acc or di n g t o t he user g ui da nce p u blis he d o n t heir h o me pa ge, H O O S vali dati o n w or k is 
o n g oi n g. 
 
H O O S is patie nt -a d mi nistere d, t he f or mat is user frie n dl y, a n d ta kes a b o ut 1 0 mi n utes t o fill 
o ut.  A R ussia n versi o n of t he q uesti o n naire is n ot a vaila ble.  

Pa ge 2 4  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
T he ori gi nal H O O S Q uesti o n naire c o ntai ns a t otal of 4 0 q uesti o ns. T o re d uce t he n u m ber of 
q uesti o ns t o 2 4 t he H O O S- p h ysical s h ort f or m ( H O O S- P S) c o ntai ni n g 5 Q uesti o ns o n 
f u ncti o n re places t he t w o s u bscales f u ncti o ns, dail y li vi n g  wit h 1 7 q uesti o ns ( A 1-A 1 7) a n d 
f u ncti o ns, s p orts a n d recr eati o nal acti vities wit h 4 q uesti o ns ( S P 1-S P 4)  
•  S y m pt o ms: 3 q uesti o ns ( S 1- S 3) fr o m H O O S  
•  Stiff ness: 2 Q uesti o ns ( S 4- S 5) fr o m H O O S  
•  Pai n: 1 0 Q uesti o ns ( P 1- P 1 0) fr o m H O O S  
•  F u ncti o n: 5 q uesti o ns fr o m H O O S- P S  
•  Q ualit y of life: 4 Q uesti o ns ( Q 1 -Q 4) fr o m H O O S  
Li n k f or f urt her i nf or mati o n: htt p:// w w w. k o os. n u/i n de x. ht ml  
9. 3. 3. 9  
P atie nt s atisf acti o n wit h T her afle x ®  
T he Satisfacti o n q u esti o n s h o ul d be c o m plete d d uri n g t he visit at t he p h ysicia n b y t he patie nt.  
Patie nt satisfacti o n meas ure d wit h a Li kert res p o nse scal e (fr o m 5 – ver y satisfie d  t o 1 -ver y 
dissatisfie d) . 
 
H o w satisfie d ar e y o u wit h y o ur treat me nt wit h T herafl e x ® ? 
•  
Ver y satisfie d  
•  
Satisfie d  
•  
Neit her satisfie d n or diss atisfie d  
•  
Dissatisfie d  
•  
Ver y dissatisfie d  
G ui da nce  t o  t he  patie nts  w hat  t he  i n di vi d ual  cate g ories  mea n  will  be  pr o vi de d  b y  t he 
i n vesti gat or.  
9. 3. 3. 1 0  
C o -m or bi dities ( m e dic al hist or y, c o nc o mit a nt dise ases)  
C o - m or bi dities are a n y me dical fi n di n gs, w het her or n ot t he y pertai n t o t h e st u d y i n dicati o n, 
t hat were prese nt bef ore start of t hera p y wit h T herafle x ®  i n de pe n de nt o n w het her or n ot t he y 
are still prese nt. T he y h a ve t o be d oc u me nte d i n t he Me dical Hist or y/ C o nc o mita nt Diseases 
secti o n.  
F or a n y c o- m or bi dit y, t he dia g n osis, t he start a n d t he st o p date/ o n g oi n g ha ve t o be 
d oc u me nte d. 
9. 3. 3. 1 1  
Dr u g Uti liz ati o n 
At e ver y visit after start of t he treat me nt wit h T herafle x ®   t he p h ysicia n s h o ul d c ollect i n detail 
start a n d e n d as well as fr e q ue nc y of T herafle x ®  treat me nt as re p orte d b y t h e patie nt i nt o t he 
C R F  
T o e val uate t he dr u g utilizati o n of t he T herafle x ® treat me nt t he p h ysicia n s h o ul d als o 
s pecificall y as k h o w ofte n T herafl e x ®  is ta ke n i n a vera ge d uri n g a treat me nt. 
•  Start Date of T herafl e x ®  
•  E n d Date of T h erafle x ®  
•  C ha n ge of d osi n g/reas o n f or c ha n g e 
•  D ose  
o  3 ca ps ules per Da y  
o  2 ca ps ules per Da y  
o  1 ca ps ules per Da y  

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•  T he d urati o n of t he p eri o d wit h o ut T herafle x ®  
T he first t hree wee ks w hic h d o ha ve a differe nt p os ol o g y ( 3 ca ps ules  per da y) acc or di n g t o t he 
la bel s h o ul d be e nter e d as a disti nct peri o d t o t he treat me nt peri o d wit h a rec o m me n de d 
p os ol o g y of 2 ca ps ules  p er  da y. 
9. 3. 3. 1 2  
Pri or a n d c o nc o mit a nt tre at me nts  
All treat me nts o btai ne d  bef ore st u d y start (i nitiate d a n d st o p pe d bef ore st u d y start) is defi ne d 
as pri or treat me nts. Pri or treat me nts meeti n g t he criteria liste d bel o w are c o nsi dere d t o be 
rele va nt t o t he st u d y i n dicati o n ha ve t o be d o c u me nte d:  
•  Sl o w-acti n g dr u gs 
o  Gl uc osa mi ne  
o  C h o n dr oiti n  
o  G ial ur o nic aci d  
o  D iacer ei n  
o  U nsa p o nifia ble matters of a v oca d o a n d s o ya 
•  Pai n s y n dr o me t hera p y 
o  A nal gesics  
o  N S AI D  
•  T o pical pai n t hera p y 
o  T o pical N S AI D  
•  I ntr a-artic ular artic ular i nj ecti o ns  
•  Ma n ual t hera p y  
•  S ur ger y  
•  P h ysi ot hera p y  
 
Treat me nt of c o m or bi d diseases ( Dia b etes mellit us, H y perte nsi o n, O besit y)  
•  A nti h y perte nsi ve dr u gs 
•  Dr u gs f or tr eat me nt of di a betes 
•  A ntic oa g ula nts 
•  Ot her  
 
All treat me nts o btai ne d i n a d diti o n t o T herafle x ®  f or a n y i n dicati o n (eit her i nitiate d bef ore 
st u d y start or d uri n g t he st u d y) is defi ne d c o nc o mita nt treat me nts  a n d has t o be d oc u me nte d. 
I nf or mati o n t o be c ollecte d f or me dicati o n i ncl u des:  
• 
T ra de n a me or I N N 
• 
Start date, st o p date/ o n g oi n g 
• 
D ose 
• 
U nit 
• 
F re q u e nc y 
• 
A p plicati o n r o ute 
• 
I n dicati o n  
9. 3. 3. 1 3  
L a b or at or y p ar a m eters 
N o la b orat or y p ara met ers will be c ollecte d.  
 

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9. 3. 3. 1 4  
E n d  of o bser v ati o n 
If a vaila bl e t he pri mar y r eas o n f or e n d of o bser vati o n/st u d y disc o nti n uati o n s h o ul d be state d: 
• 
Re g ular e n d of o bs er vati o n 
• 
Patie nt l ost t o f oll o w u p 
• 
C o nse nt wit h dra w n b y p atie nt  
• 
I n v esti gat or decisi o n 
• 
( Seri o us) A d verse E ve nt/ A d verse Dr u g Reacti o n 
• 
P re g na nc y 
• 
Lac k of efficac y  
• 
Patie nt die d  
• 
C ha n ge t o a n ot her Gl+ C h t hera p y ( w hi c h t hera p y a n d reas o n f or s witc h)  
• 
Site cl ose d 
• 
St u d y ter mi nate d  
 
9. 3. 3. 1 5  
A d verse e v e nts /A d verse e ve nts of s peci al i nterest  
( Seri o us) A d verse E ve nts nee d t o be c ollecte d as d escri be d i n secti o n 1 1. 2. I nf or mati o n 
c ollecte d i ncl u des : 
• 
Dia g n osis of A E, or s y m pt o m (if dia g n osis u n k n o w n) 
• 
Start a n d st o p date  
• 
Seri o us ness  
• 
Relate d ness t o t hera p y  
• 
Acti o n ta ke n  
• 
E ve nt o utc o me 
• 
Ot her s pecifi c treat me nt(s) of A E  
 
9. 4  
D at a s o urces  
T he i n vesti gat or c ollects hist oric data ( de m o gra p hic a n d cli nical c h aracteristics) fr o m me dical 
rec or ds if a vaila ble. Li k e wise, t he i n vesti gat or c ollects treat me nt relate d data d uri n g visits t hat 
ta ke place i n r o uti ne practice. Eac h p atie nt is i de ntifie d b y a u ni q ue ce ntral patie nt 
i de ntificati o n c o de, w hic h is o nl y use d f or st u d y p ur p oses. F or t h e d urati o n of t he st u d y a n d 
after w ar ds, o nl y t he patie nt’s treati n g p h ysicia n or a ut h orize d site pers o n nel is a ble t o i de ntif y 
t he patie nt base d o n t he p atie nt i de ntificati o n c o de.  
9. 5  
St u d y size 
T he st u d y will be a nal yze d descri pti vel y. T heref ore t he st u d y is n ot statisticall y p o were d. It is 
pla n ne d t o e nr oll 1 1 0 0 s u bjects i nt o t he st u d y. 
9. 6  
D at a m a n a ge m e nt 
A C o ntract Researc h Or g a nizati o n ( C R O) will be selecte d a n d assi g ne d f or E D C s yste m 
de vel o p me nt. T he C R F will be part of t he E D C s yste m w hic h all o ws d oc u me ntati o n of all 
o utc o me varia bles a n d c o variates b y all partici pati n g sites i n a sta n dar dize d wa y. I nf or mati o n 
o n t he E D C s yste m is a vaila ble u p o n re q u est ( Ta ble 3 , A n ne x 1). D etaile d i nf or mati o n o n data 
ma na ge me nt, i ncl u di n g pr oce d ur es f or d ata c ollecti o n, retrie val a n d pre parati o n are gi ve n i n 
t he Data Ma n a ge me nt Pla n ( D M P), w hic h is a v aila ble u p o n re q u est (see T a ble 3 , A n ne x 1).  
F or i nf or m ati o n o n q ualit y c o ntr ol, refer t o secti o n 9. 8 . 

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9. 7  
D at a a n al ysis 
All varia bles will be a n al yse d i n a n e x pl orat or y m a n ner wit h a p pr o priate d escri pti ve statistical 
met h o ds: cate g orical vari a bles b y fre q u e nc y ta bl es (a bs ol ute a n d relati ve fre q ue ncies) a n d 
c o nti n u o us varia bles b y s a m ple statistics (i.e. mea n, sta n dar d de viati o n, mi ni m u m, me dia n, 
q uartiles a n d ma xi m u m).  
 
Statistical a nal yses will be perf or me d usi n g vali date d statistical s oft ware (e. g. S A S, S A S  
I nstit ute I nc.). 
 
All statistical details i ncl u di n g calc ulate d v aria bles a n d pr o p ose d f or mat a n d c o nte nt of ta bles 
will be detaile d i n t he statistical a nal ysis pla n ( S A P). T he S A P will be fi nalize d bef ore st u d y 
data base l oc k. T he a n al ysis will be perf or me d i n acc or da n ce wit h t he E ur o pea n Net w or k of 
Ce ntres f or P har m ac o e pi de mi ol o g y a n d P har mac o vi gila nce ( E N Ce P P) G ui de o n 
Met h o d ol o gical Sta n dar ds i n P har mac oe pi de mi ol o g y.  
9. 7. 1  
St atistic al c o nsi der ati o ns 
Statistical a nal yses will be of e x pl o rati ve a n d des cri pti ve nat ure.  
All varia bles will be a n al yze d descri pti vel y wit h a p pr o priate statistical met h o ds: cate g orical 
varia bles b y fre q ue n c y ta bles (a bs ol ute a n d relati v e fre q u e ncies) a n d c o nti n u o us varia bles b y 
sa m ple statistics (i.e. mea n, sta n dar d d e viati o n, mi ni m u m, me dia n, q uartiles a n d ma xi m u m). 
C o nti n u o us varia bles will be descri be d b y a bs ol ute val ue a n d as c ha n g e fr o m baseli ne per 
a nal ysis ti me p oi nt, if a p plica ble.  
A d diti o nall y, meas ure d H O O S/ K O O S s u bscales val ues a n d c h a n ges fr o m baseli ne will be 
prese nte d usi n g 9 5 % CI. 
All a nal yses will be perf or me d f or t he t otal st u d y p o p ulati o n ( o verall a n al ysis). Patie nts 
recei vi n g at least o ne d os e of T her afle x ®  will be i n cl u de d i n t he a nal ysis. W he ne ver 
reas o na bl e, data will be stratifie d b y s u b gr o u ps (e. g. a ge, ge n d er, bas eli ne c haract eristics). 
Sa m ple size a n d dis p ositi o n i nf or mati o n b y a nal ysis ti me p oi nt will be dis pla ye d i n a 
fre q ue n c y ta ble. 
All t hera pies d oc u me nt e d will be c o de d usi n g t he W orl d Healt h Or ga nizati o n – Dr u g 
Dicti o nar y ( W H O- D D). Me dical hist or y, a n y diseases a n d A Es will be c o d e d usi n g t he latest 
Me dical Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A) versi o n.  
All statistical details i ncl u di n g calc ulate d v aria bles a n d pr o p ose d f or mat a n d c o nte nt of ta bles 
will be detaile d i n t he Statistical A nal ysis Pla n ( S A P). T he S A P will be fi nalize d bef ore st u d y 
data base l oc k . T he S A P is a vaila ble u p o n re q uest. 
It is pla n ne d t o h a ve 1  i nteri m a nal ysis after 5 0 % of (first  5 5 0 e nr olle d) s u bjects ha ve 
c o m plete d V 2. T he mai n p ur p ose of I nteri m a nal yses t o assess t he c ha n g es after t he first 
c o urse of tr eat me nt wit h T herafl e x ® . T he fi nal a n al ysis will be perf or me d after e n d of t h e 
st u d y w hic h is t he date t he a nal ytical dat aset is c o m pletel y a vaila ble. 
9. 8  
Q u alit y c o ntr ol 
9. 8. 1  
D a t a q u alit y 
Bef ore st u d y start at t he sites, all i n vesti gat ors will be s ufficie ntl y trai n e d o n t he bac k gr o u n d 
a n d o bjecti ves of t he st u d y a n d et hical as w ell as re g ulat or y o bli gati o ns. I n vesti gat ors will 
ha ve t he c h a nce t o disc uss a n d de vel o p a c o m m o n u n dersta n di n g of t he st u d y pr ot oc ol a n d t he 
C R F.  

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A C R O will be selecte d a n d assi g ne d f or E D C s yst e m de vel o p me nt, q ualit y c o ntr ol, 
verificati o n of t he d ata c ollecti o n, data a nal ysis a n d data tra nsfer t o Ba yer.  
All o utc o me varia bles a n d c o variates will be rec or de d i n a sta n dar di ze d C R F. After data 
e ntr y, missi n g or i m pla usi ble data will be q uerie d a n d t he data will be v ali date d. A c h ec k f or 
m ulti ple d oc u me nte d patie nts will be d o ne.  
Detaile d i nf or mati o n o n c hec ks f or c o m plete n ess, acc urac y, pla usi bilit y a n d vali dit y are gi ve n 
i n t he Data Ma na g e me nt Pla n ( D M P). T he sa me pla n will s pecif y meas ures f or ha n dli n g of 
missi n g data a n d per missi ble clarificati o ns. T he D M P is a vaila ble u p o n re q uest (see T a ble 3 : 
List of sta n d -al o ne d ocu me nts , A n ne x 1).  
Me dical Re vie w of t h e d ata will be perf or me d acc or di n g t o t he Me dical Re vie w Pla n ( M R P). 
T he p ur p ose of t h e Me di cal Re vie w is t o verif y t h e data fr o m a me dical p ers pecti ve f or 
pla usi bilit y, c o nsiste nc y, a n d c o m plete ness a n d t o i de ntif y p ote ntial iss ues t hat c o ul d affect 
t he r o b ust ness of t he c oll ecte d st u d y data or t he pr o gress of t he st u d y. Det aile d i nf or mati o n o n 
t he Me dical r e vie w will be descri b e d i n t he M R P, w hic h is a vaila ble u p o n re q uest (see Ta ble 
3 , A n ne x 1). 
Nati o nal a n d i nter nati o nal data pr otecti o n la ws as well as re g ulati o ns o n o bser vati o nal st u dies 
will be f o ll o we d. Electr o nic rec or ds use d f or ca pt uri n g patie nt d oc u me ntati o n (e C R F) will be 
vali date d.  
9. 8. 2  
Q u alit y re vie w  
I n a s u bset of patie nts s o urce dat a verifi cati o n will be c o n d ucte d. T h e p ur p ose is t o re vie w t he 
d oc u me nte d data f or c o m plete ness a n d pla usi bilit y, a d here n ce t o t he st u d y pr ot oc ol a n d 
verificati o n wit h s o urce d oc u me nts.  
T he data q ualit y will be ass ure d b y usi n g b y tele p h o ne i nter vie w a n d q u alit y re vie w visit:  
Tele p h o ne i nter vie w  
D uri n g t he tele p h o ne i nter vie w t he offi cer, res p o nsi ble f or t he tele p h o n e i nter vie w: 
- 
E ns ures a d here nce t o NI S pr ot oc ol a n d a n y a me n d me nts 
Q u alit y re vie w visit i n t he st u d y ce nters  
T he i n di vi d ual, res p o nsi ble f or data re vie w will ha ve a n access t o t he d ata of t he patie nts i n 
t he ce nters.  T h e q ualit y r e vie w will c o nsist of t w o parts: i nter vie w a n d v erificati o n of t he 
c o m plia nce of t he d ata pr ese nte d i n t he Case Re p ort F or ms wit h t he data of t he pri mar y 
d oc u me ntati o n. 
D uri n g c o n d ucti o n of t he NI S t he pers o n res p o nsi ble f or t he q ualit y re vi e w: 
- 
c o ntr ols o bser va n ce of t h e pr ot oc ol a n d a m e n d me nts t o it; 
- 
c o ntr ols c o m plete ness a n d acc urac y of e ntr y of t h e data i nt o C R F a n d t heir 
c o m plia nce wit h t he data of t he pri mar y d oc u m e ntati o n; 
- 
s hall ha ve a n access t o a n y d oc u me ntati o n relate d t o t he NI S. 
 
Detaile d meas ures f or q u alit y re vie ws will be descri be d i n t he Q ualit y Re vie w Pla n ( Q R P). 
T he Q R P is a vaila ble u p o n re q uest (see Ta ble 3 , A n ne x 1). 
 

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9. 9  
Li mit ati o ns of t he rese arc h  met h o ds  
T he n o n-i nter ve nti o nal st u d y desi g n was c h ose n t o all o w e val uati o n ( or assess me nt) of 
c urre nt cli nical practices. I n c o ntrast t o cli nical st u dies, t he desi g n of n o n- i nter ve nti o nal 
st u dies ( NI S) d oes n ot i ncl u de ra n d o mizati o n a n d " bli n di n g", a n d selecti o n of patie nts d oes 
n ot de pe n d o n t he strict criteria of i ncl usi o n/e xcl usi o n. T here are als o li mitati o ns t o t his 
desi g n (e. g. n o p ossi bilit y f or c o m paris o n), b ut f or t he p ur p ose of t h e o bjecti ves i n t his st u d y 
t his met h o d ol o g y s hall pr o vi de s ufficie nt data.  
N o n -i nter ve nti o nal st u dies are a val ua bl e i nstr u me nt as t he y all o w a n al ysis sa m ples of 
patie nts wit h o ut s pecial selecti o n d uri n g r o uti ne cli nical practice.  
A pr os pecti ve n o n-i nter v e nti o nal st u d y, i n c o ntrast t o a retr os pecti ve o n e, ma kes it p ossi ble t o 
pla n i n a d va nce t he desi g n, pr oce d ure of gat h eri n g a n d pr ocessi n g of d ata, w hic h c o nsi dera bl y 
i ncreas es vali dit y of t he r es ults.  
1 0.  
Pr otecti o n of h u m a n s u bjects  
1 0. 1  
Et hic al c o n d uct of t he st u d y  
T his st u d y is a n o bser vati o nal st u d y w here T h erafle x ®  is rec o m me n de d i n t he c ust o mar y 
ma n ner i n acc or d a nce wit h t he ter ms of t he mar k eti n g a ut h orizati o n. T here is n o assi g n me nt 
of a patie nt t o a partic ular t hera p e utic strate g y.  T h e treat me nt rec o m me n dati o n falls wit hi n 
c urre nt pr actice a n d t he r ec o m me n dati o n of t he m e dici nes is clearl y se parate d fr o m t he 
decisi o n t o i ncl u de t he patie nt i n t he st u d y. T he fi nal decisi o n o n w hic h pr o d uct t he patie nt 
will ta ke is d o ne b y t he patie nt t hr o u g h t he p urc h ase of t he pr o d u ct at a p har mac y.  
N o a d diti o nal dia g n ostic or m o nit ori n g pr ocess is re q uire d f or partici p ati o n or d uri n g t he 
st u d y. 
E pi de mi ol o gical met h o ds will be use d f or t he a n al ysis of t he c ollecte d data.  
1 0. 2  
Re g ul at or y a ut h orit y a p pr o v als/ a ut h oriz ati o ns 
T he st u d y will be carrie d o ut wit hi n a n a p pr o ve d i n dicati o n a n d i n acc or da nce wit h t he r o uti ne 
cli nical practice.  
Alt h o u g h t he st u d y is c o n d ucte d i n t he R ussia n Fe derati o n, t he st u d y desi g n is i n acc or da n ce 
t o t he defi niti o n of a n o n-i nter ve nti o nal st u d y as d efi ne d i n t he E ur o p ea n Cli nical Trials 
Directi ve  ( 2 0 0 1/ 2 0/ E C) w hic h are f urt her disc uss e d i n details i n t he “c o nsi derati o n o n t he 
defi niti o n of NI S trials” b y t he E ur o pea n Net w or k of Ce ntres f or P har mac oe pi de mi ol o g y a n d 
P har mac o vi gila nce ( E N Ce P P, 2 0 1 1). 
Rec o m me n dati o ns f or NI S st u dies gi ve n b y  E ur o pea n Fe derati o n of P har m ace utical I n d ustries 
a n d Ass ociati o ns ( E F PI A, Oct 2 0 0 7) will be f oll o we d as w ell as I C H- G C P g ui deli nes 
w he ne ver p ossi ble.  
C ollecti o n a n d ha n dli n g of pers o nal dat a i n t his st u d y will be d o ne i n acc or da nce wit h c urre nt 
l ocal le gislati o n ( Fe d eral La w # 1 5 2- F Z of 2 7. 0 7. 2 0 0 6 “ A b o ut pers o nal d ata”) 
Et hical assess me nt will be d o ne b y e x p ert I n de p e n de nt re vie w b o ar d (I R B), s pecialize d i n 
NI S assess me nt. Pr ot oc ol relate d d oc u m e ntati o n t o be s u b mitte d t o I R B f or t he a p pr o val, 
l ocate d atI nter-U ni versit y Et hics C o m mittee . 
1 0. 3  
I n de pe n de nt et hics c o m mittee (I E C) or i nstit uti o n al re vie w b o ar d (I R B) 
Et hical assess me nt will be d o ne b y e x p ert I n de p e n de nt re vie w b o ar d (I R B), s pecialize d i n 
NI S assess me nt. Pr ot oc ol relate d d oc u m e ntati o n t o be s u b mitte d t o I R B f or t he a p pr o val, 
l ocate d at I nter-U ni versit y Et hics C o m mitt ee: 

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e-mail: 
 
M o bil e: 
 
1 0. 4  
A u dit  a n d I ns pecti o n 
T o e ns ure c o m plia n ce r e g ulat or y re q uire m e nts, a me m ber of t he s p o ns or’s ( or a desi g nat e d 
C R O’s) q ualit y ass ura nce u nit ma y arra n ge t o c o n d uct a n a u dit t o assess t h e perf or ma nce of 
t he st u d y at t he st u d y site a n d of t he st u d y d oc u me nts ori gi nati n g fr o m t here.  
T he i n vesti gat or/i nstit uti o n will be i nf or me d of t h e a u dit o utc o me.  
I n a d diti o n, i ns pecti o ns b y re g ulat or y healt h a ut h orit y re pres e ntati ves a n d I E C(s)/I R B(s) are 
p ossi ble. T he i n vesti gat or s h o ul d n otif y t he s p o ns or i m me diatel y of a n y s u c h i ns pecti o n. 
T he i n vesti gat or/i nstit uti o n a grees t o all o w t he a u dit or or i ns pect or direct access t o all rel e va nt 
d oc u me nts a n d all ocat e his/ her ti me a n d t he ti me of his/ her staff t o t he a u dit or/i ns pect or t o 
disc uss fi n di n gs a n d a n y iss ues. A u dits a n d i ns pecti o ns ma y occ ur at a n y ti me d uri n g or after 
c o m pleti o n of t he st u d y. 
1 1.  
P atie nt i nf or m ati o n a n d c o nse nt 
Bef ore d oc u m e ntati o n of a n y data, i nf or m e d c o ns e nt is o btai ne d b y t he patie nt i n writi n g. I n 
c o u ntries w here r e q uire d b y la w or re g ul ati o n, t he i n vesti gat or m ust ha ve t he I E Cs /I R B 
writte n a p pr o val/f a v ora bl e o pi ni o n of t he writte n i nf or me d c o ns e nt f or m a n d a n y ot her writte n 
i nf or mati o n t o be pr o vi de d t o patie nts pri or t o t he be gi n ni n g of t he o bser vati o n. 
 
1 1. 1  
P atie nt i ns ur a nce  
I n t his st u d y, data o n r o uti ne treat me nt of p atients i n dail y practice are d o c u me nte d a n d 
a nal yze d wit h t he hel p of e pi de mi ol o gical met h o ds. Treat me nt i ncl u di n g dia g n osis a n d 
m o nit ori n g of t hera p y f oll o ws e xcl usi vel y r o uti ne dail y practice. C urre nt m e dical dail y 
practice is o bser ve d, a n d f or t he patie nt n o ris ks be y o n d re g ular t hera p y e xist – t here is n o 
a d diti o nal hazar d arisi n g fr o m st u d y partici pati o n. As n o st u d y relate d ris ks e xist, t here is n o 
nee d t o pr otect t he p atie nt a d diti o nall y b y a patie nt i ns ura nce. T h e ge neral re g ulati o ns of 
me dical la w a n d  t h e pr of essi o nal i n de m nit y i ns ura nce of t he i n vesti gat ors a n d, res pecti vel y, 
t he i nstit uti o ns i n v ol ve d pr o vi de s ufficie nt pr ot ecti o n f or b ot h patie nt a n d i n vesti gat or. 
N o st u d y me dicati o n will be pr o vi de d t o partici p a nts. T h us, pr o d uct i ns ura nce is c o vere d b y 
t he e xisti n g pr o d uct lia bilit y. 
1 1. 2  
C o nfi de nti alit y  
Ba yer as w ell as all i n vesti gat ors e ns ure a d h ere n ce t o a p plica ble data pri vac y pr otecti o n 
re g ulati o n. Data are tr a nsferr e d i n e nc o d e d f or m o nl y. T he e ntire d oc u m e ntati o n ma de 
a vaila ble t o Ba yer d oe s n ot c o ntai n a n y data w hi c h, o n its o w n acc o u nt or i n c o nj u ncti o n wit h 
ot her freel y a vaila bl e dat a, ca n b e use d t o re -i de ntif y nat ural pers o ns. T h e i n vesti gat ors are 
o bli gate d t o e ns ure t hat n o d oc u me nts c o ntai n s uc h data.  
All rec or ds i de ntif yi n g t h e s u b ject will be ke pt c o nfi de ntial a n d will n ot be ma de p u blicl y 
a vaila ble. Patie nt na mes will n ot be s u p plie d t o t he M A H . If t h e patie nt na me a p pears o n a n y 
d oc u me nt, it m ust be o bliterate d bef ore a c o p y of t he d oc u me nt is s u p plie d t o t he M A H . 
St u d y fi n di n gs st ore d o n a c o m p uter will be st ore d i n acc or d a nce wit h l ocal data pr otecti o n 
la ws.  
P P D
P P D
P P D

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T he i n vesti gat or will mai ntai n a list t o e na ble patie nts’ rec or ds t o be i de ntifie d i n case of 
q ueries. I n case of a r e p ort of a seri o us a d vers e e v e nt ( S A E), t he res p o nsi ble 
p har mac o vi gila nce pers o n ma y as k f or a d diti o nal clarificati o n. I n t h at case, t he c o m pa n y is 
n ot all o we d t o directl y c o ntact t he patie nt. All a d diti o nal i nf or mati o n will be pr o vi de d b y t he 
i n vesti gat or. 
1 2.  
M a n a ge m e nt a n d re p orti n g of a d verse e ve nts/ a d verse re acti o ns  
1 2. 1  
 Defi niti o ns  
A n a d vers e e ve nt ( A E) is a n y  u nt o war d me dical o cc urre nce i n a patie nt a d mi nistere d a 
me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (e. g. a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y  ass ociate d wit h t he use of a me dici nal 
pr o d uct, w het her or n ot c o nsi dere d rel ate d t o t his me dici nal  pr o d uct [ 9]. 
T he ter m als o c o v ers la b orat or y  fi n di n gs or res ults of ot her dia g n ostic pr oce d ures t hat are 
c o nsi dere d  t o be cli nicall y rele va nt (e. g. t hat re q uire u nsc he d ul e d dia g n ostic pr oce d ures or 
treat me nts or r es ult i n wit h dra wal fr o m t he st u d y). T he A E ma y be: 
• 
A ne w ill ness  
• 
W orse ni n g of a si g n or s y m pt o m of t he c o n diti o n u n der treat me nt or of a c o nc o mita nt 
ill ness 
• 
A n effect of t he st u d y me dicati o n  
• 
A n  effect  of t he c o m parat or pr o d uct 
• 
Off la bel use, occ u pati o nal e x p os ure, lac k of dr u g effect, me dicati o n err or, 
o ver d ose, dr u g  a b use, dr u g mis use or dr u g de pe n de nc y itself, as w ell as a n y 
res ulti n g e ve nt 
• 
A n effect relate d t o pre -e xisti n g c o n diti o n i m pr o ve d ( u ne x pect e d t hera pe utic 
be nefits  are  o bser ve d) 
• 
Pr o d uct e x p os ure via m ot her/ fat her (e x p os ure d uri n g c o nce pti o n, pre g na nc y, 
c hil d birt h a n d breastfee di n g)  
As me nti o ne d a b o ve n o ca usal relati o ns hi p wit h a pr o d uct is i m plie d b y t he use of t he ter m 
“a d vers e e v e nt”.  
A n A d verse R eacti o n  ( A R) is defi ne d as a res p o nse t o a me dici nal pr o d u ct w hic h is n o xi o us 
a n d u ni nte n de d. A n A R is a n y A E j u d ge d as h a vi n g a reas o n a ble s us pecte d ca usal relati o ns hi p 
t o T herafle x ® . 
Ca usal relati o ns hi p : T he assess me nt of t he ca usal relati o ns hi p bet wee n a n A E a n d t he 
a d mi nistrati o n of treat me nt is a cli nical decisi o n base d o n all a vaila bl e i nf or mati o n at t he  ti me 
of t he c o m pleti o n of t he C R F. T he assess me nt is base d o n t he q uesti o n w h et her t here was a 
"reas o na ble ca usal relati o ns hi p" t o t he st u d y treat me nt i n q uesti o n. P ossi ble a ns wers are " yes" 
or " n o". 
A n assess me nt of " n o" w o ul d i ncl u de: 
T he e xiste nce of a  clear alter nati ve e x pla n ati o n (e. g. mec ha nical blee di n g at s ur gical site)  
N o n - pla usi bilit y (e. g. t he s u bject is str uc k b y a n a ut o m o bile w he n t here is n o i n dicati o n t hat 
t he pr o d uct ca us e d dis ori e ntati o n t hat ma y ha ve ca use d t he e ve nt; ca ncer de vel o pi n g a fe w 
da ys after t h e first pr o d u ct a d mi nistrati o n)  

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A n assess me nt of " yes" i n dicates t hat t here is a reas o na ble s us pici o n t hat t he A E is ass ociate d 
wit h t he use of t he st u d y treat me nt. Fact ors t o be c o nsi dere d i n assessi n g t h e relati o ns hi p of 
t he A E t o st u d y treat me nt i ncl u de: 
T he te m p oral se q u e nce fr o m pr o d uct a d mi nistrati o n: T he e ve nt s h o ul d occ ur after t h e pr o d uct 
is gi ve n. T he le n gt h of ti me fr o m pr o d uct e x p os ure t o e ve nt s h o ul d be e v al uate d i n t he cli nical 
c o nte xt of t he e v e nt. 
Rec o ver y o n pr o d uct disc o nti n uati o n ( de-c h alle n ge), rec urre nce o n pr o d u ct re-i ntr o d ucti o n 
(re- c halle n ge): S u bject's res p o nse after de-c h alle n ge or s u bjects res p o nse after re -c h alle n ge 
s h o ul d be c o nsi dere d i n t he vie w of t he us u al cli nical c o urs e of t he e v e nt i n q uesti o n. 
U n derl yi n g, c o nc o mita nt, i nterc urr e nt diseases: E ac h e v e nt s h o ul d be e val uate d i n t he c o nte xt 
of t he nat ural hist or y a n d c o urse of t he disease b ei n g treate d a n d a n y ot her disease t he s u bject 
ma y ha ve.  
C o nc o mita nt me dicati o n or treat me nt: T h e ot her pr o d ucts t he s u bject is ta ki n g or t he 
treat me nt t he s u bject r ecei ves s h o ul d be e xa mi ne d t o deter mi ne w het her a n y of t he m ma y be 
s us pecte d t o ca us e t he e v e nt i n q uesti o n. 
T he p har mac ol o g y a n d p har mac o ki netics of t he st u d y treat me nt: T he p har mac o ki ne tic 
pr o perties ( a bs or pti o n, distri b uti o n, meta b olis m a n d e xcreti o n) of t he st u d y treat me nt, c o u ple d 
wit h t he i n di vi d ual s u bject’s p har mac o d y na mics s h o ul d be c o nsi dere d. 
A n A E is seri o us ( S A E) if it: 
• 
Res ults i n deat h  
• 
Is life-t hreate ni n g 
• 
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n (see 
e xce pti o ns bel o w) 
• 
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y  
• 
Is a c o n ge nital a n o mal y or birt h defect 
• 
Is me di call y i m p orta nt. 
Deat h  is us uall y t he o utc o me of a n u n derl yi n g cli nical e ve nt t hat ca uses it. He nce, it is t he 
ca use of d eat h t hat s h o ul d be re gar de d as t he S A E. T he o ne e x ce pti o n t o t his r ule is ‘s u d de n 
deat h’ w here n o ca use h as bee n esta blis he d. I n t his i nsta nce, ‘s u d de n d eat h’ s h o ul d be 
re gar d e d as t he A E a n d ‘fatal’ as its reas o n f or b ei n g ‘seri o us’. 
Life -t hreate ni n g: T he ter m “life-t hreate ni n g” i n t h e defi niti o n of “seri o us” refers t o a n A E i n 
w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It d o es n ot refer t o a n A E 
w hic h h y p ot heticall y mi g ht ha ve ca us e d deat h if it were m ore se vere.  
H os pitalizati o n : A n y A E lea di n g t o h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n will be 
c o nsi dere d as seri o us, u nless t he a d missi o n is: 
• 
pla n ne d bef ore s u bject's i ncl usi o n i n t he st u d y (i.e. electi ve or s c he d ule d s ur ger y) or 
• 
a m b ula nt (s h orter t ha n 1 2 h o urs) or 
• 
part of t he n or mal tr eat m e nt or m o nit ori n g of t he st u die d disease (i.e. n ot d u e t o a 
w orse ni n g of t he disease) 
H o we ver it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y h os pitalizati o n ma y f ulfill t he 
criteria of ‘ me dicall y i m p orta nt’ a n d as s u c h ma y be re p ort a ble as a S A E d e pe n de nt o n 
cli nical j u d g me nt. I n a d diti o n w here l ocal re g ulat or y a ut h orities s pecificall y re q uire a m ore 
stri n ge nt defi niti o n, t he l ocal re g ulati o n ta k es prece de nt. 

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Disa bilit y  mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s 
f u ncti o ns. 
C o n ge nital a n o mal y ( birt h defect ), i.e. a n y c o n ge nital a n o mal y o bser ve d i n a n i nfa nt, or later 
i n a c hil d, s h o ul d be re gar de d as a S A E w he n: 
• 
T he m ot her ha d b ee n e x p ose d t o a me dici nal pr o d uct at a n y sta ge d uri n g c o nce pti o n or 
pre g na nc y or d uri n g deli ver y 
• 
T he fat her was e x p ose d t o a me dici nal pr o d uct pri or t o c o nce pti o n 
Ot her me dicall y i m p orta nt seri o us e ve nt: a n y a d v erse e v e nt ma y be c o nsi dere d seri o us 
beca use it ma y je o p ar dize t he patie nt a n d ma y re q uire i nter ve nti o n t o pre v e nt a n ot her seri o us 
c o n diti o n. Me dicall y i m p orta nt e ve nts eit her refer t o or mi g ht be i n dicati ve of a seri o us 
disease state. S uc h r e p orts warr a nt s pecial atte nti o n beca use of t heir p ossi ble ass ociati o n wit h 
seri o us disease state a n d ma y lea d t o m ore decisi ve acti o n t ha n re p orts o n ot her ter ms. 
1 2. 2  
 C ollecti o n  
Starti n g  wit h  t he first a p plicati o n  of T herafle x ® aft er e nr oll me nt i nt o t he st u d y, all n o n -
seri o us  a d verse e v e nts ( A E) m ust be d oc u me nte d o n t he A E Re p ort F or m or i n t he 
C R F/ E D C s yste m a n d f or war de d t o t he M A H wit hi n 7 cale n dar da ys  of a ware n ess.  All  
seri o us A Es  ( S A E) m ust be d oc u me nte d a n d f or w ar de d i m me diatel y ( wit hi n 2 4 h o urs of 
a war e ness). F or  eac h A E,  t he i n vesti gat or m ust assess a n d d oc u me nt t he seri o us ness, 
d urati o n, relati o ns hi p t o pr o d uct, acti o n ta ke n a n d  o utc o me of t he e ve nt. 
T he q uesti o n naire relate d i nf or mati o n (as it is pri mar y a n d sec o n dar y e n d p oi nts) s h o ul d be 
e xe m pted fr o m A E re p orti n g. 
F or t he reas o ns state d bel o w, t he f oll o wi n g A Es are e xe m pt fr o m re p orti n g i n t his st u d y 
a n d will t heref ore n ot be d oc u me nte d i n t he A E R e p ort F or m i n t he C R F/e C R F.  
*  
If a pr e g na nc y occ urs d uri n g t he st u d y, alt h o u g h it is n ot a seri o us a d vers e e ve nt 
itself, it s h o ul d be d oc u me nte d a n d f or war de d t o t he M A H  wit hi n  t he sa me ti me li mits as 
a seri o us a d verse e v e nt. T he res ult of a pre g na n c y  will be f oll o we d - u p acc or di n g  t o 
a p plica ble Ba yer  S O Ps. A n y  data o n   a b n ormal  fi n di n gs c o ncer ni n g eit her t he m ot her or 
t he ba b y  will be c ollecte d as a d verse e ve nts.  
*  
T he d oc u me ntati o n of a n y A E/ S A E  e n ds wit h  t he c o m pleti o n of t he o bser vati o n 
peri o d of t he patie nt. H o we ver, a n y A E/ S A E - re gar dless of t he relati o ns hi p a n d t he 
seri o us ness - occ urri n g  u p t o 
< 3 0 da ys  aft er t he last d ose of  T h erafle x ® wit hi n t he st u d y peri o d has  t o  be d oc u me nte d 
a n d f or war de d t o t he M A H wit hi n t he gi ve n ti meli nes, e ve n if t his peri o d g oes be y o n d  t he 
e n d of o bser v ati o n. 
*  
As  l o n g as t he patie nt  has  n ot recei ve d a n y T herafl e x ®  wit hi n t he fra me of t he st u d y 
A Es / S A Es d o   n ot nee d t o be d oc u me nte d as s uc h i n t his o bser vati o nal st u d y. H o we ver, 
t he y are part  of t he patie nt’s me dical hist or y. 
*  
F or  a n y seri o us pr o d uct-relate d A E occ urri n g aft er st u d y e n d, t he sta n dar d 
pr oce d ur es t hat are i n place  f or s p o nta ne o us re p orti n g ha ve t o be f oll o we d. 
 
1 2. 3  
 M a n a ge m e nt  a n d re p orti n g  
*  
N o n -seri o us A Es 
*  
T he  o utc o me of all re p orte d A Es  will  be f oll o we d u p a n d d oc u me nte d. W here  
re q uire d, i n vesti gat ors mi g ht be c o ntacte d directl y b y t he res p o nsi ble st u d y staff t o pr o vi de 

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f urt her i nf or m ati o n. 
*  
F or n o n- seri o us A Rs  occ urri n g u n der n o n-Ba yer  pr o d ucts t he i n vesti gat or has  t o 
acc o u nt  f or a n d  c o m pl y wit h t he re p orti n g s yste m of t he pr o d uct’s Mar ket i n g A ut h orizati o n 
H ol der wit hi n  t he fra me of l ocal la ws a n d re g ulati o ns as well as ot her l ocall y  a p plica ble 
la ws a n d re g ulati o ns. 
*  
Seri o us A Es  
*  
A n y  S A E or pre g n a nc y e ntere d i nt o t he C R F/ E D C s yste m will be f or war de d 
i m me diatel y ( wit hi n o ne b usi ness da y of a ware ness) t o t he p har mac o vi gila n ce c o u ntr y  
pers o n bei n g r es p o nsi ble f or S A E pr ocessi n g. T he  o utc o me of all re p orte d S A Es  
(res ol uti o n, deat h  etc.) will  be f oll o we d u p a n d d oc u me nte d. W here  re q uire d, i n vesti gat ors 
mi g ht be c o ntacte d  directl y  b y t he p har mac o vi gila nce   c o u ntr y pers o n i n c h ar ge t o pr o vi de 
f urt her i nf or m ati o n. 
*  
S u b missi o n t o t he rele va nt a ut h orities  acc or di n g  t o nati o nal re g ulati o ns will  be d o ne 
b y  t he M A H  f or S A Es relate d T herafle x ® treat me nt; h o we ver, all i n vesti gat ors m ust o be y 
l ocal le gal re q uire me nts. 
*  
F or  a n y seri o us dr u g-r elate d A E occ urri n g aft er st u d y e n d, t he sta n dar d pr o ce d ures  
t hat are i n place   f or s p o nta ne o us re p orti n g ha ve t o be f oll o we d. 
*  
F or  S A Es  t hat occ urre d  w hile  a d mi nisteri n g  n o n -Ba yer pr o d ucts t he  i n vesti gat or has  
t o acc o u nt  f or  a n d c o m pl y wit h t he re p orti n g s yste m of t he pr o d uct’s Mar keti n g  
A ut h orizati o n H ol der wit hi n  t he fra me of l ocal la ws a n d re g ulati o ns as w ell as ot her 
l ocall y a p plica ble l a ws a n d re g ulati o ns.  
S u b missi o n of S A Es relate d t o n o n- Ba yer pr o d ucts t o t he rele va nt a ut h orities acc or di n g t o 
nati o nal re g ulati o ns will be d o ne b y  t he M A H 
 
1 2. 4  
 E v al u ati o n 
*  
W he ne ver ne w i m p orta nt safet y i nf or mati o n is recei ve d, e. g. case re p orts fr o m a n 
i n vesti gat or, t he re p orts are pr ocess e d  a n d e ntere d i nt o t he gl o bal p har mac o vi gila nce  safet y 
data base. T hese re p orts  will be re vie we d  o n a re g ular basis (f or i nf or mati o n o n c ollecti o n, 
ma na ge me nt a n d re p orti n g of case re p orts, refer t o secti o n 1 1. 2 a n d 1 1. 3 ). If a p ote ntial 
safet y si g nal is s us pecte d, a n i n vesti gati o n of  t he s us pecte d p ote ntial si g nal will  be 
perf or me d  acc or di n g  t o i nter nal sta n dar d o perati n g pr oce d ures, f or  f urt her e val uati o n wit hi n  
t he c o nte xt of be nefit  ris k. 
 
1 3.  
Pl a ns f or disse mi n ati n g a n d c o m m u nic ati n g st u d y res ults  
T his st u d y will be re gistere d at “ w w w.cli nicaltri als. g o v ”. Res ults will be discl ose d i n a 
p u blicl y a vaila ble data b ase wit hi n t he sta n dar d ti meli nes.  
 
 

Pa ge 3 5  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
1 4.  
Refere nces  
Cle g g D O. et al. ( 2 0 0 6). Gl uc osa mi ne, c h o n dr oiti n s ulfate, a n d t he t w o i n c o m bi nati o n f or 
pai nf ul k nee oste o art hritis. . N E n gl J Me d. 2 0 0 6 , Fe b 2 3; 3 5 4( 8): 7 9 5- 8 0 8. 
E F PI A. ( O ct 2 0 0 7). C o d e o n t he Pr o m oti o n of Prescri pti o n- O nl y Me dici n es t o a n d 
I nteracti o ns wit h Healt hcare Pr ofessi o nals. 
E M A. ( 0 5 N o v 2 0 1 0). E N Ce P P g ui de o n met h o d ol o gical sta n dar ds i n 
p har mac o e pi de mi ol o g y. . 
E M A. ( 0 8 Se p 2 0 1 4). G P V M o d ule VI - Ma n a ge m e nt a n d re p orti n g of a d verse reacti o ns t o 
me dici nal pr o d ucts ( Re v 1). G ui deli ne o n g o o d p h ar m ac ovi gil a nce pr actices 
( E M A/ 8 7 3 1 1 3 8/ 2 0 1 1 _ Rev 1). 
E M A. ( 1 9 A pr 2 0 1 3). G P V M o d ule VIII - P ost-a ut h orisati o n safet y st u dies ( Re v 1). G ui deli ne 
o n g o o d p h ar m ac ovi gil a nce pr actices ( E M A/ 8 1 3 9 3 8/ 2 0 1 1 _ Rev 1) . 
E M A. ( 1 9 A pr 2 0 1 3). G P V M o d ule VIII A d de n d u m 1 - Me m ber States' re q uire me nts f or 
tra ns missi o n of i nf or mati o n o n n o n-i nter ve nti o nal p ost-a ut h orisati o n safet y st u dies 
( Re v 1). G ui deli ne o n g o o d p h ar m ac ovi gil a nce pr actices ( E M A/ 3 9 5 7 3 0/ 2 0 1 2 _ Rev 1) . 
E N Ce P P. ( 2 0 1 1). Defi niti o n of n o n- i nterve nti o n al tri als u n der t he c urre nt le gisl ative 
fr a me w ork. E N Ce P P.  
E U. ( 2 0 J u n 2 0 1 2). C o m missi o n i m ple me nti n g re g ulati o n ( E U) N o 5 2 0/ 2 0 1 2 of 1 9 J u ne 2 0 1 2 
o n t he perf or m a nce of p h ar mac o vi gila nce acti vities pr o vi de d f or i n Re g ulati o n ( E C) 
N o 7 2 6/ 2 0 0 4 a n d Directi ve 2 0 0 1/ 8 3/ E C of t he E ur o pea n Parlia m e nt a n d of t he 
C o u ncil. Offici al J o ur n al of t he E ur o pe a n U ni o n . 
E U. ( 2 0 0 8). E u dr ale x - V ol u me 9 A of t he R ules G o ver ni n g Me dici nal Pr o d ucts i n t he 
E ur o pea n U ni o n: t he G ui deli nes o n P har mac o vi gil a nce f or Me dici nal Pr o d u cts f or 
H u ma n Use.  
F D A. ( 0 1 A pr 2 0 1 2). C o de of Fe deral Re g ulati o ns. Title 2 1, V ol u me 1. 2 1 C F R 1 1: Electr o nic 
rec or ds; electr o nic si g n at ures. 
Graf, C. , Battisti, W. P., Bri d ges, D., Br uce- Wi n kler, V., C o nat y, J. M., Ellis o n, J. M., et al. 
( 2 0 0 9). I nter n ati o nal S ociet y f or Me dical P u blicati o n Pr ofessi o nals. Researc h Met h o ds 
& Re p orti n g. G o o d p u blicati o n practice f or c o m m u nicati n g c o m pa n y s p o ns ore d 
me dica l res ear c h: t he G P P 2 g ui deli nes. B MJ . 
I C H. ( N o v 2 0 0 3). I C H H ar m o nize d Tri p artite G ui deli ne: Cli nical Safet y Data Ma na g e me nt: 
Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g ( E 2 D). 
J or da n, K. M. ( 2 0 0 3). E U L A R Rec o m me n dati o ns 2 0 0 3: a n e vi de nce b ase d a p pr oac h t o t he 
ma na ge me nt of t he k n ee oste oart hritis: Re p ort or a Tas k f orce of t h e Sta n di n g 
C o m mittee f or I nt er nati o nal Cli nical St u dies I ncl u di n g T hera pe utic Trials ( E S CI SI). 
A n n R he u m Dis , 3 3( 1 1), 2 2 7 1 – 2 2 7 9. 

Pa ge 3 6  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
Kell gre n J. H., L. J. ( 1 9 5 7 P. 4 9 4 – 5 0 1). R a di o gr a p h ic assess me nt of oste o art hritis . A n n. 
R he u m. Dis. 
La pa ne K L. et al., 2. L. ( 2 0 1 2). Use of c o m ple me ntar y a n d alter nati ve me dici ne a m o n g 
patie nts wit h ra di o gra p hi c-c o nfir m e d k nee ost e oart hritis. Oste o art hritis C artil a ge. , 
Ja n; 2 0( 1): 2 2- 8. 
Li p piel o, L. W. ( 1 9 9 9). Be neficial effect of cartila ge str uct ure m o dif yi n g a ge nts teste d i n 
c h o n dr oc yte a n d ra b bit i nsta bilit y m o del osteart hr osis. . Art hritis R he u m. , ( 4 2), 2 5 6. 
Mc Ali n d o n T E. et al., 1. M. ( 1 9 9 2). K nee pai n a n d disa bilit y i n t he c o m m u nit y. Br J 
R he u m at ol. , Mar; 3 1( 3): 1 8 9- 9 2. 
N uesc h, E. D. ( 2 0 1 1). All ca use a n d disease s pecific m ortalit y i n patie nts wit h k nee or hi p 
oste oart hritis: p o p ulati o n base d c o h ort st u d y. B MJ , ( 3 3 4 2), 1 1 6 5 – 1 1 7 3. 
Qi u G X., W. X. ( 2 0 0 5). A m ulti-ce ntral, ra n d o mi ze d, c o ntr olle d cli nical trial of gl uc osa mi ne 
h y dr oc hl ori de/s ulfate i n t he treat me nt of k n ee oste oart hritis. Z h o n g h u a Yi X ue Z a Z hi , 
N o v 1 6; 8 5( 4 3): 3 0 6 7- 7 0. 
Sa witz ke, A. ( 2 0 1 0). Cli nical effi cac y a n d safet y of gl uc osa mi ne, c h o n dr oiti n s ul p hate, t heir 
c o m bi nati o n, celec o xi b or place b o ta k e n t o treat oste oart hritis of t he k nee: 2-year 
res ults fr o m G AI T. . A n n R he u m Dis,. , 6 9( 8), 1 4 5 9- 6 4. 
v o n El m, E., Alt ma n, D. G., E g ger, M., P oc oc k, S. J., G øtzsc he, P. C., & Va n de n br o uc k e, J. 
P. ( 2 0 0 8). S T R O B E -I niti ati ve. T he Stre n gt he ni n g t he Re p orti n g of O bser v ati o nal 
St u dies i n E pi de mi ol o g y ( S T R O B E) state me nt: g ui deli nes f or re p orti n g of 
o bser vati o nal st u dies. J Cli n E pi de mi ol. 2. J Cli n E pi de mi ol.  
Ze gels B., C. P. ( 2 0 1 3). E q ui vale nce of a si n gle d ose ( 1 2 0 0 m g) c o m pare d t o a t hree- ti me a 
da y d ose ( 4 0 0 m g) of c h o n dr oiti n 4 & 6 s ulfate i n patie nts wit h k nee oste oart hritis. 
Res ults of a ra n d o mize d d o u ble bli n d place b o c o ntr olle d st u d y. Oste o art hritis 
C artil a ge , Ja n; 2 1( 1): 2 2- 7. 
 
 
 
 

Pa ge 3 7  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
A n ne x 1: List of st a n d -al o ne d oc u me nts  
T a ble 3 : List of st a n d-al o ne d oc u me nts  
 
D oc u m e nt N a m e  
Fi n al versi o n a n d d ate (if 
a v ail a ble) * 
In v esti gat or list  
T b d  
C R F  
T b d  
E D C S yste m  
T b d  
D ata Ma na g e me nt Pla n  
T b d  
Statistical A nal ysis Pla n  
T b d  
E D C S yste m Vali dati o n >  
T b d  
Q ualit y Re vie w Pla n ( Q R P)  
T b d  
Me dical Re vie w Pla n ( M P P)  
T b d  
* Draft versi o ns are i n dicate d b y < draft > i n brac kets a n d date. “t b d” i n dicates d oc u me nts t hat 
are n ot a v aila ble at t he ti me of pr ot oc ol creati o n, b ut will be iss ue d at a later sta ge  
 
 
 

Pa ge 3 8  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
 
A n ne x 2 : A d diti o n al i nf or m ati o n 
N ot a p plica ble 
 
 

Pa ge 3 9  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
A n ne x 3 : Descri pti o n of a m e n d m e nts  
Versi o n 1 / N/ A 
A me n d me nt 1  
C orrecti o n of e x cl usi o n criteria was c o n d ucte d, i n or der t o mi ni mize t he ris k of i ncl u di n g 
patie nt s wit h differe nt b aseli ne le vel of O A treat me nt. At t he sa me ti me it beca me o b vi o us 
t hat wit h i nitial e xcl usi o n criteria sl o w patie nt recr uit me nt is pre dictable. 
9. 2. 3. E xcl usi o n criteri a  
E xcl usi o n criteria:  
•  
Patie nts w h o ha ve b ot h Hi p a n d K nee O A a n d O A of a n y ot her l o cati o n. 
is delete d 
E xcl usi o n criteria:  
•  
Patie nts w h o c o m plete d a treat me nt wit h T herafle x ® or a n ot her c o m bi nati o n of Gl + 
C h less t ha n 5 m o nt h s bef ore start of t h e c urre nt treat me nt 
is c ha n ge d t o: 
• 
Patie nts w h o c o m plete d a treat me nt wit h T herafle x ® or t he ot her S y m pt o matic  Sl o w -
Acti n g dr u g i n Oste оart hritis ( S Y S A D O A) less t ha n 5 m o nt hs bef ore start of t he c urre nt 
treat me nt 
E xcl usi o n criteria:  
• 
Patie nts w h o c o m plete d i ntra -artic ul ar c ortic oster oi ds treat me nt i n t he last 3 m o nt hs t o 
e xcl usi o n criteria.  
is c ha n ge d t o : 
• 
Patie nts w h o c o m plete d i ntra -artic ul ar c ortic oster oi ds treat me nt i n t he last 3 m o nt hs 
bef ore e nr oll me nt . 
E xcl usi o n criteria:  
•  
Patie nts w h o c o m plete d h yal ur o nic i njecti o ns of t he l o wer li m bs i n t he last 6 m o nt hs. 
is c ha n ge d t o: 
•  
Patie nts w h o c o m plete d h yal ur o nic i njecti o ns a n d/ or platelet-ric h plas ma ( P R P) 
t hera p y of t he l o w er li m bs i n t he last 6 m o nt hs 
 
T he a p pr o ac h f or c o m pleti n g t he q uesti o n naire was clarifie d i n case t he p atie nt has m ulti ple 
j oi nt O A or bilateral K nee/ Hi p O A.  
 
I n t he s ecti o n 9. 2. 7. 2 Visit 1: E nr oll me nt/I niti al visit  
T he f oll o wi n g te xt is a d de d :  “If t he p atie nt has m ulti ple j oi nt O A or d o u ble-si de d ( bilateral) 
K nee/ Hi p O A, o nl y o ne «tar get » j oi nt t o be select e d f or t he e val uati o n, w h ere t he p atie nt 
e x perie n ces t he m ost se v ere pai n at t he ti me of e nr oll me nt. Filli n g i n a q uesti o n naire, t he 
patie nt nee ds t o ass ociat e his/ her res p o nses wit h t h e "tar get" j oi nt o nl y d uri n g t he e ntire 
f oll o w- u p peri o d » 
I n t he s ecti o n 9. 2. 7. 3   F oll o w- u p Visits I & II  
T he f oll o wi n g te xt is a d de d : 

Pa ge 4 0  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
« If patie nt s witc hes t o a n ot her S y m pt o matic  Sl o w- Acti n g dr u g i n Oste о art hritis 
( S Y S A D O A), t he o bser v ati o n of t he patie nt is ter mi nate d ». 
« T he patie nt nee ds t o assess t he o utc o me of j oi nt treat me nt, w hic h w as sel ecte d as t he 
“tar get” at t he first visit  ». 
I n t he s ecti o n 9. 2. 7. 4 Fi n al Visit / E n d of O bser v ati o n  
T he p ossi ble wi n d o w f or t he visit is c orrecte d i n acc or da n ce wit h t he s c he d ule of visits 
T he f oll o wi n g te xt is a d de d :  “Fi nal visit s h o ul d be perf or me d d uri n g t he ti me fra me wee k 5 6-
6 4 ». 
T he patie nt nee ds t o assess t he o utc o me of j oi nt treat me nt, w hic h w as selecte d as t he tar g et at 
t he first visit. 
Re q uire me nts f or c ollecti o n of vital si g ns a n d data of p h ysical e xa mi nati o n were clarifie d. 
I n s ecti o n 9. 3. 3. 3 Vit al si g ns   
t he f oll o wi n g te xt was a d de d : « if s uc h data are a vaila ble a n d t he c olleti o n of t his data is t he 
r o uti ne cli nical practice of t he I n vesti gat or » 
I n s ecti o n  9. 3. 3. 4  
P h ysic al E x a mi n ati o n  
T he f oll o wi n g te xt is a d de d : 
« I n t he a bse n ce of t he h ei g ht meter a n d scal e i n t he d oct or's offi ce. hei g ht a n d wei g ht ca n be 
re gistere d fr o m t he patie nt's w or ds ». 
I n s ecti o n  9. 3. 3. 9 
P atie nt s atisf acti o n wit h T her afle x ®  
T he f oll o wi n g te xt was a d de d : 
« Patie nt satisfacti o n meas ure d wit h a Li kert res p o nse scale (fr o m 5 – ver y satisfie d  t o 1 - ver y 
dissatisfie d)  ». 
I nf or mati o n a b o ut t he I n de pe n de nt Et hics C o m mittee res p o nsi ble f or pr ot o c ol relate d 
d oc u me ntati o n re vie w a n d a p pr o va l was u p d ate d 
I n t he s ecti o n 1 0. 2  Re g ul at or y a ut h orit y a p pr o v als/ a ut h oriz ati o ns  
t he te xt has bee n c ha n ge d fr o m: 
« l ocate d at 
 ». 
t o: 
« l ocate d atI nter-U ni versit y Et hics C o m mittee  ». 
S o me err ors  a n d t y p os w ere c orrecte d.,  
I n t he s ecti o n 1 0. 3 I n de pe n de nt et hics c o m mittee (I E C) or i nstit uti o n al re vie w b o ar d 
(I R B) 
T he c o ntact i nfr o mati o n  has bee n c h a n ge d fr o m : 
« l ocate d at 
».  
T o  : 
“ l ocate d at I nter-U ni versit y Et hics C o m mittee:  
 
e- mail: 
 
M o bile: 
 » 
 
P P D
P P D
P P D
P P D
P P D

Pa ge 4 1  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
A m e n d me nt 2  
T he n u m ber of p atie nts is re d uce d fr o m 1 5 0 0 patie nts t o 1 1 0 0 patie nts. 
J ustificati o n: Ori gi nall y pla n ne d t o c o n d uct a n o bser vati o nal st u d y of t he T herafl e x pr o d uct  
i n 8 0 st u d y ce nters of M osc o w, St. Peters b ur g a n d Yar osla vl re gi o ns. I n c o n necti o n wit h t he 
a d diti o nal a d mi nistrati ve barrier o n t h e part of t h e M osc o w Healt h Care De part me nt, i nstea d 
of 4 0 ce nters pla n ne d f or o pe ni n g i n t he M osc o w re gi o n, t he n u m ber of st u d y ce nters i n 
M osc o w has dr o p pe d t o 2 0. T h us, t he t otal n u m ber of st u d y ce nters will n ot e xcee d 6 0, w hic h 
is 7 5 % of t he pla n ne d n u m ber of cli nical ce nters. I n pr o p orti o n wit h re d uce d n u m ber of st u d y 
ce nters, t he n u m b er of p atie nts i n t he st u d y is als o re d uce d b y 2 5 %, w hic h i n n u merical ter ms 
a p pr o xi matel y c orres p o n ds t o 1 1 0 0 patie nts.  
I n or der t o calc ulate t h e i n dicat or of “ p atie nts l ost t o f oll o w-u p s u bjects”, w as ma de a si m ple 
a nal ysis  of t he V 2 fre q ue nc y o n t he gr o u p of t he first 1 0 % of s u bjects i ncl u de d i nt o t he st u d y. 
T he a nal ysis was carrie d o ut after 3 - 6 m o nt hs fr o m t he date of patie nts recr uit me nt, w hic h 
c orres p o n ds t o all o w a ble ti me- wi n d o w f or t he sec o n d visit. As a res ult of t hi s a nal yses, 
“ patie nts l ost t o f oll o w - u p” i n de x is a b o ut 7 %, w hic h is si g nifica ntl y l o wer t ha n i nitiall y 
ass u me d fi g ure f or t his i n dicat or (I n t he St u d y Ris k Re gister t his ris k fact or was re gistere d as 
2 0 % a n d a b o v e). T his a d diti o nall y ma kes p ossi ble t o re d uce t he st u d y p o p ulati o n t o 1 1 0 0 
s u bjects wit h o ut ne gati ve effect o n t he res ult of t h e w h ole st u d y.  
Si nce t he a nal ysis of all varia bles i n t he st u d y will be carrie d o ut usi n g a p pr o priate met h o ds of 
descri pti ve statistics, a decreas e i n t he n u m ber of p atie nts ca n n ot ha ve a ne g ati ve i m pact o n 
t he re pr ese ntati ve ness. 
I nitiall y It was pla n n e d t o ha ve i nteri m a nal ysis after all s u bjects ha v e c o m plete d V 2. Wit h 
t his a me n d me nt t he starti n g p oi nt is c ha n gi n g – I nteri m a nal ysis will be c o n d ucte d after 5 0 % 
of s u bjects (first 5 5 0 e nr olle d) ha ve c o m plet e d V 2 i n or der t o assess t he c ha n ges aft er t he first 
c o urse at t he h alf of t he st u d y p o p ulati o n. 
I n c o n necti o n wit h t hese c ha n ges, f oll o wi n g te xt c orrecti o n of pr ot oc ol t o o k place: 
I n t he s y n o psis i n t he t he p o p ulati o n a n d st u d y size secti o ns   
te xt “ A p pr o xi matel y 1 5 0 0 s u bjects are pla n n e d t o e nr olle d i n t he st u d y i n a b o ut 8 0 st u d y 
ce nters i n R ussia”  
 c ha n ge d t o: 
 “ A p pr o xi matel y 1 1 0 0 s u bjects are pl a n ne d t o e nr olle d i n t he st u d y i n a b o ut 6 0 st u d y ce nters 
i n R ussia.  
te xt: “It is pla n n e d t o e nr oll a p pr o xi matel y 1 5 0 0 patie nts i nt o t he st u d y” 
c ha n ge t o: 
“It is pla n ne d t o e nr oll a p pr o xi matel y 1 1 0 0 patie nts i nt o t he st u d y”.     
I n s ecti o n 9. 2. 1 Eli gi bilit y  
te xt : “ A p pr o xi matel y 1 5 0 0 s u bjects are pla n n e d t o be i ncl u de d i n t he st u d y i n a b o ut 8 0 st u d y 
ce nters i n R ussia”.  
C ha n ge d t o: 
A p pr o xi matel y 1 1 0 0 s u bjects ar e pla n ne d t o be i n cl u de d i n t he st u d y i n a b o ut 6 0 st u d y ce nters 
i n R ussia.   
I n s ecti o n 1 4. 1. 1 Statistical c o nsi derati o ns 
I n t he l ast para gra p h te xt: “It is pla n ne d t o have 1 i nteri m a nal ysis after all s u bjects ha ve 
c o m plete d V 2”.  

Pa ge 4 2  of 3 9  
I M P A C T n u m ber  1 9 6 4 9  Versi o n 3 . 0, 4 J ul y 2 0 1 8  
 
C ha n ge d t o:  
 It is pla n ne d t o h a ve 1  i nteri m a nal ysis after 5 0 % of (first 5 5 0 e nr olle d) s u bjects ha ve 
c o m plete d V 2. 
A n ne x 4: Si g n at ure p a ges  
N ot a p plica ble