Non-Steroidal Anti-inflammatory Drugs in Axial Spondyloarthritis: a Pilot Study
Phase: PHASE4
Conditions: Ankylosing Spondylitis, Axial Spondyloarthritis
Sponsor: Columbia University

C LI NI C A L R E S E A R C H P R O T O C O L
C ol u m bia U ni versit y Me dical Ce nter 
TI T L E: N o n- Ster oi dal A nti-i nfla m mat or y Dr u gs i n A xial S p o n d yl oart hritis: a Pil ot St u d y 
S H O R T TI T L E: N S AI Ds i n A S 
P RI N CI P A L I N V E S TI G A T O R: R u ns he n g Wa n g, M D, M H S 
  N C T 0 3 4 7 3 6 6 5
   V 1 2/ 1 8/ 2 0 1 8

 
2  
1. P R E CI S 
S p o n d yl oart hritis ( S p A) is a gr o u p of i nfla m mat or y s pi ne c o n diti o ns t hat affects 0. 5 - 1 % 
of t he p o p ulati o n i n t he U nite d States.  A n k yl osi n g s p o n d ylitis ( A S) is t he pr ot ot y pical disease i n 
t his fa mil y.  N o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) are t he first li ne p har mac ol o gical 
treat me nt of S p A a n d A S.  H o we ver, m ore t ha n 2 0 differe nt N S AI Ds are a vaila ble f or use.  It 
re mai ns u nclear w het her a n y partic ular N S AI D is m ore effecti ve t ha n ot hers, or if i n di vi d ual 
patie nts res p o n d t o N S AI Ds differe ntl y.  T o a d dress t his q uesti o ns, I pr o p ose a series of n- of- 1 
trials of N S AI Ds i n patie nts wit h S p A, as a pil ot st u d y f or a f ut ure m ultice nter trial.  M ore 
s pecificall y t his st u d y will: 
- 
E val uate t he o pti mal treat me nt le n gt h f or eac h N S AI D – 4 wee ks vs. 6 wee ks.  
- 
E val uate w het her a was h o ut peri o d is necessar y bet wee n differe nt N S AI Ds. 
- 
E val uate t he feasi bilit y of re m ote c ollecti o n of patie nt-re p orte d o utc o mes ( P R Os).  
 
H y p ot hesis 1 : T he c ha n ge of pai n sc ore fr o m wee k 4 t o wee k 6 is n ot cli nicall y si g nifica nt, a n d 4 
wee ks of treat me nt is s ufficie nt t o deter mi ne efficac y of N S AI Ds.  
H y p ot hesis 2: Was h o ut peri o d is n ot necessar y f or assessi n g treat me nt res p o nse i n a se q ue ntial 
desi g n.  
2. S T U D Y D E SI G N A N D M E T H O D  
2. 1 St u d y O ver vie w  
St u d y Desi g n  Eac h patie nt will be ra n d o mize d t o o ne of t he f o ur N S AI Ds, i n d o met haci n, 
dicl ofe nac, mel o xica m, a n d celec o xi b, eac h f or si x wee ks, t o get her wit h a n oral pr ot o n- p u m p 
i n hi bit or.  I n t he i nitial visit, patie nt will be e val uate d f or eli gi bilit y a n d gi ve c o nse nt t o t he 
st u d y.  All patie nts will u n der g o a o ne- wee k was h o ut peri o d wit h o ut a n y N S AI Ds, a n d ha ve a re-
e val uati o n of t heir eli gi bilit y.  Eli gi ble patie nts will be ra n d o mize d t o o ne of f o ur N S AI Ds, eac h 
f or 6 wee ks.  T he patie nts will ha ve a o ne- wee k was h o ut peri o d, a n d be ra n d o mize d t o o ne of t he 
ot her f o ur N S AI Ds.  Base d o n sa m ple size calc ulati o n (see details later), we pla n t o e nr oll 2 4 
patie nts i n t his gr o u p.   
 
Fi g ure . St u dy Overvie w.  Weeks l a bele d i n re d are t he ti me p oi nts f or cli nic al visits; weeks l a bele d i n 
bl ack are ti me p oi nts f or re m ote c ollecti o n of p atie nt re p orte d o utc o mes.   
 
 
0
6
R a n d o miz ati o n  I
1 w e e k
w as h o ut
Dr ug 
- 1
Scr e e ni ng
2
4
1
7
1 3
r a n d o miz ati o n
1 w e e k
w as h o ut
Dr ug 2
Dr ug 1
0
Scr e e ni ng
3
1 9
9
1 1
5
1 5
1 7
Dr ug 3
Dr ug 2
Dr ug 1
Dr ug 3
Gr o u p I
Gr o u p II

 
3  
St u d y p o p ulati o n  St u d y s u bjects will be o ut patie nts w h o are see n at C U M C r he u mat ol o g y cli nic 
wit h a cli nical dia g n osis of A S b y treati n g r he u mat ol o gists, or a dia g n osis of a xial S p A wit h a 
pel vis M RI wit h si g nifica nt b o ne marr o w e de ma o n S TI R se q ue nces.  Ot her i ncl usi o n criteri a 
i ncl u de 1) mi ni m u m of 1 8 years ol d; 2) are ta ki n g N S AI Ds o n a re g ular basis f or A S or S p A 
( defi ne d as m ore t ha n 2 0 da ys i n t he past m o nt h), or ha vi n g acti ve s y m pt o ms t hat re q uire 
i nitiati o n of N S AI Ds; 3) if usi n g a ntir he u matic dr u gs c o nc o mita ntl y, sta ble d ose f or t he past 
t hree m o nt hs; 4) ha ve acti ve disease after i nitial was h o ut peri o d, defi ne d b y B A S D AI > = 4/ 1 0, or 
bac k pai n V A S > = 4/ 1 0.  E xcl usi o n criteria i ncl u de: patie nts w h o ha ve c o nc urre nt r he u matic 
diseases ot her t ha n A S or a xial S p A; patie nts w h o ha ve oral c ortic oster oi d i n t he past t w o wee ks; 
patie nts w h o ha ve ac ute peri p heral art hritis; patie nts wit h hi g h fi br o m yal gia sc ore; patie nts wit h 
e xte nsi ve car diac hist or y, hist or y of gastr oi ntesti nal blee di n g t hat re q uire d bl o o d tra nsf usi o n, 
c hr o nic ki d ne y disease, or pre g na nc y.  Use of l o w d ose of as piri n ( < 1 0 0 m g dail y) is all o we d i n 
t he st u d y.   
St u d y Dr u gs  i n d o met haci n E R 7 5 m g (ca ps ules) t wice a da y ; dicl ofe nac E C  7 5 m g (ta blets) t wice 
a da y; mel o xica m 7. 5 m g (ta blets) t wice a da y; celec o xi b 2 0 0 m g (ca ps ules) t wice a da y. Wit h 
o me praz ole 2 0 m g dail y.   
Assess me nt   All patie nts will ha ve cli nical assess me nts at i nitial scree ni n g visits ( wee k - 1) a n d 
at ra n d o mizati o n ( wee k 0).  I n a d diti o n, f or Sta ge I, cli nical assess me nts ( Fi g ure 1 i n re d) will be 
perf or me d at wee k 6, a n d f or Sta ge II, it will be perf or me d at ti me w he n patie nts s witc h fr o m o ne 
N S AI D t o a n ot her.  Or, patie nts will be assesse d cli nicall y at t he ti me w he n disc o nti n ue t he 
N S AI Ds pre mat urel y d ue t o lac k of efficac y or si de effects.  Pri mar y e n d p oi nts i ncl u de s pi nal 
pai n ( V A S), patie nt gl o bal sc ore ( V A S), B A S D AI, a n d B A S FI.  I n a d diti o n, patie nt gl o bal 
assess me nt of res p o nse t o t hera p y ( P G A R T), b y a 0- 4 Li kert scale, p h ysicia n gl o bal assess me nt, 
A S D A S, C B C, E S R, C R P, a d verse e ve nts will be c ollecte d at eac h cli nic visit.  F or patie nts w h o 
disc o nti n ue d t heir N S AI D bef ore 6 wee ks, reas o ns f or disc o nti n uati o n will be assesse d.  At t he 
e n d of t he st u d y, patie nts will be as ke d t o gi ve a prefere nce of N S AI Ds.   
We will c ollect patie nt re p orte d o utc o mes at wee k 2 a n d wee k 4 of eac h N S AI D 
treat me nt, i ncl u di n g s pi nal pai n ( V A S), patie nt gl o bal sc ore ( V A S), B A S D AI ( 6 q uesti o ns b y 
V A S) a n d B A S FI ( 1 0 q uesti o ns b y V A S).  A li n k t o t he q uesti o n naires will be e maile d t o 
patie nts via Re d Ca p.  B y clic ki n g t he li n k, patie nts will be a ble t o a ns wer t he q uesti o n naires 
usi n g eit her a m o bile de vice or a des kt o p c o m p uter.  If a patie nt d oes n ot res p o n d i n 2 4 h o urs, 
a n ot her e mail wit h li n k t o q uesti o n naires will be se nt as a re mi n der.  After t hree atte m pts, if t here 
is still n o re pl y, t he patie nt will be c o ntacte d via p h o ne t o c ollect t he a ns wers t o q uesti o n naires.  
At t he e n d of t he st u d y, we will s ur ve y t he patie nts t o ha ve a q ualitati ve assess me nt of re m ote 
c ollecti o n.   
2. 2 St u d y Visits  
 
Wee k -1 ~ 0  
(scree n) 
Wee k 0  
(ra n d o mizati o n) 
2 wee ks   
+/ - 2 da ys  
(re m ote) 
4 wee ks   
+/ - 2 da ys  
(re m ote) 
6 wee ks   
+/ - 2 da ys  
(e n d of st u d y) 
 
Visit 1  
Visit 2  
 
 
Visit 3  
Bac k gr o u n d 
Q uesti o n naire  
X 
 
 
 
 
Eli gi bilit y Criteria 
O ver vie w  
X 
X 
 
 
 

 
4  
I nf or me d C o nse nt 
X 
 
 
 
 
Hist or y/ P h ysical E xa m  
X 
X 
 
 
 
B A S D AI  
X 
X 
X 
X 
X 
B A S FI  
X 
X 
X 
X 
X 
Ot her P R Os  
X 
X 
X 
X 
X 
Me dicati o n 
Q uesti o n naires  
X 
X 
 
 
X 
E S R  
 
X 
 
 
X 
C R P  
 
X 
 
 
X 
A d verse E ve nts  
 
 
X 
X 
X 
Bli n de d Treat me nt  
 
X 
X 
X 
X 
Bl o o d c ollecti o n 
 
X 
 
 
X 
St o ol c ollecti o n  
 
X 
 
 
X 
 
Scree ni n g visit  ( Visit 1; Ti me ~ Wee k - 1) 
Le n gt h of visit: A p pr o xi matel y 1 h o ur 
P ote ntial s u bjects will ha ve t he st u d y e x plai ne d t o t he m a n d pr o vi de d t he o p p ort u nit y t o 
as k q uesti o ns a b o ut t he st u d y.  All partici pa nts will pr o vi de writte n i nf or me d c o nse nt.  Eli gi bilit y 
is c o nfir me d t hr o u g h patie nt i nter vie w a n d re vie w of past me dical rec or ds b y t he st u d y 
i n vesti gat ors.  S u bjects will ha ve a me dical hist or y a n d p h ysical e xa mi nati o n.  T he y will 
c o m plete t he Bac k gr o u n d I nf or mati o n, B A S D AI, B A S FI a n d q uesti o n naires f or ot her P R Os f or 
assess me nt of A S acti vit y.  
If patie nt’s A S is n ot acti ve base d o n i ncl usi o n criteria, t he s u bject will e xit t he st u d y.  
T he y w o ul d be eli gi ble f or re-scree ni n g i n t he f ut ure.  Patie nts c o nfir me d t o ha ve acti ve disease 
will be eli gi ble f or t he st u d y, a n d will be as ke d t o n ot ta ki n g a n y N S AI Ds f or 7 da ys, as t he 
i nitial was h - o ut peri o d.  If t he y ha ve n ot ta ke n a n y t y pe of N S AI Ds, t he y are eli gi ble f or Visit 2 
o n t he sa me da y.   
Q uesti o n naires ma y be c o m plete d usi n g pa per f or ms a n d will be tra nsfer t o Re d Ca p, 
w hic h will ser ve as t he st u d y data base.   
R a n d o miz ati o n ( Visit 2; Ti me: Wee k 0) 
Le n gt h of visit: a p pr o xi matel y 1 h o ur 

 
5  
T his visit pr o vi des s u bjects t he o p p ort u nit y t o as k a d diti o nal q uesti o ns a b o ut t he st u d y, 
a n d t he i n vesti gat ors t o c o nfir m o n g oi n g disease acti vit y of s u bjects.  F or t he p ur p oses of 
statistical a nal ysis, t his visit ser ves as t he baseli ne visit.  S u bjects will ha ve a me dical hist or y a n d 
p h ysical e xa mi nati o n.  T he y ha ve a cli nical assess me nt of disease acti vit y t o e ns ure o n g oi n g 
disease acti vit y.  If t he disease is i nacti ve, t he s u bject will e xit t he st u d y.  T he y w o ul d be eli gi ble 
f or re-scree ni n g i n t he f ut ure if t heir treati n g r he u mat ol o gist pla n t o escalate t heir t hera p y. 
S u bjects c o nfir me d wit h acti ve disease will pr ocee d wit h t he f oll o wi n g assess me nts.  
T he y will c o m plete healt h self-assess me nts wit h B A S D AI a n d B A S FI q uesti o n naires, 
Me dicati o n q uesti o n naire, Healt h Stat us q uesti o n naire.  T he B A S D AI q uesti o n naire has 6 
q uesti o ns a n d ta kes 3 mi n utes t o c o m plete.  T he B A S FI q uesti o n naire has 1 0 q uesti o ns a n d ta kes 
5 mi n utes t o c o m plete.  T he Healt h Stat us q uesti o n naire i ncl u des t he H A Q disa bilit y i n de x, wit h 
2 0 q uesti o ns o n p h ysical f u ncti o n, a n d t he S F- 3 6 wit h 3 6 q uesti o ns assessi n g p h ysical a n d 
me ntal healt h.  T he healt h stat us q uesti o n naire ta kes 1 5 mi n utes t o c o m plete.  Fiftee n milliliters 
of ve n o us bl o o d will be dra w n f or testi n g hi g h-se nsiti vit y C R P, se di me ntati o n rate, H L A- B 
alleles, ser u m f or st ora ge f or researc h p ur p oses.  I n s o me patie nts, st o ol will be c ollecte d f or 
f ut ure researc h p ur p oses.   
C o nfir mati o n of disease acti vit y base d B A S D AI or pai n V A S sc ore is nee de d f or s u bjects 
t o recei ve a ra n d o mize d treat me nt assi g n me nt a n d c o nti n ue i n t he st u d y.  Ra n d o mize d treat me nt 
assi g n me nt is ma de, a n d st u d y me dicati o n is dis pe nse d, t o get her wit h a pr ot o n p u m p i n hi bit or, 
f or a t otal of 6- wee k s u p pl y.   
F oll o w- u p E v al u ati o n  ( Re m ote e val uati o n; Ti me: Wee k 2 a n d Wee k 4) 
Le n gt h of c o m pleti n g q uesti o n naires: 2 0 mi n.  
We will c ollect patie nt re p orte d o utc o mes at wee k 2 a n d wee k 4 after starti n g N S AI D 
treat me nt, i ncl u di n g s pi nal pai n ( V A S), patie nt gl o bal sc ore ( V A S), B A S D AI ( 6 q uesti o ns b y 
V A S) a n d B A S FI ( 1 0 q uesti o ns b y V A S), a n d a re vie w of si de effects.  A li n k t o t he 
q uesti o n naires will be e maile d t o patie nts via Re d Ca p.  B y clic ki n g t he li n k, patie nts will be a ble 
t o a ns wer t he q uesti o n naires usi n g eit her a m o bile de vice or a des kt o p c o m p uter.  If a patie nt 
d oes n ot res p o n d i n 2 4 h o urs, a n ot her e mail wit h li n k t o q uesti o n naires will be se nt as a 
re mi n der.  After t hree atte m pts, if t here is still n o re pl y, t he patie nt will be c o ntacte d via p h o ne t o 
c ollect t he a ns wers t o q uesti o n naires.   
Fi n al e v al u ati o n  ( Visit 3, Ti me: Wee k 6) 
Le n gt h of visit: 3 0- 6 0 mi n utes.   
S u bjects will ha ve a me dical hist or y a n d p h ysical e xa mi nati o n.  Disease acti vit y is 
assesse d t hr o u g h p h ysical e xa mi nati o n a n d q uesti o n naires.  T hree milliliters of ve n o us bl o o d will 
be dra w n a n d teste d f or C R P a n d se di me ntati o n rate.  Patie nt will als o be gi ve n q uesti o n naire 
re gar di n g user e x perie nce wit h re m ote c ollecti o n of P R Os.   
2. 3 St u d y Visits ( St a ge II) 
 
T he s pecific ti me f or st u d y visits will be base d o n res ults fr o m Sta ge I.   
2. 4 St u d y Pers o n nel 
S u bjects will be e xa mi ne d b y t he sa me r he u mat ol o gist t hr o u g h o ut t he st u d y.  S u bjects 
will c o nti n ue t o recei ve sta n dar d A S care fr o m t heir r he u mat ol o gist, w h o will ma ke treat me nt 

 
6  
decisi o ns base d o n his or her cli nical j u d g me nt.  T he decisi o n t o c ha n ge t hera p y beca use of 
i ncrease d A S acti vit y or beca use of me dicati o n si de effects will be t he res p o nsi bilit y of t he 
s u bject’s r he u mat ol o gist.  I n s o me cases, t he treati n g r he u mat ol o gist ma y als o be t he st u d y 
i n vesti gat or.  I n cases w here t he st u d y i n vesti gat or is n ot t he treati n g r he u mat ol o gist, pr oce d ures 
f or c o m m u nicati n g a b o ut c ha n ges i n A S acti vit y a n d i n me dicati o n will be esta blis he d s o cli nical 
e val uati o ns a n d wit h dra wal fr o m bli n de d treat me nt (if necessar y) ca n be d o ne e x pe diti o usl y.   
2. 5 Bli n di n g a n d U n b li n di n g 
S u bjects, t heir treati n g r he u mat ol o gists, st u d y i n vesti gat ors will be bli n de d t o treat me nt 
assi g n me nt.  St u d y dr u g is pre pare d b y t he p har macist at C U M C researc h p har mac y w h o is 
u n bli n de d b ut has n o direct i nteracti o n wit h s u bjects.  S u bjects will als o be bli n de d t o t heir 
la b orat or y test res ults. 
E xce pt i n t he e ve nt of a n e mer ge nc y, st u d y dr u g c o des will n ot be a vaila ble t o bli n de d 
pers o n nel u ntil after t he c o ncl usi o n of t he trial d uri n g data a nal ysis.   
U n bli n di n g ma y be re q uire d i n t he e ve nt of a s us pecte d me dicati o n-relate d a d verse e ve nt 
or me dicati o n-relate d c o m plicati o n, s uc h as GI blee di n g.  F or a s u bject w h o bec o mes u n bli n de d 
f or a me dical e mer ge nc y, he or s he will disc o nti n ue st u d y me dicati o n f or t he d urati o n of t he 
st u d y b ut will re mai n i n f oll o w- u p.  All st u d y i n vesti gat ors will be n otifie d of t he u n bli n di n g a n d 
i nf or mati o n re gar di n g t he date, ti me, a n d reas o n f or u n bli n di n g will be d oc u me nte d i n t he case 
re p ort f or m. 
2. 6 R a n d o miz ati o n 
S u bjects will recei ve a u ni q ue i de ntif yi n g n u m ber at st u d y e ntr y.  F or Sta ge 1, t he st u d y 
I D will be N 1 0 1, N 1 0 2, N 1 0 3 …  F or Sta ge 2, t he st u d y I D will be N 2 0 1, N 2 0 2, N 2 0 3 … O nce 
assi g ne d, a s u bject i de ntif yi n g n u m ber ca n n ot be re use d.  At visit 2, e nr olle d s u bjects w h o meet 
eli gi bilit y criteria wit h c o nfir mati o n of o n g oi n g A S acti vit y will recei ve a ra n d o mize d treat me nt 
all ocati o n.  S u bjects are ra n d o mize d i n a 1: 1: 1: 1 rati o t o recei ve o ne of t he f o ur st u d y N S AI Ds 
(celec o xi b, mel o xica m, dicl ofe nac, i n d o met haci n), res pecti vel y.  T he ra n d o mizati o n ta ble will be 
c o m p uter- ge nerate d, a n d will t he n be se nt b y a statisticia n w h o is n ot relate d t o t he st u d y directl y 
t o t he p har mac y de part me nt f or treat me nt all ocati o n.  Ra n d o mizati o n data will be ke pt strictl y 
c o nfi de ntial —accessi ble o nl y t o a ut h orize d pers o ns — u ntil t he ti me of u n bli n di n g. 
4. 7 St u d y E v al u ati o n  
Pri mar y E n d p oi nt: T he pri mar y e n d p oi nt of t he st u d y is t he c ha n ge of pai n sc ore o n vis ual 
a nal o g scale fr o m Wee k 4 t o Wee k 6.  T he n ull h y p ot hesis t hat n o cli nicall y si g nifica nt 
differe nce ca n be detecte d at wee k 4 a n d wee k 6.   
Sec o n dar y E n d p oi nt : T he sec o n dar y e n d p oi nts i ncl u de patie nt gl o bal sc ore ( V A S), B A S D AI, 
a n d B A S FI.  I n a d diti o n, patie nt gl o bal assess me nt of res p o nse t o t hera p y ( P G A R T), b y a 0- 4 
Li kert scale, p h ysicia n gl o bal assess me nt, A S D A S, C B C, E S R, C R P, a d verse e ve nts.   
 
3. I N C L U SI O N A N D E X C L U SI O N C RI T E RI A 
I ncl usi o n Criteri a: 
St u d y s u bjects will be o ut patie nts w h o are see n at C U M C r he u mat ol o g y cli nic wit h: 

 
7  
1.  a cli nical dia g n osis of A S b y treati n g r he u mat ol o gists, or a dia g n osis of a xial S p A wit h a 
pel vis M RI wit h si g nifica nt b o ne marr o w e de ma o n S TI R se q ue nces;  
2.  mi ni m u m of 1 8 years ol d;  
3.  are ta ki n g N S AI Ds o n a re g ular basis f or A S or S p A ( defi ne d as m ore t ha n 2 0 da ys i n t he 
past m o nt h) a n d willi n g t o wit h h ol d me dicati o n f or o ne wee k; or ha vi n g acti ve s y m pt o ms 
t hat re q uire i nitiati o n of N S AI Ds;  
4.  if usi n g a ntir he u matic dr u gs c o nc o mita ntl y, sta ble d ose f or t he past t hree m o nt hs;  
5.  ha ve acti ve disease after i nitial was h o ut peri o d, defi ne d b y B A S D AI > = 4/ 1 0, or bac k 
pai n V A S > = 4/ 1 0.   
E xcl usi o n Criteri a:  
1.  Patie nts w h o ha ve c o nc urre nt r he u matic diseases ot her t ha n A S or a xial S p A;  
2.  Patie nts w h o ha ve oral c ortic oster oi d i n t he past t w o wee ks; patie nts w h o ha ve ac ute 
peri p heral art hritis.   
3.  Patie nts wit h a fi br o m yal gia sc ore > = 1 3.    
4.  Use of l o w d ose of as piri n ( < 1 0 0 m g dail y) is all o we d i n t he st u d y. 
St u d y e ntr y is n ot li mite d b y ge n der or et h nicit y.  C hil dre n are e xcl u de d beca use 
i nfla m mat or y p ol yart hritis de vel o pi n g bef ore a ge 1 6 is c o nsi dere d j u ve nile i di o pat hic art hritis 
a n d n ot A S. 
Partici pa nts will lar gel y be recr uite d fr o m C U M C r he u mat ol o g y cli nic.  T o i de ntif y 
p ote ntial s u bjects, i n vesti gat ors ma y searc h r osters of patie nts i n t he practice f or s u bjects w h o 
meet t he i ncl usi o n criteria.  T he n u m ber of patie nts scree ne d a n d reas o ns f or e xcl usi o n will be 
ta b ulate d.  S u bjects ma y als o be recr uite d b y p h ysicia n referral.  I nf or mati o n a b o ut t he st u d y will 
be maile d t o l ocal r he u mat ol o gists a n d p oste d o n t he C U M C r he u mat ol o g y we bsite.  We d o n ot 
a ntici pate self-referral of s u bjects b ut eli gi ble self-referre d s u bjects will n ot be e xcl u de d. 
Partici pa nts w h o c o m pletes t he st u d y, a n d e x press t heir i nterest t o be e nr olle d f or a 
sec o n d ti me t o tr y a differe nt N S AI Ds w o ul d be all o we d.  H o we ver, o ne partici pa nts ma y n ot 
e nter t he st u d y f or m ore t ha n t w o ti mes.   
 
4. M O NI T O RI N G S U B J E C T S A N D C RI T E RI A F O R WI T H D R A W A L  
S u bjects will be m o nit ore d f or safet y b y t he st u d y i n vesti gat or.  S u bjects will be 
i nter vie we d re gar di n g p ote ntial a d verse e ve nts relate d t o t he st u d y me dicati o n at eac h cli nic visit 
a n d via e maile d q uesti o n naires, a n d will be as ke d t o c o ntact st u d y i n vesti gat ors if a n y 
me dicati o n-relate d a d verse e ve nts occ ur bet wee n st u d y visits.  I n t hese cases, s u bjects will ha ve 
a cli nical assess me nt as i n dicate d b y t he nat ure of t he e ve nt.  S u bjects will be as ke d t o c o ntact 
i n vesti gat or t o re p ort a n y w orse ni n g of art hritis s y m pt o ms d uri n g 6 wee ks of treat me nt.  S u bjects 
will be as ke d t o re p ort a n y misse d me dicati o n d oses a n d reas o ns f or misse d d oses.  
S u bjects will be wit h dra w n fr o m st u d y if t he y 1) w orse ni n g of s y m pt o ms, defi ne d b y 
i ncrease i n pai n V A S b y 1 0/ 1 0 0 m m a n d i ncrease of B A S D AI b y 1/ 1 0 at Wee k 4; or 2) de vel o p 
a d verse e ve nts relate d t o t he st u d y me dicati o n; or 3) if t he y bec o me pre g na nt; 4) t he y de vel o p a 
c o m or bi d ill ness t hat precl u des treat me nt wit h N S AI Ds.   
S u bjects ma y be wit h dra w n fr o m t he st u d y if t he y fail t o c o m pl y wit h st u d y 
re q uire me nts, i ncl u di n g fail ure t o atte n d sc he d ule d f oll o w- u p visits, t o c o nti n ue treat me nt, or t o 

 
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a ns wer e mail q uesti o n naires. Reas o ns t hat a s u bject ma y disc o nti n ue partici pati o n i n t he st u d y 
ma y i ncl u de:  pr ot oc ol vi olati o n, a d verse e ve nt(s), l ost t o f oll o w- u p, c o nse nt wit h dra w n, 
a d mi nistrati ve pr o ble ms, or deat h.  S u bjects ma y als o be wit h dra w n at t he discreti o n of t he 
i n vesti gat ors. 
5. D A T A A N A L Y SI S  
5. 1 St atistic al A n al ysis  
T he st u d y is desi g ne d t o test w het her t he c ha n ge of pai n sc ore fr o m 4 wee ks t o 6 wee ks 
after i nitiati o n of N S AI Ds is cli nicall y i m p orta nt.   
T he pri mar y a nal ysis will be p o ole d res ult fr o m patie nts ra n d o mize d t o differe nt 
N S AI Ds, a n d will be li mite d t o patie nts w h o c o m plete t he 6- wee k st u d y me dicati o ns.  T he st u d y 
is n ot desi g ne d t o c o m pare me dicati o n efficac y.     
5. 2 S a m ple size a n d St atistic al P o wer  
We will test t he n ull h y p ot hesis t hat n o cli nicall y si g nifica nt differe nce ca n be detecte d at 
wee k 4 a n d wee k 6.  F or sa m ple size calc ulati o n, we use paire d t-test t o c o m pare t he c ha n ge of 
pai n sc ore fr o m baseli ne t o 4 wee ks a n d 6 wee ks.  F or a = 0. 0 5, t w o-si de d, b = 0. 2, mi ni mal 
cli nicall y i m p orta nt differe nce f or pai n = 1 7/ 1 0 0 ( 2 0), sta n dar d de viati o n of c ha n ge of pai n sc ore 
2 2- 3 0/ 1 0 0 (esti mates fr o m o ur s yste mic re vie w), t he sa m ple size will be 1 5- 2 6. Gi ve n t he 
c o nsi derati o n t hat 1) patie nts w h o gi ve t he c o nse nts ma y n ot pass t he scree ni n g visits, 2) u na ble 
t o c o m plete t he st u d y d ue t o l oss of f oll o w u p a n d/ or me dicati o n si de effects, we pla n t o recr uit 
4 0 patie nts.  
6. H U M A N S U B J E C T P R O T E C TI O N S  
6. 1 Selecti o n  
All s u bjects will ha ve A S, be a ge 1 8 years or ol der, a n d be acti ve at scree ni n g visit.  
S u bjects wit h o ut a dia g n osis of A S a n d t h ose n ot acti ve will be e xcl u de d.  Pre g na nt w o me n will 
be e xcl u de d d ue t o p ote ntial si de effect.  H u ma n s u bjects m ust be use d f or t his st u d y beca use t he 
q uesti o ns c o ncer n t he treat me nt of A S i n h u ma ns.  Ot her v ul nera ble p o p ulati o ns —t h ose w h o 
ma y be easil y c oerce d (e. g. pris o ners) or u na ble t o pr o vi de i nf or me d c o nse nt — will n ot be 
e nr olle d. 
S u bjects of b ot h ge n ders a n d all et h nic gr o u ps will be eli gi ble t o partici pate.  Base d o n 
t he e pi de mi ol o g y of A S, we a ntici pate t hat a p pr o xi matel y 7 0 % of s u bjects will be me n a n d 3 0 % 
will be w o me n.  We a ntici pate t he distri b uti o n of et h nicities of s u bjects will reflect t he 
distri b uti o n of et h nicities i n t he l ocal c o m m u nit y.  T here will be n o e xcl usi o ns base d o n ge n der 
or et h nicit y. 
6. 2 Be nefits a n d Ris ks  
Be nefits.  S u bjects ma y n ot recei ve a n y direct be nefit fr o m partici pati n g i n t his st u d y.  It is 
p ossi ble t hat s u bjects w h o partici pate a n d res p o n d t o t he st u d y dr u gs a n d ac hie ve re missi o n.  
S u bjects ma y als o be nefit fr o m recei vi n g me dicati o n at n o c har ge d uri n g t he st u d y peri o d.  All 
s u bjects ma y be nefit fr o m k n o wi n g t he y are hel pi n g us u n dersta n d t he ma na ge me nt a n d 
pat h o ge nesis of A S, w hic h ma y hel p us better treat patie nts i n t he f ut ure. 
Ris ks/ Disc o mf orts.  Ris ks t o s u bjects fr o m t he st u d y me dicati o n are n o differe nt fr o m t he ris ks 
t he y ha ve acce pte d w he n a greei n g t o be treate d wit h N S AI Ds.  T hese i ncl u de a n i ncrease d ris k 

 
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of GI blee di n g, hea dac he, he patic a n d/ or re nal t o xicit y, i ncrease of bl o o d press ure.  A ris k 
s pecific t o t his researc h is w orse ni n g of s pi nal s y m pt o ms d uri n g t he was h o ut peri o d ( 1 wee k), or 
n o i m pr o ve me nt o n s pi nal s y m pt o ms wit hi n t he st u d y peri o d ( 6 wee ks).  If a s u bject e x perie nces 
i ncrease d s y m pt o ms of A S 2 wee ks after i nitiati o n of treat me nt, t he y will recei ve pr o m pt 
treat me nt b y his or her r he u mat ol o gist, a n d ma y wit h dra w fr o m t he st u d y.  
Ris ks relate d t o p hle b ot o m y a n d i ntra ve n o us cat heter place me nt i ncl u de te m p orar y pai n 
at t he site, l ocal br uisi n g, a n d l o w pr o ba bilities of i nfecti o n, dizzi ness, a n d fai nti n g.  Sta n dar d 
ase ptic tec h ni q ue will be use d.  P h ysical ris ks relate d t o ra di o gra p h y i ncl u de e x p os ure u p t o 
0. 0 0 1 2 re m, w hic h is less t ha n o ne-t hir d of o ne perce nt of t he a vera ge le vel of nat ural 
bac k gr o u n d ra diati o n e x p os ure t o a U nite d States resi de nt o ver o ne year ( 0. 3 6 re m). 
I nter ve nti o ns. Partici pa nts will c o nti n ue t o recei ve sta n dar d me dical care fr o m t heir 
r he u mat ol o gist a n d/ or pri mar y care p h ysicia n. 
C o nfi de ntialit y a n d Discl os ure.  I nf or mati o n o btai ne d i n t his st u d y will be a vaila ble o nl y t o st u d y 
i n vesti gat ors.  All cli nical data will be st ore d i n l oc ke d ca bi nets a n d i n sec ure d c o m p uter files 
a n d st ora ge me dia.  Re d Ca p will be re g ulate d b y pass w or d pr otecte d access, wit h vie wi n g 
pri vile ges restricte d t o data base a d mi nistrat or a n d t he PI or desi g nees.  C o m p uter files will 
i ncl u de a u ni q ue s u bject i de ntif yi n g n u m ber t o all o w f or c o de d data a nal ysis b y statisticia ns.  
T he ke y li n ki n g s u bjects’ i de ntities wit h t he st u d y n u m ber will be ke pt sec urel y b y t he Pri nci pal 
I n vesti gat or.  All p u blicati o ns a n d re p orts will be base d o n a g gre gate data a n d will n ot c o ntai n 
i de ntif yi n g i nf or mati o n a b o ut i n di vi d ual s u bjects. 
S u bjects will be i nf or me d t hat t heir data a n d sa m ples will be retai ne d f or f ut ure st u dies.  
T he y will als o be i nf or me d of t heir ri g ht t o ha ve t heir bl o o d sa m ples destr o ye d at a n y ti me i n t he 
f ut ure, b ut a n y st u d y data will be retai ne d. 
6. 3 A d verse E ve nt Re p orti n g 
At eac h st u d y visit, safet y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g all 
a d verse e ve nts ( w het her v ol u nteere d b y t he s u bject, disc o vere d b y i n vesti gat or i n q uir y, or 
detecte d t hr o u g h p h ysical e xa mi nati o n, la b orat or y testi n g or ot her mea ns) o n t he a d verse e ve nt 
pa ge of t he case re p ort f or m.  A n a d verse e ve nt is defi ne d as a n y u nfa v ora ble or u ni nte n de d 
dia g n osis, s y m pt o m, si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y n dr o me, or disease 
w hic h occ urs d uri n g t he st u d y, ha vi n g bee n a bse nt at baseli ne, or, if prese nt at baseli ne, a p pears 
t o w orse n.  As m uc h as p ossi ble, eac h a d verse e ve nt will be descri be d b y: ( 1) its d urati o n, ( 2) t he 
se verit y gra de ( mil d, m o derate, se vere), ( 3) its relati o ns hi p t o t he st u d y dr u g (s us pecte d/ n ot 
s us pecte d), a n d ( 4) t he acti o n(s) ta ke n a n d, as rele va nt, t he o utc o me.  All a d verse e ve nts will be 
f oll o we d as a p pr o priate.  E ve nts i n v ol vi n g a d verse dr u g reacti o ns, ill nesses wit h o nset d uri n g t he 
st u d y, or e xacer bati o ns of pre-e xisti n g me dical ill nesses will be rec or de d.  E xacer bati o n of pre-
e xisti n g me dical ill nesses, e xcl u di n g t he disease u n der st u d y, is defi ne d as a cli nical 
ma nifestati o n (s y m pt o ms a n d/ or si g ns) of t he ill ness t hat i n dicates a si g nifica nt i ncrease i n t he 
se verit y of t he ill ness as c o m pare d t o t he se verit y n ote d at t he start of t he trial.  It ma y i ncl u de 
w orse ni n g or i ncrease i n se verit y of s y m pt o ms a n d/ or si g ns of t he ill ness, i ncrease i n fre q ue nc y 
of s y m pt o ms a n d/ or si g ns of a n i nter mitte nt ill ness, or t he a p peara nce of a ne w ma nifestati o n 
a n d/ or c o m plicati o n.   
Seri o us a d verse e ve nts ( S A E) are defi ne d as a n y u nt o war d me dical occ urre nce t hat 
res ults i n deat h, is life-t hreate ni n g ( defi ne d as at i m me diate ris k of deat h i n vie w of t he 

 
1 0  
i n vesti gat ors), re q uires h os pitalizati o n l o n ger t ha n 2 4 h o urs or pr ol o n gs e xisti n g h os pitalizati o n, 
res ults i n per ma ne nt, persiste nt or si g nifica nt disa bilit y/i nca pacit y, res ults i n a c o n ge nital 
a n o mal y or birt h defect, or is a n y ot her c o n diti o n w hic h i n t he j u d g me nt of t he st u d y 
i n vesti gat ors re prese nts a si g nifica nt hazar d.  All st u d y i n vesti gat ors will be n otifie d i m me diatel y 
of a n y S A E.  S A Es at a n y st u d y site will be re p orte d i n writi n g wit hi n 7 da ys t o C U M C I R B i n 
t he case of deat h or life-t hreate ni n g seri o us a d verse e ve nts, a n d wit hi n 1 5 da ys of occ urre nce f or 
all ot her f or ms of S A E.   
E x pecte d, n o n-seri o us a d verse e ve nts relate d t o t he st u d y pr oce d ures will n ot be re p orte d.  
T hese i ncl u de ris ks relate d t o p hle b ot o m y —te m p orar y pai n at t he site of t he nee dle-stic k, l ocal 
br uisi n g, dizzi ness, fai nti n g, a n d l ocal i nfecti o n.  U ne x pecte d, n o n-seri o us a d verse e ve nts 
re prese nt t h ose n ot meeti n g t he criteria f or S A E n ote d a b o ve.  T hese e ve nts, occ urri n g at a n y 
st u d y site, will be i ncl u de d i n t he s u m mar y re p ort of all a d verse e ve nts a n d prese nte d t o t he 
D S M C f or re vie w at sc he d ule d ti mes a n d at t he a n n ual I R B re vie w. 
6. 4 S afet y a n d M o nit ori n g 
T he Pri nci pal I n vesti gat or will ha ve o verall res p o nsi bilit y f or m o nit ori n g scie ntific 
i nte grit y a n d patie nt safet y f or t he f ull d urati o n of t he st u d y.  
W hile t he ris ks a n d safet y c o ncer ns f or t he c urre nt st u d y are s mall t o mi ni mal, t he PI will 
n o net heless meet wee kl y wit h t he researc h c o or di nat or a n d staff i n C U M C R he u mat ol o g y Cli nic 
t o disc uss st u d y accr ual a n d pr o gress, patie nt safet y a n d a d verse e ve nts, a n d data ma na ge me nt 
a n d sec urit y. T hese iss ues will be a d dresse d a n n uall y f or pr ot oc ol re ne wal a n d f or pr o gress 
re p orts re q uire d f or t he I nstit uti o nal Re vie w B oar ds at C U M C. I n t he u nli kel y e ve nt t hat a n 
a d verse e ve nt d uri n g st u d y pr oce d ures were t o occ ur, a n a d verse e ve nt re p ort will be ge nerate d 
a n d c o m plete d b y t he PI f or s u b missi o n t o t he C U M C I nstit uti o nal Re vie w B oar d.  
 
7. R E F E R E N C E S 
1.   War d M M, K uzis S. Me dicati o n t o xicit y a m o n g patie nts wit h a n k yl osi n g s p o n d ylitis. 
Art hritis R he u m. 2 0 0 2 J u n 1 5; 4 7( 3): 2 3 4 – 4 1.   
2 0.  T u bac h F, Ra va u d P, Marti n- M ola E, A wa da H, Bella m y N, B o m bar dier C, et al. Mi ni m u m 
cli nicall y i m p orta nt i m pr o ve me nt a n d patie nt acce pta ble s y m pt o m state i n pai n a n d f u ncti o n 
i n r he u mat oi d art hritis, a n k yl osi n g s p o n d ylitis, c hr o nic bac k pai n, ha n d oste oart hritis, a n d 
hi p a n d k nee oste oart hritis: Res ults fr o m a pr os pecti ve m ulti na. Art hritis Care Res. 2 0 1 2 
N o v; 6 4( 1 1): 1 6 9 9 – 7 0 7.