Clinical trial NCT03473665
Conditions: Ankylosing Spondylitis Axial Spondyloarthritis
Keywords: ankylosing spondylitis spondyloarthritis
Sponsor: Columbia University
Start date: 2018-03-01; Completion date: 2019-08-02
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 6-week randomized, double-blind trial of 4 different non-steroidal anti-inflammatory drugs in patients with axial spondyloarthritis to compare the change of pain score from baseline at 4 weeks to the change of pain score from baseline at 6 weeks.

Detailed description:
Patients with ankylosing spondylitis or axial spondyloarthritis who fulfills the inclusion and exclusion criteria will be randomized into one of the four arms after an initial one week washout period, including: 1) indomethacin 75mg every 12 hours (Q12H); 2) diclofenac 75mg Q12H; 3) meloxicam 7.5mg Q12H; 4) celecoxib 200mg Q12H. The treatment length will be 6 weeks. Primary outcome is the change of pain score from baseline to week 4 and to week 6.

Arms: arm 1: Indomethacin Extended Release Oral Tablet 75mg by mouth, every 12 hours for 6 weeks arm 2: Diclofenac Delayed Release Oral Tablet 75mg by mouth, every 12 hours for 6 weeks arm 3: Meloxicam tablet 7.5mg by mouth, every 12 hours for 6 weeks arm 4: Celecoxib 200mg capsule by mouth, every 12 hours for 6 weeks
Interventions: intervention 1: Indomethacin intervention 2: Diclofenac intervention 3: Meloxicam intervention 4: Celecoxib
Intervention descriptions: intervention 1: Indomethacin Extended Release Oral Tablet 75mg every 12 hours for 6 weeks; omeprazole 20mg daily for 6 weeks intervention 2: Diclofenac Delayed Release Oral Tablet 25mg tablets x 3 tablets every 12 hours for 6 weeks; omeprazole 20mg daily for 6 weeks intervention 3: meloxicam 7.5mg tablets every 12 hours for 6 weeks; omeprazole 20mg daily for 6 weeks intervention 4: Celecoxib 200mg capsule every 12 hours for 6 weeks; omeprazole 20mg daily for 6 weeks

Protocol documents:
Prot_SAP_002.pdf: 
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: 


 
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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.