Clinical trial NCT03500159
Conditions: Chronic Prostatitis Chronic Pelvic Pain Syndrome
Sponsor: Aquinox Pharmaceuticals (Canada) Inc.
Start date: 2018-04-18; Completion date: 2018-07-17
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multi-center, double-blind, parallel-group study, enrolling approximately 100 male subjects diagnosed with CP/CPPS to evaluate the effect of 12-week treatment with AQX-1125 (active drug) compared to placebo.

The subjects will be randomized to receive orally once-daily either AQX-1125 (200 mg) or placebo in a 1:1 ratio across approximately 30 centers in North America (United States and Canada). The study will consist of a screening period of up to 3 weeks, a 12-week treatment period followed by a 4-week off drug safety follow-up period, and an ophthalmic safety follow-up call at 3 months and visit at 6 months post last dose, for a total study duration of about 41 weeks.

Detailed description:

Arms: arm 1: AQX-1125 200 mg arm 2: Matching placebo
Interventions: intervention 1: AQX-1125 200 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Synthetic SHIP1 activator intervention 2: Appearance and weight matched tablets without the active product ingredient

Protocol documents:
Prot_001.pdf: 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 of 8 0
C L I NI C A L S T U D Y P R O T O C O L 
TI T L E P A G E 
Title:  
A 1 2 -W ee k, Ra n d o mize d, M ulti -Ce nter, D o u ble -Bli n d, Place b o -
C o ntr olle d, P arallel -Gr o u p, P hase 2 Trial t o E val uate t he Effi cac y a n d 
Safet y of A Q X -1 1 2 5 ( 2 0 0 m g) i n Male S u bj ects wit h C hr o nic 
Pr ostatitis/ C hr o nic P el vic P ai n S y n dr o me  
Test Pr o d uct:  
A Q X -1 1 2 5  
Pr ot oc ol I de ntific ati o n:  
A Q X -1 1 2 5 -2 0 5  
S p o ns or N a me, A d dress, a n d 
Tele p h o ne N u m b er:  
A q ui n o x P har mace uticals ( Ca na da) I nc.  
S uite 4 5 0 – 8 8 7 Great N ort her n W a y  
Va nc o u ver, B C   
Ca na da, V 5 T 4 T 5  
t: 6 0 4. 6 2 9. 9 2 2 3 
C o m pli a nce St ate me nt:  
T he trial will be c o n d ucte d i n acc or da nce wit h sta n dar ds of G o o d 
Cli nical Practice, as defi ne d b y t he I nter nati o nal C o u ncil f or 
Har m o nisati o n a n d all a p plica ble nati o nal a n d l ocal re g ulati o ns.  
D ate / Versi o n of Pr ot oc ol:  
 0 8 Marc h 2 0 1 8/ V ersi o n 3. 0, A me n d me nt  2 
A q ui n o x P h ar m ace utic als  
( C A N A D A) I nc. M e dic al M o nit or 
Alis o n E. Heal d , M D 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
 
 
 
 
 
Date:  
C o nfi de nti al I nf or m ati o n 
T he i nf or mati o n c o ntai ne d her ei n is c o nfi de ntial a n d ma y n ot be use d, di v ul ge d, p u blis he d, or ot her wise discl ose d 
wit h o ut t he pri or writte n c o ns e nt of A q ui n o x P har mace uticals ( Ca na da) I nc . 
0 8 M ar c h 2 0 1 8


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 of 8 0  
 
P R O T O C O L SI G N A T U R E P A G E  
Pr ot oc ol: A Q X - 1 1 2 5- 2 0 5 
Title:  A 1 2 - Wee k, R a n d o mize d, M ulti-Ce nter, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P a r allel -
Gr o u p, P h ase 2 Tri al t o E v al u ate t he Effic ac y a n d S afet y of A Q X- 1 1 2 5 ( 2 0 0 m g) i n M ale 
S u bjects wit h C hr o nic Pr ost atitis/ C hr o nic Pel vic P ai n S y n dr o me  
 
I n vesti g at or St ate me nt: I h a ve r ecei ve d a n d c o m pletel y re vie w e d t he a b o ve-na m e d pr ot oc ol, 
i ncl u di n g all a p p e n dices a n d a me n d me nts. As I n v esti gat or, I a gree t o c o n d uct t he trial i n 
acc or d a nce wit h all sti p ulati o ns of t he pr ot oc ol a n d i n acc or d a nce wit h t he I nter nati o nal C o u ncil 
f or Har m o nisati o n (I C H) G ui deli nes f or G o o d Cli nical Practices ( G C P), all a p plica ble nati o nal 
a n d l ocal re g ul ati o ns, t he Declar ati o n of Helsi n ki a n d its a me n d me nts. 
I N V E S TI G A T O R SI G N A T U R E A N D C O N T A C T I N F O R M A TI O N 
I n vesti g at or (si g n at ure) 
 
I n vesti g at or (ple ase pri nt ) 
 
D ate of Si g n at ure  
 
I n vesti g at or’s A d dress 
 
Cit y, St ate, C o u ntr y, Zi p C o de  
 
Tele p h o ne N o.  
 
F a x N o.  
 
E m ail  
 
Si g nat ure o n t his pa ge ass ures A q ui n o x  t hat, t o t he best of t he I n vesti gat or’s k n o wle d ge, t he affiliate d I nstit uti o nal 
Re vie w B oar d ( I R B) or I n de pe n de nt  Et hics C o m mittee (I E C) o perates i n acc or da nce wit h a p plica ble l ocal a n d 
nati o nal re g ulati o ns, a n d t hat t he I n vesti gat or u n dersta n ds a n d a grees t o a bi de b y all re g ulat or y o bli gati o ns a n d I C H 
G C P G ui deli nes w hile c o n d ucti n g t his cli nical trial.  
 
O nce si g ne d , t he ori gi nal of t his f or m s h o ul d be detac he d fr o m t he pr ot oc ol a n d ret ur ne d t o t he S p o ns or . 
( Ple ase ret ai n a c o py f or y o ur files) 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 of 8 0  
 
S T U D Y C O N T A C T I N F O R M A TI O N  
Seri o us A d verse E ve nts  a n d Tre at me nt E mer g e nt A d verse E ve nts of S peci al I nterest    
A n y S A E, or treat me nt e mer ge nt a d verse e v e nts of s pecial i nterest  (T E A E SI ) o cc urri n g i n a 
s u bject w hile recei vi n g st u d y dr u g or wit hi n 3 0 da ys of recei vi n g st u d y dr u g, e v e n t h o u g h t he 
e ve nt ma y n ot a p pear t o be st u d y dr u g relate d, m ust be pr o m ptl y re p orte d ( wit hi n 2 4 h o u rs) b y 
tele p h o ne, fa x, or e-m ail t o t he S p o ns or ( or desi g n ee).  
U nless ot her wise i nstr uct e d, S A E a n d T E A E SI re p orts are t o be s u b mitte d b y e m ail or fa x t o:  
C T D S Dr u g Saf et y Ma na ger  
E mail:  A q ui n o x P V G @cli nicaltrial data.c o m  
Fa x:  9 7 8. 4 8 6. 4 0 5 5 
Tel e p h o ne: 9 7 8. 4 8 6. 4 0 2 2 
 
W h o will f or war d a c o p y t o: 
Me dic al M o nit or:  
Alis o n Heal d , M D 
A q ui n o x Me dical M o nit or 
E mail: c o ns ulti n g @alis o n heal d.c o m  
Tele p h o ne: 2 0 6. 4 6 5. 3 9 1 2 
 
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 of 8 0  
 
1  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
Title:  A 1 2 -W ee k, Ra n d o mize d, M ulti -Ce nter, D o u ble -Bli n d, Place b o -C o ntr olle d, P arallel -Gr o u p, P hase 2 Trial  
t o E val uate t he Efficac y a n d S afet y of A Q X-1 1 2 5 ( 2 0 0 m g) i n Male S u bj ects wit h C hr o nic Pr ostatitis/ C hr o nic 
P el vic P ai n S y n dr o me  
De vel o p me nt P h ase:  2 
O bjecti ves:  
Pri m ary O bjective  
T he pri mar y o bj ecti ve of t his st u d y is t o e val uate t he effect of 1 2 wee k s of treat me nt wit h A Q X -1 1 2 5 ( 2 0 0  m g) 
a d mi nistere d orall y o nce -dail y c o m pare d t o place b o o n t he c ha n ge fr o m B aseli ne  (Visit  2) t o W ee k  1 2 ( Visit  4) i n 
ma xi m u m dail y pel vic pai n ( mea n) i n male s u bj ects wit h n o n -bacterial c hr o nic pr ostatitis/c hr o nic pel vic pa i n 
s y n dr o me ( C P/ C P P S) usi n g a sta n dar dize d 1 1-p oi nt N u meri cal Rati n g Scale ( N R S) pai n s c ore rec or de d dail y b y 
a n electr o nic diar y (e D iar y). 
Sec o n d ary O bjectives  
T he sec o n dar y o bj ecti ves of t his st u d y are t o e val uate:  
•  T he effects of 1 2 w ee ks of tre at me nt wit h A Q X-1 1 2 5 ( 2 0 0 m g) a d mi nistere d orall y o nce -dail y c o m pare d 
t o place b o o n t he c ha n ge fr o m B aseli ne  (Visit  2) t o W ee k 1 2 ( Visit  4) f or eac h of t he f oll o wi n g:  
o  
Nati o nal I nstit utes of Healt h C hr o nic Pr ostatitis S y m pt o m I n de x ( NI H -C P SI) pai n s u bscale a n d all 
d o mai ns t otal sc ore  
o  
Male se x ual healt h as meas ure d usi n g t he I nter nati o nal I n de x of Erectile F u ncti o n Q uesti o n naire, 
Erectile F u ncti o n D o mai n (II E F -E F)  
o  
A vera ge dail y pel vic pai n (e D iar y), a vera ge a n d ma xi m u m p el vic pai n ( P a per -base d  N R S,  i n cli nic), 
usi n g t he sta n dar dize d 1 1-p oi nt N R S  
o  
2 4 -h o ur v oi di n g  fre q ue nc y (e Diar y)  
•  Ti me c o urse of effects: A Q X -1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o o n t he c ha n ge fr o m B as eli ne  (Visit  2) at 
W ee k  6 ( Visit  3), W ee k  1 2 ( Visit  4), a n d W ee k  1 6 ( i.e. 4 w e e ks after e n d of treat me nt) f or eac h of t he pai n 
a n d s y m pt o m scale e n d p oi nts  
•  T he o verall res p o nse t o treat me nt f or A Q X -1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o as meas ur e d b y t he 
s u bj ect’s Gl o bal Res p o nse Assess me nt ( G R A), P atie nt’s Gl o bal I m pressi o n of C ha n ge sc ale ( P GI-C) a n d 
P atie nt’s Gl o bal I m pressi o n of Se verit y scale  ( P GI-S)  at W ee k  1 2 ( Visit  4)  
•  T he pr o p orti o n of s u bj ects wit h ≥3 0 % a n d ≥5 0 % i m pr o ve me nt i n ma xi m u m dail y pel vic pai n ( mea n) usi n g 
t he sta n dar dize d 1 1 -p oi nt N R S rec or de d b y t he e Diar y a n d t he NI H-C P SI pai n s u bscale c o m pare d t o 
place b o, at W ee k s 6 ( Visit 3) a n d 1 2  ( Visit 4) 
•  Res p o n der a nal ysis: r es p o nse t o treat me nt defi ne d b y a n y of t he f oll o wi n g:  
o  
Decrease i n ma xi m u m dail y p el vic pai n fr o m B aseli ne t o W ee k 1 2 (e Diar y) wit h n o c ha n ge i n t he 
a m o u nt or stre n gt h of c o nc o mita nt a na l gesic me dicati o ns 
o  
Decrease i n ma xi m u m dail y p el vic pai n fr o m B aseli ne t o W ee k 1 2 (e Diar y) wit h a decrease i n t he 
a m o u nt or stre n gt h of c o nc o mita nt a nal gesic me dicati o ns  
•  Disc o nti n uati o n of st u d y me di cati o n  d ue t o treat me nt fail ure ( % meeti n g treat me nt fail ure criteria a n d ti me 
t o e ve nt) 
S afety O bjectives  
T he safet y o bj ecti ves of t his st u d y are t o e val uate:  
•  Safet y a n d t olera bilit y of A Q X -1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o d uri n g t he 1 2 - wee k tr eat me nt peri o d 
•  Oc ular safet y base d u p o n assess me nt of le ntic ular o pacificati o n usi n g Le ns O paci ficati o n Classificati o n 
S yste m  ( L O C S) III, best c orrecte d vis ual ac uit y  ( B C V A) usi n g t he L o garit h m of t he Mi ni m u m A n gle of 
Res ol uti o n ( L o g M A R) c hart, intra oc ular p ress ure (I O P), c or neal stai ni n g, a n d slit la m p e xa mi nati o n  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 of 8 0  
 
N a me of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
M et h o d ol o g y:  
I n t his d o u ble-bli n d, place b o -c o ntr olle d st u d y, a p pr o xi matel y 1 0 0 male s u bj ects dia g n ose d wit h C P/ C P P S will be 
ra n d o mize d t o eit her A Q X-1 1 2 5 ( 2 0 0 m g) or place b o i n a 1: 1 rati o acr oss a p pr o xi matel y  3 0  ce nters i n N ort h 
A merica. T he st u d y will c o nsist of a scree ni n g peri o d of u p t o 3 w ee ks, a 1 2- wee k treat me nt peri o d f oll o we d b y a 
4- w ee k Off-Treat me nt Safet y F oll o w -u p peri o d, a n d a n O p ht hal mic Safet y F oll o w -u p Visit  6 m o nt hs p ost last 
d ose, f or a t otal st u d y d urati o n of a b o ut 4 1 w ee k s. T here will als o be a f oll o w -u p tele p h o ne call 3  m o nt h s after 
t he last d ose.  
At Scree ni n g Visit  1, eac h s u bj ect will  c o m plete a set of q uesti o n naires , a n d recei ve (a n d be trai ne d t o use) a n 
e Diar y. S u bj ects will rec or d t heir a vera ge a n d ma xi m u m dail y pel vic pai n sc ore, at a p pr o xi matel y t he sa me ti me 
eac h da y (i n t he e ve ni n g  pri or t o t he last d ose of pai n me d icati o n), as well as t heir dail y use of a nal gesic pai n 
me dicati o ns. B aseli ne  o p ht hal mic assess me nts, i ncl u di n g le ntic ular o pacificati o n assess me nt usi n g L O C S III , ca n 
be c o m plete d as a se parate visit a n y ti me d uri n g t he scree ni n g peri o d (a n y ti me bef ore Visit 2) . 
At B aseli ne  (Visit  2), all s u bj ects will ret ur n t o t he cli nic f or re vie w of eli gi bilit y  a n d t o c o m plete t he efficac y 
q uesti o n naires a n d assess me nts t o esta blis h B aseli ne  val ues . A vera ge dail y pel vic pai n sc ores rec or de d i n t he 
e Diar y wit hi n t he  7 da ys pri or t o B aseli ne  (Visit  2) will be part of t he st u d y e ntr y criteria.  If all e ntr y criteria are 
met, t he s u bj ect will be ra n d o mize d ( 1: 1) t o recei ve a si n gle dail y oral d ose of 2 ta blets f or 1 2 wee ks as f oll o ws:  
•  A Q X -1 1 2 5 2 0 0 m g d ose gr o u p: 2 A Q X -1 1 2 5 1 0 0 m g ta blets ; or,  
•  Place b o  gr o u p: 2 place b o ta blets  
All e nr olle d s u bj ects will rec or d t he f oll o wi n g i n t he e Diar y (fr o m Scree ni n g Visit  1 t o  W ee k 1 6 [ Off -Treat me nt 
Safet y F oll o w -u p Visit ]): 
•  Ma xi m u m dail y pel vic pai n : su bj ects will assess t heir ma xi m u m pel vic pai n f or t hat da y o n a scale of 0 t o 
1 0, wit h 0 i n dicati n g ‘ n o pel vi c pai n’ a n d 1 0 i n dicati n g ‘ pel vic pai n as ba d as y o u ca n i ma gi ne ’ 
•  A vera ge dail y pel vic pai n. S u bj ects will assess t heir a vera ge pel vic pai n f or t hat da y o n a s cale of 0 t o 1 0, 
wit h 0 i n dicati n g ' n o pel vic pai n' a n d 1 0 i n dicati n g ' pel vic pai n as ba d as y o u ca n i ma gi ne'  
•  A nal gesic me dicati o n ta ke n eac h da y  
•  2 4 -h o ur v oi di n g  fre q ue nc y: voi di n g fre q ue nc y will be meas ure d o ver a 2 4 -h o ur peri o d, wit hi n a 3 -da y 
( 7 2-h o urs) wi n d o w bef ore t he ne xt sc he d ule d v isit (Visit 2, 3,  4 a n d Off -Treat me nt Safet y F oll o w - u p 
Visit ) 
At W ee k  6 ( Visit  3) , a n d W ee k  1 2  (Visit  4) , a n d W ee k 1 6 (Off -Treat me nt Safet y F oll o w -u p Visit ) d uri n g t he  
cli nic visit,  s u bj ects will c o m plete NI H-C P SI, pa per -base d 1 1 -p oi nt N R S  (a vera ge a n d ma xi m u m pel vic pai n 
e x perie nce d o ver t he last 2 4 h o urs ), G R A,  P H Q -9,  P GI -C, II E F, P GI -S, ha ve vital si g ns assesse d a n d ret ur n 
u n use d st u d y dr u g  ( W ee k 6 a n d  1 2) . An y  a d verse e ve nts ( A Es) are t o be rec or de d. 
S u bj ect c o m plia nce wit h t he e D iar y will be m o nit ore d b y trai ne d st u d y site pers o n nel at ea c h st u d y visit. 
All s u bj ects c o m pleti n g t he 1 2 w ee ks of treat me nt (Visit  4) will be c o nsi dere d c o m pleters of treat me nt. S u bj ects 
w h o wit h dra w fr o m t he st u d y d uri n g t he treat me nt peri o d s h o ul d c o m plete a n Earl y T er mi nati o n Visit . Su bj ects 
w h o disc o nti n ue t he d o u ble -bli n d treat me nt f or a n y reas o n will be e nc o ura ge d t o c o nti n ue wit h all s u bse q ue nt 
st u d y-relate d visits a n d e val uati o ns, wit h e m p hasis o n o btai ni n g pel vic pai n data, a nal gesic  me dicati o n data a n d 
v oi di n g  fre q ue nc y data t o assess efficac y e n d p oi nts. S u bj ects w h o c o m plete t he st u d y or earl y ter mi nate d uri n g 
t he st u d y will be as ke d t o ret ur n f or t he Safet y F oll o w-u p Visit  4 wee ks after disc o nti n ui n g st u d y dr u g, a n d t he 
O p ht hal mic Safet y F oll o w -u p Visit  6 m o n t hs after t he last d ose. S u bj ects will als o be c o nt acte d via tele p h o ne f or 
t he foll o w -u p tele p h o ne call 3  m o nt hs after t heir last d ose.  
N u m ber of S u bjects:  
A p pr o xi matel y 1 0 0 male s u bj ects  at a p pr o xi matel y 3 0 sites i n N ort h A merica . 
Di a g n osis a n d M ai n Cri teri a f or I ncl usi o n: 
I ncl usi o n Criteri a  
F or i ncl usi o n i nt o t he scree ni n g peri o d s u bj ects m ust meet t he f oll o wi n g criteria:  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 6 of 8 0  
 
N a me of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
1.  Pr o vi de writte n i nf or me d c o ns e nt a n d t he willi n g ness a n d a bilit y t o c o m pl y wit h all as pects of t he st u d y 
re q uire me nts 
2.  Males, ≥1 8 a n d  ≤8 0 years of a ge at Scree ni n g Visit  1 
3.  Ha ve pai n or disc o mf ort i n t he pel vic re gi o n f or at least 3 m o nt hs i n t he last 6 m o nt hs, i n t he a bse nce of 
a uri nar y tract i nfecti o n  or ot her pel vic/ ur ol o gical ca use, a n d ha ve a p h ysicia n dia g n osis of C P/ C P P S 
( NI H Pr ostatitis Cate g or y III)  
4.  NI H -C P SI of ≥1 5 o n t he t otal sc ore  
5.  S u bj ects m ust a gree t o use a c o n d o m f or se x ual i nterc o urse fr o m Scree ni n g Visit  1 u ntil at least 9 0  da ys 
after t he last d ose of st u d y dr u g, u nless t he y ha ve bee n s ur gi call y sterilize d ( vasect o m y) f or a mi ni m u m 
of 6 m o nt hs . Tr ue a bsti ne nce fr o m se x ual i nterc o urse i n acc or da nce wit h t he preferre d a n d us ual 
lifest yle of t he s u bj ect is als o acce pta ble  
6.  Ha ve  a n a vera ge dail y pel vic pai n sc ore of ≥4 o ut of 1 0 o n t he 1 1 -p oi nt N R S pai n scale ( mea n of t he 
a vera ge dail y pel vic pai n sc ore rec or de d at eac h of t he 7 da ys pri or t o B aseli ne  [Visit  2]). A mi ni m u m of 
5 dail y rec or ds wit hi n 7 da ys pri or t o B aseli ne  (Visit  2) m ust be rec or de d  
7.  M ust be ca pa ble of v oi di n g i n de pe n de ntl y f or 3 0 da ys pri or t o scree ni n g (t o  all o w c o m pleti o n of 2 4 -h o ur 
v oi di n g diar y)  
E xcl usi o n Criteri a  
S u bj ects meeti n g a n y of t he f oll o wi n g criteria are i neli gi ble f or trial:  
1.  Dia g n osis of N I H Pr ostatitis C ate g ories I (ac ute pr ostatitis) or II ( c hr o nic bacterial ) p r ostatitis 
2.  Dia g n osis of i nterstitial c ystitis/ bla d der pai n s y n dr o me (I C/ B P S) wit h s y m pt o ms of pai n, press ure, or 
disc o mf ort percei ve d t o be relate d t o  t he bla d der, a n d ass ociate d l o wer uri nar y s y m pt o ms f or > 6 wee ks 
i n t he a bse nce of i nfecti o n or ot her i de ntifia ble ca uses 
3.  Relief o f pel vic  pai n after v oi di n g or ha ve > 1 5 v oi ds per da y  
4.  P ost -v oi d resi d ual v ol u me > 1 5 0 m L  
5.  Ha ve ha d a n u nres ol ve d ( p ositi ve bacterial uri ne c ult ure) uri nar y tract i nfecti o n  wit hi n 8 wee ks 
(i ncl usi ve) pri or t o Scree ni n g Visit  1 (s u bj ects ca n rescree n [ u p t o 1 ti me] o nce i nfecti o n clears) 
6.  Hist or y of pre vi o us pr ostate or bla d der i nter ve nti o n ( i.e. pr ostate bi o ps y , c yst osc o p y, or i n d welli n g 
uri nar y cat heter ) wit hi n 1 m o nt h of Scree ni n g Visit  1, hist or y of micr o wa ve t hera p y, tra ns uret hral 
resecti o n of t he pr ostate, tra ns uret hral ra di ofre q ue nc y t her m ot hera p y, tra ns uret hral i ncisi o n of t he 
pr ostate, tra ns uret hral nee dle a blati o n, tra ns uret hral laser va p orizati o n of t he pr ostate, Ur olift ® , Rez u m, 
a n d ot her ur ol o gical i nter ve nti o ns  (e. g., b ot uli n u m t o xi n) wit hi n 6 m o nt hs of Scree ni n g Visit  1 
7.  U nilateral testic ular or scr otal pai n as t he s ole s y m pt o m of C P/ C P P S  
8.  O n g oi n g, s y m pt o matic uret hral strict ure disease  
9.  Catastr o p hizi n g pai n sc ore of  ≥3 0 as deter mi ne d b y t he P ai n Catastr o p hizi n g Scale  ( P C S) 
1 0.  C urre nt maj or de pre ssi ve dis or der (i.e. P atie nt Healt h Q uesti o n naire - 9 [ P H Q-9]  sc ore ≥1 0)  
1 1.  Ne ur ol o gic disease or dis or der affecti n g t he bla d der, a bilit y t o v oi d s p o nta ne o usl y, or directl y 
c o ntri b uti n g t o uri nar y s y m pt o ms ( e. g., m ulti ple scler osis, a ut o n o mic ne ur o pat h y)  
1 2.  Se vere, e xcr uciati n g pai n d uri n g rectal e xa m ( i.e. a n “i na bilit y t o perf or m t he e xa m”)  
1 3.  Hist or y of c hr o nic s u bsta nce a b use, de pe n de nc y or a b use of o pi oi d s, or ot her narc otics wit hi n t he last 
2 years  
1 4.  C urre ntl y recei vi n g, or e x pect t o recei ve, a n y of t he f oll o wi n g pr o hi bite d me dicati o ns or pr oce d ures: 
•  N o n -ster oi d al a nti-i nfl a m m at or y dr u g or ot her me dic ati o n (e. g. al p h a -bl oc kers) f or C P/ C P P S, 
u nless o n a sta ble d ose f or ≥3 0 da ys pri or t o Scree ni n g Visit  1 
•  L o n g -acti n g o pi oi d s: wit hi n 2 wee ks pri or t o B aseli n e ( Visit 2) or e x pecte d t o ta ke a n y l o n g -acti n g 
o pi oi ds  at a n y ti me d uri n g t he st u d y  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 7 of 8 0  
 
N a me of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
•  S h ort -acti n g o pi oi d  or o pi oi d -c o nt ai ni n g a n al gesic s: mor e t ha n 1 0  d oses/ m o nt h , or m or e t ha n a 
si n gle d ose > 2 da ys per wee k, or a n y s h ort-acti n g o pi oi d wit hi n 3 da ys pri or t o ra n d o mizati o n  
•  Or al ster oi d t her a p y, i m m u n os u p press a nts / i m m u n o m o d ul at ors  (i ncl u di n g dail y 
p h os p h o diesterase T y pe 4 i n hi bit ors) wit hi n 3 0 da ys pri or t o Scree ni n g Visit  1 a n d t hr o u g h o ut t he 
st u d y 
•  Ha ve ta ke n a n y i n vesti g ati o n al dr u g or de vice wit hi n  9 0 da ys pri or t o Scree ni n g Visit  1, or ha ve ha d 
pre vi o us e x p os ure t o A Q X -1 1 2 5  
1 5.  A n y p ri or hist or y of pel vic ca ncer (e. g., c ol orectal, ge nit o uri nar y) or treat me nt (ra diati o n or 
c he m ot hera p y) t here of  
1 6.  Maj or s ur ger y wit hi n 3 m o nt hs pri or t o Scree ni n g Visit  1 
1 7.  Ha ve a n y ot her c o n diti o n/ dise ase w hic h, i n t he o pi ni o n of t he I n vesti gat or, c o ul d c o m pr o mise s u bj ect 
safet y or i nterfere wit h t he s u bj ect’s partici pati o n i n t he st u d y or i n t he e val uati o n of t he st u d y res ults.  I n 
case of a n y d o u bt, t he I n vesti gat or s hall c o ns ult t he m e dical m o nit or.  
1 8.  K n o w n i nt olera nce t o micr o -cr ystalli ne cell ul ose ( A vicel ®  P H -1 0 2), ma n nit ol or ot her i n gr e die nt of  
A Q X -1 1 2 5 ta blets  
Test Pr o d uct, D ose a n d M o de of A d mi nistr ati o n:  
T w o A Q X -1 1 2 5 ( acti vat or of t he Src h o m ol o g y 2-c o ntai ni n g  i n osit ol-5' -p h os p hatase 1  pr otei n) 1 0 0  m g ta blets 
will be a d mi nistere d orall y o nce dail y  wit h a glass of water , ar o u n d t he sa me ti me of da y, f or 1 2 wee ks. T a blets 
s h o ul d be ta ke n wit h f o o d or eat a li g ht meal no m ore t ha n 4 h o urs pri or t o c o ns u m pti o n . 
Refere nce T her a p y, D ose a n d D ur ati o n of A d mi nistr ati o n:  
Matc hi n g place b o is i de ntical i n a p peara nce t o t he test pr o d uct a n d c o ntai ns n o acti ve i n gre die nt.  T w o place b o 
ta blets will be a d mi nistere d orall y o nce dail y wit h a glass of water , ar o u n d t he sa me ti me of da y, f or 1 2 wee k s. 
T a blets s h o ul d be ta ke n wit h f o o d or eat a li g ht meal n o m or e t ha n 4 h o urs pri or t o c o ns u m pti o n . 
D ur ati o n of Tre at me nt:  
S u bj ects will partici pate i n a 1 2 -wee k, d o u ble -bli n d treat me nt p hase. After t he treat me nt p hase, t here will be a 
4- wee k p ost last d ose Safet y F oll o w -u p, as well as a 6 -m o nt h p ost last d ose O p ht hal mic S afet y F oll o w -u p.  T here 
will als o be a 3- m o nt h p ost last d ose T ele p h o ne Call F oll o w -u p . 
V ari a bles:  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is t he  c ha n ge fr o m B aseli ne ( Visit 2) t o W ee k 1 2 ( Visit 4) i n t he ma xi m u m dail y pel vic 
pai n ( mea n)  usi n g a sta n dar dize d 1 1 -p oi nt N R S pai n sc ore rec or de d dail y b y  a n e Diar y. 
Sec o n d ar y E n d p oi nts  
T he sec o n dar y e n d p oi nts are : 
•  T he c ha n ge fr o m B aseli ne  t o W ee k 1 2 f or eac h of t he f oll o wi n g: 
o  
NI H -C P SI pai n s u bscale a n d all d o mai ns t otal sc ore  
o  
Male se x ual healt h  as meas ure d usi n g t he II E F-E F  
o  
Mea n of a vera ge d ail y pel vic p ai n sc ores (e Diar y), a vera ge a n d ma xi m u m pel vic pai n ( P a per -base d 
N R S i n cli nic) 
o  
2 4 - ho ur  v oi di n g  fre q ue nc y (e Diar y) 
•  Ti me c o urse of effects:  A Q X -1 1 2 5 ( 2 0 0 m g o nce -dail y ) c o m pare d t o place b o o n t he c ha n ge fr o m B aseli ne 
( Visit 2) t o W ee k 6 ( Visit 3), W ee k 1 2 ( Visit 4), a n d W ee k 1 6  (i.e. 4 wee ks after e n d of tr eat me nt) f or eac h 
of t he f oll o wi n g:  
o  
Mea n of ma xi m u m dail y pel vi c pai n  sc ore (e Diar y)  
o  
NI H -C P SI pai n s u bscale a n d all d o mai ns t otal s c ore 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 8 of 8 0  
N a me  of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
o
II E F-E F
o
Mea n of a vera ge d ail y pel vic p ai n sc ores (eDiar y ), a vera ge a n d ma xi m u m pel vic pai n ( P a per -base d
N R S i n cli nic)
o
2 4- h o u r v oi di n g  fre q ue nc y (e Diar y)
•
R es p o nse t o treat me nt  c o m pare d t o place b o as meas ure d b y t he G R A, P GI - C, a n d P GI - S at W ee k 1 2  ( Visit
4)
•
A ≥3 0 %  an d ≥5 0 % i m pr o ve me nt i n ma xi m u m dail y pel vic p ai n ( usi n g t he 1 1 -p oi nt N R S rec or de d b y
e Diar y a n d t he NI H -C P SI pai n s u bscale) c o m pare d t o place b o, at W ee k 6  ( Visit 3) a n d Wee k 1 2 ( Visit 4)
•
Res p o n der a nal ysis: Res p o nse t o treat me nt defi ne d b y a n y of t he f oll o wi n g:
o
Decrease i n ma xi m u m dail y p el vic pai n fr o m B aseli ne t o W ee k 1 2 (e Diar y) wit h n o c ha n ge i n t he
a m o u nt or stre n gt h of c o nc o mita nt a nal gesic me dicati o ns
o
Decrease i n ma xi m u m dail y p el vic pai n fr o m B aseli ne t o W ee k 1 2 (e Diar y) wit h a decrease i n t he
a m o u nt or stre n gt h of c o nc o mita nt a nal gesic me dicati o ns
•
Disc o nti n uati o n of  st u d y me di cati o n d ue t o treat me nt fail ure ( % meeti n g treat me nt fail ure criteria a n d ti me
t o e ve nt)
S afet y E n d p oi nts  
T he safet y e n d p oi nts are : 
•
T he fre q ue nc y a n d se verit y of A Es will be re p orte d f or t he treat me nt p hase a n d will i ncl u d e:
o
A b n or mal, cli nicall y si g nifica nt vital si g ns, la b orat or y tests, electr ocar di o gra m ( E C G), wei g ht or
fin di n gs o n p h ysical e xa mi nati o ns
o
O p ht hal mic safet y  base d u p o n assess me nt of le ntic ular o pacificati o n usi n g L O C S III,  B C V A usi n g t he
L o g Mar c hart , I O P, c or neal stai ni n g a n d slit la m p e xa mi nati o n at B aseli ne , 1 2 w ee ks, a n d 6 m o nt hs
p ost last  d ose , a n d at Earl y T er mi nati o n ( E T ).
St atistic al M et h o ds:  
T his st u d y will i n vesti gate t he c o m parati ve treat me nt effect of A Q X -1 1 2 5  vers us place b o i n s u bj ects wit h 
C P/ C P P S . T he statistical a nal ysis will use i nfere ntial met h o ds (P  val ues) a n d esti mati o n ( p oi nt esti mates wit h 
c o nfi de nce i nter vals) t o e val uate t he effect of A Q X -1 1 2 5 c o m pare d t o place b o. T his st u d y is p o were d t o 
de m o nstrate a statisticall y si g nifica nt effect of A Q X -1 1 2 5  vers us place b o ( P  < 0. 0 5) i n t he pri mar y e n d p oi nt , if 
t he treat me nt effect is s ufficie ntl y lar ge. If a statisticall y si g nifica nt res ult is n ot o btai ne d b ut t he esti mate d effect 
pre dicts a statisticall y si g nific a nt effect i n a lar ger, s u bse q ue nt st u d y c o m pari n g A Q X -1 1 2 5  t o place b o, t his st u d y 
will be c o ns i dere d a s uccess. 
S a m ple Size a n d P o w er  
Sa m ple size was calc ulate d usi n g t he 2- sa m ple mea ns state me nt i n t he P O W E R pr oce d ure i n S A S. A sa m ple size 
of 4 5  s u bj ects per treat me nt gr o u p will pr o vi de  8 0 % p o wer t o detect a 1. 2 -p oi nt differe nce i n t he c ha n ge fr o m 
B aseli ne  ma xi m u m pel vic pai n sc ore bet wee n A Q X -1 1 2 5 a n d place b o ass u mi n g a bet wee n -s u bj ect sta n dar d 
de viati o n  of 2. 0 a n d a 2 -si de d 5 % si g nifica nce le vel.  
Ass u mi n g a 1 0 % rate of disc o nti n uati o n fr o m st u d y dr u g, t he t otal n u m ber of s u bj ects t o be ra n d o mize d is 
a p pr o xi matel y 1 0 0 . S u bj ects w h o disc o nti n ue will be i ncl u de d i n t he pri mar y a nal ysis, res ulti n g i n a sli g ht 
decrease i n p o wer if t he disc o nti n ui n g s u bj ects i n t he place b o gr o u p ha ve n o a d diti o nal c ha n ge after 
disc o n ti n uati o n of st u d y dr u g w hile t he disc o nti n ui n g s u bj ects i n t he A Q X -1 1 2 5 gr o u p ha ve a l oss of efficac y 
after disc o nti n ui n g st u d y dr u g.  
A n al ysis  
S u bject  pel vic  pai n  as assesse d by  the 1 1 - poi nt N R S  (e Diar y) will  be s u m marize d  at eac h we e k d uri n g t he  st u d y. 
A n al yses in t he  we e k pri or  to t he  Wee k  6 Visit , Wee k 12  Visit a n d Wee k 16  Visit ( Off-T reat me nt Safet y F oll o w -
U p)  will  be  pro d uce d wit h  mea n,  me dia n,  sta n dar d de viati o n, a n d q uartiles  for  b oth  pel vic  pai n  sc ore a n d  the 
c ha n ge fr o m  ba seli ne in pel vic  pai n  sc ore, usi n g th e mea n  of t he ma xi m u m  obser ve d  val ue fr o m  eac h of th e 7 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 9 of 8 0  
N a me  of S p o ns or/ C o m p a n y: A q ui n o x P har mace uticals ( Ca na da) I nc.  
N a me of Pr o d uct:  A Q X -1 1 2 5  
N a me of Acti ve I n gre die nt:  A Q X -1 1 2 5  
da ys  pri or t o eac h visit (B aseli ne , W ee k  6 , W ee k  1 2  a n d Wee k 1 6 ). T his  will  be rep orte d f or  ma xi m u m dail y 
pel vic  pai n  sc ore a n d  si milarl y f or a vera ge dail y  pel vi c pai n  sc ore. T he  pro p orti o n  of su bjects  w h o res p o n d t o 
treat me nt at Wee k  6, Wee k  1 2 a n d at Wee k 16  will  be s u m marize d.  Use of c onc o mita nt  a nal gesic me dicati o n 
will b e s u m marize d  wit h  the perce nta g e ( %) of  s u bjects ta ki n g eac h class of  me dicati o n  ( per mitte d sh ort -acti n g 
o pi oi d -c o ntai ni n g a nal gesics an d  n o n -o pi oi d  co ntai ni n g  anal gesics: e. g., aceta mi n o p he n)  an d  the dail y  dose 
( mea n, me dia n,  sta n dar d de viati o n, a n d quartiles,  usi n g  s u bjects w h o  to o k a n y s uc h me dicati o n o n at  least 1 of t he 
7 da ys  pri or to t he  B a seli ne, Wee k  6, Wee k  1 2 or  Wee k 1 6 Visit ). 
Ot her sec o n dar y e n d p oi nts will be s u m marize d at B aseli ne , W ee k  6, W ee k  1 2 , a n d W ee k  1 6, i ncl u di n g o bser ve d 
val ues at eac h ti me p oi nt a n d c ha n ge fr o m B aseli ne  at p ost- baseli ne ti me p oi nts, wit h mea n, me dia n, sta n dar d 
de viati o n , a n d q uartiles f or c o nti n u o us data , a n d c o u nts a n d perce nta ges f or cate g orical a n d bi nar y data.  
C o m paris o n of A Q X -1 1 2 5  t o place b o at W ee k  1 2 f or t he pri mar y efficac y e n d p oi nt will us e re peate d meas ures 
a nal ysis of varia nce t o c o m pare c ha n ge fr o m B aseli ne  i n ma xi m u m pai n sc ore ( N R S sc ore ) ( de pe n de nt varia ble) 
bet wee n treat me nt ar ms ( A Q X -1 1 2 5 a n d place b o). B aseli ne ma xi m u m pai n sc ore ( N R S s c ore ) will be i ncl u de d i n 
t he m o del as a c o variate. C ha n ge fr o m B aseli ne  t o W ee k  6 a n d W ee k  1 2 will be i ncl u de d  i n t he a nal ysis. A P  
val ue less t ha n or e q ual t o 0. 0 5 f or t he c ha n ge fr o m B aseli ne  at W ee k  1 2 will be c o nsi dere d statisticall y 
si g nifica nt. All ra n d o mize d s u bj ects will be i ncl u de d i n t he pri mar y a nal ysis.  
C o m paris o n of A Q X -1 1 2 5  t o place b o f or pr o p orti o n of s u bj ects w h o are res p o n ders will be use d t o f urt her 
u n dersta n d t he effect of A Q X -1 1 2 5  o n pel vic pai n. P  val ues f or t he test of e q ual n u m bers of res p o n ders i n eac h 
gr o u p will be re p orte d, wit h o ut a dj ust me nt f or m ulti plicit y, a n d use d descri pti vel y.  
Ot her sec o n dar y e n d p oi nts will be teste d i n a n a nal o g o us pr oce d ure, wit h P  val ues use d f or descri pti ve p ur p oses 
rat her t ha n f or statistical i nfere nce. 
Safet y data will be s u m marize d wit h n o i nfere ntial a nal ysis pla n ne d. A Es a n d treat me nt-e mer ge nt A Es ( T E A E) 
will be s u m marize d b y S yste m O r ga n C lass ( S O C) a n d Preferre d T er m ( P T) wit h c o u nts b y treat me nt gr o u p. 
O p ht hal m ol o gical fi n di n gs will be liste d a n d s u m marize d.  
D ate of t he S y n o psis:  0 8 Marc h 2 0 1 8  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
 
P a ge 1 0  of 8 0  
 
 
 
 
 
 
Fi g ure 1. A Q X -1 1 2 5 -2 0 5 st u d y desi g n fl o w c h art  
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
 
P a ge 1 1  of 8 0  
 
 
 
 
T a ble 1 . A Q X -1 1 2 5 -2 0 5 Sc he d ule of E ve nts  
E ve nt  
Scree ni n g  Peri o d a 
B aseli ne  Tre at me nt P eri o d 
E T j 
S afet y F oll o w -u p  
Assess me nt  
Visit 1  
B aseli ne  O pt h al.  
Visit 1 a  
Visit 2  
Visit 3  
Visit 4  
Off -
T re at me nt  
Tele p h o ne 
c all k  
O p ht h al mic k  
Wee k  
 
 
1  
6  
1 2  
N A  
1 6  
2 5  
3 8  
D a y ( ± wi n d o w)  
-1 4  ( ±7)  
B ef ore Visit 2  
1  
4 2 ( ± 3)  
8 4 ( ±3)  
N A  
1 1 2 ( ±3)  
1 7 5 ( ±7)  
2 6 6 ( ± 7) 
I nf or me d co nse nt  
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n criteria 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n  
 
 
 
 
 
 
 
 
 
De m o gra p hics b 
 
 
 
 
 
 
 
 
 
Me dical/ S ur gical h ist or y 
 
 
 
 
 
 
 
 
 
P h ysical e xa mi nati o n  
 
 
 
 
 
 
 m  
 
 
U P OI N T classificati o n  
 
 
 
 
 
 
 
 
 
NI H -C P SI c  
 
 
 
 
 
 
 
 
 
P a per -base d 1 1 -p oi nt N R S c, d 
 
 
 
 
 
 
 
 
 
P C S c 
 
 
 
 
 
 
 
 
 
P H Q -9  c 
 
 
  
 n 
 n 
 n 
 n 
 
 
G R A c 
 
 
 
 
 
 
 
 
 
P GI -C c 
 
 
 
 
 
 
 
 
 
II E F, P GI-S c 
 
 
 
 
 
 
 
 
 
O p ht hal mic assess me nts e 
 
 
 
 
 
 
 m  
 
 
1 2 -lea d s u pi ne E C Gf 
 
 
 
 
 
 
 m  
 
 
Vital si g ns ( H R, B P , te m perat ure) 
 
 
 
 
 
 
 
 
 
Hei g ht  
 
 
 
 
 
 
 
 
 
W ei g ht  
 
 
 
 
 
 
 
 
 
Cli nical c he mistr y, g he mat ol o g y, uri nal ysis  
 
 
 
 
 
 
m  
 
 
Uri ne: bacterial c ult ure & se nsiti vit y, le u k oc yte 
esterase test  
 
 
 
 
 
 
 
 
 
2 4 -h o ur v oi di n g fre q ue nc y h 
 
 
 
 
 
 
 
 
 
A E c ollecti o n  
 
 
 
 
 
 
 
l 
l 
C o nc o mita nt me dicati o ns  
 
 
 
 
 
 
 
 
 
St u d y  dr u g dis pe nsi n g i 
 
 
 
 
 
 
 
 
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
 
P a ge 1 2  of 8 0  
 
 
 
 
E ve nt  
Scree ni n g  Peri o d a 
B aseli ne  Tre at me nt P eri o d 
E T j 
S afet y F oll o w -u p  
Assess me nt  
Visit 1  
B aseli ne  O pt h al.  
Visit 1 a  
Visit 2  
Visit 3  
Visit 4  
Off -
T re at me nt  
Tele p h o ne 
c all k  
O p ht h al mic k  
Wee k 
 
 
1 
6 
1 2  
N A  
1 6  
2 5  
3 8  
D a y ( ± wi n d o w)  
-1 4  ( ±7)  
B ef ore Visit 2  
1  
4 2 ( ± 3)  
8 4 ( ±3)  
N A  
1 1 2 ( ±3)  
1 7 5 ( ±7)  
2 6 6 ( ± 7) 
St u d y dr u g c o m plia nce c hec k  
 
 
 
 
 
 
 
 
 
St u d y dr u g acc o u nta bilit y  
 
 
 
 
 
 
 
 
 
e Diar y Iss ue/ Trai n/ Re vie w/ C ollect  
I/ T 
 
R  
R  
R  
R  
R/ C  
 
 
A b bre vi ati o ns: A E =a d verse e ve nt; B C V A = best c orrecte d  vis ual ac uit y ; B P = bl o o d press ure; C =c ollect; E C G =electr ocar di o gra m; e Diar y =electr o nic di ar y; 
E T = Earl y T er mi nati o n; G R A = Gl o bal Res p o nse Assess me nt; H R = heart rate; I =iss ue; II E F  =I nter nati o nal I n de x of Erectile F u ncti o n; I O P =i ntra oc ular press ure; 
L O C S =  Le ns O pacit y Classifi cati o n S yste m ; L o g M A R = L o garit h m of t he Mi ni m u m A n gle of Res ol uti o n ; N A = n ot a p plic a ble; NI H -C P SI = Nati o nal I nstit ute of 
Healt h C hr o nic Pr ostatitis S y n dr o me I n de x; N R S = N u merical Rati n g Scale; P C S = P ai n Cat astr o p hizi n g Scale; P GI -C = P atie nt’s Gl o bal I m pr essi o n of C ha n ge 
scale; P GI-S = P atie nt’s Gl o bal I m pressi o n of Se verit y scale; P H Q -9 = P atie nt Healt h Q uesti o n naire; R =re vie w; T =trai n; U P OI N T = Uri nar y, Ps yc h os ocial, Or ga n 
S pecific, I nfecti o n, Ne ur ol o gi c/ S yste mic, T e n der ness of S keletal M uscles.  
a  
Mi ni m u m scree ni n g peri o d is 7 da ys , w hic h i ncl u des t he bas eli ne o p ht h al mic assess me nt at Visit 1a.  
b 
De m o gra p hics i ncl u de a ge, birt h year, se x, race a n d et h nicit y . 
c 
Q uesti o n naires m ust be c o m plete d pri or t o ot her assess me nts . 
d 
P a per -base d 1 1 -p oi nt N R S will be a d mi ni stere d i n-cli nic d uri n g t he st u d y visit  t o assess t he a vera ge a n d ma xi m u m dail y pel vic pai n .  
e 
O p ht hal mic assess me nts i ncl u de B C V A  usi n g t he L o g M A R c hart  (i.e. after ma nifest refracti o n), I O P ( prefera bl y meas ure d b y G ol d ma nn t on o metr y , bef ore 
a n d after dilati o n wit h m y driatic a ge nt) c or neal stai ni n g, slit la m p e xa mi nati o n , a n d le ntic ular o pacificati o n usi n g L O C S III. B aseli ne o p ht hal m ol o g y 
assess me nt ca n be c o m plete d as a se parate visit a n y ti me d uri n g t he scree ni n g peri o d (a n y ti me bef o re Visit 2). B ac k gr o u n d i nci de nce of cataracts i n s u bj ects 
n ote d pri or t o d osi n g s h o ul d be rec or de d as me dical hist or y.  O p ht hal mic assess me nts at all p ost -B aseli ne Visits s h o ul d oc c ur wit hi n t he s pecifie d Visit 
wi n d o ws.  
f 
S u bj ects will be resti n g s u pi ne f o r at least 5 mi n utes bef ore t he E C G rec or di n g. 
g 
Cli nical c he mistr y d oes n ot ne e d t o be fasti n g . 
h 
V oi di n g fre q ue nc y will be me as ure d o ver a 2 4 -h o ur peri o d, wit hi n a 3 -da y ( 7 2 h o urs) wi n d o w bef ore t he sc he d ule d visits . 
i 
T he first d ose of st u d y dr u g at B a seli ne (Visit  2) will be a d mi nistere d i n t he cli nic. At s u bs e q ue nt Visit s, s u bj ects are t o refrai n fr o m ta ki n g st u d y dr u g at 
h o me o n t he m or ni n g of t he cli nic visit  da y a n d s h o ul d be d ose d i n t he cli nic.  
j 
If a s u bj ect wit h dra ws fr o m t he st u d y, all assess me nts f or t he E T Visit  s h o ul d be c o n d ucte d. 
k 
S u bj ects w h o wit h dra w fr o m t he st u d y a n yti me d uri n g t he st u d y will ha ve a f oll o w -u p peri o d of 6 m o nt hs, c o nsisti n g of a n Off - Treat me nt S afet y F oll o w -u p 
V isit ( 4 wee ks p ost last d ose), tele p h o ne call f oll o w-u p  ( 3 m o nt hs p ost last d ose) a n d o p ht hal mic assess me nt ( 6 m o nt hs p ost last d ose) .  
l 
S u bj ects will be as ke d f or u p dates o n ne w a n d o n g oi n g (after t he 2 8 da ys f oll o w -u p) oc ular A Es o nl y . 
m  
Re peat at O ff- Treat me nt Safet y F oll o w-u p is o nl y nee de d if t here are o utsta n di n g safet y c o ncer ns fr o m W ee k  1 2 . 
n 
Sc ore will n ot be rec or de d i n t he data base , assess me nt will be perf or me d f or patie nt safet y/ m o nit ori n g p ur p oses o nl y cli nicall y si g nifica nt fi n di n gs will be 
re p orte d as a d verse e ve nts.  
N O T E: U nsc he d ule d visits ma y be c o n d ucte d at a n y ti me d uri n g t he st u d y a n d ma y  i ncl u d e t he sa me assess me nts as W ee k 1 2. 


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 3  of 8 0
 
 
 
2  
T A B L E O F C O N T E N T S  
TI T L E P A G E  .................................................................................................................................. 1 
P R O T O C O L SI G N A T U R E P A G E  ................................................................................................ 2 
S T U D Y C O N T A C T I N F O R M A TI O N  .......................................................................................... 3 
1  
S Y N O P SI S  .............................................................................................................................. 4 
2  
T A B L E O F C O N T E N T S  ...................................................................................................... 1 3 
3  
LI S T O F A B B R E VI A TI O N S A N D T E R M S ........................................................................ 1 8 
4  
I N T R O D U C TI O N ................................................................................................................. 2 0 
4. 1  
Bac k gr o u n d of Disease  ............................................................................................... 2 0 
4. 2  
Rati o nale f or Use of t he Pr o d uct ................................................................................. 2 0  
4. 2. 1  
N o ncli nical St u dies  ...................................................................................... 2 1 
4. 2. 2  
Cli nical E x perie nce  ...................................................................................... 2 3 
4. 2. 2. 1  Healt h y V ol u nteer St u dies  ............................................................ 2 3 
4. 2. 2. 2  Ast h ma St u d y  ................................................................................ 2 4 
4. 2. 2. 3  I nterstitial C ystitis/ Bla d der Pai n S y n dr o m e, C hr o nic O bstr ucti ve 
P ul m o nar y Disease, a n d At o pic Der matitis St u dies  ..................... 2 4 
5  
T RI A L O BJ E C TI V E S  ........................................................................................................... 2 5 
5. 1  
Pri mar y O bj ecti ve  ....................................................................................................... 2 5 
5. 2  
Sec o n dar y O bj ecti ves .................................................................................................. 2 5 
5. 3  
Safet y O bjecti ves  ........................................................................................................ 2 6 
6  
I N V E S TI G A TI O N A L P L A N ................................................................................................ 2 6 
6. 1  
O v erall Trial D esi g n a n d Pla n: Descri pti o n  ................................................................ 2 6 
6. 2  
Disc ussi o n of Trial Desi g n I n cl u di n g t he C h oice of C o ntr ol Gr o u p .......................... 2 8  
7  
S E L E C TI O N O F S U BJ E C T S  ............................................................................................... 2 8 
7. 1  
I n cl usi o n Criteria ........................................................................................................ 2 8 
7. 2  
E x cl usi o n Criteria ....................................................................................................... 2 8 
7. 3  
Criteria f or I n di vi d ual S u bject Disc o nti n uati o n of St u d y Dr u g .................................. 2 9  
7. 4  
Criteria f or I n di vi d ual S u bject Wit h dra wal fr o m t h e Trial  ......................................... 3 0 
8  
T R E A T M E N T S  ..................................................................................................................... 3 0 
8. 1  
A Q X - 1 1 2 5 Ta bl et Dr u g Pr o d uct ................................................................................. 3 0 
8. 2  
Place b o Ta blet Dr u g Pr o d uct  ...................................................................................... 3 0 
8. 3  
St u d y Dr u g  A d mi nistrati o n  ......................................................................................... 3 0 


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 4  of 8 0
 
 
 
8. 4  
Ra n d o mizati o n ............................................................................................................ 3 1  
8. 5  
St u d y Dr u g Bli n di n g  ................................................................................................... 3 2 
8. 6  
St u d y Dr u g Pac k a gi n g  ................................................................................................ 3 2 
8. 7  
St u d y Dr u g La b elli n g  .................................................................................................. 3 3 
8. 8  
St u d y Dr u g St ora ge  ..................................................................................................... 3 3 
8. 9  
St u d y Dr u g H a n dli n g a n d Acc o u nta bilit y................................................................... 3 3  
8. 1 0  Treat me nt a n d El ectr o nic Diar y C o m plia nce  ............................................................. 3 3 
8. 1 1  C o nc o mita nt Me dicati o ns ........................................................................................... 3 3  
8. 1 1. 1  
Per mitte d Me dicati o ns  ................................................................................. 3 3 
8. 1 1. 2  
Pr o hi bite d Me dicati o ns ................................................................................ 3 4  
9  
S T U D Y A S S E S S M E N T S  ..................................................................................................... 3 4 
9. 1  
Eli gi bilit y O nl y Assess m e nts  ...................................................................................... 3 4 
9. 1. 1  
De m o gra p hics, Bas eli ne C haracteristics, Me dical/ S ur gical Hist or y  ........... 3 4 
9. 1. 2  
Uri nar y, Ps yc h os ocial, Or ga n S pecific, I nfecti o n, Ne ur ol o gic/ S yste mic, 
Te n der n ess of S keletal M uscles Dia g n osis  .................................................. 3 4 
9. 1. 3  
Pai n Catastr o p hizi n g Scale  .......................................................................... 3 5 
9. 1. 4  
Patie nt Healt h Q uesti o n naire 9 -Q u esti o n  ..................................................... 3 5 
9. 1. 5  
Uri ne: Bacteri al C ult ure & Se nsiti vit y, Le u k o c yt e Esterase T est  ................ 3 5 
9. 2  
Efficac y Assess me nts .................................................................................................. 3 5 
9. 2. 1  
1 1- p oi nt N u merical Rati n g Scal e  ................................................................. 3 5 
9. 2. 2  
Nati o nal I nstit utes of Healt h, C hr o nic Pr ostatitis S y m pt o m I n d e x .............. 3 6 
9. 2. 3  
I nter nati o nal I n d e x of Erectile F u n cti o n Q uesti o n naire ............................... 3 6 
9. 2. 4  
Gl o bal Res p o nse Assess me nt ...................................................................... 3 6  
9. 2. 5  
Patie nt’s Gl o bal I m pressi o n of C ha n ge Scale .............................................. 3 6  
9. 2. 6  
Patie nt’s Gl o bal I m pressi o n of Se verit y Scale ............................................. 3 6 
9. 2. 7  
T we nt y -f o ur H o ur V oi di n g Fre q u e nc y ........................................................ 3 6 
9. 3  
Safet y Assess me nts  ..................................................................................................... 3 7 
9. 3. 1  
P h ysical E x a mi nati o n, Vital Si g ns  ............................................................... 3 7 
9. 3. 2  
O p ht hal mic Assess me nts  ............................................................................. 3 7 
9. 3. 3  
1 2- lea d S u pi ne Electr o car di o gra m ............................................................... 3 7 
9. 3. 4  
Cli nical C he mistr y & H e mat ol o g y/ Uri nal ysis  ............................................. 3 7 
9. 3. 5  
A d verse E v e nt Defi niti o ns/ Re p orti n g Re q uire me nts................................... 3 8  


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 5  of 8 0
 
 
 
9. 3. 5. 1  E x pecte d E ve nts  ............................................................................ 3 9 
9. 3. 5. 2  S us pecte d A d vers e Reacti o n  ......................................................... 3 9 
9. 3. 5. 3  A d verse Reacti o n  .......................................................................... 3 9 
9. 3. 5. 4  Seri o us A d verse E v e nt D efi niti o ns / Re p orti n g Re q uire me nts..... 3 9  
9. 3. 5. 4. 1  Seri o us A d verse E v e nt or Seri o us S us pecte d A d v erse 
Rea cti o n ...................................................................... 3 9 
9. 3. 5. 4. 2  Seri o us U ne x pecte d a n d S us pecte d A d vers e Reacti o n  4 0 
9. 3. 5. 5  O p ht hal mic E ve nt Re p orti n g ........................................................ 4 0  
9. 3. 5. 6  Rec or di n g A d verse E ve nts ............................................................ 4 1  
9. 3. 5. 7  Deter mi ni n g R elati o ns hi p of A d vers e E ve nts t o St u d y Dr u g ....... 4 2  
9. 3. 5. 8  Re p orti n g D eat hs a n d Ot her Seri o us A d verse E ve nts .................. 4 2  
9. 3. 5. 8. 1  E ve nts t o Be Re p ort e d a n d Ti mefra me  ....................... 4 2 
9. 3. 5. 8. 2  G o ver ni n g Re g ulat or y R e q uire me nts ......................... 4 2  
9. 3. 5. 9  I nitial I nf or mati o n Pr o vi de d b y t h e I n vesti gat or .......................... 4 3 
9. 3. 5. 1 0  F oll o w- u p I nf or mati o n  .................................................................. 4 4 
9. 3. 5. 1 1  Seri o us A d verse E v e nt a n d Seri o us a n d U ne x pect e d S us pecte d 
A d verse Reacti o n Re vie w a n d P ote ntial I m p act o n Trial C o n d uct
 ...................................................................................................... 4 4 
9. 4  
Ti mi n g of Assess me nts  ............................................................................................... 4 4 
9. 4. 1  
Scree ni n g Peri o d  .......................................................................................... 4 4 
9. 4. 1. 1  Visit 1  ............................................................................................ 4 4 
9. 4. 1. 2  Baseli ne O p ht hal mic Testi n g ( Visit 1a)  ........................................ 4 5 
9. 4. 2  
Baseli ne ( Visit 2)  ......................................................................................... 4 5 
9. 4. 3  
Treat me nt Peri o d  .......................................................................................... 4 6 
9. 4. 3. 1  Visit 3  ............................................................................................ 4 6 
9. 4. 3. 2  Visit 4  ............................................................................................ 4 6 
9. 4. 4  
Earl y Ter mi nati o n  ........................................................................................ 4 7 
9. 4. 5  
Safet y F oll o w - u p .......................................................................................... 4 7 
9. 4. 5. 1  Off -Treat me nt Safet y F oll o w - u p .................................................. 4 7 
9. 4. 5. 2  Tele p h o ne Call  .............................................................................. 4 8 
9. 4. 5. 3  O p ht hal mic  .................................................................................... 4 8 
9. 4. 5. 4  U nsc he d ule d Visit ......................................................................... 4 8  
1 0  S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S  .............................................. 4 8 
1 0. 1  Ge ner al C o nsi derati o ns ............................................................................................... 4 8  
1 0. 2  Sa m ple Size Deter mi nati o n ......................................................................................... 4 9 


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 6  of 8 0
 
 
 
1 0. 3  St u d y P o p ulati o ns ....................................................................................................... 4 9  
1 0. 4  Statistical A nal yses  ..................................................................................................... 4 9 
1 0. 4. 1  
S u bject Acc o u nta bilit y, De m o gra p hics, a n d Baseli ne C haracteristics ........ 4 9  
1 0. 4. 2  
Efficac y Data  ............................................................................................... 4 9 
1 0. 4. 2. 1  Wee kl y Sc ores base d o n Dail y Ass ess me nts  ................................ 5 0 
1 0. 4. 2. 2  Pri mar y Efficac y E n d p oi nt ........................................................... 5 0  
1 0. 4. 2. 3  Pri mar y Efficac y E n d p oi nt A nal ysis ............................................ 5 0  
1 0. 4. 2. 4  Sec o n dar y Efficac y E n d p oi nts ...................................................... 5 0  
1 0. 4. 2. 5  Sec o n dar y Efficac y E n d p oi nts A nal yses ...................................... 5 1  
1 0. 4. 2. 6  C o ntr ol f or M ulti plicit y ................................................................. 5 2 
1 0. 4. 2. 7  I nteri m a nal yses ............................................................................ 5 2 
1 0. 4. 3  
Safet y Data  ................................................................................................... 5 2 
1 1  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .................................................... 5 3 
1 2  D O C U M E N T A TI O N A N D I N S P E C TI O N S  ........................................................................ 5 3 
1 2. 1  St u d y M o nit ori n g ........................................................................................................ 5 3  
1 2. 2  A u dits a n d I ns p ecti o ns ................................................................................................ 5 4  
1 3  E T HI C A L A N D L E G A L I S S U E S  ........................................................................................ 5 4 
1 3. 1  Et hical C o n d uct/ G o o d Cli nical Practice  ..................................................................... 5 4 
1 3. 2  I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee....................................... 5 4 
1 3. 3  Writte n I nf or m e d C o nse nt .......................................................................................... 5 4  
1 3. 4  Rec or ds a n d Cas e Re p ort F or ms ................................................................................. 5 5  
1 3. 5  Pr ot oc ol De viati o ns ..................................................................................................... 5 5  
1 3. 6  Ter mi nati o n of t he St u d y ............................................................................................ 5 5  
1 3. 7  Rete nti o n of Rec or ds................................................................................................... 5 5  
1 4  I N V E S TI G A T O R R E S P O N SI BI LI TI E S .............................................................................. 5 6 
1 5  R E F E R E N C E S  ...................................................................................................................... 5 8 
1 6  A P P E N DI C E S  ....................................................................................................................... 5 9 
A p pe n di x 1. Pa i n Catastr o p hizi n g Scale ............................................................................... 5 9 
A p pe n di x 2. Patie nt Healt h Q uesti o n naire 9- It e ms ............................................................... 6 1 
A p pe n di x 3. 1 1- p oi nt N u merical Rati n g Scale  ..................................................................... 6 4 
A p pe n di x 4. Nati o nal I nstit utes of Healt h C hr o nic Pr ostatitis S y m pt o m I n d e x ................... 6 6  
A p pe n di x 5. I nter n ati o nal I n de x of Erectile F u n cti o n Q uesti o n naire ................................... 6 8  
A p pe n di x 6. Gl o bal Res p o nse Assess me nt ........................................................................... 7 5  


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 7  of 8 0
 
 
 
A p pe n di x 7. Patie nt’s Gl o bal I m pressi o n of C ha n ge Scale .................................................. 7 7  
A p pe n di x 8. Patie nt’s Gl o bal I m pressi o n of Se verit y Scale ................................................. 7 9  
 
LI S T O F T A B L E S  
Ta ble 1. A Q X- 1 1 2 5- 2 0 5 Sc he d ule of E ve nts ............................................................................... 1 1  
Ta ble 2. A Q X- 1 1 2 5 Safet y acr oss P hase 2 Tri als (at Least 6 Wee ks of D osi n g) ......................... 2 5  
Ta ble 3. St u d y Dr u g D osi n g ......................................................................................................... 3 1  
Ta ble 4. Cli nical La b orat or y T ests  ................................................................................................ 3 8 
 
LI S T O F  FI G U R E S  
Fi g ure 1. A Q X- 1 1 2 5- 2 0 5 st u d y desi g n fl o w c hart ........................................................................ 1 0  
Fi g ure 2. T a blet pac k a gi n g  ........................................................................................................... 3 2 
 


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 8  of 8 0
 
 
 
3  
LI S T O F A B B R E VI A TI O N S A N D T E R M S  
A b bre vi ati o n  
Defi niti o n  
A D  
At o pic d er matitis  
A E  
A d verse e v e nt  
A N C O V A  
A n al ysis of C o varia n ce  
A L T  
Ala ni n e a mi n otra nsferase  
A P  
Al kali n e p h os p h atase  
A S T  
As p artate a mi n otra nsferase  
A U C  
Are a u n d er t h e c ur ve  
B C V A 
Best C orrecte d Vis u al Ac uit y  
B C R P 
Breast ca n cer resista n ce pr otei n  
B P 
Bl o o d press ure  
C 
C ollect  
C F R 
C o d e of Fe d eral Re g ulati o ns  
CI 
C o nfi d e n ce i nter val  
C ma x  
Ma xi m u m c o n ce ntrati o n  
C M H 
C o c hra n -Ma ntel -Hae nszel  
C P/ C P P S  
C hr o nic Pr ostatitis/ C hr o nic P el vic P ai n S y n dr o me  
C O P D  
C hr o nic o bstr u cti ve p ul m o n ar y disease  
C P K 
Creati n e p h os p h o ki n ase  
C R F 
Case Re p ort F or m  
D L  
Lact ati o n d a ys  
E C G 
Electr o car di o gra m  
e C R F 
Electr o nic Case Re p ort F or m  
e Diar y 
Electr o nic diar y  
E T  
Earl y Ter mi n ati o n  
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  
GI  
Gastr oi ntesti n al  
G G T  
Ga m ma gl uta m yl tra ns p e pti d ase 
G R A  
Gl o b al Res p o nse Assess me nt  
H R  
Heart rate  
I 
Iss u e 
I B 
I n vesti gat or’s Br o c h ure 
I C/ B P S 
I nterstitial c ystitis / bla d d er p ai n s y n dr o me 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter n ati o n al C o u n cil o n Har m o nisati o n, f or merl y calle d t h e I nter n ati o n al C o nfere n ce o n Har m o nisati o n 
I E C 
I nd e p e n d e nt  Et hics C o m mittee  
II E F 
I nter n ati o n al I n d e x of Erectile F u n cti o n Q u esti o n n aire 
II E F-E F  
I nter n ati o n al I n d e x of Erectile F u n cti o n Q u esti o n n aire, Erectile F u n cti o n D o main 
I N D 
I n vesti gati o n al Ne w Dr u g 
I O P 
I ntra o c ular press ure 


A q ui n o x P har mace uticals ( Ca na da ) I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 1 9  of 8 0
 
 
 
A b bre vi ati o n  
Defi niti o n  
I R B 
I nstit uti o n al Re vie w B o ar d 
I T T 
I nte nt-t o-Treat  
I V 
I ntra ve n o us 
I W R S 
I nteracti ve We b Res p o nse S yst e m 
L A R  
Late ast h matic res p o nse  
L D H  
Lact ate d e h y dr o ge n ase  
L o g M A R  
L o garit h m of t h e Mi ni m u m A n gl e of Res ol uti o n  
L O C S  
Le ns O p aci ficati o n Classificati o n S yst e m  
Me d D R A  
Me dical Dicti o n ar y f or Re g ulat or y Acti vities  
M M R M  
Mi xe d m o d el re p eate d meas ures  
N A  
N ot a p plica ble  
NI H - C P SI 
Nati o n al I nstit utes of Healt h  C hr o nic Pr ostatitis S y m pt o m I n d e x  
N O A E L  
N o o bser ve d a d verse effe ct le vel 
N R S  
N u meric al Rati n g Scale  
P C S  
P ai n Catastr o p hizi n g Scale  
P GI - C 
P atie nt’s Gl o b al I m pressi o n of C h a n ge scale  
P GI - S 
P atie nt’s Gl o b al I m pressi o n of Se verit y  scal e 
P- g p  
P er mea bilit y gl yc o pr otei n  
P H Q - 9 
P atie nt Healt h Q u esti o n n aire - 9 
P P  
P er Pr ot o c ol  
P T  
Preferre d ter m  
Q A  
Q u alit y Ass ura n ce  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a n al ysis pla n  
S HI P 1  
Src h o m ol o g y 2 -c o ntai ni n g i n osit ol -5' -p h os p h atase 1  
S O C  
S yst e m Or g a n Class  
S U S A R  
S us p ecte d U n e x p ecte d A d verse R eacti o ns  
t1/ 2 
Ter mi n al eli mi n ati o n h alf -life 
T E A E  
Treat me nt e mer g e nt a d verse e v e nt  
T E A E SI  
Treat me nt e mer g e nt a d verse e v e nt of s p ecial i nterest  
T ma x  
Ti me t o reac h ma xi m u m c o nce ntrati o n  
U P OI N T  
Uri n ar y, Ps yc h os o cial, Or ga n S p ecific, I nfe cti o n, Ne ur ol o gic/ S yste mic, Te n d er n ess of S keletal M uscles  
U S  
U nite d State s 
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 0  of 8 0  
 
4  
I N T R O D U C TI O N 
A q ui n o x P har mace uticals ( Ca na da) I nc. ( A q ui n o x) is e val uati n g A Q X - 1 1 2 5, a n oral, s mall- 
m olec ule, a nti -i nfla m mat or y a ge nt f or t h e treat me nt of C hr o nic Pr ostatitis/ C hr o nic Pel vic Pai n 
S y n dr o me ( C P/ C P P S ) a n d other i nfla m mat or y dis eases.  
4. 1  
B ac k gr o u n d of Dise ase 
C hr o nic n o n bacteri al pr ostatitis (als o k n o w n as c hr o nic pel vic pai n s y n dr o me, C P/ C P P S) is a 
c o m m o n male ge nit o uri nar y c o n diti o n t hat ca us es pai n a n d i nfla m mati o n i n t he pr ostate, pel vis, 
a n d t he l o wer uri nar y tr act  (H ar v ar d P ers p e cti v es o n Pr ost at e Dis e as e, 2 0 1 7; R o d di c k et al ., 
2 0 1 7 ). T he pr e d o mi na nt s y m pt o m of C P/ C P P S is pai n i n t he s u pra p u bic area, peri n e u m a n d 
pe nis b ut ca n als o occ ur i n t he testes, l o wer bac k or gr oi n. Pai n o n ejac ulati o n is o ne of t he m ost 
pr o mi ne nt a n d b ot hers o me s y m pt o ms i n ma n y p atie nts. V oi di n g s y m pt o ms s uc h as ur ge nc y, 
fre q ue n c y a n d p o or i nterr u pte d uri nar y fl o w are c o m m o n al o n g wit h se x ual d ysf u n cti o n (Ni c k el, 
2 0 1 7 ). 
Of t he 3 cat e g ories of s y m pt o matic pr ostatitis defi ne d b y t he Nati o nal I nstit utes of Healt h ( NI H), 
C P/ C P P S  ( T y pe III) is t he m ost c o m m o n, acc o u nti n g f or a b o ut 9 0 % of all cases. N o k n o w n 
eti ol o g y has bee n esta blis he d, a n d wit h o ut a defi n e d ca usati ve a ge nt, treat me nt ma y b e g ui de d 
lar gel y b y a d oct or's cli nical e x perie nce a n d i nsti ncts rat her t ha n h ar d e vi de nce. Alt h o u g h n ot 
life-t hreat e ni n g, a dia g n osis of C P/ C P P S h ol ds t he p ote ntial f or a re d uce d q ualit y of life 
(H ar v ar d P ers p e cti v es o n Pr ost at e Dis e as e, 2 0 1 7 ). 
T he g o al of treat me nt is t o i m pr o ve s y m pt o ms . Alt h o u g h a nti bi otics ma y be prescri be d, little 
be nefit ma y r es ult as t he c o n diti o n ma y be c hr o nic a n d n ot ca use d b y a n acti ve i nfecti o n. Ot her 
c o m m o n treat me nts i ncl u de me dicati o ns t o rela x t he m uscles ar o u n d t he pr ostate a n d bla d der 
nec k  ( α-a dr e ner gic bl oc k er s), m uscle r ela x a nts or tric ycli c a nti de pressa nts, a n d prescri pti o n pai n 
me dicati o n or n o n- ster oi dal a nti-i nfla m mat or y dr u gs t o re d u ce p ai n a n d s welli n g. Alter n ati ve a n d 
nat ural re m e dies t hat ma y r e d uce o n g oi n g p ai n i ncl u de war m b at hs ; ac u p u nct ure; pel vic fl o or 
p h ysical t hera p y; r ela x ati o n e x ercises; massa ge t h era p y ; dietar y ma na ge m e nt ; a n d bi ofee d bac k 
(R o d di c k et al ., 2 0 1 7). 
4. 2  
R ati o n ale f or Use of t he Pr o d uct  
A Q X - 1 1 2 5 is bei n g de v el o pe d as a n o vel, s mall m olec ule f or t h e treat me nt of i nfla m mat or y 
diseases. A Q X -1 1 2 5 re pr ese nts a ne w p h ar mace utical class of c o m p o u n ds t hat acti vate t he Src 
h o m ol o g y 2-c o ntai ni n g i n osit ol- 5'- p h os p hatas e 1 ( S HI P 1 ) pr otei n, a m o d ul at or of 
p h os p h oi n ositi de si g nali n g f or di verse pr ocesses i ncl u di n g cell gr o wt h, acti vati o n, a n d 
i m m u ne/i nfla m mat or y r e g ulati o n (St e nt o n et al ., 2 0 1 3).  
O ne of t he f u n cti o ns of S HI P 1 is t he meta b olis m of p h os p hati d yli n osit ol 3, 4, 5-tri p h os p hate, 
PI( 3, 4, 5) P 3, a ke y si g nali n g m olec ul e i n v ol ve d i n t he re g ulati o n of a variet y of si g nal 
tra ns d ucti o n pat h wa ys. Base d o n t he cli nical a n d n o ncli nical data, it is pr o p ose d t hat acti vati o n 
of S HI P 1 ca n m o d ulate t he i nf la m mat or y pr ocess b y li miti n g i m m u ne cell acti vati o n, 
pr oi nfla m mat or y me diat or pr o d ucti o n a n d cell mi grati o n i n m ulti ple i m m u ne cell t y pes a n d ma y 
t heref ore pr o vi de a t her a pe utic be nefit i n t he treat me nt of C P/ C P P S  a n d ot her i nfla m mat or y 
diseases.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 1  of 8 0  
 
T he i n vi v o a nti- i nfla m mat or y acti vit y of A Q X- 1 1 2 5 has bee n d e m o nstrate d i n n o ncli nical 
m o dels of i nfla m mat or y pai n i ncl u di n g a carra gee na n-i n d uce d m o del of c hr o ni c 
pr ostatitis/c hr o nic pel vic pai n a n d a n ac ute m o del of c ycl o p h os p ha mi de-i n d uce d bla d der c ystitis. 
I n vitr o, A Q X- 1 1 2 5 ca n r e d uce mast cell de gra n ulati o n, i m m u ne cell c he m ota xis a n d pr o-
i nfla m mat or y m e diat or r elease. T a ke n t o get her, t hese data s u p p ort t he p ote ntial effecti ve ness of 
A Q X - 1 1 2 5 i n treati n g c o n diti o ns i n v ol vi n g pai n a n d i nfla m mati o n.  
4. 2. 1  
N o ncli nic al St u dies  
T he ke y fi n di n gs fr o m t h e n o ncli nical st u dies were: 
•  A Q X - 1 1 2 5 e x hi bite d d ose- de pe n d e nt p har m ac ol o gic effects i n vitr o, i ncl u di n g acti vati o n 
o f rec o m bi na nt h u ma n S HI P 1 a n d re d u cti o n of p h os p h or ylat e d pr otei n-seri ne/t hre o ni ne 
ki nase acti vate d b y p h os p hati d yli n osit ol 3, 4, 5-tri p h os p hate, PI( 3, 4, 5) P 3 ( A kt) at seri ne 
4 7 3 ( p A kt [ S 4 7 3]) i n p h os p h oi n ositi de- 3- ki nase -acti vate d h u ma n T-cells. F u ncti o nall y, 
A Q X - 1 1 2 5 i n hi bite d c he m ota xis i n h u ma n le u k oc yt e s u bsets. 
•  I n s afet y p har mac ol o g y st u dies, A Q X- 1 1 2 5 pr o d u ce d a n o n-st atisticall y si g nifica nt 
tra nsie nt decr eas e i n ar o usal a n d l oc o m ot or acti vit y i n t he rat ce ntral ner v o us s yste m 
st u d y. A Q X- 1 1 2 5 i n hi bite d t he h u ma n Et her-a-g o -g o -Relate d G e ne p otassi u m c urre nt at 
a half ma xi mal i n hi bit or y c o nce ntrati o n  of 1 8 8. 9 μ M or 6 0, 7 3 1 n g/ m L, w hi c h is 
a p pr o xi matel y 2 8-f ol d hi g her t ha n t he h u ma n e x p os ure re p orte d at t he hi g h est cli nical 
d ose t o date of 5 4 2 m g. Fi nall y, t here were n o bi ol o gicall y si g nifica nt car di o vasc ular 
effects i n d o gs or res pir at or y effects i n rats.  
•  I n vitr o assa ys i n dicate d t hat per mea bilit y gl yc o pr otei n ( P-g p) a n d breast ca ncer 
resista nce pr otei n ( B C R P) are i n v ol ve d i n t he acti ve tra ns p ort of A Q X- 1 1 2 5, but A Q X -
1 1 2 5 is n ot a n i n hi bit or of P- g p, B C R P , or a n y ot her c o m m o n dr u g tra ns p orters e val uat e d 
at cli nicall y rele v a nt c o n ce ntrati o ns.  
•  A Q X - 1 1 2 5 w as rea dil y bi oa vaila ble a n d ra pi dl y a bs or be d wit h a mea n t er mi nal  
eli mi nati o n half -life (t1/ 2) of a p pr o xi matel y 6 h o urs i n t he rat a n d 9 h o urs i n t he d o g. 
E x p os ures were ge n erall y d ose - pr o p orti o nal or greater t ha n d os e pr o p orti o nal i n t he rat, 
a n d d ose- pr o p orti o nal or less t ha n d ose- pr o p orti o n al i n t he d o g, d e pe n di n g o n t he 
d urati o n of d osi n g. Acc u m ulati o n rati os s h o we d hi g her e x p os ures f oll o wi n g m ulti ple 
da ys of d osi n g c o m par e d wit h si n gle d oses. 
•  I n vitr o bi n di n g t o plas ma pr otei ns fr o m m o use, rats, d o gs, ra b bits, m o n ke ys, a n d h u m a ns 
ra n ge d fr o m 2 6 t o 5 2 %, a n d pr otei n bi n di n g t o h u ma n ser u m al b u mi n was 3 8 %. I n t he 
m o use, t he hi g hest c o nce ntrati o ns of A Q X- 1 1 2 5 (e x cl u di n g t he e x cret or y or ga ns) w ere 
o bser ve d i n t he l u n g, t h yr oi d, a n d a dre nal gla n ds, a n d t he l o west c o nce ntrati o n was 
o bser ve d i n t he br ai n. F oll o wi n g i ntra ve n o us ( I V) a d mi nistrati o n of [1 4C] - A Q X - 1 1 2 5 i n 
the al bi n o rat, t he hi g hest c o nce ntrati o ns (e x cl u di n g t he e x cret or y or ga ns) w ere i n t he 
c h or oi d ple x us, se mi nal vesicles, pa ncreas, st o mac h gastric m uc osa, a n d pit uitar y gla n d, 
a n d t he l o west c o nce ntrati o n was o bser ve d i n t he brai n. F oll o wi n g oral a d mi nistr ati o n of 
[1 4C] -A Q X - 1 1 2 5 i n partiall y pi g me nte d rats, t he hi g hest c o n ce ntrati o ns (e x cl u di n g t he 
e x cret or y or ga ns) wer e o bser ve d i n t he u veal tract, pit uitar y gla n d, pa n creas, har deria n 
gla n d, e x - or bital lac hr y m al gla n d a n d st o mac h m u c osa a n d t he l o w est c o nce ntrati o n was 
o bser ve d i n t he br ai n, s pi nal c or d a n d o c ular le ns. A Q X - 1 1 2 5 acc u m ulate d i n t he testes 
u p o n re peat e d d osi n g i n t he rat. I n a d diti o n, A Q X- 1 1 2 5 distri b ute d t o t he oc ular tiss ues i n 
t he rat (le ns a n d a q ue o us h u m o ur) a n d t he d o g (le ns, c or nea a n d a q u e o us h u m o ur) 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 2  of 8 0  
 
f oll o wi n g r e peat e d dail y d osi n g. Esti mate d oc ular le ns half-life of A Q X- 1 1 2 5 is 
a p pr o xi matel y 2 0 da ys i n t he rat a n d 7 t o 9 da ys i n t he d o g. 
•  T here w as n o si g nifica nt i n vitr o meta b olis m of A Q X- 1 1 2 5 wit h li ver micr os o mes of 
a ni mals a n d h u ma ns. I n t he rat, 5 meta b olites ( R 1- R 5) were i de ntifi e d i n t he plas ma, 
uri ne a n d f eces. I n t he d o g, 4 a d diti o nal meta b olites ( D 1- D 4) were i de ntifie d i n t he 
plas ma, uri ne a n d f eces. A Q X- 1 1 2 5 i n hi bite d C Y P 3 A 4/ 5 at t he e x pecte d i ntesti nal 
l u mi nal c o nce ntrati o ns f or a 2 0 0 m g d ose a n d i n d u ce d i n vitr o C Y P 3 A 4 m R N A 
e x pressi o n i n h u ma n he pat oc yt es. 
•  I n rats, [1 4C] -A Q X - 1 1 2 5 was e x crete d i n t he feces ( ~ 6 0 %) a n d uri ne ( ~ 3 0 %) f oll o wi n g 
oral a d mi nistrati o n a n d a b o ut e q uall y i nt o t he uri n e a n d feces f oll o wi n g I V 
a d mi nistrat i o n. I n d o gs [1 4C] -A Q X - 1 1 2 5 was e x crete d e q uall y i nt o t he uri n e a n d feces 
f oll o wi n g or al a d mi nistrati o n. Mass bala nce rec o v er y i n all st u dies was ≥9 0 %. 
•  T he ma xi m u m t olerate d d ose i n si n gle d ose t o xicit y st u dies was 5 0 0 m g/ k g i n t he m o use 
a n d 1 0 0 0 m g/ k g i n eac h of t he rat a n d d o g s p ecies.  
•  A series of re peat d ose t o xicit y st u dies i n t he rat h a ve bee n c o n d uct e d f or d urati o ns of 
7 da ys u p t o 2 6 w ee ks.  I n t he 2 6- wee k rat st u d y, t he n o o bser ve d a d verse effect le vel 
( N O A E L) was 3 0 m g/ k g/ da y, b ase d o n t he fi n di n gs i n fe males of bilateral p osteri or 
c ortical cataracts a n d micr osc o pic le ns s welli n g/cataracts, persiste nt estr o us c haracterize d 
b y t he i nterrelate d eff ects t o t he re pr o d ucti ve tract a n d ma m mar y gla n ds, a n d fi n di n gs i n 
males of re d u ce d ca u dal e pi di d y mal s per m de nsit y a n d c o u nts a n d e pi di d y mal e pit helial 
micr o vesic ular v ac u olati o n at 1 0 0 m g/ k g/ da y. At t he N O A E L, t he mea n m a xi m u m 
o bser ve d plas ma c o nce ntrati o n ( C ma x ) a n d area u n der t he plas ma c o nce ntrati o n– ti me 
c ur ve fr o m ti me 0 t o 2 4 h ( A U C 0- 2 4) val ues were 1 1 10 n g/ m L a n d 7 1 0 0 n g• hr/ m L, 
res pecti vel y, i n males a n d 1 5 8 0 n g/ m L a n d 9 9 4 0 n g•hr/ m L , res pecti vel y, i n fe males. 
•  A series of re peat d ose t o xicit y st u dies i n t he d o g ha ve bee n c o n d uct e d f or d urati o ns of 
1 0 da ys u p t o 3 9 w ee ks. I n t he 3 9- wee k d o g st u d y, dail y a d mi nistrati o n of A Q X - 1 1 2 5 at 
d ose le vels of 1 0, 3 0, a n d 5 0 m g/ k g/ da y res ulte d i n n o a d verse fi n di n gs. At t he N O A E L 
of 5 0 m g/ k g/ da y, t he mea n C ma x  a n d A U C 0- 2 4  val ues  were  6 1 6 0 n g/ m L a n d 
5 9, 3 0 0 n g• hr/ m L , r es pecti vel y, i n males a n d 6 8 2 0 n g/ m L a n d 6 9, 3 0 0 n g •hr/ m L , 
res pecti vel y, i n f e males.  
•  N o m uta ge nic p ote ntial was o bser v e d f or A Q X- 1 1 2 5 i n t he bacterial m utati o n, 
c hr o m os o me a berrati o n, or rat micr o n ucl e us tests. 
•  A Q X - 1 1 2 5 ha d n o eff ect o n rat male or fe male fertilit y or o n earl y e m br y o nic 
de vel o p me nt at d oses u p t o t he hi g hest d ose teste d of 3 0 0 m g/ k g/ da y. 
•  A Q X - 1 1 2 5 w as terat o ge nic i n rats, b ut n ot i n ra b bits. T he rat e m br y o-fetal de vel o p me nt 
N O A E L was 3 0 m g/ k g/ d a y ( Cma x  4 3 9 n g/ m L; A U C0- 2 4 4, 7 1 0 n g•hr/ m L)  b ase d o n 
terat o ge nic eff ects (e xter nal, s oft tiss ue a n d s kelet al malf or mati o ns a n d variati o ns a n d 
dela ys i n s k eletal ossificati o ns) o bser ve d at d oses ≥1 0 0 m g/ k g/ d a y. I n ra b bits, A Q X- 1 1 2 5 
was n ot terat o ge ni c at t he hi g hest d ose teste d of 8 0 m g/ k g/ da y ( Cma x  1 6, 0 0 0 n g/ m L; 
A U C 0- 2 4 7 8, 7 0 0 n g• hr/ m L).  
•  A Q X - 1 1 2 5 ca use d r e d uce d p u p via bilit y at d oses ≥7 5 m g/ k g/ d a y i ncl u di n g i ncreas es i n 
da ms wit h n o li ve b or n p u ps ( 1 5 0 m g/ k g/ da y), p u ps d yi n g wit hi n t he first 4 da ys after 
birt h a n d still b or n p u ps. T he deat hs occ urri n g i n t he late sta ge of gestati o n/s h ortl y aft er 
part uriti o n was s u g gesti ve of stress a n d/ or p h ysi ol o gical c ha n ges ass ociate d wit h t he late 
sta ge of pre g n a nc y. At 7 5 m g/ k g/ da y, t he F 0 da ms ha d b o d y wei g ht l oss i n lactati o n da ys 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 3  of 8 0  
 
( D L) 1 t o 4 a n d r e d uce d f o o d c o ns u m pti o n t hr o u g h o ut t he lactati o n peri o d ( D L 1 t o 1 4). 
Base d o n t h ese r es ults, t he mater nal N O A E L, de v el o p me ntal N O A E L a n d N O A E L f or 
gr o wt h a n d re pr o d ucti o n i n t he F 1 ge nerati o n i n male a n d fe male rats was 3 0 m g/ k g/ da y 
( Cma x  4 6 9 n g/ m L a n d A U C0- 2 4 4, 5 2 0 n g•hr/ m L) . 
•  A Q X - 1 1 2 5 w as distri b ute d fr o m mater n al circ ul ati o n t o fetal circ ulati o n i n pre g na nt rats 
wit h fetal plas ma le vels a p pr o xi matel y e q ual t o mater nal plas ma le v els.  
•  N o eff ects o n bl o o d, s plee n, b o ne marr o w, or l y m p h n o des were o bser v e d i n t he m o use. 
I n a m o use Stre pt oc occ us p ne u m o ni ae  h ost-resist a nce m o del, A Q X- 1 1 2 5 di d n ot c ha n ge 
t he ma g nit u de of p ost-i nf ecti o n Stre pt oc occ us p n e u m o ni ae  T y pe 1 4 titers i n t he l u n g or 
t he rate of b acterial clear a nce fr o m t he l u n g, w he n c o m pare d t o t he v e hicle c o ntr ol gr o u p. 
Refer t o t he A Q X - 1 1 2 5 I n vesti gat or’s Br oc h ure (I B) f or a d diti o nal details. 
4. 2. 2  
Cli nic al E x perie nce  
A t otal of 7 cli nical st u dies of A Q X - 1 1 2 5 ha ve b ee n c o m plete d. T hree w ere st u dies i n healt h y 
n or mal v ol u nteers ( A Q X- 1 1 2 5- 1 0 0, A Q X- 1 1 2 5- 1 0 1, a n d A Q X- 1 1 2 5- 1 0 2), i n w hic h safet y, 
t olera bilit y, p har mac o ki n etics , f o o d effects, cell ular a n d bi oc h e mical c h a n ges i n s p ut u m , a n d 
bi oe q ui vale nce of A Q X- 1 1 2 5 i m me diate releas e ta blets a n d ca ps ul es  were assesse d. Si n gle -
asce n di n g d oses of A Q X- 1 1 2 5 ra n ge d fr o m 1 7 m g t o 5 4 2 m g. M ulti ple-as ce n di n g d oses ra n ge d 
fr o m 1 0 0 m g t o 5 4 2 m g . 
O ne st u d y eac h was c o n d ucte d i n s u bjects wit h mil d at o pic ast h ma ( A Q X- 1 1 2 5- 2 0 0), i nterstitial 
c ystitis/ bla d der pai n  s y n dr o me (I C/ B P S, A Q X- 1 1 2 5- 2 0 1), c hr o ni c o bstr ucti ve p ul m o nar y disease 
(C O P D, A Q X - 1 1 2 5- 2 0 2), a n d at o pic der m ati tis (A D , A Q X - 1 1 2 5- 2 0 4). 
4. 2. 2. 1  
He alt h y V ol u nteer St u dies  
F oll o wi n g a d mi nistrati o n of a si n gl e oral d ose b y ca ps ule (si n gle as ce n di n g d ose), A Q X- 1 1 2 5 
was ra pi dl y a bs or b e d wit h a me dia n ti me t o reac h ma xi m u m c o nce ntrati o n ( Tma x ) ra n gi n g fr o m 
1. 0 t o 1. 5 h o urs p ost d ose. Plas ma dr u g c o nce ntrati o n s u bse q ue ntl y decli ne d sl o wl y i n a l o g-
li near fas hi o n wit h a t1/ 2 ra n gi n g fr o m 1 9. 5 t o 2 2. 4 h o urs. Mea n t1/ 2 was i n de pe n de nt of d ose. 
Fr o m 1 7 m g t o 5 4 2 m g, plas ma e x p os ure i ncrease d i n a d ose pr o p orti o nal ma n ner ( A U C0- ∞) or a 
slig htl y hi g her t ha n d ose pr o p orti o nal  ma n ner ( C ma x ). 
F oll o wi n g re peate d o nce dail y d osi n g f or u p t o 1 0 da ys ( 1 0 0 m g t o 5 4 2 m g), stea d y st ate tr o u g h 
plas ma c o nce ntrati o ns ( mea n c o nce ntrati o n 2 4 h o urs p ost d ose ) of A Q X-1 1 2 5 were reac he d at 
~ 5 t o 7 da ys. A Q X- 1 1 2 5 was ra pi dl y a bs or b e d wit h me dia n T ma x  reac he d b y 1. 0 t o 2. 0 h o urs. 
Plas ma dr u g c o nce ntr ati o n s u bse q ue ntl y d ecli ne d sl o wl y i n a l o g-li near fas hi o n wit h a t 1/ 2 
ra n gi n g fr o m 1 9. 3 t o 2 1. 1 h o urs. Fr o m 1 0 0 m g t o 5 4 2 m g, plas ma e x p os ure para meters i ncr ease d 
i n, or near, a d ose pr o p orti o nal ma n ner a n d mea n t1/ 2 was i n de pe n de nt of d ose. Plas ma A U C0- 2 4 
val ues i ncrease d at stea d y state c o m pare d t o si n gl e  d ose, i n dicati n g plas ma acc u m ulati o n u p o n 
re peat e d d osi n g i n dicati n g c o n ce ntr ati o ns ~ 5 0 % hi g her t ha n f oll o wi n g a si n gle d ose. 
T he eff ect of f o o d o n t he plas ma p har mac o ki netics of A Q X -1 1 2 5 was t o i ncrease i n t he m e dia n 
T ma x  fr o m 1 t o 4 h o urs. T he a bs or pti o n of a si n gle 2 0 0 m g d ose of A Q X- 1 1 2 5 was n ot altere d b y 
f o o d. 
T here w ere n o d eat hs, seri o us A Es (S A E s), la b orat or y treat me nt e mer ge nt a d verse e ve nts 
(T E A Es ), or s u bject disc o nti n uati o ns d ue t o T E A Es re p orte d d uri n g t hes e st u dies. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 4  of 8 0  
 
4. 2. 2. 2  
Ast h m a St u d y  
O ne st u d y was c o n d u cte d i n s u bjects wit h mil d at o pic ast h ma ( A Q X- 1 1 2 5- 2 0 0), i n w hic h t he 
late ast h matic res p o ns e ( LA R) t o i n hale d aller ge n c halle n ge w as assess e d. A Q X - 1 1 2 5 d osi n g 
was 4 5 0 m g.  Ster oi d-naï ve male a n d f e male ast h matics were assesse d f or L A R  f oll o wi n g i n hale d 
aller ge n c h alle n ge. A si g nifica nt, 2 0 % i m pr o ve me nt i n t he A U C 4- 1 0 of L A R was de m o nstrate d 
wit h 4 5 0 m g A Q X - 1 1 2 5 as c o m par e d wit h  place b o ( P = 0. 0 2 7). T h ere were n o deat hs, S A Es, or 
s u bject disc o nti n uati o ns d ue t o T E A Es i n t his st u d y. 
4. 2. 2. 3  
I nterstiti al C ystitis/ Bl a d der P ai n S y n dr o me, C hr o nic O bstr ucti ve P ul m o n ar y 
Dise ase, a n d At o pic Der m atitis St u dies  
O nce dail y  or al d osi n g wit h 2 0 0 m g A Q X- 1 1 2 5 h as bee n st u die d i n 3 P has e 2 trials: f or 6 wee ks 
i n s u bjects wit h I C/ B P S, a n d 1 2 wee ks i n s u bjects wit h C O P D  or A D .  
I n t he P h ase 2 I C/ B P S st u d y, or al A Q X - 1 1 2 5 2 0 0 m g o nce dail y f or 6 w ee ks re d uce d m a xi m u m 
pel vic pai n, v oi di n g fre q ue nc y a n d ot her uri nar y s y m pt o ms (as meas ure d b y t he O’ Lear y- Sa nt 
I nterstitial C ystitis S y m pt o m a n d Pr o ble m Q uesti o n naire a n d t he Bla d d er Pai n/I nterstitial 
C ystitis S y m pt o m Sc ore ) i n 6 9 w o me n wit h m o derate t o se vere I C/ B P S. M ore pr o gra ms f or t his 
i n dicati o n are pla n n e d i n t he f ut ure. 
A Q X - 1 1 2 5 di d n ot ha ve a treat me nt effect o n rec urre nt e x acer bati o ns i n s u bjects wit h C O P D 
f oll o wi n g a rece nt e x acer bati o n or o n A D si g ns a n d s y m pt o ms i n s u bjects wit h mil d t o m o derate 
A D i n P hase 2 cli nical tri als. T here f ore, t here are c urre ntl y n o pla ns t o de vel o p A Q X- 1 1 2 5 f or 
C O P D or A D.  
Acr oss all t he P hase 2 st u dies, t he perce nta ge of A Q X - 1 1 2 5 s u bjects w h o e x perie nce d a n y 
T E A E ( 5 6 % o v erall) w as si milar t o t he perce nta ge i n place b o ( 5 5 % o v erall), a n d i n t he 6 wee k 
Lea ders hi p st u d y of I C/ B P S patie nts, was l o wer i n A Q X- 1 1 2 5 ( 6 0 %) t ha n place b o ( 7 8 %). 
A Es of i nterest i ncl u de G astr oi ntesti nal ( GI ) Dis or ders, si nce t he mai n t y pe of A E  i n P hase 1 
safet y st u dies were mil d n o n-seri o us GI Dis or d ers, w hic h occ urre d at great er t ha n 2-f ol d 
i nci de nce f oll o wi n g tr eat me nt wit h 4 5 0 m g  t o 5 4 2 m g A Q X- 1 1 2 5 c o m pare d t o place b o. I n t he 
P hase 2 st u dies, wit h a o nce dail y 2 0 0 m g d ose of A Q X- 1 1 2 5 o ver 6 or 1 2 wee ks, t he i nci de n ce 
of GI Dis or ders was 2 1 % i n A Q X- 1 1 2 5 s u bjects c o m pare d wit h 1 6 % of place b o s u bjects. As 
wit h t he P hase 1 st u dies i n healt h y s u bjects, t he GI Dis or ders were ge nerall y mil d a n d t olera bl e. 
E ye Dis or ders are a n ot her A E  cat e g or y of i nterest base d o n t he fi n di n gs of n o ncli nical st u dies. I n 
t hese P hase 2 cli nical st u dies, t he o verall i nci de n ce of E ye Dis or d ers w as l o wer i n A Q X- 1 1 2 5 
s u bjects ( 7 %) c o m pare d wit h place b o s u bjects ( 1 0 %).  
T he fre q u e nc y of S A Es was l o wer i n s u bjects treate d wit h A Q X- 1 1 2 5 ( 5 %) as c o m pare d wit h 
place b o ( 7 %), i ncl u di n g 1 deat h i n eac h gr o u p ( 0. 4 % eac h). T hes e t y p es of e ve nts were o bser v e d 
o nl y i n s u bjects wit h C O P D, w h o ha d se vere u n derl yi n g diseas e, a n d w ere n ot relate d t o t he 
st u d y treat me nts. 
St u d y treat me nt disc o nti n uati o ns d ue t o T E A Es occ urre d i n 6 % of s u bjects treate d wit h 
A Q X - 1 1 2 5 a n d 5 % of pl ace b o s u bjects, m ost of w hic h were c o nsi dere d u nrelate d t o t he st u d y 
treat me nt. T her e were m ore disc o nti n uati o ns d ue t o T E A Es i n t he 1 2-wee k st u dies of s u bjects 
wit h C O P D a n d A D t ha n i n t he 6- wee k st u d y of I C/ B P S. T his is relate d t o t he relati vel y p o or 
hea lt h of t he C O P D s u bjects st u die d, b ut t he l o n ger d urati o n of treat me nt a n d f oll o w- u p c o ul d 
als o be a f act or.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 5  of 8 0  
 
T a ble 2 . A Q X -1 1 2 5 S afet y acr oss  P h ase 2 Tri als ( at Le ast 6 Wee ks of D osi n g)  
 
6 w ee ks o f d osi n g 
I C/ B P Sa 
1 2 w ee ks of d osi n g  
C O P D b  + A D c 
O ver all  
( all P h ase 2 co m bi ne d)  
Pl ace b o 
N = 3 2  
A Q X - 1 1 2 5 
N = 3 7  
Pl ace b o 
N = 2 2 8  
A Q X -1 1 2 5 
N = 2 2 6  
Pl ace b o 
N = 2 6 0  
A Q X -1 1 2 5 
N = 2 6 3  
A n y T E A E, n ( %)  
2 5 ( 7 8)  
2 2 d ( 6 0) 
1 1 8 ( 5 2)  
1 2 6 ( 5 6)  
1 4 3 ( 5 5)  
1 4 8 ( 5 6)  
GI Dis or ders e 
1 1 ( 3 4)  
1 1 ( 3 0)  
3 1 ( 1 4)  
4 3 ( 1 9)  
4 2 ( 1 6)  
5 4 ( 2 1)  
E ye Dis or ders f 
3 ( 9)  
2 ( 5)  
2 2 ( 1 0)  
1 6 ( 7)  
2 5 ( 1 0)  
1 8 ( 7)  
S A Es, n ( %)  
0 ( 0)  
0 ( 0)  
1 8 ( 8)  
1 2 ( 5)  
1 8 ( 7)  
1 2 ( 5)  
Deat h  
0 ( 0)  
0 ( 0)  
1 ( 0. 4)  
1 ( 0. 4)  
1 ( 0. 4)  
1 ( 0. 4)  
T E A Es lea di n g t o  
disc o nti n uati o n, n ( %)  
1 ( 3)  
2 ( 5)  
1 1 ( 5)  
1 3 ( 6)  
1 2 ( 5)  
1 5 ( 6)  
A b bre viati o ns: A D =at o pic der matitis; C O P D =c hr o nic o bstr ucti ve p ul m o nar y disease; GI = gastr oi ntesti nal; 
I C/ B P S =i nterstitial c ystitis/ bla d der pai n s y n dr o me; S A E =seri o us a d verse e ve nt; T E A E =treat me nt e mer ge nt a d verse 
e ve nt  
a L E A D E R S HI P St u d y ( A Q X -1 1 2 5 -2 0 1) i n  I C/ B P S 
b F L A G S HI P St u d y ( A Q X -1 1 2 5 -2 0 2) i n C O P D  
c KI N S HI P St u d y ( A Q X -1 1 2 5 -2 0 4) i n A D  
d T E A Es s h o w n are t h ose re p orte d fr o m t he start of d osi n g t hr o u g h t o t he e n d of t he W ee k  1 0 f oll o w -u p  
e GI Dis or ders Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ) S yste m Or ga n Class  
f E ye Dis or ders Me d D R A S yste m Or ga n Class  
 
T he safet y pr ofile of A Q X - 1 1 2 5 was als o re vie w e d i n t he c o nte xt of ge n der. W hile t he 
Lea ders hi p st u d y of I C/ B P S o nl y i ncl u de d fe male s u bjects, a p pr o xi matel y half of t he s u bjects i n 
t he ot her P hase 2 st u dies were mal e. T here was n o differe n ce i n t he i nci d e n ce of T E A Es bet wee n 
A Q X - 1 1 2 5 a n d pl ace b o i n t he s u bsets of male s u bjects ( 4 8 % f or eac h treat me nt; St u dies A Q X -
1 1 2 5- 2 0 2 a n d A Q X- 1 1 2 5- 2 0 4 c o m bi ne d data ) or fe male s u bjects ( 6 2 % wit h A Q X- 1 1 2 5 a n d 
6 1 % wit h place b o; St u dies A Q X - 1 1 2 5- 2 0 2 a n d A Q X- 1 1 2 5- 2 0 4 c o m bi ne d data ). 
Refer t o t he A Q X - 1 1 2 5 I B f or a d diti o nal details. 
5  
T RI A L O B J E C TI V E S  
5. 1  
Pri m ar y  O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y is t o e val u ate t he effect of 1 2 w ee ks of treat me nt wit h 
A Q X - 1 1 2 5 ( 2 0 0 m g) a d mi nistere d orall y o n ce- dail y c o m pare d t o place b o o n t he c ha n ge fr o m 
Baseli ne  (Visit  2) t o Wee k  1 2 (Visit  4) i n ma xi m u m dail y pel vic p ai n ( mea n) i n male s u bjects 
wit h n o n- bacteri al C P/ C P P S usi n g a sta n dar dize d 1 1 - p oi nt N u merical Rati n g Scal e (N R S ) pai n 
sc ore r ec or d e d dail y b y a n electr o nic diar y (e Diar y). 
5. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t his st u d y are t o e val u ate:  
•  T he eff ects of 1 2 w ee ks of treat me nt wit h A Q X- 1 1 2 5 ( 2 0 0 m g) a d mi nistere d orall y o nce-
dail y c o m p are d t o place b o o n t he c ha n ge fr o m Baseli ne  (Visit  2) t o Wee k  1 2 (Visit  4) f or 
eac h of t h e f oll o wi n g: 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 6  of 8 0  
 
o  N I H C hr o nic Pr ostatitis S y m pt o m I n d e x ( NI H -C P SI ) pai n s u bscale a n d all d o mai ns 
t otal sc ore 
o  Male se x ual healt h as meas ure d usi n g t he I nter nati o nal I n d e x of Erectile F u ncti o n 
Q uesti o n naire, Er ectile F u ncti o n D o mai n ( II E F-E F ) 
o  A vera ge dail y pel vic pai n (e Diar y), a vera ge a n d ma xi m u m pel vic pai n ( Pa per- b ase d 
N R S, i n cli nic), usi n g t he sta n dar dize d 1 1- p oi nt N R S 
o  2 4- h o ur v oi di n g fre q u e nc y (e Diar y) 
•  Ti me c o urse of eff ects:  A Q X - 1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o o n t he c h a n ge fr o m 
Baseli ne  ( Visit 2) at Wee k  6 (Visit  3), Wee k  1 2 (Visit  4), a n d Wee k  1 6 (i.e. 4 wee ks after 
e n d of treat me nt) f or eac h of t he pai n a n d s y m pt o m scale e n d p oi nts 
•  T he o ver all res p o nse t o tr eat me nt  f or A Q X- 1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o as 
meas ure d b y t he s u bject’s Gl o b al Res p o nse Assess me nt (G R A ), Patie nt’s Gl o bal 
I m pr essi o n of C ha n ge s cale (P GI - C) a n d Patie nt’s Gl o bal I m pressi o n of Se verit y s cale 
(P GI - S) at W ee k 1 2 (Visit  4) 
•  T he pr o p orti o n of s u bjects wit h ≥3 0 % a n d ≥5 0 % i m pr o ve me nt i n ma xi m u m dail y pel vic 
pai n  ( mea n) usi n g t he 1 1- p oi nt N R S rec or de d b y e D iar y a n d t h e NI H - C P SI p ai n s u bscale 
c o m pare d t o place b o, at Wee k s 6 ( Visit 3) a n d 1 2 ( Visit 4) 
•  Res p o n der a n al ysis: r es p o nse t o treat me nt defi n e d b y a n y of t he f oll o wi n g:  
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne t o Wee k 1 2 (e Diar y) wit h 
n o c ha n ge i n t he a m o u nt or stre n gt h of c o n c o mita nt a nal gesic me dicati o ns 
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne t o Wee k 1 2 (e Diar y) wit h 
a decr eas e i n t he a m o u nt or stre n gt h of c o n c o mita nt a nal gesic me dicati o ns  
•  Disc o nti n uati o n of st u d y me dicati o n d ue t o treat m e nt fail ure ( % meeti n g treat me nt fail ure 
criteria a n d ti me t o e ve nt) 
5. 3  
S af et y  O bjecti ves  
T he safet y o bjecti ves of t his st u d y ar e t o e val uate:  
•  Safet y a n d t oler a bilit y of A Q X - 1 1 2 5 ( 2 0 0 m g) c o m pare d t o place b o d uri n g t he 1 2- wee k  
treat me nt peri o d 
•  Oc ular safet y bas e d u p o n assess me nt of le ntic ular o pacificati o n usi n g Le ns O pacificati o n 
Classificati o n S yst e m  (L O C S ) III, best c orrecte d  vis ual ac uit y ( B C V A) usi n g t he 
L o garit h m of t he Mi ni m u m A n gle of Res ol uti o n  (L o g M A R)  c hart, intra o c ular p ress ure 
(I O P), c or n eal stai ni n g, a n d slit la m p e x a mi nati o n 
6  
I N V E S TI G A TI O N A L P L A N 
6. 1  
O ver all Tri al Desi g n a n d Pl a n: Descri pti o n  
I n t his d o u ble- bli n d, place b o-c o ntr olle d st u d y, a p pr o xi matel y 1 0 0 mal e s u bjects dia g n ose d wit h 
C P/ C P P S will be r a n d o mize d t o eit her A Q X- 1 1 2 5 ( 2 0 0 m g) or place b o i n a 1: 1 rati o acr oss 
a p pr o xi matel y 3 0 ce nt ers i n N ort h A merica. T h e st u d y will c o nsist of a scree ni n g peri o d of u p t o 
3 wee ks , a 1 2 - wee k treat me nt peri o d f oll o we d b y a 4-wee k O ff- Treat me nt Safet y F oll o w - u p 
peri o d, a n d a n O p ht hal mic Safet y F oll o w- u p Visit 6  m o nt hs p ost last d ose, f or a t otal st u d y 
d urati o n of a b o ut 4 1 wee ks. T here will als o be a f oll o w- u p tele p h o ne call 3 m o nt hs after t he last 
d ose.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 7  of 8 0  
 
At Scree ni n g Visit 1, eac h s u bject will c o m plete a set of q uesti o n naires, a n d recei v e (a n d b e 
trai ne d t o use) a n e Diar y. S u bjects will rec or d t heir a vera ge a n d ma xi m u m dail y pel vic p ai n 
sc ore, at a p pr o xi matel y t he sa me ti me eac h da y (i n t he e ve ni n g pri or t o t he last d ose of pai n 
me dicati o n), as w ell as t heir dail y us e of a n al gesic pai n me dicati o ns. Baseli ne o p ht hal mic 
assess me nts, i ncl u di n g le ntic ular o pacificati o n ass ess me nt usi n g L O C S III, ca n be c o m plete d as 
a se par ate visit a n y ti me d uri n g t he s cree ni n g p eri o d (a n y ti me bef o re Visit 2).  
At Baseli ne ( Visit 2), all s u bjects will ret ur n t o t he cli nic f or re vi e w of eli gi bilit y a n d t o c o m plete 
t he efficac y q u esti o n nair es a n d assess me nts t o est a blis h Baseli ne v al ues. A vera ge d ail y p el vic 
pai n sc ores r ec or d e d i n t he e Diar y wit hi n the 7 da ys pri or t o Bas eli ne ( Visit 2) will be part of t he 
st u d y e ntr y criteria. If all e ntr y criteri a are met, t he s u bject will be ra n d o mize d ( 1: 1) t o recei ve a 
si n gle dail y or al d ose of 2 ta blets f or 1 2 wee ks as f oll o ws:  
•  A Q X - 1 1 2 5 2 0 0 m g d ose gr o u p: 2 A Q X- 1 1 2 5 1 0 0 m g ta blets; or,  
•  Place b o gr o u p: 2 place b o ta blets 
All e nr olle d s u bjects will rec or d t h e f oll o wi n g i n t he e Diar y (fr o m Scree ni n g Visit 1 t o Wee k 1 6 
[Off -Treat me nt Safet y F oll o w - u p Visit]): 
•  Ma xi m u m dail y pel vic p ai n: s u bjects will assess t heir ma xi m u m pel vic pai n f or t hat da y 
o n a scale of 0 t o 1 0, wit h 0 i n dicati n g ‘ n o p el vic pai n’ a n d 1 0 i n dicati n g ‘ pel vic pai n as 
ba d as y o u ca n i ma gi n e’  
•  A vera ge dail y pel vic pai n. S u bjects will assess t heir a vera ge p el vic pai n f or t hat da y o n a 
scale of 0 t o 1 0, wit h 0 i n dicati n g ' n o p el vic pai n' a n d 1 0 i n dicati n g ' pel vic p ai n as ba d as 
y o u ca n i ma gi ne' 
•  A nal gesic me dicati o n ta ke n eac h da y  
•  2 4- h o ur v oi di n g fre q u e nc y: v oi di n g fre q u e nc y will be meas ure d o ver a 2 4- h o ur peri o d, 
wit hi n a 3 - da y ( 7 2 h o urs) wi n d o w bef ore t he ne xt sc he d ule d visit ( Visit 2, 3, 4 a n d Off-
Treat me nt Saf et y F oll o w - u p Visit ) 
At Wee k 6 ( Visit 3) , Wee k 1 2 ( Visit 4) a n d Wee k 1 6 (Off -Treat me nt Safet y F oll o w - u p Visit), 
d uri n g t he cli nic visit, s u bjects will c o m plete NI H - C P SI, pa per- bas e d 1 1- p oi nt N R S (a vera ge a n d 
ma xi m u m pel vic pai n e x perie nce d o ver t h e last 2 4 h o urs), G R A, P GI- C, II E F, P GI -S,  P H Q - 9, 
ha ve vital si g ns assesse d, a n d ret ur n u n us e d st u d y dr u g ( Wee k 6 a n d 1 2). A n y a d v erse e ve nts 
( A Es) are t o be r ec or d e d. 
S u bject c o m plia nce wit h t he e Diar y will  be m o nit ore d b y trai ne d st u d y site pers o n nel at eac h 
st u d y visit. 
All s u bjects c o m pleti n g t he 1 2 wee ks of treat me nt ( Visit 4) will be c o nsi dere d c o m pleters of 
treat me nt. S u bjects w h o wit h dra w fr o m t he st u d y d uri n g t he treat me nt peri o d s h o ul d c o m plete a n 
Earl y Ter mi nati o n Visit. S u bjects w h o disc o nti n ue t he d o u ble- bli n d treat me nt f or a n y reas o n will 
be e nc o ur a ge d t o c o nti n u e wit h all s u bse q ue nt st u d y-relate d visits a n d e v al uati o ns, wit h 
e m p hasis o n o btai ni n g pel vic pai n data, a nal gesic me dicati o n data a n d v oi di n g fre q ue n c y data t o 
assess effi cac y e n d p oi nts. S u bjects w h o c o m plete t he st u d y or earl y ter mi nate d uri n g t he st u d y 
will be as ke d t o ret ur n f or t he Safet y F oll o w- u p Visit 4  wee ks after disc o nti n ui n g st u d y dr u g, a n d 
t he O p ht hal mic Safet y F oll o w- u p Visit 6 m o nt hs after t he l ast d ose. S u bjects will als o be 
c o ntacte d via tel e p h o ne f or t he f oll o w- u p tele p h o n e call 3  m o nt hs after t h eir last d ose.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 8  of 8 0  
 
6. 2  
Disc ussi o n of Tri al Desi g n I ncl u di n g t he C h oice of C o ntr ol Gr o u p  
T he r a n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, parallel - gr o u p d esi g n use d f or t his st u d y is 
t he c urr e nt sta n dar d f or i nter ve nti o nal h u ma n trials.  
7  
S E L E C TI O N O F S U B J E C T S 
A p pr o xi matel y 1 0 0 m ale s u bjects at a p pr o xi matel y 3 0 sites i n N ort h A merica  are pla n ne d.  
7. 1  
I ncl usi o n Criteri a 
F or i ncl usi o n i nt o t he scr ee ni n g peri o d s u bjects m ust meet t he f oll o wi n g criteria:  
1.  Pr o vi de writte n i nf or me d c o nse nt a n d t he willi n g n ess a n d a bilit y t o c o m pl y wit h all 
as pects of t he st u d y r e q uire me nts  
2.  Males, ≥1 8 a n d ≤8 0 years of a ge at S cree ni n g Visit  1 
3.  Ha ve pai n or disc o mf ort i n t he pel vic re gi o n f or at least 3 m o nt hs i n t he last 6 m o nt hs, i n 
t he a bse nce of a uri nar y tract i nfecti o n or ot her p el vic/ ur ol o gical ca us e, a n d ha ve a 
p h ysicia n dia g n osis of C P/ C P P S ( NI H Pr ostatitis , Cate g or y III)  
4.  NI H - C P SI of ≥1 5 o n t he t otal sc ore 
5.  S u bjects m ust a gree t o us e a c o n d o m f or se x ual i nterc o urs e fr o m S cree ni n g Visit  1 u ntil 
at least 9 0 da ys aft er t he l ast d ose of st u d y dr u g, u nless t he y h a ve bee n s ur gicall y 
sterilize d ( vasect o m y) f or a mi ni m u m of 6 m o nt hs. Tr ue a bsti ne nce fr o m s e x ual 
i nterc o urse i n acc or da nce wit h t he preferre d a n d us ual lifest yle of t he s u bject is als o 
acce pta ble  
6.  Ha ve a n a ver a ge d ail y p el vic pai n sc ore of ≥4 o ut of 1 0 o n t he 1 1- p oi nt N R S pai n scale 
( mea n of t he a ver a ge d ail y pel vic p ai n sc ore rec or de d at eac h of t he 7 d a ys pri or t o 
Baseli ne  [Visit  2]).  A mi ni m u m of 5 dail y rec or ds wit hi n 7 da ys pri or t o Baseli ne  (Visit  
2) m ust be rec or de d  
7.  M ust be ca pa ble of v oi di n g i n de p e n de ntl y f or 3 0 da ys pri or t o scree ni n g (t o all o w 
c o m pleti o n of 2 4- h o ur v oi di n g diar y) 
7. 2  
E xcl usi o n Cr iteri a 
S u bjects meeti n g a n y of t he f oll o wi n g criteria are i neli gi ble f or t he trial: 
1.  Dia g n osis of N I H Pr ostatitis Cate g ories I (ac ut e pr ostatitis) or II (c hr o ni c bacterial) 
p r ostatitis 
2.  Dia g n osis of I C/ B P S wit h s y m pt o ms of pai n, press ure, or disc o mf ort p erce i ve d t o be 
relate d t o t he bla d d er, a n d ass ociate d l o wer uri nar y s y m pt o ms f or > 6 w ee ks i n t he 
a bse nce of i nfecti o n or ot her i de ntifia ble ca uses 
3.  Relief of pel vic pai n after v oi di n g or h a ve > 1 5 v oi ds per da y  
4.  P ost- v oi d resi d ual v ol u me > 1 5 0 m L 
5.  Ha ve ha d a n u nres ol v e d ( p ositi ve bacterial uri ne c ult ure) uri nar y tract i nfecti o n  wit hi n 8 
wee ks (i ncl usi ve) pri or t o Scree ni n g Visit  1 (s u bjects ca n rescree n [ u p t o 1 ti me] o nce 
i nfecti o n clears)  
6.  Hist or y of pre vi o us pr ost ate or bla d der i nter ve nti o n ( i.e. pr ostate bi o ps y, c yst osc o p y, or 
i n d welli n g uri nar y cat h eter) wit hi n 1 m o nt h of Scree ni n g Visit  1, hist or y of micr o wa ve 
t hera p y, tra ns uret hral res ecti o n of t he pr ostate, tra ns uret hral ra di ofre q u e nc y 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 2 9  of 8 0  
 
t her m ot hera p y, tr a ns uret hral i ncisi o n of t he pr ostate, tra ns uret hral nee dle a blati o n, 
tra ns uret hr al laser v a p ori zati o n of t he pr ostate, Ur olift® , Rez u m, a n d ot her ur ol o gical 
i nter ve nti o ns (e. g., b ot uli n u m t o xi n) wit hi n 6 m o nt hs of Scree ni n g Visit  1  
7.  U nilateral testic ular or scr otal pai n as t he s ole s y m pt o m of C P / C P P S 
8.  O n g oi n g, s y m pt o matic uret hral strict ure disease  
9.  Catastr o p hizi n g pai n sc or e of ≥3 0 as deter mi ne d b y t he Pai n Catastr o p hizi n g Scal e ( P C S ) 
1 0.  C urre nt maj or de pr essi ve dis or der ( i.e. Patie nt H ealt h Q uesti o n naire - 9 [P H Q - 9] sc ore 
≥1 0) 
1 1.  Ne ur ol o gic diseas e or dis or der affecti n g t h e bla d d er, a bilit y t o v oi d s p o nta ne o usl y, or 
directl y c o ntri b uti n g t o uri nar y s y m pt o ms (e . g., m ulti ple scler osis, a ut o n o mic 
ne ur o pat h y) 
1 2.  Se vere, e x cr u ciati n g p ai n d uri n g rectal e x a m (i.e.  a n “i na bilit y t o perf or m t he e x a m”)  
1 3.  Hist or y of c hr o nic s u bsta nce a b use, d e pe n d e nc y or a b use of o pi oi ds, or ot h er narc otics 
wit hi n t he last 2  years  
1 4.  C urre ntl y recei vi n g , or e x pect t o recei ve , a n y of t he f oll o wi n g pr o hi bite d me dicati o ns or 
pr oce d ur es: 
o  N o n -ster oi d al a nti-i nfl a m m at or y dr u g or ot her me dic at i o n (e. g. al p h a-bl oc kers) 
f or C P/ C P P S, u nless o n a sta ble d ose f or ≥3 0 da ys pri or t o Scree ni n g Visit 1 
o  L o n g- acti n g o pi oi d s: wit hi n 2 wee ks pri or t o Bas eli ne ( Visit 2) or e x pecte d t o ta ke 
a n y l o n g-acti n g o pi oi d s at a n y ti me d uri n g t he st u d y  
o  S h ort - acti n g o pi oi d or o pi oi d-c o nt ai ni n g a n al gesics: m ore t ha n 1 0 d oses/ m o nt h, or 
m ore t ha n a si n gle d ose > 2 da ys per wee k, or a n y s h ort- acti n g o pi oi ds wit hi n 3 da ys 
pri or t o ra n d o mizati o n 
o  Or al ster oi d t her a p y, i m m u n os u p press a nts/i m m u n o m o d ul at ors  (i ncl u di n g dail y 
p h os p h o diesterase T y p e 4 i n hi bit ors) wit hi n 3 0 da ys pri or t o Scree ni n g Visit  1 a n d 
t hr o u g h o ut t he st u d y 
o  Ha ve ta k e n a n y i n vesti g ati o n al dr u g or de vice wit hi n 9 0 da ys pri or t o S cree ni n g 
V isit 1, or ha ve ha d pr e vi o us e x p os ure t o A Q X- 1 1 2 5 
1 5.  A n y p ri or hist or y of pel vic ca ncer (e . g., c ol orectal, ge nit o uri nar y) or treat m e nt (ra diati o n 
or c he m ot her a p y) t here of 
1 6.  Maj or s ur ger y wit hi n 3 m o nt hs pri or t o Scree ni n g Visit  1 
1 7.  Ha ve a n y ot h er c o n diti o n/ disease w hic h, i n t he o pi ni o n of t he I n vesti gat or , c o ul d 
c o m pr o mise s u bject s af et y or i nterfere wit h t he s u bject’s partici pati o n i n t h e st u d y or i n 
t he e val uati o n of t he st u d y r es ults. I n cas e of a n y d o u bt, t he I n v esti gat or s hall c o ns ult t he 
me dical m o nit or  
1 8.  K n o w n i nt olera nce t o micr o- cr ystalli ne cell ul ose ( A vicel ®  P H - 1 0 2), ma n nit ol or ot her 
i n gre di e nt of A Q X-1 1 2 5 ta blets  
7. 3  
Criteri a f or I n di vi d u al S u bject Disc o nti n u ati o n of St u d y Dr u g  
S u bjects s h o ul d be disc o nti n ue d fr o m st u d y dr u g , w hile e nc o ura ge d t o f oll o w all ot her pr ot oc ol-
s pecifie d pr o ce d ur es, f or t he f oll o wi n g reas o ns: 
•  N o nc o m pli a nce wit h trial or f oll o w - u p pr oce d ures t hat i n t he I n v esti gat or’s o pi ni o n 
w o ul d je o par dize t he s u bject’s safet y  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 0  of 8 0  
 
•  Disc o nti n u ati o n of st u d y dr u g at t he I n vesti gat or’s re q uest f or a n y reas o n t h at t he 
I n v esti gat or belie ves c o nti n uati o n of st u d y dr u g t h era p y w o ul d n ot be i n t he s u bject’s 
best i nterest   
•  S u bjects ma y disc o nti n ue st u d y dr u g  at a n y ti me f or dr u g i nt olera bilit y, dis ease 
pr o gressi o n, a vaila bilit y of ot her t hera pe utic o pti o ns, or s u bject j u d g me nt 
7. 4  
Criteri a f or I n di vi d u al S u bject Wit h dr a w al fr o m t he Tri al 
S u bjects ma y wit h dr a w fr o m f urt her p artici pati o n i n t he st u d y at a n y ti me a n d f or a n y reas o n 
wit h o ut prej u dice. T he d e gree t o w hi c h a s u bject wit h dra ws ca n v ar y a n d eff orts will be ma de t o 
c ollect i m p orta nt safet y d ata if feasi ble a n d t he s u bject c o nse nts. A s u bject will be c o nsi dere d t o 
be wit h dra w n fr o m t he trial f or t he f oll o wi n g reas o ns: 
•  Wit h dra w n c o nse nt fr o m all treat me nt a n d f oll o w- u p 
•  Deat h  
•  L ost t o f oll o w- u p 
•  Ter mi nati o n of t he trial b y t he S p o ns or 
A n y s u bject w h o is wit h dra w n s h o ul d c o m plete all Earl y Ter mi nati o n ( E T ) Visit  assess me nts .  
S u bjects will be as ke d t o ret ur n f or t h e Off - Treat me nt Safet y F oll o w - u p Visit 4 wee ks after 
disc o nti n ui n g st u d y dr u g, a n d t he O p ht hal mic Safet y F oll o w- u p Visit 6 m o nt hs after t he last 
d ose. S u bjects will als o be c o ntact e d via tele p h o ne f or t he f oll o w- u p tel e p h o ne call 3 m o nt hs 
after t heir l ast d ose.   
8  
T R E A T M E N T S  
8. 1  
A Q X - 1 1 2 5 T a blet Dr u g Pr o d uct  
A Q X - 1 1 2 5 ta blet dr u g pr o d uct is s u p plie d as r o u n d, w hite, bic o n ve x, fil m-c oate d ta blets 
c o ntai ni n g 1 0 0 m g A Q X- 1 1 2 5 (fr ee bas e) acti ve i n gre die nt a n d p har mace utical gra de e x ci pie nts.  
T he e x ci pie nts use d i n t he A Q X- 1 1 2 5 1 0 0 m g ta bl et d osa ge f or m are: micr ocr ystalli ne cell ul ose 
( A vicel®  P H - 1 0 2), ma n nit ol ( Pearlit ol®  5 0 C), s o di u m la ur yl s ulfat e, c oll oi dal silic o n di o xi de, 
cr os p o vi d o ne, ma g nesi u m stearate, a n d O pa dr y II W hite (c oati n g mi xt ure).  
T otal ta blet wei g ht will be a p pr o xi matel y 3 1 4 m g.  
F urt her d etails o n t he acti ve i n gr e die nt of A Q X- 1 1 2 5 are pr o vi d e d i n t he A Q X - 1 1 2 5 I B. 
8. 2  
Pl ace b o T a blet Dr u g Pr o d uct 
Matc hi n g place b o is i de ntical i n a p pear a nce t o t he test pr o d uct a n d c o ntai ns n o acti ve i n gre die nt. 
Place b o ta blet dr u g pr o d uct is s u p plie d as wei g ht a n d a p peara n ce matc h e d ta blets wit h t he acti ve 
i n gre di e nt c o m p o ne nt of t he ta blets s u bstit ute d wit h a c o m bi nati o n of t he 2 mai n fillers 
micr ocr ystalli ne cell ul ose ( A vicel ®  P H -1 0 2) a n d ma n nit ol ( Pearlit ol ®  2 0 0 S D). 
8. 3  
St u d y Dr u g A d mi nistr ati o n  
St u d y dr u g is t o be a d mi nistere d o nl y t o s u bjects w h o ha ve pr o vi d e d writte n i nf or me d c o ns e nt 
a n d ha ve met t he criteria o utli ne d i n S e cti o ns 7. 1  a n d 7. 2 . St u d y dr u g will be a d mi nistere d orall y 
o nce dail y  f or 1 2 wee ks. (T a bl e 3 ).  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 1  of 8 0  
 
T a ble 3 . St u d y Dr u g D osi n g 
St u d y Dr u g Gr o u p  
D ose  
Tre at me nt Re gi me n  
A Q X -1 1 2 5 2 0 0 m g  
2 A Q X -1 1 2 5 1 0 0 m g ta blets  
2 ta blets, o nce dail y  
Place b o  
2 place b o ta blets  
 
T he first d ose of st u d y dr u g will be a d mi nistere d i n t he cli nic at Baseli ne  (Visit  2), o nce all 
Baseli ne  pr oce d ures are c o m plete d a n d t he s u bject has bee n ra n d o mize d. N o i n vesti gati o nal or 
c o m mercial a ge nts or t hera pies ot her t ha n t h os e descri be d i n S e cti o n 8. 1 1  ma y b e a d mi nistere d 
wit h t he i nte nti o n t o treat t he s u bject’s c o n diti o n.  
S u bjects will be i nstr ucte d t o ta ke t he st u d y dr u g wit h a glass of water  ar o u n d t he sa me ti me of 
da y wit h f o o d, or eat a li g ht meal n o m ore t ha n 4 h o urs pri or t o c o ns u m pti o n, f or 1 2 wee ks. O n 
st u d y visit da ys, s u bjects will be i nstr ucte d n ot t o ta ke t he st u d y dr u g bef ore t he visit a n d t o eat a 
li g ht meal n o m ore t ha n 2 h o urs pri or t o t he sc he d ule d visit. T he st u d y dr u g will be ta k e n duri n g 
t he st u d y visit after all assess me nts ha ve bee n c o m plete d. If t he s u bject h as i na d verte ntl y ta ke n 
t he st u d y dr u g pri or t o atte n di n g t he cli nic, t he cli nic d ose s h o ul d n ot be gi v e n. 
If a d ose is misse d, s u bjects s h o ul d ta ke t he d ose as s o o n as t he y re me m ber o n t he sa me da y. 
H o we ver, if it is t he ne xt da y, t h e misse d d ose s h o ul d be s ki p pe d a n d ne xt d ose ta ke n as n or mal. 
O nl y 1 d ose of st u d y dr u g ( 2 ta bl ets) s h o ul d be ta ke n eac h da y a n d a d o u bl e d ose s h o ul d n ot be 
ta ke n. 
Re mai ni n g  u n use d st u d y dr u g will be c ollecte d at  Wee k 6 a n d at  t he e n d of t he 1 2-wee k 
treat me nt. S u bjects will be i nstr ucte d t o ret ur n all use d wallets (i ncl u di n g p artiall y us e d a n d 
t h ose wit h u n use d s pare d oses) f or r ec o n ciliati o n at eac h st u d y visit. 
8. 4  
R a n d o miz ati o n 
Ra n d o mizati o n will be c o n d ucte d at Baseli ne  (Visit  2), after verif yi n g t hat t he s u bject meet s all 
i ncl usi o n criteria a n d h as n o ne of t he e x cl usi o n criteria. A p pr o xi matel y 1 0 0 male s u bjects wit h 
dia g n ose d C P/ C P P S will be ra n d o mize d t o eit her A Q X- 1 1 2 5 ( 2 0 0 m g) or place b o i n a 1: 1 rati o.  
A ce ntral, p er m ute d bl oc k ra n d o mizati o n sc he me will be use d wit h a select e d bl oc ki n g fact or 
( bl oc k size) deter mi ne d b ase d o n t he pr o p os e d all ocati o n rati o a n d n u m ber of s u bjects. 
A n I nteracti ve We b Res p o nse S yste m (I W R S) will be use d f or t he ra n d o mi zati o n t o eit her A Q X-
1 1 2 5 ( 2 0 0 m g) or place b o a n d s u bse q ue nt wallet assi g n me nts. S t u d y staff will l o g i n t o t he 
I W R S usi n g a p pr o priate cre de ntials a n d i n p ut s u bject-s pecifi c i nf or mati o n (i.e. s u bject n u m ber 
a n d ot her basic i d e ntifiers). I n acc or da n ce wit h t h e ra n d o mizati o n sc he d ule, t he I W R S will 
assi g n t he ra n d o mizati o n n u m ber a n d t he u ni q ue wallet  n u m bers t o t he s u bject. Eac h s u bject 
m ust be gi ve n o nl y t he w allet s assi g ne d b y IW R S. T he st u d y staff will d oc u me nt t he wallet 
n u m bers i n t he Case R e p ort For m ( C R F) . S u bjects are t o be ra n d o mize d i n t he or der i n w hi c h 
t he y q u alif y fr o m t he scr ee ni n g p hase f or i ncl usi o n i n t he st u d y. 
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 2  of 8 0  
 
8. 5  
St u d y Dr u g Bli n di n g  
Bli n di n g will be mai ntai ne d via pac k a gi n g ( S e cti o n 8. 6 ) a n d la b elli n g (S e cti o n 8. 7 ). La bels will 
c o ntai n fi x e d (e. g., pr ot o c ol n u m ber) a n d v aria ble i nf or mati o n ( e. g., wallet n u m ber) i n a ma n n er 
t hat pr otects t he bli n d.  
T he I n vesti gat ors, st u d y pers o n nel, s u bjects, me di cal m o nit or, a n d cli nical m o nit or will re mai n 
bli n de d t hr o u g h o ut t he st u d y, u nless safet y c o n cer ns necessitate u n bli n di n g. 
If a me dical e mer ge nc y o cc urs a n d a decisi o n re gar di n g t he s u bject’s cli nical treat me nt re q uires 
k n o wle d ge of t he tr eat me nt assi g n me nt, t he st u d y bli n d ma y be br o k e n f or t he s pecific s u bject. 
U nless t he me dical e m er ge n c y is dee me d t o b e life -t hreate ni n g, the me dical m o nit or m ust first be 
c o ns ulte d bef or e u n bli n di n g. T he I n vesti gat or w o ul d t he n utilize  t he I WR S  f or u n bli n di n g a n d 
t he u n bli n di n g pr oce d ure will be pr o vi de d i n t he I W R S Ma n ual. T he date, ti me, a n d reas o n f or 
u n bli n di n g m ust be d oc u me nte d i n t he s o urce d o c u me nts a n d o n t he a p plica ble electr o nic Case 
Re p ort F or m ( e C R F ). I n v esti gat ors s h o ul d n ote t hat t he occ urre nce of a S A E s h o ul d n ot 
r o uti nel y tri g ger i m me diate u n bli n di n g. If t he me dical m o nit or was n ot n otifie d pri or t o brea ki n g 
t he bli n d, t he I nv esti gat or  m ust n otif y t he me dical m o nit or of a n y a n d all bli n ds br o ke n wit hi n 2 4 
h o urs of eac h occ urre n ce. 
8. 6  
St u d y Dr u g P ac k a gi n g 
T he ta blets ar e pac k a ge d i n blister pac ks,  wit h 2 blister pac ks c o ntai ni n g a t otal of a 1 4- da y 
s u p pl y a n d 2 s pare d oses, asse m ble d i nt o a c hil d-resista nt car d b oar d wallet. Base d o n a d osi n g 
re gi me n of 2 ta blets a d a y, t he w allet desi g n will c o ntai n a t otal of 3 2 ta blets/ 1 6 d oses.  
 
Fi g ure 2 . T a blet p ac k a gi n g 
 
S ufficie nt q ua ntities of w allets will be dis pe nse d t o e na ble t he s u bject t o c o nti n ue t o ta ke t he 
me dicati o n u p t o t he ne xt st u d y visit. T he s pare d oses will all o w t he s u bjects t o re mai n o n 
treat me nt if t heir visit is a fe w d a ys p ost t he tar get visit date b ut wit hi n pre defi ne d acce pt a ble 
wi n d o ws. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 3  of 8 0  
 
8. 7  
St u d y Dr u g L a belli n g  
T he wallet will be la belle d wit h a si n gle pa n el la bel, wit h tra nslati o ns pr o vi de d f or official 
la n g u a ges of t he c o u ntries/cli nical sites partici pati n g i n t he st u d y. B ot h p ac ka gi n g a n d la belli n g 
will be c o n d ucte d as p er re g ulat or y g ui de li nes. 
La b els will c o ntai n fi x e d (e . g., pr ot oc ol n u m ber) a n d varia ble i nf or m ati o n (e. g., wallet n u m ber) 
i n a ma n ner t hat pr ot ects t he bli n d.  
8. 8  
St u d y Dr u g St or a ge 
St u d y dr u g s h o ul d be st ore d at r o o m te m perat ure ( 1 5 t o 2 5° C/ 5 9 t o 7 7° F wit h e x c ursi o ns u p t o 
3 0° C/ 8 6° F per mitte d). I nstr ucti o ns f or ha n dli n g t e m perat ure e x c ursi o ns are detaile d i n t he St u d y 
Ma n ual.  R o o m te m perat ure rea di n gs at site are t o be rec or de d wit h a n y d e viati o ns o utsi de of t he 
per mitte d ra n ge d re p ort e d. St u d y dr u g s h o ul d be st ore d i n a sec ur e, l oc k e d facilit y accessi ble 
o nl y t o a ut h orize d st u d y pers o n nel u ntil dis pe nse d t o t he st u d y s u bject. I nstr ucti o ns f or or d eri n g 
dr u g will be s pecifie d i n t he St u d y Ma n ual a n d will be distri b ute d t o t he st u d y ce nters b y a 
ce ntralize d distri b uti o n ser vice.  
8. 9  
St u d y Dr u g H a n dli n g a n d Acc o u nt a bilit y  
Rec or ds s hall be mai ntai ne d of t he deli ver y of st u d y dr u g(s) t o t he st u d y ce nter(s), t he i n ve nt or y 
at t he st u d y ce nter(s), t he use b y eac h s u bj ect a n d t he ret ur n of u n use d st u d y dr u g t o t he 
distri b uti o n ce nters ( per t he St u d y Ma n u al ). 
T hese rec or ds s hall i ncl u de dates, q ua ntities, batc h n u m bers, e x pir y dates a n d t he u ni q ue wallet  
n u m bers assi g n e d t o t he st u d y me dicati o n a n d t o t he st u d y s u bjects. 
T he I n vesti gat or s hall be res p o nsi ble f or e ns uri n g a de q uate d o c u me ntati o n of st u d y dr u g 
recei v e d, dis pe nse d, a n d ret ur ne d.  
8. 1 0  
Tre at me nt a n d Elect r o nic Di ar y C o m pli a nce  
T reat me nt c o m plia nce will be assesse d t hr o u g h ta blet c o u nts. T he s u bject will be i nstr ucte d t o 
bri n g all dis pe nse d wallets bac k  t o t he cli nic at eac h visit (e ve n if t he w allet is e m pt y). T he 
n u m ber of use d a n d re mai ni n g ta blets will be rec or de d o n t he eC R F.  
S u bject c o m plia nce wit h t he e Diar y will be m o nit ore d b y trai ne d st u d y site pers o n nel at eac h 
st u d y visit. 
8. 1 1  
C o nc o mit a nt Me dic ati o ns  
8. 1 1. 1  
Per mitte d Me dic ati o ns  
T he use of sta ble c o nc o mita nt t hera p y is all o we d t hr o u g h o ut t he st u d y, e x ce pt f or t h ose 
me dicati o ns pr o hi bite d i n S e cti o n 8. 1 1. 2 . All c o n c o mita nt me dicati o n s m ust be rec or d e d i n t he 
a p pr o priate s ecti o ns of t h e e C R F  or t he e Diar y as a p pr o priate , a n d u p date d if a n y c ha n ges occ ur. 
C o nc o mita nt me dicati o ns s h o ul d i ncl u de all me dicati o ns ta ke n wit hi n 3 0 da ys pri or t o Scree ni n g 
Visit 1 a n d t hr o u g h o ut t h e st u d y.  
T he f oll o wi n g m e dicati o ns are per mitte d f or use d uri n g t he st u d y: 
•  S h ort-acti n g o pi oi d or o pi oi d- c o ntai ni n g a n al gesics  (e. g., aceta mi n o p he n + c o dei ne) f or 
treat me nt of pai n, i ncl u di n g C P/ C P P S s y m pt o m flares b ut treat me nt per pr ot oc ol is o nl y 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 4  of 8 0  
 
per mitte d f or f e wer t h a n 5 da ys p er w ee k or n o m ore t ha n 1 0 d oses p er m o nt h 
•  N o n - o pi oi d-c o ntai ni n g a nal gesics (e . g., acet a mi n o p he n) 
•  N o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) o nl y if o n a sta bl e d ose (i.e. sta ble 
patter n  a n d fre q ue n c y of use) f or ≥3 0 d a ys pri or t o Scree ni n g Visit  1 
•  M e dicati o ns f or treati n g disease s ot her t ha n C P/ C P P S are per mitte d, pr o vi de d t he y are 
n ot i ncl u de d i n t he list of pr o hi bite d me dicati o ns liste d i n S e cti o n 8. 1 1. 2 . 
•  Me dicati o ns f or treati n g C P/ C P P S are per mitte d, pr o vi de d t he y are n ot i ncl u de d i n t he list 
of pr o hi bite d me dicati o ns liste d i n S e cti o n 8. 1 1. 2 , a n d t he s u bject has b ee n o n a sta ble 
d ose f or ≥3 0 da ys pri or t o Scree ni n g Visit 1 a n d pla ns t o  c o nti n ue c urre nt patter n of 
usa ge f or t he d urati o n of t he st u d y. 
8. 1 1. 2  
Pr o hi bite d Me dic ati o ns 
T he f ol l o wi n g m e dicati o ns are pr o hi bite d f or use d uri n g t he st u d y: 
•  A n y l o n g -acti n g o pi oi ds 
•  Oral ster oi d t her a p y, i m m u n os u p pressa nts/i m m u n o m o d ulat ors (i ncl u di n g dail y 
p h os p h o diesterase t y pe 4 i n hi bit ors)  
If a s u bject re q uires s h ort-acti n g o pi oi d a nal gesics f or ≥5  da ys per wee k o n > 1 occ urre n ce d uri n g 
t he st u d y or > 1 0 ti mes per m o nt h o n > 1 occ urre nce d uri n g t h e st u d y, or re q uire a pr o hi bite d 
me dicati o n t o treat a n A E, t he s u bject ma y re m ai n i n t he st u d y . T he use of t he pr o hi bite d 
me dicati o n s h o ul d be ca pt ure d o n t he e C R F.  
9  
S T U D Y A S S E S S M E N T S  
Refer t o T a bl e 1  f or sc he d uli n g of st u d y assess me nts.  
9. 1  
Eli gi bilit y  O nl y Assess me nts  
9. 1. 1  
De m o gr a p hics, B aseli ne C h ar acteristics , Me dic al/ S ur gic al Hist ory  
De m o gra p hic i nf or mati o n, i ncl u di n g a ge, birt h ye ar, se x, race a n d et h nicit y. 
Baseli ne c har acteristics c o nsist of a c o m plete me dical hist or y a n d detaile d disease hist or y. 
Me dical hist or y i n cl u des pri or a n d o n g oi n g me dical dia g n os es a n d c o n diti o ns, s ur gical 
pr oce d ur es, a n d me dicati o ns ta ke n wit hi n t he pre vi o us 3 0 da ys. Bac k gr o u n d i nc i de nce of 
catar acts i n s u bjects n ote d pri or t o d osi n g s h o ul d be rec or de d as me dical hist or y. 
T his i nf or mati o n will be c ollecte d at scree ni n g ( Visit 1).  
9. 1. 2  
Uri n ary, Psyc h os oci al, Or g a n S pecific, I nfecti o n, Ne ur ol o gic/ Syste mic, Te n der ness 
of S kelet al M uscles Di a g n osis 
T he  Uri nar y, Ps yc h os o ci al, Or ga n S pecific, I nfecti o n, Ne ur ol o gic/ S yste mic, Te n der n ess of 
S keletal M uscles  (U P OI N T ) s yst e m is desi g n e d t o classif y patie nts wit h a n esta blis he d dia g n osis 
of C P/ C P P S i nt o a cli nicall y r ele va nt p he n ot y p e t hat ca n rati o nall y g ui de t hera p y. Usi n g t he 
we bsite  htt p:// w w w. u p oi nt m d.c o m  ( S h os kes, et al., 2 0 1 3), s u bjects will be classifie d  i nt o t he 6 
d o mai ns of t he U P OI N T s yste m ( Uri nar y, Ps yc h os ocial, Or ga n S pecific, I nfecti o n, 
Ne ur ol o g ic/ S yste mic, T e n der ness of S kelet al M uscles). T he classificati o n will be d o ne at 
scree ni n g ( Visit 1) o nl y. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 5  of 8 0  
 
9. 1. 3  
P ai n C at astr o p hizi n g Sc ale 
T his 1 3- state me nt P C S is ca pt ure d o nl y at s cree ni n g (Visit  1), (A p p e n di x 1. P ai n 
C at a str o p hi zi n g S c al e) a n d atte m pts t o elicit t he s u bject’s t y p es of t h o u g hts a n d feeli n g w h e n i n 
pai n. Catastr o p hizi n g is defi ne d as a n e x a g gerat e d ne gati ve me ntal set br o u g ht t o bear d uri n g 
act ual or a ntici p ate d pai nf ul e x perie nce ( S ulli v a n et al., 2 0 0 1 ). A s u bject is e x cl u de d fr o m t he 
st u d y if t he t otal sc or e fr o m t hese q uesti o ns is ≥3 0 (S ulli v a n et al ., 1 99 5) . 
9. 1. 4  
P atie nt He alt h Q uesti o n n aire  9-Q uesti o n  
T he P H Q - 9 is a 9-ite m p atie nt self-r e p orti n g t o ol use d t o assist st u d y pers o n nel i n i de ntif yi n g 
m o o d c ha n ges b y scree ni n g f or s y m pt o ms of d e pressi o n ( Kr o e n k e et al., 2 0 0 1 , A p pe n di x 2. 
Patie nt Healt h Q uesti o n naire 9 -It e ms). Q uesti o n 9 scree ns f or t he prese n ce of s uici dal i deati o n.  
A s u bject wit h a t otal sc ore ≥1 0 fr o m t hese q u esti o ns at Scree ni n g ( Visit 1) or Bas eli ne ( Visit 2), 
or if i n t he o pi ni o n of t he I n v esti gat or, fi n di n gs o n t he Bas eli ne ( Visit 2) P H Q -9 i n dicate n e wl y 
i de ntifie d or p o orl y ma na ge d m e ntal healt h c o n cer ns w hic h w o ul d p ut t he s u bject at ris k or 
c o m pr o mise t heir a bilit y t o partici pate i n t he st u d y a n d c o m pl y wit h st u d y re q uire me nts, t he 
s u bject will  be e x cl u de d fr o m t he st u d y. 
S u bjects wit h a n o verall sc ore o n t he s elf -re p orte d P H Q- 9 ≥1 0 or a sc ore o n Q uesti o n 9, relate d 
t o t h o u g hts of wa nti n g t o h urt o neself, of ≥1 ha v e a hi g h er li keli h o o d of t he prese nce of a m o o d 
dis or der.  A n y s u bject wit h a sc ore a b o ve t hese t hres h ol ds will be see n b y a me m ber of t he 
cli nical st u d y staff pri or t o lea vi n g t h at st u d y visit.  St u d y st aff will f urt her cli nicall y ass ess 
w het her t he s u bject is e x perie nci n g de pressi ve s y m pt o ms, s uici dal t h o u g hts or be ha vi ors, a n d 
w het her t hes e s y m pt o ms, if prese nt, are c h a n ge d fr o m baseli ne.  If t he fi n di n gs re pres e nt a 
c ha n ge, t his c ha n ge i n s y m pt o ms/ m o o d, n ot t he P H Q- 9 sc ore,  will be rec or de d as a n A E, a n d t he 
s u bject will be cli nicall y ma na ge d b y t he I n v esti gat or.  T his pr oce d ure all o ws f or s u bjects t o be 
i de ntifie d a n d ma na ge d i n a cli nical setti n g a n d t h e data t o be ca pt ure d i n t he cli nical st u d y 
data base  as A Es.  
T his will be perf or me d at Visits 1, 2, 3, 4, E T (if nee de d), a n d at t he Off- Treat me nt Safet y 
F oll o w- u p Visit.  
9. 1. 5  
Uri ne: B acteri al C ult ure & S e nsitivity, Le u k ocyte Ester ase Test 
A uri ne bact erial c ult ur e will be o btai ne d at scree ni n g (Visit  1) o nl y. A s u bj ect will be e x cl u de d 
fr o m t he st u d y if t h e s u bject has s y m pt o ms c o nsiste nt wit h a uri nar y tract i nfecti o n a n d a p ositi ve 
uri ne bacterial c ult ure, d efi ne d as ≥1 0 5 c ol o n y f or mi n g u nits ( C F U) p er m L or ≥1 0 4 Gra m 
ne gati ve r o d C F U  per m L . A s u bject ca n rescree n u p t o 1 ti me o nce t he i nfecti o n clears.  A 
le u k oc yt e esterase test will be c o n d ucte d b y t he sit e at scree ni n g (Visit  1) o nl y.  
9. 2  
Effic ac y Assess me nts  
9. 2. 1  
1 1- p oi nt N u m er ic al R ati n g Sc ale 
T his scale will be use d t o deter mi ne t he pri mar y a n d sec o n dar y N R S pai n e n d p oi nts ( A p pe n di x 
3. 1 1- p oi nt N u merical Rati n g Scale ). T he s u bject will be as ke d t o rate b ot h t heir a vera ge a n d 
ma xi m u m  ( w orst) pel vic pai n i nte nsit y f or t he d a y o n a dail y b asis usi n g t h e e Diar y . S u bjects 
will als o be as ke d t o rate b ot h t heir a vera ge a n d m a xi m u m ( w orst) pel vic pai n i nte nsit y usi n g t h e 
pa per versi o n d uri n g t he i n- cli nic visits ( Visits 1, 2, 3, 4, E T (if nee d e d), a n d at t he Off-


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 6  of 8 0  
 
Treat me nt Saf et y F oll o w -u p Visit) . S u bjects will be as ke d t o rate t heir pel vic pai n o n a scal e of 
0- 1 0, b y i n dicati n g t he n u m ber t hat best descri bes t he pai n i nte nsit y. 
9. 2. 2  
N ati o n al I nstit utes of He alt h, C hr o nic Pr ost atitis Sy m pt o m I n de x   
T he  NI H - C P SI is a c o m m o nl y use d 1 3-ite m q uesti o n naire f or t he assess me nt of s y m pt o m 
se verit y i n me n wit h C P/ C P P S. F or eac h ite m, sc ore ra n ges are 0– 1 ( 6 ite ms), 0 – 3 ( 2 ite ms), 0 – 5 
( 3 ite ms), 0– 6 ( 1 ite m), a n d 0 – 1 0 ( 1 ite m) ( Lit wi n et al ., 1 9 9 9, A p p e n di x 4. N ati o n al I nstit ut es 
of H e alt h  C hr o ni c Pr ost atitis S y m pt o m I n d e x ). T his will be perf or me d at Visits 1, 2, 3, 4, E T 
(if nee d e d), a n d at t he Off-Treat me nt Safet y F oll o w -u p Visit.  
9. 2. 3  
I nter n ati o n al I n de x of Erectile F u ncti o n Q uesti o n n aire  
T he 1 5- q uesti o n II E F Q u esti o n naire is a vali date d, m ulti - di me nsi o nal, self-a d mi nistere d 
i n vesti gati o n t hat has bee n f o u n d usef ul i n t he cli nical assess me nt of erectile d ysf u ncti o n a n d 
treat me nt o utc o mes i n cli nical trials (R ose n  et al., 1 9 9 7). A sc ore of 0- 5 is a war de d t o eac h of t he 
1 5 q uesti o ns t hat e x a mi ne t he 5 mai n di me nsi o ns of male se x ual f u ncti o n: erectile f u ncti o n, 
or gas mic f u ncti o n, se x ual desire, i nterc o urse satisfacti on a n d o verall satisfacti o n  (A p p e n di x 5. 
I nt er n ati o n al I n d e x of Er e ctil e F u n cti o n Q u esti o n n air e). T he e ntire q uesti o n naire will be 
a d mi nistere d t o t he s u bject, h o we ver, o nl y t he first 5 q uesti o ns ass ociate d wit h t he Erectile 
F u ncti o n d o mai n will be use d f or t he efficac y ass ess me nts.  
T his i nf or mati o n will be c ollecte d at Visits 2, 3, 4, E T (if nee d e d), a n d at t he Off- Treat me nt 
Safet y F oll o w -u p Visit.  
9. 2. 4  
Gl o b al Res p o nse Assess m e nt  
Assess me nt of t he s u bject’s gl o bal s y m pt o ms, c o m pare d wit h Baseli ne  s y m pt o ms, will be 
perf or me d b y t h e s u bject  usi n g a 7-ite m scale (A p pe n di x 6. Gl o bal Res p o nse Assess me nt ). T his 
i nf or mati o n will be c ollecte d at Visits 3, 4, E T (if nee de d), a n d at t he Off-Treat me nt Safet y 
F oll o w- u p Visit.  
9. 2. 5  
P atie nt’s Gl o b al I m pressi o n of C h a n ge Sc ale 
Assess me nt of t he s u bject’s o verall stat us si nce Baseli ne, will be  perf or me d b y t he s u bject usi n g 
a 7- ite m scale (A p pe n di x 7. Patie nt’s Gl o bal I m pressi o n of C ha n ge Scale ). T his i nf or mati o n will 
be c ollecte d at Visits 3, 4, E T (if nee d e d) , a n d at t he Off-Treat me nt Safet y F oll o w - u p Visit. 
9. 2. 6  
P atie nt’s Gl o b al I m pressi o n of Severity Sc ale  
Assess me nt of t he s u bject’s c urre nt s y m pt o ms will be perf or m e d b y t he s u bject usi n g a 5- ite m 
scale (A p p e n di x 8. Patie nt’s Gl o bal I m pressi o n of Se verit y Scale ). T his i nf or mati o n will be 
c ollecte d at Visits 2, 3, 4, E T (if nee d e d), a n d at t he Off- Treat me nt Safet y F oll o w -u p Visit.  
9. 2. 7  
T we nty -f our H o ur V oi di n g Fre q ue ncy 
V oi di n g fr e q ue n c y will be meas ur e d o ver a 2 4- h o ur peri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore s c he d ule d v isits ( Visit 2, 3, 4, E T (if nee de d), a n d at t he Off-Treat m e nt Safet y F oll o w - u p 
Visit.   


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 7  of 8 0  
 
9. 3  
S af et y Assess me nts  
9. 3. 1  
P hysic al E x a mi n ati o n, Vit al Si g ns  
A c o m plete ge n eral p h ysical e x a mi nati o n  cate g ori ze d b y b o d y s yste m (e. g ., hea d, e yes, ears, 
n ose t hr oat; nec k ; c h est; l u n gs; bac k ; a b d o me n; di gital rectal e x a m [at Scree ni n g Visit 1 o nl y]; 
e xtre mities ; a n d ne ur ol o gical), a n d vital si g ns, will be assesse d a n d rec or de d at Visits 1, 2, 4, E T 
(if nee d e d), a n d at t he Off-Treat me nt Safet y F oll o w -u p Visit.  Vital si g ns will als o be ta ke n at 
Visit 3.  Wei g ht will be d o ne at Visits 1, 4, E T (if nee de d), a n d at t he Off- Treat me nt Safet y 
F oll o w- u p Visit. Hei g ht will be meas ure d at Visit 1. Seate d bl o o d press ure ( B P ) ( m m H g), h eart 
rate (H R ) ( beats p er mi n ute) a n d te m perat ure ( de grees Celsi us) will be meas ure d after t he s u bject 
has bee n sitti n g f or at least 5 mi n utes.  
9. 3. 2  
O p ht h al mic Assess m e nts  
O p ht hal mic assess me nts will be perf or me d d uri n g t he st u d y. Scree ni n g o p ht hal mic assess me nts 
ca n be p erf or m e d a n y ti me wit hi n t he scree ni n g wi n d o w ( Visit 1a).  P ost- Baseli ne o p ht h al mic 
assess me nts  ( Visit 4, E T [if nee de d], Off-Treat me nt Safet y F oll o w - u p Visit, a n d O p ht hal mic 
F oll o w- u p Visit) s h o ul d occ ur wit hi n t he s pecifie d Visit wi n d o ws. 
T he assess me nts will i ncl u de t he f oll o wi n g: 
•  B C V A  usi n g t he L o g M A R  c hart (i.e., after ma nifest refracti o n) 
•  I O P, pr ef era bl y meas ure d b y  G ol d ma n n t o n o metr y, bef ore a n d aft er dilati o n wit h 
m y driatic a ge nt  
•  C or neal stai ni n g 
•  S lit la m p e x a mi nati o n  
•  Le ntic ul ar o pacificati o n usi n g L O C S III   
Bac k gr o u n d i nci de n ce of catar acts i n s u bjects n ote d pri or t o d osi n g s h o ul d be rec or de d as 
me dical hist or y.  A n y cli nicall y si g nifica nt oc ular fi n d i n gs m ust be re p ort e d as A Es . Refer t o 
S e cti o n 9. 3. 5. 5  f or s pecific details c o ncer ni n g oc ular A Es a n d d efi niti o n of oc ular S A Es. 
9. 3. 3  
1 2-le a d S u pi ne Electr oc ar di o gr a m 
S u bjects will be resti n g s u pi ne f or at least 5 mi n utes bef ore t he electr ocar di o gra m (E C G ) 
rec or di n g. T h e I n vesti gat or will deter mi ne if a n y a b n or mal E C G res ults  are cli nicall y si g nifica nt 
a n d if s o, rec or d t hese o n t he a p pr o priat e s o urce d oc u me nt a n d o n t he A E C R F pa ge. T his 
assess me nt will be perf or me d at Visits 1, 4, E T (if nee de d), a n d at t he Off-Treat me nt Safet y 
F oll o w- u p Visit.  
9. 3. 4  
Cli nic al C he mistry & He m at ol o gy, Uri n alysis  
Bl o o d sa m ples will be c ollecte d f or cli nical la b orat or y tests a n d pr ocess e d b y a ce ntral 
la b orat or y. S u bjects d o n ot nee d t o be fasti n g f or t he bl o o d dra w. T his ass es s me nt will be 
perf or me d at Visits 1, 2, 4, E T (if nee d e d), a n d at t he Off- Treat me nt Safet y F oll o w - u p Visit. T he 
f oll o wi n g la b or at or y tests will be assesse d  (T a bl e 4 ): 
 
 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 8  of 8 0  
 
T a ble 4 . Cli nic al  L a b or at or y Tests  
Ser u m C he mistr y  
He m at ol o g y  
Uri n al ysis  
 
Urea  
 
Gl uc ose  
 
As partate a mi n otra nsferase ( A S T)  
 
Ala ni ne a mi n otra nsferase ( A L T)  
 
Al kali ne p h os p hatase ( A P)  
 
Lactate de h y dr o ge nase ( L D H)  
 
S o di u m  
 
P h os p hate  
 
P otassi u m  
 
C hl ori de  
 
Creati ne p h os p h o ki nase ( C P K)  
 
Gl o b uli n  
 
C h olester ol  
 
Creati ne  
 
Ser u m calci u m  
 
T otal bilir u bi n  
 
Tri gl yceri de  
 
Ga m ma gl uta m yl tra ns pe pti dase 
( G G T) 
 
Uric aci d  
 
He mat ocrit  
 
He m o gl o bi n  
 
Re d Bl o o d Cell C o u nt  
 
W hite Bl o o d Cell C o u nt 
wit h Differe ntial  
 
Platelet C o u nt  
 
Mea n c or p usc ular v ol u me  
 
Mea n c or p usc ular 
he m o gl o bi n  
 
Mea n c or p usc ular 
he m o gl o bi n c o nce ntrati o n  
 p H  
 Pr otei n  
 Gl uc ose  
 Ket o nes  
 Bilir u bi n  
 S pecific Gra vit y  
 Bl o o d  
 Nitrites  
 Ur o bili n o ge n  
 B acterial c ult ure & 
se nsiti vit y, le u k oc yte 
esterase test  (Scree ni n g 
Vi sit o nl y) 
 
T he ce ntr al la b orat or y will pr o vi de a la b orat or y m a n ual a n d a p pr o priate s u p plies (c o ntai ners a n d 
la bels). La b or at or y val ues t hat are o ut of ra n ge will be i de ntifie d a n d ma y b e re peate d at t he 
I n v esti gat or’s discr eti o n. T he I n vesti gat or will det er mi ne if a n y o ut -of -ra n ge la b orat or y v al ues 
are cli nicall y si g nifica nt a n d if s o, rec or d t hese o n t he a p pr o priat e s o urce d oc u me nt a n d o n t he 
A E C R F pa ge. All cli nicall y si g nifica nt o ut -of -ra n ge l a b orat or y v al ues will be f oll o we d u ntil 
t he y r et ur n t o n or mal, or bec o me me dicall y sta bl e.  
9. 3. 5  
A dverse Eve nt Defi niti o ns/ Re p orti n g Re q uire m e nts  
A n A E (als o k n o w n as a n “a d vers e e x perie nce”) is defi ne d as a n y u nt o war d me dical occ urre n ce 
i n a patie nt  or cli nical i n vesti gati o n s u bject a d mi nistere d  a p har mace utical  pr o d uct a n d w hic h  
d oes n ot necess aril y h a ve t o ha ve a ca usal relati o ns hi p wit h t his treat me nt  (I C H E 2 A Cli nical 
Safet y Data M a na ge m e nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g ).  
A n A E ca n t h eref ore b e a n y u nf a v ora bl e a n d u ni nt e n de d 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 m pt o m, or dis ease te m p or all y ass ociate d wit h t he use of t he dr u g, wit h o ut a n y 
j u d g me nt a b o ut ca usalit y.  
All cli nical A Es  n ote d d uri n g t he st u d y will be re p orte d o n t he a p pr o priate A E pa ge of t h e eC R F.  
A E s t hat are s eri o us, u ne x pecte d, a n d at least p ossi bl y relat e d t o st u d y p artici pati o n will be 
re p orte d t o t he I nstit uti o nal Re vie w B o ar d (I R B) or I E C a n d t o t he U nite d States ( U S ) F o o d a n d 
Dr u g A d mi nistrati o n ( F D A ) or Healt h Ca na da wit hi n t he ti meli nes des cri be d bel o w. All ot her 
A Es, s uc h as t h ose t hat are e x pecte d, or n ot relate d t o t he st u d y partici p ati o n, are t o be re p orte d 
a n n uall y t o t he i nstit uti o n’s I R B/I E C at t he ti me of t he a n n ual C o nti n ui n g Re vie w a n d t o F D A as 
part of re g ul ar dat a s u b missi o n at t he ti me of a n n ual I n v esti gati o nal Ne w Dr u g (I N D) re p ort.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 3 9  of 8 0  
 
9. 3. 5. 1  
E x pecte d E ve nts  
E x pecte d e ve nts ar e t h ose t hat ha ve b ee n pre vi o usl y i de ntifie d as res ulti n g fr o m a d mi nistrati o n 
of t he st u d y dr u g. A n A E  is c o nsi dere d u ne x pecte d, f or e x pe dite d re p orti n g p ur p oses o nl y, w he n 
eit her t he t y pe of e ve nt or t he se verit y of t h e e ve nt is n ot liste d i n t he c urre nt I B. 
9. 3. 5. 2  
S us pecte d A d verse Re a cti o n  
A s us pecte d a d v erse reacti o n is a s u bset of all A Es f or w hic h t here is a reas o na ble p ossi bilit y 
(i.e. e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E) t hat t he dr u g ca use d 
t he e ve nt. S us pecte d a d v erse r eacti o n i m plies a lesser de gree of cert ai nt y a b o ut ca usalit y t ha n 
a d verse reacti o n.   
9. 3. 5. 3  
A d verse R e acti o n  
A n a d vers e reacti o n is a s u bset of all s us pecte d a d verse reacti o ns, a n d is defi ne d as a n y A E 
ca use d b y a dr u g.   
9. 3. 5. 4  
Seri o us A d verse E ve nt Defi niti o ns / Re p orti n g Re q uire me nts  
9. 3. 5. 4. 1  Seri o us A dverse Eve nt or Seri o us S us pecte d A dverse Re acti o n  
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d seri o us if, i n t he vie w of eit her t he 
I nvesti g at or or S p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes:  
De at h : 
T his i ncl u des a n y d eat h t hat occ urs w hile t h e s u bject  is o n st u d y a n d/ or wit hi n 2 8 da ys after t he 
last d ose of st u dy dr u g.  A n a ut o ps y will be re q ueste d, a n d if perf or me d, res ults will be s u b mitte d 
t o t he S p o ns or.  
A life -t hre ate ni n g A E : 
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d life-t hreat e ni n g if, i n t he vie w of eit her t he 
I nvesti g at or or S p o ns or, its occ urre n ce places t he s u bject at i m me diate ris k of deat h.  It d oes n ot 
i ncl u de a reacti o n t hat ha d it occ urre d i n a m ore se vere f or m, mi g ht ha v e ca use d deat h. 
I n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n: 
I n t he a bse n ce of a n A E, h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n s h o ul d n ot be re p orte d 
as a n S A E i n t he f oll o wi n g sit uati o ns: 
•  H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n is nee de d f or a pr o ce d ure re q uire d b y 
t he pr ot oc ol 
•  H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n is part of r o uti ne pr oce d ure f oll o we d b y 
st u d y ce nt er  
•  H os pitalizati o n f or s u r ve y visits or a n n ual p h ysicals 
•  F or a h os pitalizati o n pla n ne d (a n d d oc u m e nte d) b ef ore t he start of t he st u d y f or a pre-
e xisti n g c on diti o n w hic h has n ot w orse ne d 
 
A persis te nt or si g nific a nt i nc a p acity or s u bst a nti al disr u pti o n of t he a bility to c o n d uct n or m al 
life f u ncti o ns 
A c o n ge nit al a n o m aly/ birt h defect 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 0  of 8 0  
 
A n i m p ort a nt m e dic al eve nt:  
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w h e n, base d u p o n a p pr o priate me dical j u d g m e nt, t he y 
ma y je o p ar dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter v e nti o n t o pre ve nt o ne of t h e 
o utc o mes liste d i n t his defi niti o n.  E x a m ples i ncl u de aller gic br o n c h os pas m re q uiri n g i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de p e n de n c y or dr u g a b use.  
T he S p o ns or s h o ul d be n otifie d wit hi n 2 4 h o urs of t he I n v esti gat or bec o mi n g a ware of a S A E 
a n d t he e ve nt d o c u me nte d o n t he e C R F. 
9. 3. 5. 4. 2  Seri o us U ne x pecte d a n d S us pecte d A dverse Re acti o n  
A n u ne x pecte d A E ( or S U S A R ) is a n y A E or s us pecte d a d v erse reacti o n t hat is n ot liste d i n t he 
I B or is n ot liste d at t he s peci ficit y or se v erit y t hat has bee n o bser ve d, or, if a n I B is n ot 
re q uire d/a v aila ble, is n ot c o nsiste nt wit h t he ris k i nf or mati o n descri b e d i n t he ge neral 
i n vesti gati o nal pla n. T his als o refers t o A Es or s us pecte d a d v erse reacti o ns me nti o ne d i n t he I B 
as occ urri n g wit h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t h e 
dr u g, b ut are n ot s pecificall y me nti o ne d as occ urri n g wit h t he st u d y dr u g. A S U S A R  re q uires 
ma n dat or y e x pe dite d re p orti n g t o t he a p plica ble re g ul at or y a ut h orit y(ies) ( refer t o S e cti o n 
9. 3. 5. 8 ). T he S p o ns or will f or war d t he f or mal n otificati o n descri bi n g t he S U S A R t o 
I n v esti gat ors. Eac h I n vesti gat or m ust t he n n otif y his/ her I R B /I E C of t he S U S A R, i n acc or da n ce 
wit h t he I R B /I E C’s p olic y. 
9. 3. 5. 5  
O p ht h al mic E ve nt Re p orti n g  
A ll cli nicall y si g nifica nt oc ular fi n di n gs m ust be re p orte d as A Es.  
Oc ul ar Tre at m e nt E m er ge nt A dverse Eve nts of S peci al I nterest  
T he f oll o wi n g Oc ular A Es will be treate d as treat me nt e mer ge nt A Es  of s pecial i nterest  
(T E A E SIs ) 
•  A Class II or Class III gr a di n g s hift i n L O C S III as defi ne d i n t he O p ht hal m ol o g y Ma n ual 
c o m pare d t o Baseli ne   
•  A re d ucti o n of 2 li nes or m ore o n t he L o g M A R c h art i n B C V A c o m pare d t o Baseli ne 
•  Oc ular A Es wit h o ut clear eti ol o g y 
•  Oc ular A Es c o nsi der e d p ossi bl y or pr o ba bl y relate d t o st u d y dr u g 
Oc ular A Es wit h  clear eti ol o g y will be re vi e we d o n a case b y cas e basis t o deter mi ne if t he y 
s h o ul d be treate d as T E A E SIs. 
A dj u dic ati o n  
Oc ular T E A E SIs  will be assesse d b y a n i n de p e n de nt, bli n de d a dj u dicat or.  
Re p o rti n g of T E A E SI   
T E A E SIs will be  c o m m u nicate d t o t he Dr u g Safet y Ma n a ger t o e x pe dite S p o ns or re vie w of 
e ve nts. I n vesti gat ors m ust desi g nate w het her t he e ve nt is a n A E or w h et her it meets t he criteria 
of a n S A E (S e cti o n 9. 3. 5. 4. 1 ). 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 1  of 8 0  
 
9. 3. 5. 6  
Rec or di n g A d verse E ve nts  
F or t he p ur p os es of t his st u d y, a n y d etri me ntal c ha n ge i n t he s u bject's c o n diti o n, fr o m si g ni n g of 
i nf or me d c o nse nt u p t o c o m pleti o n of t he treat me nt peri o d s h o ul d be c o nsi dere d a n A E (i.e. f or 
u p t o 2 8 da ys after last d ose of i n vesti gati o nal pr o d uct has bee n ta k e n). 
A Es s h o ul d be ca pt ur e d w here v er p ossi ble as a dia g n osis a n d it is t he I n v esti gat or’s 
res p o nsi bilit y t o e ns ure t his is d o ne. If a precise dia g n osis ca n n ot be ma de, a s y n dr o me ca n be 
rec or d e d. Rar el y s h o ul d it be necess ar y t o rec or d o ne or m ore i n di vi d ual s y m pt o ms. 
All o n g oi n g n o n- oc ular A Es s h o ul d be f oll o we d u p u ntil t he Off -Treat me nt Safet y F oll o w - u p 
Visit ( f or 2 8 da ys aft er t h e last a d mi nistrati o n of st u d y dr u g), wit h t he e x ce pti o n of a n y o n g oi n g 
st u d y dr u g-relate d A Es, w hic h s h o ul d be f oll o we d u ntil res ol uti o n, u nless i n t he I n v esti gat or 's 
o pi ni o n t he A E is u nli kel y t o res ol v e d ue t o t he s u bject's u n d erl yi n g disease. O n g oi n g oc ul ar 
A Es will be q uerie d a t t h e F oll o w-u p call 3  m o nt hs p ost last d ose a n d at t he O p ht hal mic Safet y 
F oll o w- u p Visit 6  m o nt hs p ost last d ose. 
O c ular A Es  m ust be f oll o we d u ntil t he 6- m o nt h O p ht hal mic Safet y F oll o w- u p Visit.   
A n y n e w S A Es occ urri n g u p t o 2 8 da ys  after t he l ast a d mi nis trati o n of st u d y dr u g s h o ul d be 
re p orte d t o t he dr u g s afet y ma n a ger.   
At a n y ti me after t h e Off -Treat me nt Safet y F oll o w - u p Visit, if a n I n vesti gat or lear ns of a n S A E 
t hat ca n be r eas o n a bl y rel ate d t o st u d y dr u g, h e/s he s h o ul d pr o m ptl y n otif y t he dr u g s afet y 
ma na ger.   
All A Es (i ncl u di n g S A Es) are t o b e acc urat el y rec or de d o n t he A d v erse E v e nt pa ge(s) of t he 
eC R F.  T he I n v esti gat or will caref ull y e v al uate eac h A E t o deter mi ne:  
•  d urati o n (start a n d e n d dates) 
•  i nte nsit y ( gra d e) 
•  seri o us ness 
•  relati o ns hi p t o st u d y dr u g  ( U nli kel y, P ossi ble, Pr o ba ble) 
•  acti o n ta ke n wit h st u d y dr u g (st u d y dr u g m o dificati o n  or i nterr u pti o n, st u d y dr u g 
disc o nti n uati o n) 
•  acti o n ta ke n ( n o n e, me di cati o n, me dical i nter v e nti o n) 
•  o utc o me (res ol ve d wit h o ut se q uelae, res ol ve d wit h se q uelae, o n g oi n g) 
T he I n vesti gat or will e v al uate all A Es a n d S A Es wit h re gar d t o ma xi m u m i nte nsit y a n d 
relati o ns hi p t o st u d y dr u g. Ma xi m u m i nte nsit y s h o ul d be assi g n e d usi n g o ne of t he se v erit y 
gr a des as o utli ne d i n t he Nati o nal Ca ncer I nstit ute ’s C o m m o n Ter mi n ol o g y Criteria f or A d v erse 
E ve nts v 4. 0. If t he A E is n ot s pecificall y liste d i n C o m m o n Ter mi n ol o g y Criteria f or A d vers e 
E ve nts v 4. 0, t he f oll o wi n g gr a des will be use d: 
•  Gra de 1: mil d  
•  Gra de 2: m o derate 
•  Gra de 3: se v ere  
•  Gra de 4: life -t hreate ni n g or disa bli n g 
•  Gra de 5: deat h  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 2  of 8 0  
 
9. 3. 5. 7  
Deter mi ni n g Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g  
T he I n vesti gat or m ust att e m pt t o deter mi ne if a n A E or S A E is relate d t o t he use of t he st u d y 
dr u g. T his r elati o ns hi p s h o ul d be descri be d as f oll o ws: 
Pr o b a ble  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na bl e ti me 
se q ue nce t o a d mi nistrati o n of t he st u d y dr u g, u nli kel y t o be attri b ute d t o 
c o nc urr e nt disease or ot her dr u gs or c he micals, a n d w hic h f oll o ws a cli nicall y 
reas o na bl e res p o ns e o n wit h dra wal ( d ec halle n ge). Rec halle n ge i nf or mati o n is n ot 
re q uire d t o f ulfil t his defi niti o n. 
P ossi ble  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na bl e ti me 
se q ue nce t o a d mi nistrati o n of t he st u d y dr u g, b ut w hic h c o ul d als o be e x plai ne d 
b y  c o n c urr e nt disease or ot her dr u gs or c h e micals. I nf or mati o n o n st u d y dr u g 
wit h dra wal ma y be l ac ki n g or u n clear.  
U nli kely  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a te m p oral 
relati o ns hi p t o st u d y dr u g a d mi nistrati o n w hic h ma kes a ca usal rel ati o ns hi p 
i m pr o ba ble, a n d i n w hic h ot her dr u gs, c h e micals or u n derl yi n g disease pr o vi de 
pla usi ble e x pla nati o ns. 
9. 3. 5. 8  
Re p orti n g De at hs a n d Ot her Seri o us A d verse E ve nts  
9. 3. 5. 8. 1  Eve nts t o Be Re p orte d a n d Ti m efr a m e  
A n y d eat h or ot her S A E  e x perie nce d b y t he s u bject d uri n g treat me nt or wit hi n 3 0 da ys of 
recei vi n g st u d y dr u g, r e gar dless of r elati o ns hi p t o st u d y dr u g, or a n y deat h t hat occ urs m ore t ha n 
2 8 da ys after recei vi n g st u d y dr u g a n d is belie ve d t o be st u d y dr u g-relat e d, m ust be pr o m ptl y 
re p orte d t o t he S p o ns or (wit hi n 2 4 h o urs of t he I nvesti g at or bec o mi n g a w are of t he eve nt ) b y 
tele p h o ne, telef a x, or e-mail tra ns missi o n.  
9. 3. 5. 8. 2  G over ni n g Re g ul at ory Re q uire m e nts  
C o m plia nce wit h t his re q uest f or pr o m pt re p orti n g is esse ntial i n t hat t he S p o ns or is res p o nsi ble 
f or i nf or mi n g t he F D A a n d ot her re g ulat or y a ut h orities as well as all ot her partici pati n g 
I n v esti gat ors of t he e v e nt.  
U n der F D A r uli n g ( U S C o de of Fe der al Re g ulati o ns [ C F R ], Title 2 1 Part 3 1 2. 3 2) a n d t he I C H 
G ui deli nes f or Cli nical Safet y Dat a Ma na ge 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, t he S p o ns or is re q uire d t o s u b mit writte n d oc u me ntati o n, i n t he f or m of a n I N D 
Safet y R e p ort, o n t he f oll o wi n g: 
•  S U S A Rs  
•  Fi n di n gs fr o m ot her st u di es t hat s u g gest a si g nifi ca nt ris k t o h u ma ns e x p ose d t o dr u g 
•  Fi n di n gs fr o m a ni mal or i n vitr o testi n g t hat s u g gest a si g nifica nt  ris k t o h u ma ns e x p ose d 
t o dr u g 
•  I n crease d r ate of o cc urre nce of seri o us s us pecte d a d verse reacti o ns fr o m w hat is re porte d 
i n t he I B or t he pr ot oc ol 
Writte n s u b missi o n m ust b e ma de b y t he S p o ns or t o t he F D A/ ot her re g ulat or y a ut h orities (a n d 
b y t he I n vesti gat or t o t he I R B/I E C) as s o o n as p ossi ble, a n d i n n o e ve nt later t ha n 1 5 c ale n d ar 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 3  of 8 0  
 
d a ys  after t he S p o ns or deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g. T he S p o ns or s h all 
als o i nf or m all I n vesti gat ors. 
I n a d diti o n, t he S p o ns or is f urt her r e q uire d t o re p ort, b y eit her tele p h o n e or facsi mile 
tra ns missi o n or i n writi n g t o t he F D A/ ot her re g ul at or y a ut h orities t he occ urre nce of a n y 
u ne x pecte d fatal or lif e -t hreate ni n g e v ent ass ociat e d wit h t he use of t he dr u g ( S U S A Rs) n o later 
t ha n 7 c ale n d ar d a ys  after n otificati o n of t he e ve nt, f oll o we d b y a writte n re p ort n o l ater t h a n 
1 5 c ale n d ar d a ys  after t he i nitial re p ort recei pt d ate. T he S p o ns or s hall als o i nf or m all 
I n v esti gat ors. 
T he S p o ns or will pr o vi de e x pe dite d re p orts of t he f oll o wi n g S U S A Rs t o t he I n vesti gat or s f or 
re p orti n g t o t heir I R B/I E C: 
•  S U S A Rs t hat ha ve arise n i n t he cli nical tri al t hat was assesse d b y t h e I R B /I E C 
•  S U S A Rs t hat ha ve arise n i n ot her cli nical trials of t h e sa me S p o ns or a n d wit h t he sa me 
me dici nal pr o d uct, a n d t h at c o ul d ha ve c o nse q ue n ces f or t he s afet y of t he s u bjects 
i n v ol ve d i n t he cli nical trial t hat was assesse d b y t he I R B /I E C 
I n v esti gat ors ar e re q uir e d t o pr o m ptl y re p ort t o t he I R B/I E C all u na ntici pat e d pr o ble ms 
i n v ol vi n g ris k t o h u ma n s u bjects, i ncl u di n g A Es t h at s h o ul d be c o nsi dere d u na ntici pate d 
pr o ble ms ( 2 1 C F R 3 1 2. 5 3(c)( 1)( vii), 3 1 2. 6 6, a n d 2 1 C F R 5 6. 1 0 8( b)( 1)). 
9. 3. 5. 9  
I niti al I nf or m ati o n Pr o vi de d b y t he I n vesti g at or 
T he I n vesti gat or m ust tra ns mit s ufficie nt i nitial i nf or mati o n t o t he S p o ns or ( or desi g n ee) s h o ul d 
a n S A E re p ort meet t he criteria f or c o m pleti o n of a n I N D Safet y Re p ort. As m uc h of t he 
f oll o wi n g i nf or mati o n a b o ut t he s u bject a n d t he e v e nt will be re q ueste d:  
•  S u bject  i de ntificati o n c o de, ge n der, a n d a ge or date of birt h 
•  U n derl yi n g dia g n osis a n d e xte nt of disease 
•  L ot n u m ber a n d e x pirati o n da te of st u d y dr u g (if a vaila ble) 
•  D ose, r o ute, fre q ue n c y, a n d d urati o n of st u d y dr u g a d mi nistere d 
•  Date of last st u d y dr u g a d mi nistrati o n 
•  Descri pti o n of e v e nt, i ncl u di n g date of o nset a n d d urati o n 
•  Date of deat h (if a p plica ble)  
•  I nter ve nti o n(s) re q uire d 
•  C o nc o mita nt t hera p y (i ncl u di n g re gi me ns a n d i n dicati o ns) 
•  Perti ne nt la b orat or y dat a/ dia g n ostic st u d y (i ncl u di n g dat es) 
•  Perti ne nt me dical hist or y  
•  St u d y dr u g stat us ( d ose i nterr u pte d, disc o nti n ue d) 
•  Di d e ve nt a bat e after i nterr u pti o n of st u d y dr u g a d mi nistrati o n (if a p plica ble)?  
•  Di d e ve nt rec ur after st u d y dr u g was rei ntr o d uce d (if a p plica ble)? 
•  Se verit y of t he A E  
•  Relati o ns h i p of t he A E t o st u d y dr u g  
•  O u tc o me of t he A E 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 4  of 8 0  
 
9. 3. 5. 1 0  F o ll o w- u p I nf or m ati o n  
F oll o w- u p data c o ncer ni n g t he S A E ( e. g., dia g n ostic test re p orts, p h ysi cia n's s u m maries, etc.) 
m ust als o be s u b mitte d t o t he S p o ns or as t he y bec o me a vaila ble, prefera bl y b y telefa x or e -mail, 
as s o o n as t he y bec o me a vaila ble, a n d u ntil t he e v e nt res ol ves or sta bilizes. 
9. 3. 5. 1 1  Seri o us A d verse E ve nt a n d Seri o us a n d U ne x pecte d S us pecte d A d verse Re acti o n  
Re vie w a n d P ote nti al I m p act o n Tri al C o n d uct 
T he I n vesti gat or will re vi e w eac h S A E re p ort a n d e val uate f urt her t he relati o ns hi p of t he S A E t o 
st ud y dr u g a n d t o t he s u bject’s u n derl yi n g diseas e. 
Base d o n t h e I n vesti gat or’s a n d S p o ns or’s assess m e nt of ca us alit y of t he A E  a n d disc ussi o ns 
wit h t he me dical m o nit or , a decisi o n will be ma de b y t he S p o ns or c o n cer ni n g t he n ee d f or f urt her 
acti o n wit h res pect t o t he f ut ure c o n d u ct of t he st u d y. T he pri mar y c o nsi d erati o n g o ver ni n g 
f urt her acti o n is w het her ne w fi n di n gs affect t he s afet y of ot her s u bjects partici pati n g i n t he 
cli nical st u d y.  If t he disc o ver y of a n e w A E relate d t o st u d y dr u g raises c o ncer n o ver t he safet y 
of its c o nti n ue d a d mi nistrati o n t o s u bjects, t he S p o ns or will ta ke i m me diate ste ps t o n otif y t he 
F D A, ot her re g ulat or y a ut h orities, a n d all I n v esti gat or s partici pati n g i n cli nical st u dies wit h t he 
st u d y dr u g. 
F urt her acti o n re q uire d ma y i ncl u d e a n y of t he f oll o wi n g: 
•  Alterati o n of t he e xisti n g researc h pr o gra m b y m o dificati o n of  t he pr ot oc ol 
•  Disc o nti n uati o n or s us pe nsi o n of t he st u d y 
•  Alterati o n of t he i nf or m e d c o nse nt pr ocess b y m o dificati o n of t he e xisti n g I nf or me d 
C o nse nt F or m (I C F) a n d i nf or mi n g c urre nt st u d y partici pa nts of ne w fi n di n gs 
•  M o dificati o n of pre vi o usl y i de ntifie d e x pecte d s us pecte d a d v erse reacti o n lists t o i ncl u de 
A Es ne wl y i de ntifie d as st u d y dr u g- relate d 
9. 4  
Ti mi n g of Assess me nts  
9. 4. 1  
Scree ni n g  Peri o d  
9. 4. 1. 1  
Visit 1  
•  I nf or me d c o ns e nt 
•  I n cl usi o n/ E x cl usi o n criteria 
•  De m o gra p hics 
•  Me dical/ S ur gi cal hist or y  
•  P h ysical  e x a mi nati o n  
•  U P OI N T  classificati o n  
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S 
•  P C S  
•  P H Q - 9 
•  1 2- lea d s u pi ne E C G  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 5  of 8 0  
 
•  V ital si g ns (H R, B P , te m perat ure) 
•  Hei g ht  
•  Wei g ht  
•  Cli nical c he mistr y  ( d o es n ot nee d t o be fasti n g), h e mat ol o g y, uri n al ysis 
•  Uri ne: bacterial c ult ure & se nsiti vit y, le u k o c yt e esterase test  
•  A E c ollecti o n  
•  Re vie w c o nc o mita nt me dicati o n  
•  e Diar y iss ue/trai n  
9. 4. 1. 2  
B aseli ne O p ht h al mic T esti n g ( Visit 1 a)  
O p ht hal mic assess me nt  at Visit 1a ma y occ ur at a n y ti me d uri n g t he Scree ni n g peri o d. 
O p ht hal mic assess me nts i ncl u de :  
•  B C V A usi n g t he L o g M A R c hart (i.e. after ma nifest refracti o n)  
•  I O P ( pref er a bl y m eas ur e d b y G ol d ma nn t o n o metr y bef ore a n d aft er dilati o n wit h 
m y driatic a ge nt ) 
•  C or neal stai ni n g 
•  Slit la m p e x a mi nati o n  
•  Le ntic ul ar o pacificati o n usi n g L O C S III   
9. 4. 2  
B aseli ne ( Visit 2)  
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S 
•  P H Q - 9 
•  II E F 
•  P GI - S 
•  Re vie w I ncl usi o n/ E x cl usi o n criteria  
•  e Diar y r e vie w f or I ncl usi o n/ E x cl usi o n criteria  
•  P h ysical e x a mi nati o n  
•  V ital si g ns ( H R, B P, te m perat ure) 
•  Cli nical c he mistr y  ( d o es n ot nee d t o be fasti n g), h e mat ol o g y, uri n al ysis  
•  V oi di n g fr e q ue n c y meas ure d o ver a 2 4- h o ur p eri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore t h e sc he d ule d Visit  
•  A E c ollecti o n  
•  Re vie w co nc o mita nt me dicati o n  
•  Ra n d o mizati o n after c o nfir mi n g s u bject c o nti n ues t o meet eli gi bilit y criteria 
•  St u d y dr u g dis pe nsi n g  
•  A d mi nistrati o n of first d ose of st u d y dr u g (after all assess me nts perf or me d) 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 6  of 8 0  
 
9. 4. 3  
Tre at m e nt Peri o d  
9. 4. 3. 1  
Visit 3  
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S 
•  P H Q - 9 
•  G R A  
•  P GI - C 
•  II E F 
•  P GI - S 
•  V oi di n g fr e q ue n c y meas ure d o ver a 2 4- h o ur p eri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore t h e sc he d ule d visit 
•  Vital si g ns ( H R, B P , te m perat ure) 
•  A E c ollecti o n  
•  Re vie w c o nc o mita nt me dicati o n  
•  St u d y dr u g dis pe nsi n g 
•  St u d y dr u g c o m plia nce c hec k  
•  St u d y dr u g acc o u nta bilit y  
•  e Diar y r e vie w  
9. 4. 3. 2  
Visit 4  
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S  
•  P H Q - 9 
•  G R A  
•  P GI - C 
•  II E F  
•  P GI - S 
•  V oi di n g fr e q ue n c y meas ure d o ver a 2 4- h o ur p eri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore t h e sc he d ule d visit 
•  P h ysical e x a mi nati o n  
•  O p ht hal mic assess me nts ( B C V A, I O P, c or neal stai ni n g, slit la mp, L O C S III)   
•  1 2-lea d s u pi ne E C G 
•  Vital si g ns ( H R, B P , te m perat ure) 
•  Wei g ht  
•  Cli nical c he mistr y ( d o es n ot nee d t o be fasti n g), h e mat ol o g y, uri n al ysis 
•  A E c ollecti o n  
•  Re vie w c o nc o mita nt me dicati o n  
•  St u d y dr u g c o m plia nce c hec k  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 7  of 8 0  
 
•  St u d y dr u g acc o u nta bilit y  
•  e Diar y r e vie w  
9. 4. 4  
E arly Ter mi n ati o n 
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S 
•  P H Q - 9 
•  G R A  
•  P GI - C 
•  II E F  
•  P GI - S 
•  V oi di n g fr e q ue n c y meas ure d o ver a 2 4- h o ur p eri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore t h e sc he d ule d visit 
•  P h ysical e x a mi nati o n  
•  O p ht hal mic asses s me nts (B C V A, I O P, c or neal stai ni n g, slit la m p, L O C S III)  
•  1 2-lea d s u pi ne E C G   
•  Vital si g ns ( H R, B P , te m perat ure) 
•  Wei g ht  
•  Cli nical c he mistr y ( d o es n ot nee d t o be fasti n g), h e mat ol o g y, uri n al ysis   
•  A E c ollecti o n  
•  Re vie w c o nc o mita nt me dicati o n  
•  St u d y dr u g c o m plia nce c hec k  
•  St u d y dr u g acc o u nta bilit y  
•  e Diar y r e vie w  
9. 4. 5  
S afety F oll o w- u p  
9. 4. 5. 1  
Off - Tre at me nt S af et y F oll o w -u p  
•  NI H -C P SI  
•  Pa per - bas e d 1 1- p oi nt N R S 
•  P H Q - 9 
•  G R A  
•  P GI - C 
•  II E F  
•  P GI - S 
•  V oi di n g fr e q ue n c y meas ure d o ver a 2 4- h o ur p eri o d, wit hi n a 3- da y ( 7 2 h o urs) wi n d o w 
bef ore  t h e sc he d ule d visit 
•  P h ysical e x a mi nati o n ( o nl y nee de d if t here are o utsta n di n g safet y c o ncer ns fr o m Wee k 
1 2) 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 8  of 8 0  
 
•  O p ht hal mic assess me nts ( o nl y nee de d if t h ere are o utsta n di n g safet y c o ncer ns fr o m Wee k 
1 2) 
•  1 2-lea d s u pi ne E C G ( o nl y nee de d if t here are o utsta n di n g safet y c o n cer ns fr o m Wee k 1 2)  
•  Vital si g ns ( H R, B P , te m perat ure) 
•  Wei g ht  
•  Cli nical c he mistr y ( d o es n ot nee d t o be fasti n g), h e mat ol o g y, uri n al ysis ( o nl y nee de d if 
t here are o utsta n di n g saf et y c o ncer ns fr o m Wee k 1 2) 
•  A E c ollecti o n  
•  Re vie w c o nc o mita nt me dicati o n 
•  e Diar y r e vie w/c ollect  
9. 4. 5. 2  
Tele p h o ne C all  
•  A E c ollecti o n  ( o p ht hal mic relate d A Es o nl y) 
9. 4. 5. 3  
O p ht h al mic  
•  O p ht hal mic assess me nts  
•  A E c ollecti o n  ( o p ht hal mic relate d A Es o nl y) 
9. 4. 5. 4  
U nsc he d ule d Visit  
U nsc he d ule d visits ma y be c o n d ucte d at a n y ti me d uri n g t he st u d y a n d m a y  i ncl u de t h e sa me 
assess me nts as Wee k 1 2 ( Visit 4 ). 
1 0  
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S  
S tatistical met h o d s a n d c o n ve nti o ns are des cri be d  i n t his secti o n. F ull details o n t he a nal ysis 
met h o ds a n d prese ntati o n of st u d y r es ults will be pr o vi de d i n t he s tatistical a nal ysis pla n ( S A P). 
T he S A P will be fi nalize d pri or t o u n bli n di n g of t he trial . 
1 0. 1  
Ge ner al C o nsi der ati o ns  
All statistical a nal yses will be perf or me d usi n g S A S  Versi o n 9. 4 or hi g her. 
All cli nical st u d y data will be prese nte d i n s u bject data listi n gs. Descri pti ve statistics ( n, mea n, 
sta n dar d de viati o n, me di a n, mi ni m u m, a n d ma xi m u m) will be calc ulate d b y treat me nt gr o u p f or 
c o nti n u o us varia bles. C o nfi de nce i nter vals ( CIs) will be pr o vi de d w here a p pr o priate. 
Fre q u e ncies a n d per ce nta ges will be prese n te d b y treat me nt gr o u p f or cate g orical a n d or di n al 
varia bles.  
Mea ns, me dia ns, a n d CIs  will be re p orte d t o 1 deci mal place m ore t ha n t h e data re p orte d o n t he 
e C R F or b y t he la b or at or y/ ve n d or. Sta n dar d de vi ati o ns will be re p orte d t o 2 deci mal places m ore 
t ha n t he data r e p orte d. Mi ni m u m a n d ma xi m u m will be re p orte d t o t he sa m e n u m ber of d eci mal 
places dis pla ye d o n t he e C R F or b y t h e la b orat or y/ ve n d or. P  val ues will be re p orte d t o 4 deci mal 
places.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 4 9  of 8 0  
 
1 0. 2  
S a m ple Size D eter mi n ati o n   
Sa m ple size was calc ulat e d usi n g t he 2- sa m ple mea ns state me nt i n t he P O W E R pr oce d ure i n 
S A S. A sa m ple size of 4 5 s u bjects per treat me nt gr o u p will pr o vi de 8 0 % p o wer t o detect a 1. 2-
p oi nt differe nce i n t he c h a n ge fr o m Bas eli ne  ma xi m u m pel vic pai n sc ore b et wee n A Q X - 1 1 2 5 
a n d place b o ass u mi n g a bet wee n -s u bj ect sta n dar d de viati o n of 2. 0 a n d a 2-si de d 5 % si g nifica nce 
le vel.  
Ass u mi n g a 1 0 % rate of disc o nti n uati o n fr o m st u d y dr u g, t h e t otal n u m ber of s u bjects t o be 
ra n d o mize d is a p pr o xi matel y 1 0 0. Su bjects w h o  disc o nti n ue will be i ncl u de d i n t he pri mar y 
a nal ysis, res ulti n g i n a sli g ht decrease i n p o wer if t he disc o nti n ui n g s u bjects i n t he place b o gr o u p 
ha ve n o a d diti o nal c h a n ge after disc o nti n uati o n of st u d y dr u g w hile t he dis c o nti n ui n g s u bjects i n 
the A Q X - 1 1 2 5 gr o u p h a ve a l oss of efficac y aft er disc o nti n ui n g st u d y dr u g. 
1 0. 3  
St u d y P o p ul ati o ns  
T he f oll o wi n g are t h e a n al ysis p o p ulati o ns t o be use d: 
•  I nte nt-t o- Treat (I T T) P o p ulati o n: T he I T T P o p ulati o n will i ncl u de all ra n d o mize d s u bjects . I n 
t he e ve nt of st u d y dr u g a d mi nistrati o n err or, a nal yses o n t he I T T P o p ulati o n will be 
perf or me d acc or di n g t o t he treat me nt t o w hic h t he s u bject was ra n d o mize d t o recei ve.  
•  Safet y P o p ulati o n: T he S afet y P o p ulati o n will i ncl u de all s u bjects w h o recei ve d a n y a m o u nt 
of st u d y dr u g. I n t he e v e nt of st u d y dr u g a d mi nistrati o n err or, a nal yses o n t he Safet y 
P o p ulati o n will be perf or me d acc or di n g t o t he treat me nt t he s u bject act uall y recei v e d . 
•  Per -Pr ot oc ol ( P P) P o p ulati o n : T he P P P o p ulati o n will i ncl u de all I T T s u bjects w h o d o n ot 
ha ve a n y maj or  pr ot oc ol de viati o ns a n d ha ve n o n-missi n g Bas eli ne  a n d Wee k  1 2 assess me nts 
of ma xi m u m dail y pel vic pai n  (i.e. t he pri mar y efficac y ass ess me nt). I n t he e ve nt of st u d y 
dr u g a d mi nistrati o n err or, a nal ys es o n t he P P  P o p ulati o n will be perf or me d a cc or di n g t o t he 
treat me nt t he s u bject act uall y r ecei v e d . 
1 0. 4  
St atistic al A n al yses 
1 0. 4. 1  
S u bject  Acc o u nt a bility, De m o gr a p hics, a n d B aseli ne C h ar acteristics 
S u bject  dis p ositi o n (e nr oll me nt, ra n d o mizati o n, st u d y c o m pleti o n) a n d reas o ns f or n ot 
c o m pleti n g t he st u d y will  be prese nt e d b y treat me nt gr o u p a n d o verall. A d diti o nall y, t h e n u m ber 
of s u bjects i n eac h of t he a nal ysis p o p ulati o ns ( S e cti o n 1 0. 3 ) will be pres e nte d b y treat me nt 
gr o u p a n d o ver all. 
S u bject de m o gr a p hics a n d b aseli ne c haracteristics will be s u m marize d b y treat me nt gr o u p a n d 
o verall  f or t he I T T, Saf et y, a n d P P P o p ulati o ns. Descri pti ve statistics will be pr o vi de d f or a ge, 
hei g ht, a n d wei g ht. Fr e q ue ncies a n d p erce nta ges will be ta b ulate d f or se x, race, a n d et h nicit y.  
1 0. 4. 2  
Effic acy D at a  
T he pri mar y efficac y a n al ysis p o p ulati o n will be t he I T T P o p ulati o n. Se nsiti vit y a nal ysis f or 
selecte d e n d p oi nt a n al yses will be perf or me d o n t h e P P P o p ulati o n.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 0  of 8 0  
 
1 0. 4. 2. 1  Wee k l y Sc ores b ase d o n D ail y Assess me nts  
F or w ee kl y sc or es t hat ar e base d o n dail y s u bject assess me nts (e. g., ma xi m u m dail y pel vic sc ore 
rec or d e d dail y b y t he  e Diar y) a s u bject’s sc ore f or a wee k will be t he a vera ge ( mea n) of t he dail y 
sc ores acr oss t hat wee k.  
1 0. 4. 2. 2  Pri m ar y Effic ac y E n d p oi nt 
T he pri mar y e n d p oi nt is t he c ha n ge fr o m Baseli ne  (Visit  2) t o Wee k  1 2 (Visit  4) i n t he ma xi m u m 
dail y pel vic p ai n ( mea n)  usi n g a sta n d ar dize d 1 1- p oi nt N R S pai n sc ore rec or de d dail y b y a n 
e Diar y. 
1 0. 4. 2. 3  Pri m ar y Effic ac y E n d p oi nt A n al ysis 
C o m paris o n of A Q X - 1 1 2 5 t o place b o at Wee k 1 2 f or t he pri mar y effi cac y e n d p oi nt will use 
mi x e d m o del re peate d meas ures ( M M R M) a nal ysis of c o varia n ce  ( A N C O V A) t o c o m pare 
c ha n ge fr o m Baseli ne  i n N R S sc ore ( de p e n de nt varia ble) bet w ee n treat me nt ar ms (A Q X - 1 1 2 5 
a n d place b o). T he m o del will i ncl u de t he Wee ks 6 a n d 1 2 c ha n ge fr o m bas eli ne sc ores f or eac h 
s u bject. T he M M R M m o del will ha ve fact ors f or Visit, Visit × Treat me nt  i nteracti o n, a n d a 
Visit × B aseli ne i nteracti o n c o variate. T he treat me nt effects  f or eac h gr o u p a n d t he treat me nt 
gr o u p differ e nce will be esti mate d b y least -sq uares mea ns  f or Wee k  1 2 a n d teste d at t he 2 -si de d 
0. 0 5 le vel. 
T he least -s q uares mea ns treat me nt gr o u p esti mates a n d t he differe nce bet w ee n treat me nt gr o u ps 
will be prese nte d f or all Wee ks 1  t hr o u g h 1 2 wit h c orres p o n di n g c o nfi de nce i nter vals. 
1 0. 4. 2. 4  Sec o n d ar y Effic ac y E n d p oi nts 
T he sec o n d ar y efficac y e n d p oi nts are: 
•  T he c ha n ge fr o m Baseli n e  t o Wee k 1 2 f or eac h of t he f oll o wi n g:  
o  NI H - C P SI p ai n s u bscale a n d all d o mai ns t otal sc ore 
o  Male se x ual healt h as meas ure d usi n g t he II E F- E F  
o  Mea n of a v era ge dail y pel vic pai n sc ores (e D iar y), a vera ge a n d ma xi m u m dail y 
pel vic pai n ( pa p er -b ase d N R S i n cli nic) 
o  2 4- h o ur v oi di n g fre q u e nc y (e Diar y) 
•  Ti me c o urse of eff ects: A Q X - 1 1 2 5 ( 2 0 0 m g o nce- dail y) c o m pare d t o place b o o n the 
c ha n ge fr o m Baseli ne  (Visit  2) t o Wee k  6 (Visit  3), Wee k  1 2 (Visit  4), a n d Wee k  1 6 (i.e. 
4 wee ks after e n d of treat me nt) f or eac h of t h e f oll o wi n g:  
o  Mea n of m axi m u m dail y pel vic pai n  sc ore (e Di ar y) 
o  NI H -C P SI p ai n s u bscale a n d all d o mai ns t otal sc ore  
o  II E F-E F  
o  Mea n of a v era ge dail y pel vic pai n sc ores (e D iar y), a vera ge a n d ma xi m u m pel vic pai n 
( Pa per-b ase d N R S i n cli nic).  
o  2 4- h o ur v oi di n g fre q u e nc y (e Diar y) 
•  Res p o nse t o treat me nt as meas ure d b y t he G R A , PGI - C, a n d P GI- S at Wee k  1 2 (Visit  4).  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 1  of 8 0  
 
•  A ≥3 0 % a n d ≥5 0 % i m pr o ve me nt i n ma xi m u m dail y pel vic pai n ( usi n g t he 1 1- p oi nt N R S 
rec or d e d b y e Di ar y a n d t he NI H- C P SI pai n s u bscale) c o m pare d t o place b o, at W ee k 6 
( Visit 3) a n d Wee k 1 2 ( Visit 4). 
•  Res p o n der a n al ysis: Res p o nse t o treat me nt defi n e d b y a n y of t he f oll o wi n g: 
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne t o Wee k 1 2 (e Diar y) wit h n o 
c ha n ge i n t he a m o u nt or stre n gt h of c o nc o mita nt a nal gesic me dicati o ns 
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne t o Wee k 1 2 (e Diar y) wit h a 
decrease i n t he a m o u nt or stre n gt h of c o n c o mita nt a nal gesic me dicati o ns 
•  Disc o nti n uati o n of st u d y me dicati o n d ue t o treat m e nt fail ure ( % meeti n g treat me nt fail ure 
criteria a n d ti me t o e ve nt)  
 
1 0. 4. 2. 5  Sec o n d ar y Effic ac y E n d p oi nts A n al yse s 
F or t he f oll o wi n g dic h ot o m o us sec o n dar y efficac y e n d p oi nts, t he rates f or eac h treat me nt gr o u p 
a n d t he differe nce bet w ee n t he treat me nt gr o u ps will be prese nte d wit h c orres p o n di n g 9 5 % CIs. 
A C oc hra n – Ma nt el – Hae nszel test will be use d t o test f or differe nces i n rat es bet wee n t h e 
treat me nt gr o u ps c o ntr olli n g f or b aseli ne pel vic p ai n. 
•  Treat me nt r es p o nse  as d efi ne d b y m eeti n g eit her of t he f oll o wi n g:  
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne  t o Wee k 1 2 usi n g a 
sta n dar dize d 1 1- p oi nt N R S wit h n o c ha n ge i n t he a m o u nt or stre n gt h of c o nc o mita nt 
a nal gesic me dicati o ns  
o  Decr ease i n ma xi m u m dail y pel vic pai n fr o m Baseli ne  t o Wee k 1 2 usi n g a 
sta n dar dize d 1 1- p oi nt N R S wit h a decreas e i n t he a m o u nt or stre n gt h of c o nc o mita nt 
a nal gesic me dicati o ns  
•  A ≥3 0 % a n d ≥5 0 % i m pr o ve me nt i n ma xi m u m dail y pel vic pai n ( usi n g t he 1 1- p oi nt N R S 
rec or d e d b y e Di ar y a n d t he NI H- C P SI pai n s u bscale), at Wee k s 6 ( Visit 3) a n d 1 2 ( Visit 
4).  
•  Disc o nti n uati o n of st u d y me dicati o n d ue t o treat m e nt fail ure ( % meeti n g treat me nt fail ure 
criteria a n d ti me t o e ve nt)  
 
T he f oll o wi n g c ha n ge fr o m Baseli ne  t o Wee k  1 2 e n d p oi nts will be a nal yz e d i n a ma n ner si milar 
t o t he pri mar y efficac y a nal ysis as d escri be d i n S e cti o n 1 0. 4. 2. 3 . 
•  NI H - C P SI p ai n s u bscale a n d all d o mai ns t otal sc ore.  
•  Male se x ual healt h as meas ure d usi n g t he II E F -E F.  
•  Mea n of a v era ge dail y pel vic pai n sc ores (e Diar y), dail y pel vic p ai n (i n cli nic), a n d 
ma xi m u m dail y pel vic pai n (i n cli nic).  
•  2 4- h o ur v oi di n g fre q u e nc y 
A d diti o nall y, f or t he II E F- E F d o mai n e n d p oi nt, t he fre q u e nc y distri b uti o n of t he 5 cate g or y 
II E F-E F s c ore (i.e. des cri be d i n  A p p e n di x 5. I nt er n ati o n al I n d e x of Er e ctil e F u n cti o n 
Q u esti o n n air e ) will be prese nte d b y tr eat me nt gr o u p f or Wee k 1 2 as w ell as a s hift ta ble fr o m 
Baseli ne . Treat me nt gr o u p differe n ce i n t he 5-cate g or y II E F-E F will be ass esse d b y a C oc hra n -
Ma ntel -Hae nszel ( C M H) test c o ntr olli n g f or Bas eli ne  II E F-E F sc ore.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 2  of 8 0  
 
T he f oll o wi n g ti me c o urs e sec o n dar y e n d p oi nts will be assesse d b y M M R M A N C O V A m o del 
w here t he c ha n ge fr o m Baseli ne  is t he de pe n d e nt varia ble a n d li near tre n ds acr oss ti me (i.e., 
visit) are assess e d.  
Ti me c o urse of eff ects: A Q X - 1 1 2 5 ( 2 0 0 m g o nce- dail y) c o m pare d t o place b o o n the c ha n ge fr o m 
Baseli ne ( Visit 2) t o Wee k 6 ( Visit 3), Wee k 1 2 ( Visit 4) a n d Wee k 1 6 (i.e. 4 wee ks after e n d of 
treat me nt) f or eac h of t he f oll o wi n g:  
•  Mea n of ma xi m u m dail y pel vic pai n sc ore (e Di ar y).  
•  NI H - C P SI p ai n s u bscale a n d all d o mai ns t otal sc ore.  
•  II E F-E F.  
•  Mea n of a v era ge dail y pel vic pai n sc ores (e Diar y), dail y pel vic p ai n (i n cli nic), a n d 
ma xi m u m dail y pel vic pai n (i n cli nic).  
•  2 4- h o ur v oi di n g fre q u e nc y.  
F or t he f oll o wi n g sec o n d ar y e n d p oi nts, t he fre q ue nc y distri b uti o n of eac h res p o nse scale will be 
prese nte d b y tr eat me nt gr o u p. F or t he G R A a n d P GI- C, treat me nt gr o u p differe nces will be 
assesse d b y mea ns of a c hi -s q uare test. F or t he P GI-S, treat me nt differe nces will be assesse d b y 
mea ns of a C M H test c o ntr olli n g f or Baseli ne  P GI - S.  
•  Res p o nse t o t reat me nt as meas ure d b y t he G R A , P GI- C, P GI- S at Wee k 1 2 ( Visit  4).  
1 0. 4. 2. 6  C o ntr ol f or M ulti plicit y  
T he T y pe 1 err or rate f or t he pri mar y e n d p oi nt a n al ysis is at t he 0. 0 5 le vel ( 2-si de d). T he T y p e I 
err or rate will n ot be c o ntr olle d f or t he sec o n dar y efficac y e n d p oi nts.  
1 0. 4. 2. 7  I nteri m a n al yses 
T here are n o i nteri m a nal ys es pla n n e d f or t his trial.  
1 0. 4. 3  
S afety D at a  
Safet y a nal yses will be base d o n t he Safet y P o p ul ati o n. Safet y d ata will be prese nte d b y 
treat me nt gr o u ps. Des cri ptive statistics will be prese nte d; i nfere ntial  statistical tests  will n ot be 
perf or me d.  
T he safet y assess me nts i ncl u de A Es, cli nical la b orat or y tests, p h ysical e x a mi nati o n, vital si g ns, 
a n d E C G assess me nts . C ha n ge fr o m Bas eli ne  will be s u m marize d f or safet y la b orat or y tests, 
vital si g ns, a n d E C G assess me nts. S hif t ta bles f or t he la b tests ( hi g h, l o w or n or mal) will als o be 
prese nte d.  
All A Es will be classifie d acc or di n g t o t he M e d D R A dicti o nar y. A Es will be s u m marize d b y t he 
n u m ber a n d perce nt a ge of s u bjects e x perie nci n g a n y A E, a n y S A E, a n d a n y A E lea di n g t o st u d y 
disc o nti n uati o n d uri n g t h e treat me nt peri o d. A Es will als o be s u m marize d b y 1) S yste m Or ga n 
Class  ( S O C) a n d Preferre d Ter m  ( P T); 2) S O C , PT,  a n d se verit y; a n d 3) S O C , P T, a n d 
relati o ns hi p t o st u d y dr u g.  
O p ht hal mic safet y  will b e s u m marize d b y treat me nt gr o u ps i ncl u di n g: assess me nt of le ntic ular 
o p acificati o n usi n g L O C S III, B C V A usi n g t he L o g M A R  c h art, I O P, c or n eal stai ni n g, a n d slit 
la m p e x a mi nati o n at Baseli ne a n d 6 m o nt hs p ost last d ose, a n d at E T. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 3  of 8 0  
 
1 1  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Q ualit y Ass ur a nce ( Q A) a n d Q ualit y C o ntr ol s yst e ms will be i m ple me nte d a n d mai ntai ne d wit h 
Sta n dar d O per ati n g P r o ce d ures, as a p pr o pri ate, t o e ns ure t hat t his cli nical st u d y is c o n d ucte d a n d 
data  ar e ge nerate d, d o c u me nte d a n d re p orte d i n c o m plia nce wit h t he pr ot o c ol, I C H E 6 G C P , a n d 
a p plica ble r e g ulat or y r e q uire me nt s. 
Bef ore e nr olli n g a n y s u bject s i n t his st u d y, a S p o ns or re prese ntati ve a n d t h e I n vesti gat or will 
re vie w t he pr ot oc ol, I B, e C R Fs a n d i nstr ucti o ns f or t heir c o m pleti o n, as well as t he pr oce d ures 
f or o btai ni n g i nf or me d c o nse nt a n d f or re p orti n g A Es a n d S A Es. A q ualifi e d re prese ntati ve of 
t he S p o ns or will m o nit or t he c o n d uct of t he st u d y b y visiti n g t he site a n d b y c o nt acti n g t he site 
b y tele p h o n e a n d e mail. D uri n g site visits, t he st u d y m o nit or will ass ure acc urate a n d relia ble 
data c ollecti o n b y verif yi n g t he i nf or mati o n rec or de d o n t he e C R Fs a gai nst s o urce d oc u m e nts 
a n d me dical r ec or ds (i.e.  s o urce d oc u m e nt verificati o n).  
Meas ures will be u n d erta ke n t o pr o tect t he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y s u bjects 
res pecti n g t he pri v ac y a n d c o nfi de ntialit y r ules i n acc or d a nce wit h a p plica ble re g ulat or y 
re q uire me nts. 
1 2  
D O C U M E N T A TI O N A N D I N S P E C TI O N S  
1 2. 1  
St u d y M o nit ori n g  
T he S p o ns or has res p o nsi bilit y t o g o ver ni n g re g ul at or y a ut h orities t o ta ke all reas o na ble ste ps t o 
e ns ure t he pr o per c o n d uct of t he st u d y wit h res p ect t o trial et hics, pr ot oc ol a d here n ce, a n d data 
i nte grit y a n d v ali dit y. 
T his trial will be cl osel y m o nit ore d b y S p o ns or re prese ntati ves t hr o u g h o ut its d urati o n. 
M o nit ori n g will be i n t he f or m of pers o n al visits wit h t he I n v esti gat or a n d staff as w ell as a n y 
a p pr o priate c o m m u nicati o ns b y tele p h o n e, telefa x, mail, or e -mail tra ns missi o n. T he p ur p ose of 
t hese c o ntacts is t o re vi e w trial pr o gress, I n v esti gat or a n d s u bject a d here nce t o t he pr ot oc ol, a n d 
t o deter mi ne if t her e ar e a n y pr o ble ms ass ociat e d wit h t he c o n d uct of t he st u d y. T he f oll o wi n g 
ma y b e assesse d d uri n g site m o nit ori n g visits:  
•  Re q uire d re g ulat or y d oc u me ntati o n 
•  Si g ne d I C Fs 
•  S u bject  accr u al an d f oll o w- u p 
•  St u d y dr u g i n ve nt or y r ec or ds 
•  I n v esti gat or a n d s u bject c o m plia nce t o t he st u d y pr ot oc ol 
•  C o nc o mita nt me dicati o n use 
•  A E  d oc u me ntati o n 
•  Pr ot oc ol de viati o n d oc u me ntati o n 
•  Data ar e  acc ur ate, c o m pl ete, a n d verifia ble w h e n c o m pare d t o s o urce d oc u me nts 
T he I n vesti gat or a n d st u d y staff ar e e x pecte d t o c o o perate wit h m o nit ors d uri n g s uc h visits a n d 
pr o vi de all rele v a nt st u d y d oc u me nts. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 4  of 8 0  
 
1 2. 2  
A u dits a n d I ns pecti o ns  
All d oc u me ntati o n pertai ni n g t o t his cli nical trial ma y b e s u bject t o a Q A a u dit b y t he S p o ns or, 
or Re g ul at or y A ut h orities (e. g., t he F D A). U p o n re q uest, t he a u dit or will h a ve access t o i ns pect, 
c o p y, re vie w, a n d a u dit all s o urce d oc u me nts, e C R Fs, me dical rec or ds, c orres p o n de n ce, a n d 
I C Fs pertai ni n g t o t he s u bjects i n t he trial. T he I n vesti gat or a grees t o pr o m ptl y ta ke a n y 
reas o na bl e ste ps t hat ar e re q ueste d b y t he S p o ns or as a res ult of a n a u dit t o c ure deficie n cies i n 
t he st u d y d oc u me nts a n d eC R Fs.  Ot her d oc u m e ntati o n s u bject t o Q A a u dit i ncl u des t he I R B/I E C 
files, certificati o n a n d q u alit y c o ntr ol of s u p p orti n g la b orat ories, a n d rec or ds rele va nt t o t he trial 
i n a n y s u p p orti n g p har mac y facilities. C o n diti o ns of st ora ge of st u d y materials are als o s u bject t o 
i ns pecti o n. S p o ns or re prese ntati ves ma y o bser v e t he c o n d uct of a n y as pect of t he cli nical trial or 
its s u p p orti n g acti vities b ot h wit hi n a n d o utsi de of t he I n v esti gat or's i nstit uti o n. 
1 3  
E T HI C A L A N D L E G A L I S S U E S  
1 3. 1  
Et hic al C o n d uct/ G o o d Cli nic al Pr actice  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he et hical pri nci ples t hat ha ve t heir ori gi n i n 
t he c urr e nt Decl arati o n of Helsi n ki a n d will be c o nsiste nt wit h I C H G C P a n d a p plica ble 
re g ulat or y r e q uire me nts.  
1 3. 2  
I nstit uti o n al Re vie w B o ar d/I nde pe n de nt  Et hics C o m mittee  
T his st u d y m ust be re vie we d a n d a p pr o ve d b y t he I R B /I E C re prese nti n g t h e i nstit uti on pri or t o 
e nr olli n g patie nts. T h e I R B /I E C m ust be a p pr o priatel y c o nstit ute d a n d meet all re q uire me nts as 
descri be d i n Part 5 6, Titl e 2 1 of t he C F R  a n d l ocal la ws a n d re g ulati o ns, as a p plica ble. T he 
re vie w m ust i ncl u de b ot h t he pr ot oc ol a n d t he I C F f or t he trial. A c o p y of t he Letter or N otice of 
A p pr o val fr o m t he I R B /I E C m ust be recei ve d b y t he S p o ns or pri or t o s hi p me nt of dr u g s u p plies 
t o t he I n v esti gat or. T he I R B /I E C me m bers hi p list m ust be s u b mitte d t o t he S p o ns or wit h t he 
writte n I R B /I E C a p pr o val a n d up date d lists, if a p plica ble.  
T he I n vesti gat or m ust pr o m ptl y re p ort all c ha n ges i n t he researc h acti vit y a n d all u na ntici pate d 
pr o ble ms i n v ol vi n g ris k t o t he s u bjects or ot hers t o t heir I R B/I E C. T he I n v esti gat or will pr o vi de 
pr o gress r e p orts as r e q uir e d b y t h e I R B/I E C. T h e I n vesti gat or is res p o nsi ble f or ass uri n g 
c o nti n ui n g re vi e w a n d a p pr o val of t he cli nical st u d y o n a n a n n ual basis a n d s u b mitti n g 
d oc u me ntati o n of re n e wal t o t he S p o ns or. T he I n v esti gat or will gi ve n otice t o t he I R B /I E C w he n 
partici pati o n i n  t he st u d y has bee n c o m plet e d. 
1 3. 3  
Writte n I nf or me d C o nse nt  
T he I n vesti gat or a grees t o pr otect t he ri g hts, safet y, a n d welfare of t h e s u bject s e ntere d i nt o t he 
st u d y, i ncl u di n g o bt ai ni n g writte n i nf or me d c o ns e nt pri or t o perf or mi n g a n y st u d y-relate d 
pr oce d ur es a n d i nf or mi n g eac h s u bject t hat t he st u d y dr u g is bei n g us e d f or i n vesti gati o nal 
p ur p oses. A c o p y of t h e I R B -a p pr o v e d I C F t o b e use d d uri n g t h e st u d y m ust be s u b mitte d f or 
S p o ns or re vie w pri or t o st u d y i nitiati o n. 
Pri or t o e ntr y i nt o t he st u d y, t he p ur p ose a n d n at ure of t he st u d y a n d p ossi ble a d vers e effects 
m ust be e x plai ne d t o eac h patie nt. All q uesti o ns a b o ut t he st u d y s h o ul d be a ns were d t o t he 
patie nt’s satisfacti o n or t he patie nt’s le gal re pres e ntati ve. It is t he res p o nsi bilit y of t h e 
I n v esti gat or or desi g nee t o o btai n writte n i nf or me d c o nse nt fr o m eac h pati e nt, t here b y attesti n g 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 5  of 8 0  
 
t hat c o nse nt was freel y gi ve n. A c o p y of t h e si g n e d a n d date d I C F will be gi ve n t o t he patie nt.  
D oc u me ntati o n of t he i nf or me d c o nse nt pr o cess m ust be e vi de nt i n t he patie nt’s cli nical files, 
a n d t he ori gi nal e x ec ute d I C F m ust be a vaila ble f or re vie w b y t h e st u d y m o nit or.  
I n t he e ve nt t hat m o dificati o ns i n t he ex peri me ntal desi g n, d osa ges, tests a n d assess me nts, 
s u bject selecti o n, etc., of t he pr ot oc ol are i n dicate d or re q uire d, a n d i n t he e ve nt t hat s uc h 
m o dificati o ns s u bsta ntiall y alter t h e st u d y d esi g n or i ncrease t he p ote ntial ris k t o s u bjects, 
re visi o ns t o the e xisti n g I C F are als o re q uire d . S uc h a re visi o n will be re vie we d a n d a p pr o ve d b y 
t he a p pr o priat e I R B, a n d d oc u me ntati o n of t his a p pr o val will be f or w ar de d t o t he S p o ns or f or 
s u b missi o n t o t he a p pr o priate re g ul at or y b o d y.  
I n a d diti o n, all c urre nt st u d y partici pa nts, as well as s u bse q ue nt st u d y ca n di dates, will be 
i nf or me d of t he st u d y desi g n m o dificati o n or i ncrease i n p ote ntial ris k, a n d writte n i nf or me d 
c o nse nt will be o btai ne d. 
1 3. 4  
Rec or ds a n d C ase Re p o rt F or ms  
T he I n vesti gat or is r e q uir e d t o pre pare a n d m ai ntai n a de q uate a n d acc urate case hist ories 
desi g ne d t o rec or d all o bser vati o ns a n d ot her d ata perti ne nt t o t he i n vesti gati o n o n eac h 
i n di vi d ual treate d wit h t he st u d y dr u g. Data re p ort e d o n t he e C R F t hat are d eri ve d fr o m s o urce 
d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre p a ncies m ust be e x plai ne d. 
All re q ueste d i nf or m ati o n m ust be e ntere d o n t he e C R F i n t he fiel ds pr o vi d e d.  
1 3. 5  
Pr ot oc ol D e vi ati o ns 
T he st u d y is t o be c o n d u cte d as des cri be d i n t his pr ot oc ol wit h o ut de viati o n u nless t he re is a 
safet y c o n cer n. T h e pr ot o c ol s h o ul d n ot be m o difie d f or a n y s u bject wit h o ut t he pri or c o nse nt of 
t he S p o ns or a n d, if necessar y, t he I R B /I E C res p o nsi ble at t he i n vesti gati ve site. 
I n t he e ve nt of a vi olati o n, a re p ort will be s u b mitte d t o t he I R B/I E C (as a p plica ble). 
1 3. 6  
Ter mi n ati o n of t he St u d y  
S h o ul d t he S p o ns or a n d/ or t he I n vesti gat or disc o v er c o n diti o ns d uri n g t h e c o urse of t he trial t hat 
i n dicate t hat t he st u d y s h o ul d be disc o nti n ue d, a n a p pr o priate pr oce d ure f or ter mi nati o n will be 
i nstit ute d. 
Reas o ns f or t he cl os ure of a st u d y site or ter mi nati o n of a st u d y b y t h e S p o ns or ma y i n cl u de ( b ut 
are n ot li mite d t o) t he f oll o wi n g:  
•  S uccessf ul c o m pleti o n of t he st u d y at t he st u d y site  
•  T he re q uir e d n u m ber of s u bjects f or t he st u d y has bee n recr uite d 
•  Fail ur e of t he I n vesti gat or  t o c o m pl y wit h t he pr ot oc ol, G C P g ui deli nes or re g ul at or y 
re q uire me nts 
•  Safet y c o ncer ns  
•  I n a de q uat e recr uit me nt of s u bjects b y t he I n vesti gat or 
1 3. 7  
Rete nti o n of Rec or ds  
T he I n vesti gat or/I nstit uti o n s h o ul d mai ntai n t he st u d y d oc u m e nts as s pe cifi e d i n t he I C H 
g ui deli nes o n G C P a n d as re q uire d b y t he a p plica ble re g ulat or y re q uire m e nts. Ca na dia n fe deral 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 6  of 8 0  
 
la w re q uir es all rec or ds create d d uri n g t h e c o n d uct of a cli nical trial f or 2 5 years u n der Di visi o n 
5 of t he Healt h Ca n a da F o o d a n d Dr u g Re g ulati o ns. U S fe deral la w re q uires t hat t he I n v esti gat or 
retai n c o pies of all files p ertai ni n g t o t he trial (i.e. me dical rec or ds, la b orat or y re p orts, dr u g 
i n ve nt or y/ dis p ositi o n rec or ds, si g ne d I C Fs, e C R Fs, all c orres p o n d e nce, d at es a n d re p orts of 
m o nit ori n g visits) f or a p eri o d of 2 years f oll o wi n g t he d ate of mar keti n g a p plicati o n a p pr o val of 
t he dr u g f or t he i n dicati o n i n vesti gate d i n t he st u d y, a n d u ntil t here is n o pe n di n g or 
c o nte m plate d mar k eti n g a p plicati o n, or f or 2 years f oll o wi n g t he S p o ns or’s disc o nti n ui n g 
w orl d wi de cli nical de v el o p me nt of t he st u d y dr u g, as n otifie d b y t h e S p o ns or, w hic he ver is 
l o n ger.  
If t he I n vesti gat or rel ocat es, retires, or wit h dra ws f or a n y reas o n fr o m t he st u d y, trial rec or ds 
ma y b e tra nsf err e d t o a n acce pta ble desi g nee, s uc h as a n ot her I n vesti gat or wit hi n t he i nstit uti o n.  
Pri or n otice of s uc h tra nsfer will be pr o vi de d i n writi n g t o t he S p o ns or. T h e I n vesti gat or m ust 
o btai n writte n per missi o n fr o m t he S p o ns or pri or t o dis p osi n g of a n y rec or ds.  
1 4  
I N V E S TI G A T O R R E S P O N SI BI LI TI E S 
A n I n vesti gat or c o n d u cti n g a cli nical st u d y wit h a n i n vesti gati o nal a ge nt is re q uire d t o c o m pl y 
wit h re g ul ati o ns descri be d i n t he U S C F R , Title 2 1 Part 3 1 2, I C H G C P  g ui deli nes, as well as 
l ocal la ws a n d r e g ulati o ns.  
T he I n vesti gat or: 
•  Will pers o nall y c o n d uct or s u per vise t he c o n d uct of t he st u d y. T h e I n vesti gat or will 
e ns ure t hat all s u b-I n v esti gat ors a n d ot hers assisti n g i n t he trial are a de q uat el y i nf or me d 
a b o ut t he pr ot oc ol, t he st u d y dr u g, a n d t heir trial-relate d d uties a n d f u n cti o ns. 
•  Will ma ke c ha n ges t o t he c o n d uct of t he trial o nl y after recei vi n g t he S p o ns or’s a p pr o v al, 
e x ce pt t o pr otect t he saf et y, ri g hts, or w elfare of s u bject s. 
•  Will n ot discl ose a n y g o o ds, materials, i nf or mati o n ( oral or writte n) a n d u n p u blis he d 
d oc u me ntati o n pr o vi de d b y t he S p o ns or (i n cl u di n g t his pr ot oc ol, t he s u bject e C R Fs, a n d 
t he I B) t o a n y u na ut h orize d pers o n wit h o ut t he S p o ns or’s pri or writte n c o nse nt. 
•  Will mai ntai n a S u bject  Scree ni n g L o g listi n g all s u bjects e ntere d i nt o t he trial, t h ose 
c o nsi dere d f or trial e ntr y a n d s u bse q ue ntl y e x cl u de d, a n d t he reas o n f or e x cl usi o n. 
•  Will st ore st u d y dr u g i n a sec ure l o cati o n, u n der t h e c o n diti o ns i n dicate d i n S e cti o n 8. 9 , 
a n d will mai ntai n a Dr u g I n v e nt or y F or m. Will destr o y use d s u p plies i n a n a p pr o priate 
ma n ner acc or di n g t o i nstit uti o nal p olic y a n d d oc u me nt s uc h destr ucti o n. At t he 
c o m pleti o n of t he trial, t he I n vesti gat or will ret ur n all u n use d trial materials t o t he 
S p o ns or, u nless ot her wise a ut h orize d i n writi n g. 
•  Will rec or d trial data o n eC R Fs f or eac h s u bject w h o recei ves a n y a m o u nt of st u d y dr u g, 
i ncl u di n g t h ose w h o wit h dra w bef ore c o m pleti o n of t he trial. Will e ns ure t he acc urac y, 
c o m plete ness, le gi bilit y,  a n d ti meli ness of t he data re p orte d o n t he e C R F a n d i n re q uire d 
re p orts. Will re vie w eC R Fs f or c o m plete ness a n d acc urac y pri or t o s u b missi o n f or data 
e ntr y. 
•  Will i ncl u de s o urce d oc u me nts s uc h as h os pital, cli nic, or office c harts; la b orat or y 
re p orts; trial w or ks heets; a n d si g ne d I C Fs i n t he I n vesti gat or’s files al o n g wit h s u bject 
trial rec or ds. Will i ncl u de i n t he I C F a stat e me nt all o wi n g t he S p o ns or ( or d esi g nee), as 
well as a ut h orize d re g ulat or y a ge ncies, t o h a ve direct access t o s o urce data t hat s u p p ort 
data re p orte d o n t he e C R F.  


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 7  of 8 0  
 
•  Will per mit direct m o nit ori n g a n d a u diti n g b y t he S p o ns or or S p o ns or ’s re prese ntati ves 
a n d i ns pecti o n b y t h e a p pr o priate re g ulat or y a ut h orities. 
•  Will pr o vi de t he S p o ns or wit h t he n or mal la b orat or y ra n ges f or t he la b orat ories t o be 
use d i n t he trial as well as t he la b orat or y certificati o n n u m ber.  Will pr o vi de c o pies of a n y 
a d diti o nal rec or ds p erti ne nt t o t he trial (e . g., ra di ol o g y re p orts, c h art s u m maries, a ut o ps y 
re p orts) t o t he S p o ns or or re g ulat or y a ut h orities, if re q ueste d, wit h d ue preca uti o n ta ke n 
t o e ns ure s u bject c o nfi de ntialit y.  
•  Will mai ntai n s u bject c o nfi de ntialit y at all ti mes d uri n g t he tri al b y usi n g c o de d 
i de ntifiers w he n r eferri n g t o a partic ular s u bject (i ncl u di n g i n a n y p u blicati o ns). 
•  Will i nf or m s u bjects t hat t he st u d y dr u g is bei n g use d f or i n vesti gati o nal p ur p oses 
•  Will re p ort t o t he S p o ns or a n y A Es t hat occ ur d uri n g t he trial i n acc or da nce wit h I C H, 
C F R 2 1 Part 3 1 2. 6 4 a n d l ocal la ws. 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 8  of 8 0  
 
1 5  
R E F E R E N C E S  
C hr o ni c n o n b a ct eri al pr ost atitis ( c hr o ni c p el vi c p ai n s y n dr o m e). H ar v ar d H e alt h P u blis hi n g, 
H ar v ar d M e di c al S c h o ol, H ar v ar d P ers p e cti v es o n Pr ost at e Dis e as e , ac c ess e d 0 7 N o v 2 0 1 7, 
w w w. h e alt h. h ar v ar d. e d u/ n e wsl ett er _ arti cl e/ c hr o ni c -n o n b a ct eri al -pr ost atitis -c hr o ni c -p el vi c -
p ai n . 
Kr o n e n k e K., S pit z er R. L., Willi a ms J. B., T h e P H Q -9: v ali dit y of a bri ef d e pr essi o n s e v erit y 
m e as ur e. J G e n I nt er n M e d, 2 0 0 1. 1 6( 9): p. 6 0 6 -1 3 . 
Lit wi n M S, M c N a u g ht o n -C olli ns M, F o wl er FJ, et al. T h e N ati o n al I nstit ut es of H e alt h 
c hr o ni c pr ost atitis s y m pt o m i n d e x: d e v el o p m e nt a n d v ali d ati o n of a n e w o ut c o m e  m e as ur e. J 
Ur ol. V ol. 1 6 2, 3 6 9 -3 7 5, A u g ust 1 9 9 9.  
Ni c k el, J C. I nfl a m m at or y a n d P ai n C o n diti o ns of t h e M al e G e nit o uri n ar y Tr a ct: Pr ost atitis 
a n d R el at e d P ai n C o n diti o ns, Or c hitis, a n d E pi di d y mitis. I n: C a m p b ell -W als h Ur ol o g y, 
Els e vi er ; 2 0 1 7: 3 0 4 -3 3 3 e 1 3 . 
R o d di c k, J, Hi g u er a V. C hr o ni c N o n b a ct eri al Pr ost atitis. H e alt hli n e , H e alt hli n e M e di a, 2 5 
A u g 2 0 1 7, a c c ess e d 0 7 N o v 2 0 1 7, w w w. h e alt hli n e. c o m/ h e alt h/ pr ost atitis -n o n b a ct eri al -
c hr o ni c . 
R os e n R, Ril e y A, W a g n er G, et al. T h e I nt er n ati o n al I n d e x of Er e ctil e F u n cti o n (II E F): A 
m ulti di m e nsi o n al s c al e f or ass ess m e nt of er e ctil e d ysf u n cti o n. Ur ol o g y, 1 9 9 7, 4 9: 8 2 2 -8 3 0.  
S h os k es D A, a n d Ni c k el J C. Cl assifi c ati o n a n d tr e at m e nt of m e n wit h c hr o ni c 
pr ost atitis/ c hr o ni c p el vi c p ai n s y n dr o m e usi n g t h e U P OI N T s yst e m. W orl d J Ur ol. 2 0 1 3 
A u g; 3 1( 4): 7 5 5 -6 0.  
S ulli v a n M , T h or n B , H a yt h or nt h w ait e J , et al. T h e or eti c al P ers p e cti v es o n t h e R el ati o n 
B et w e e n C at astr o p hi zi n g a n d P ai n . T h e Cli ni c al J o ur n al of P ai n  (2 0 0 1 ) 1 7 : 1 5 2 -6 4.  
S ulli v a n MJ L, Bis h o p S, Pi vi k J. T h e p ai n c at astr o p hi zi n g s c al e: d e v el o p m e nt a n d 
v ali d ati o n. Ps yc h ol Ass ess  (1 9 9 5 ) 7: 5 2 4 -5 3 2.  
St e nt o n G R, M a c k e n zi e L F, T a m P, Cr oss J L, H ar wi g C, R a y m o n d J, T o e ws J, W u J, O g d e n 
N, M a c R ur y T, a n d S z a b o C. C h ar a ct eri z ati o n of A Q X -1 1 2 5, a s m all -m ol e c ul e S HI P 1 
a cti v at or P art 1. Eff e cts o n i nfl a m m at or y c ell a cti v ati o n a n d c h e m ot a xis i n vitr o a n d 
p h ar m a c o ki n eti c c h ar a ct eri z ati o n i n vi v o. BJ P ( 2 0 1 3) 1 6 8 1 5 0 6 – 1 5 1 8.  
St e nt o n G R, M a c k e n zi e L F, T a m P, Cr oss J L, H ar wi g C, R a y m o n d J, T o e ws J, C h er n off D, 
M a c R ur y T, a n d S z a b o  C. C h ar a ct eri z ati o n of A Q X -1 1 2 5, a s m all -m ol e c ul e S HI P 1 
a cti v at or. P art 2. Effi c a c y st u di es i n all er gi c a n d p ul m o n ar y i nfl a m m ati o n m o d els i n vi v o. 
BJ P ( 2 0 1 3) 1 6 8 1 5 1 9 – 1 5 2 9 1 5 1 9 .


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
 
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 5 9  of 8 0  
 
1 6  
A P P E N DI C E S  
A p pe n di x 1. P ai n C at astr o p hizi n g Sc ale 
 
 
 
 


Ψ   
C o p yri g ht  1 9 9 5  
 Mic hael J L S ulli va n   
P C S
 
A g e: _ _ _ _ _  
S e x:  
M( _ _)  
F( _ _)  
 
E v er y o n e e x p eri e n c e s p ai nf ul sit u ati o n s at s o m e p oi nt i n t h eir li v e s. T h e s e e x p eri e n c e s m a y i n cl u d e 
h e a d a c h e s, t o ot h p ai n, j oi nt or m u s cl e p ai n. P e o pl e ar e oft e n e x p o s e d t o sit u ati o n s t h at m a y c a u s e 
p ai n s u c h a s ill n e s s, i nj ur y, d e nt al pr o c e d ur e s or s ur g er y.  
 
W e ar e i nt er e st e d i n t h e t y p e s of t h o u g ht s a n d f e eli n g s t h at y o u h a v e w h e n y o u ar e i n p ai n. T hirt e e n 
st at e m e nt s ar e li st e d b el o w d e s cri bi n g diff er e nt t h o u g ht s a n d f e eli n g s t h at m a y b e a s s o ci at e d wit h 
p ai n. U si n g t h e f oll o wi n g s c al e, pl e a s e i n di c at e t h e d e gr e e t o w hi c h y o u h a v e t h e s e t h o u g ht s a n d 
f e eli n g s w h e n y o u ar e e x p eri e n ci n g p ai n. 
 
0  ‒  n ot at all  1  ‒  t o a sli g ht d e gr e e 2  ‒  t o a m o d er at e d e gr e e 3  ‒  
t o a gr e at d e gr e e 4  ‒  all t h e ti m e  
 
W he n I’ m i n p ai n... 
1  
I w orr y all t he ti me a b o ut w het her t he pai n will e n d. 
2  
I feel I ca n’t g o o n. 
3  
It’s terri ble a n d I t hi n k it’s ne ver g oi n g t o get a n y better. 
4  
It’s a wf ul a n d I feel t hat it o ver w hel ms me. 
5    I feel I ca n’t sta n d it a n y m ore. 
6  
 I bec o me afrai d t hat t he pai n will get w orse. 
7  
I kee p t hi n ki n g of ot her pai nf ul e ve nts. 
8  
I a n xi o usl y wa nt t he pai n t o g o a wa y. 
9  
I ca n’t see m t o kee p it o ut of m y mi n d. 
1 0  
I kee p t hi n ki n g a b o ut h o w m uc h it h urts. 
1 1  
I kee p t hi n ki n g a b o ut h o w ba dl y I wa nt t he pai n t o st o p. 
1 2  
T here’s n ot hi n g I ca n d o t o re d uce t he i nte nsit y of t he pai n. 
1 3  
I w o n der w het her s o met hi n g seri o us ma y ha p pe n. 
 
 
 
... T ot al 
 
P C S - Unit e d S t at e s/ E n gli s h - V er si o n of 2 4 A pril  1 7 - M a pi.  
I D 0 5 8 1 2 7 / P C S _ AU 1. 0 _ e n g -U S . d o c 


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 6 1  of 8 0  
A p pe n di x 2. P a tie nt He alt h Q uesti o n n aire  9-Ite ms 


P A TI E N T H E A L T H Q U E S TI O N N AI R E ( P H Q- 9)
D A T E:
N A M E:
O v er t h e l a st 2 w e e k s, h o w oft e n h a v e y o u b e e n
b ot h er e d b y a n y of t h e f oll o wi n g pr o bl e m s ?
N ot at all
S e v er al
d a y s
M or e t h a n
h alf t h e
d a y s
N e arl y
e v er y d a y
( u s e "ⁿ " t o i n di c at e y o ur a n s w er)
0
1
2
3
Littl e i nt er e st or pl e a s ur e i n d oi n g t hi n g s
1.
0
1
2
3
F e eli n g d o w n, d e pr e s s e d, or h o p el e s s
2.
0
1
2
3
Tr o u bl e f alli n g or st a yi n g a sl e e p, or sl e e pi n g t o o m u c h
3.
0
1
2
3
F e eli n g tir e d or h a vi n g littl e e n er g y
4.
0
1
2
3
P o or a p p etit e or o v er e ati n g
5.
0
1
2
3
F e eli n g b a d a b o ut y o ur s elf   or t h at y o u ar e a f ail ur e or
h a v e l et y o ur s elf or y o ur f a mil y d o w n
6.
0
1
2
3
Tr o u bl e c o n c e ntr ati n g o n t hi n g s, s u c h a s r e a di n g t h e
n e w s p a p er or w at c hi n g t el e vi si o n
7.
0
1
2
3
M o vi n g or s p e a ki n g s o sl o wl y t h at ot h er p e o pl e c o ul d
h a v e n oti c e d. Or t h e o p p o sit e    b ei n g s o fi g et y or
r e stl e s s t h at y o u h a v e b e e n m o vi n g ar o u n d a l ot m or e
t h a n u s u al
8.
0
1
2
3
T h o u g ht s t h at y o u w o ul d b e b ett er off d e a d, or of
h urti n g y o ur s elf
9.
a d d c ol u m n s
+
+
T O T A L:
( H e alt h c ar e pr of e s si o n al: F or i nt er pr et ati o n of T O T A L,
pl e a s e r ef er t o a c c o m p a n yi n g s c ori n g c ar d).
N ot diffi c ult at all
If y o u c h e c k e d off a n y pr o bl e m s, h o w diffi c ult
h a v e t h e s e pr o bl e m s m a d e it f or y o u t o d o
y o ur w or k, t a k e c ar e of t hi n g s at h o m e, or g et
al o n g wit h ot h er p e o pl e ?
1 0.
S o m e w h at diffi c ult
V er y diffi c ult
E xtr e m el y diffi c ult
C o p yri g ht 
 1 9 9 9 Pfi z er I nc. All ri g hts res er v e d. Re pr o d uc e d wit h per missi o n. P RI M E- M D
 is a tr a de m ar k of Pfi zer I nc.
A 2 6 6 3 B 1 0- 0 4- 2 0 0 5
 
  
 
 
P A TI E N T H E A L T H Q U E S TI O N N AI R E ( P H Q- 9)
A q ui n o x A Q X- 1 1 2 5- 2 0 5 
S u bject Scree n N u m ber/ Ra n d o mizati o n N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _  
Visit Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ Visit N u m ber _ _ _ _ _ _ _ _ _ _ _ _ 


P H Q- 9 Patie nt De pressi o n Q uesti o n naire 
F or i niti al di a g n osis: 
1. 
Patie nt c o m pletes P H Q- 9 Q u ic k De pressi o n Assess me nt.
2.
If t here are at least 4 
s i n t he s ha de d secti o n (i ncl u di n g Q uesti o ns # 1 a n d # 2), c o nsi der a de pressi ve
dis or der. A d d sc ore t o deter mi ne se verit y.
C o nsi der M aj or De pressive Dis or der 
 
- if t here are at least 5 
s i n t he s ha de d secti o n ( o ne of w hic h c orres p o n ds t o Q uesti o n # 1 or # 2)
C o nsi der Ot h er De pressive Dis or der 
 
- if t here are 2- 4 
s i n t he s ha de d secti o n ( o ne of w hic h c orres p o n ds t o Q uesti o n # 1 or # 2)
N o te: Si nce t he questi o n naire relies o n patie nt self-re p ort, all res p o nses s h o ul d be verifie d b y t he cli nicia n, 
a n d a defi niti ve dia g n osis is ma de o n cli nical gr o u n ds ta ki n g i nt o acc o u nt h o w we ll t he patie nt u n derst o o d 
t he q uesti o n naire, as well as ot her releva nt i nf or mati o n fr o m t he patie nt.  
Dia g n oses of Maj or De pressi ve Dis or der or Ot her De pressi ve Dis or der als o re q uire i m p air me nt of s ocial, 
occ u pati o nal , or ot her i m p orta nt areas of f u ncti o ni n g ( Q uesti o n # 1 0) a n d r uli n g o ut n or mal berea ve me nt, a 
hist or y of a Ma nic E pis o de ( Bi p olar Dis or der), a n d a p h ysical dis or der, me dicati o n, or ot her dr u g as t he 
bi ol o gical ca use of t he de pressi ve s y m pt o ms.  
T o m o nit or se verit y o ver ti me f or ne wl y di a g n ose d p atie nts or p atie nts i n c urre nt tre at me nt f or 
de pressi o n: 
1. 
Patie nts ma y c o m plete q uesti o n naires at baseli ne a n d at re g ular i nter vals (e g, e ver y 2 wee ks) at
h o me a n d bri n g t he m i n at t heir ne xt a p p oi nt me nt f or sc ori n g or t he y ma y c o m plete t he
q uesti o n naire d uri n g eac h sc he d ule d a p p oi nt me nt.
2.  
A d d u p 
s b y c ol u m n. F or e ver y 
: Se veral da ys = 1 M ore t ha n half t he da ys = 2 Nearl y e ver y da y = 3
3.  
A d d t o get her c ol u m n sc ores t o get a T O T A L sc ore.
4. 
Refer t o t he acc o m pa n yi n g  P H Q- 9 Sc ori n g B o x t o i nter pret t he T O T A L sc ore.
5.
Res ults ma y be i ncl u de d i n patie nt files t o assist y o u i n setti n g u p a treat me nt g oal, deter mi ni n g de gree of
res p o nse, as well as g ui di n g treat me nt i nter ve nti o n.
Sc ori n g:  a d d u p all c hec ke d b o xes o n P H Q- 9 
F or e ver y   N ot at all = 0; Se veral da ys = 1; 
M ore t ha n half t he da ys = 2; Nearl y e ver y da y = 3 
I nter pret ati o n of T ot al Sc ore  
T ot al Sc ore 
De pressi o n Se verit y 
1- 4
 Mi ni mal de pressi o n 
5- 9
 Mil d de pressi o n 
1 0- 1 4
 M o derate de pressi o n
1 5- 1 9
 M o deratel y se vere de pressi o n 
2 0- 2 7
 Se vere de pressi o n
P H Q 9 C o p yri g ht © Pfizer I nc.  All ri g hts reser ve d .  Re pr o d uce d wit h per missi o n. P RI M E- M D ® is a 
tra de mar k of Pfizer I nc. 
A 2 6 6 2 B 1 0- 0 4- 2 0 0 5 
Versi o n 3 . 0/ A me n d me nt 2
A q ui n o x A Q X- 1 1 2 5- 2 0 5 
S u bject Scree n N u m ber/ Ra n d o mizati o n N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _  
Visit Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ Visit N u m ber _ _ _ _ _ _ _ _ _ _ _ _ 
C O N FI D E N TI A L
Pa ge 6 3  of 80


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 6 4  of 8 0  
A p pe n di x 3. 1 1- p oi nt N u meric al R ati n g Sc ale 


1 1- P oi nt N u meric al R ati n g Sc ale f or P ai n * ( Cli nic)
P E L VI C  P AI N C LI NI C A S S E S S M E N T  
Ple as e assess y o ur a ver a ge a n d w orst pel vic  p ai n f or e ac h d a y o n a sc ale of 0- 1 0: 
W h at n u m ber w o ul d y o u gi ve y o ur a ver a ge pel vic p ai n o ver t he l ast 2 4 h o urs ? 
N o  
    Pel vic   
Pel vic   0  
 1  
 2  
 3  
 4  
 5  
 6  
 7  
 8  
 9 
1 0     Pai n as ba d  
Pai n
as y o u ca n 
i ma gi ne 
W h at n u m ber w o ul d y o u gi ve y o ur w orst pel vic p ai n o ver t he l ast 2 4 h o urs ? 
N o  
     Pel vic  
Pel vic   0  
 1  
 2  
 3  
 4  
 5  
 6  
 7  
 8  
 9  
1 0      Pai n as  ba d    
Pai n  
           as y o u ca n   
          i ma gi ne 
*A da pte d fr o m Mc Caffer y, M. Bee be A, et al. ( 1 9 8 9). Pai n: Cli nical ma n ual f or n ursi n g practice,
M os b y St. L o uis, M
      0  
  1  
  2  
  3  
  4  
  5  
  6  
  7  
  8  
  9  
   1 0  
N o P el vic P ai n  
P el vic P ai n as 
b a d a s y o u 
c a n im a gi ne
Versi o n 3 . 0/ A me n d me nt 2
 
C O N FI D E N TI A L
Pa ge 6 5  of 8 0


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 6 6  of 8 0  
A p pe n di x 4. N ati o n al I nstit utes of He alt h  C hr o nic Pr ost atitis S y m pt o m I n de x 


A q ui n o x A Q X- 1 1 2 5- 2 0 5  
S u bj e ct S cr e e n N u m b er/ R a n d o mi z ati o n N u m b er _ _ _ _ _ _ _ _ _ _ _ _ _  
Vi sit D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ Vi sit N u m b er _ _ _ _ _ _ _ _ _ _ _ _  
NI H- C hr o ni c Pr o st atiti s S y m pt o m I n d e x ( NI H- C P SI) 
P ai n or Di s c o mf ort 
1. I n t h e l a st w e e k, h a v e y o u e x p eri e n c e d a n y p ai n or di s c o mf ort 
i n t h e f oll o wi n g ar e a s ? 
 Y e s      
   N o 
a. 
Ar e a b et w e e n r e ct u m a n d  
    ❑1        
     ❑0 
t e sti cl e s ( p eri n e u m) 
b.  T e sti cl e s
   ❑1         
    ❑0 
c.  Ti p of t h e p e nis ( n ot r el at e d t o      ❑1  
    ❑0 
uri n ati o n) 
d.  B el o w y o ur w ai st, i n y o ur 
    ❑1        
     ❑0 
p u bi c or bl a d d er ar e a 
2.  I n t h e l a st w e e k, h a v e y o u e x p eri e n c e d: 
  Y e s     
    N o 
a. 
P ai n or b ur ni n g d uri n g
      ❑1       
  ❑0 
uri n ati o n ? 
b. 
P ai n or disc o mf ort d uri n g or
 ❑1       
    ❑0 
aft er s e x u al cli m ax ( ej ac ul ati o n) ? 
3.  H o w oft e n h a v e y o u h a d p ai n or di s c o mf ort i n a n y of 
t h e s e ar e a s o v er t h e l a st w e e k ? 
❑ 0 N e v er 
❑ 1 R ar el y
❑ 2 S o m eti m es 
❑ 3 Oft e n 
❑ 4 U s u all y 
❑ 5 Al w ays 
4.  
W hi c h n u m b er b e st d e s cri b e s y o ur A V E R A G E p ai n or
di s c o mf ort o n t h e d a y s t h at y o u h a d it, o v er t h e l a st w e e k ? 
❑ 
❑   ❑  ❑    ❑ 
❑    ❑ 
❑    ❑ 
❑   ❑
0      1      2     3        4      5       6     7      8     9     1 0 
N O        
 P AI N A S 
P AI N
B A D A S 
  Y O U C A N 
 I M A GI N E 
Uri n ati o n 
5.  
H o w oft e n h a v e y o u h a d a s e n s ati o n of n ot e m pt yi n g y o ur bl a d d er 
c o m pl et el y aft er y o u fi ni s h e d uri n ati n g, o v er t h e l a st w e e k ? 
❑0  N ot at all 
❑1  L e s s t h a n 1 ti m e i n 5
❑2 L e s s t h a n h alf t h e ti m e 
❑3  A b o ut h alf t h e ti m e 
❑4 M or e t h a n h alf t h e ti m e 
❑5  Al m ost al w ays 
6.  H o w oft e n h a v e y o u h a d t o uri n at e a g ai n l e s s t h a n t w o 
h o ur s aft er y o u fi ni s h e d uri n ati n g, o v er t h e l a st w e e k ? 
❑0   N ot at all
❑1  L e s s t h a n 1 ti m e i n 5
 ❑2   L e s s t h a n h alf t h e ti m e 
❑3  A b o ut h alf t h e ti m e
❑4  M or e t h a n h alf t h e ti m e
❑5   Al m ost al w ays 
I m p a ct of S y m pt o m s
7.  H o w m u c h h a v e y o ur s y m pt o m s k e pt y o u fr o m d oi n g 
t h e ki n d s of t hi n g s y o u wo ul d u s u all y d o, o v er t h e 
l a st w e e k ? 
❑0  N o n e
❑1  O nl y a littl e  
 ❑2   S o m e
❑3  A l ot 
8.  H o w m u c h di d y o u t hi n k a b o ut y o ur s y m pt o m s, o v er t h e 
l a st w e e k ? 
❑0  N o n e
❑1  O nl y a littl e  
 ❑2   S o m e
❑3  A l ot 
Q u alit y of Lif e
9.  If y o u w er e t o s p e n d t h e r e st of y o ur lif e wit h y o ur 
s y m pt o m s j u st t h e w a y t h e y h a v e b e e n d uri n g t h e l a st 
w e e k, h o w w o ul d y o u f e el a b o ut t h at ? 
❑0   D eli g ht e d
❑1  Pl e a s e d  
 ❑2   M o stl y s ati sfi e d
❑3  Mi x e d ( a b o ut e q u all y s atisfi e d a n d dis s ati sfi e d)
 ❑4   M ostly diss atisfi e d 
❑5   U n h a p p y 
❑6   T erri bl e 
Sc ori n g t he NI H- C hr o nic Pr os tatitis S y m pt o m I n de x D o mai ns 
P ai n : T otal of ite ms 1a, 1 b, 1c, 1 d, 2a, 2 b, 3, a n d         = _ _ _ _ _ 
Uri n ary Sy m pt o ms : T otal of ite ms 5 a n d 6    
 = _ _ _ _ _ 
Q u ality of Life I m p act : T otal of ite ms 7, 8, a n d 9       = _ _ _ _ _ 
Versi o n 3 . 0/ A me n d me nt 2
C O N FI D E N TI A L
Pa ge 6 7  of 80


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 6 8  of 8 0  
A p pe n di x 5. I nter n ati o n al I n de x of Erectile F u ncti o n Q uesti o n n aire  














A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 7 5  of 8 0  
A p pe n di x  6. Gl o b al Res p o nse Assess me nt  


A q ui n o x A Q X- 1 1 2 5- 2 0 5  
S u bject Scree n N u m ber/ Ra n d o mizati o n N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _   
Visit Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ Visit N u m ber _ _ _ _ _ _ _ _ _ _ _ _  
Gl o b al Res p o nse Assess me nt ( G R A) 
“ As c o m pare d t o w he n y o u starte d t he st u d y dr u g, h o w w o ul d y o u rate y o ur C hr o nic 
Pr ostatitis/ C hr o nic Pel vic Pai n S y n dr o me s y m pt o ms n o w? ”  
- 3:
  M A R K E D L Y W O R S E 
- 2:
  M O D E R A T E L Y W O R S E 
- 1:
  S LI G H T L Y W O R S E 
0: 
  N O C H A N G E 
+ 1:
  S LI G H L T Y I M P R O V E D 
+ 2:
  M O D E R A T E L Y I M P R O V E D 
+ 3:
Versi o n 3 . 0/ A me n d me nt 2
  M A R K E D L Y I M P R O V E D 
Nic kel J C, At ki ns o n G, Krie ger J N et al.: Pr eli mi nar y Assess me nt of Safet y a n d Efficac y 
i n Pr o of- of- C o nce pt, Ra n d o mize d Cli nical Trial of Ta nez u ma b f or C hr o nic 
Pr ostatitis/ C hr o nic Pel vic Pai n S y n dr o me. Ur ol o g y. 2 0 1 2 N o v; 8 0( 5): 1 1 0 5- 1 0. 
C O N FI D E N TI A L
Pa ge 7 6  of 8 0


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 7 7  of 8 0  
A p pe n di x  7. P atie nt’s Gl o b al I m pressi o n of C h a n ge Sc ale 


A q ui n o x A Q X -1 1 2 5 -2 0 5  
S u bj ect Scree n N u m ber/ Ra n d o mizati o n N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _  
Visit Date _ _ _ _ _ _ _ _ _ _ _ _ _ _  Visit N u m ber _ _ _ _ _ _ _ _ _ _ _ _  
P GI -C Q u e sti o n n air e  
P GI -C Q u e sti o n n air e C o m pl et e d ?  
_ _   
D at e P GI -C  Q u e sti o n n air e C o m pl et e d 
m o nt h _ _ _ _     d a y _ _ _ _     y e ar _ _ _ _ _ _ _ _   
Pl e a s e c h o o s e t h e r e s p o n s e b el o w t h at b e st d e s cri b e s t h e o v er a ll c h a n g e i n y o ur p el vi c p ai n si n c e y o u 
st art e d t h e st u d y  
1. V er y m u c h i m pr o v e d
2.  M u c h i m pr o v e d
3.  Mi ni m all y i m pr o v e d
4.  N o c h a n g e
5.  Mi ni m all y w or s e
6.  M u c h w or s e
Versi o n 3 . 0/ A me n d me nt 2
7. V er y m u c h w or s e
C O N FI D E N TI A L
Pa ge 7 8 of 8 0


A q ui n o x P har mace uticals ( Ca na da)  I nc. 
Pr ot oc ol A Q X -1 1 2 5 -2 0 5  
V ersi o n 3. 0/ A me n d me nt 2  
C O N FI D E N TI A L  
P a ge 7 9  of 8 0  
A p pe n di x  8. P atie nt’s Gl o b al I m pressi o n of Se verit y Sc ale  


A q ui n o x A Q X -1 1 2 5 -2 0 5  
S u bj ect Scree n N u m ber/ Ra n d o mizati o n N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _  
Visit Date _ _ _ _ _ _ _ _ _ _ _ _ _ _  Visit N u m ber _ _ _ _ _ _ _ _ _ _ _ _  
P GI -S Q u e sti o n n air e  
P GI -S Q u e sti o n n air e C o m pl et e d ?  
_ _   
D at e P GI -S  Q u e sti o n n air e C o m pl et e d 
m o nt h _ _ _ _     d a y _ _ _ _     y e ar _ _ _ _ _ _ _ _   
Pl e a s e c h o o s e t h e r e s p o n s e t h at b e st d e s cri b e d t h e s e v erit y of y o ur c hr o ni c pr o st atiti s, c hr o ni c p el vi c 
p ai n s y m pt o m s o v er t h e p a st w e e k  
1.  N o n e
2.  Mil d
3.  M o d er at e
4. S e v er e
Versi o n 3 . 0/ A me n d me nt 2
5. V er y S e v er e
C O N FI D E N TI A L
Pa ge 8 0  of 80

SAP_000.pdf: 
 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 1 of 40 
 
 
 
 
 
 
Aquinox Pharmaceuticals (Canada), Inc. 
Protocol #: AQX-1125-205 
A 12-Week, Randomized, Multi-Center, Double-
Blind, Placebo-Controlled, Parallel-Group, Phase 2 
Trial to Evaluate the Efficacy and Safety of AQX-
1125 (200 mg) in Male Subjects with Chronic 
Prostatitis/Chronic Pelvic Pain Syndrome 
 
Protocol Version 3.0/Amendment 2.0  
 
 
Statistical Analysis Plan 
 
 
 
Created by:  Clinical Trial Data Services, Inc. 
40 Nagog Park, Suite #210 
Acton, MA 01720 


FM DMO15.1
Statistical Analysis Plan 
Rev: A
AQX-Ir2s-2Qs
Page 2 of 40
By signing the following, I agree to the contents in the Statistical Analysis Plan and its
associated attachments. Any modifications to the SAP made after signing will result in a
change order.
Approved by:
Name
Title
Sienature
Date
Brian Wiens, Ph.D,
Senior Director,
Biostatistics
Aquinox Pharmaceuticals,
Inc
James MacDougall, Ph.D.
Senior Biostatistician.
CTDS
L5frntT
Terri Sampo, MPH
Principal Consultant,
CTDS
at
Jill Young
Clinical Project Manager,
ProTrials Research. Inc.
U


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 3 of 40 
 
LIST OF ABBREVIATIONS 
Abbreviation
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCVA 
Best Corrected Visual Acuity 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMH 
Cochran-Mantel Haenszel Test 
CP/CPPS 
Chronic Prostatitis/Chronic Pelvic Pain Syndrome  
CRF 
Case Report Form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GRA 
Global Response Assessment 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IC/BPS 
Interstitial Cystitis/Bladder Pain Syndrome 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation, formerly called the International 
Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
IIEF-EF 
International Index of Erectile Function Questionnaire, Erectile Function 
Domain 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
LOCS III 
Lens Opacification Classification System III 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 4 of 40 
 
Abbreviation
Definition 
MAR 
Missing at Random 
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at random  
NIH 
National Institutes of Health 
NIH-CPSI 
National Institutes of Health, Chronic Prostatitis Symptom Index 
NRS 
Numerical Rating Scale 
PCS 
Pain Catastrophizing Scale 
PGI-C 
Patient’s Global Impression of Change  
PGI-S 
Patient’s Global Impression of Severity 
PHQ-9 
Patient Health Questionnaire-9 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TEAESI 
Treatment Emergent Adverse Event of Special Interest 
UPOINT 
Urinary, Psychosocial, Organ Specific, Infection, Neurologic/Systemic, 
Tenderness of Skeletal Muscles 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 5 of 40 
 
Table of Contents 
 
LIST OF ABBREVIATIONS ..................................................................................................................................... 3 
1 
PROTOCOL SYNOPSIS .................................................................................................................................... 6 
2 
STATISTICAL METHODOLOGY ................................................................................................................ 14 
2.1 
GENERAL CONSIDERATIONS ......................................................................................................................... 14 
2.2 
SUBJECT POPULATION .................................................................................................................................. 14 
2.2.1 
SAMPLE SIZE JUSTIFICATION .................................................................................................................... 14 
2.2.2 
Study Assessment Time Points ............................................................................................................. 15 
2.2.3 
Schedule of Events ............................................................................................................................... 16 
2.2.4 
Randomization/Unblinding .................................................................................................................. 19 
2.2.4.1 
Randomization Methodology ........................................................................................................................... 19 
2.2.4.2 
Unblinding ....................................................................................................................................................... 19 
2.2.5 
Study Populations for Analysis ............................................................................................................ 20 
2.2.5.1 
Intent to Treat (ITT) Population ....................................................................................................................... 20 
2.2.5.2 
Safety Population ............................................................................................................................................. 20 
2.2.5.3 
Per-Protocol (PP) Population ........................................................................................................................... 20 
2.2.6 
Baseline Characteristics/Medical History ........................................................................................... 20 
2.2.7 
Subject Disposition .............................................................................................................................. 20 
2.2.9 
Dose Regimen ...................................................................................................................................... 21 
2.2.10 
Methods for Handling Missing Data ................................................................................................... 21 
2.2.10.1 Missing Daily Data in the Weekly Scores ............................................................................................ 21 
2.2.10.2 Imputation Methods ............................................................................................................................. 21 
2.2.11 
Safety Monitoring ................................................................................................................................ 23 
2.2.12 
Interim Analysis ................................................................................................................................... 23 
2.2.13 
Efficacy Analyses ................................................................................................................................. 24 
2.2.13.1 
Primary Endpoint ............................................................................................................................................. 24 
2.2.13.2 
Supplementary Analysis to the Primary Endpoint............................................................................................ 25 
2.2.13.3 
Secondary Endpoints ........................................................................................................................................ 26 
2.2.14 
Concomitant Analgesic Medication Change Definitions ..................................................................... 29 
2.2.15 
Safety Analyses .................................................................................................................................... 30 
2.2.15.1 
Extent of Exposure and Compliance ................................................................................................................ 30 
2.2.15.2 
Adverse Events ................................................................................................................................................ 31 
2.2.15.2.1 
Serious Adverse Events ............................................................................................................................ 32 
2.2.15.2.2 
Deaths ....................................................................................................................................................... 32 
2.2.15.2.3 
Interruptions or Discontinuations of Study Medication Due to an AE ..................................................... 32 
2.2.15.2.4 
Ocular Treatment Emergent AEs of Special Interest ................................................................................ 32 
2.2.15.2.5 
Ophthalmic Safety .................................................................................................................................... 33 
2.2.15.3 
Laboratory Data ............................................................................................................................................... 33 
2.2.15.4 
Vital Signs, 12-Lead ECG, physical examination and Other Observations Related to Safety ......................... 33 
2.2.15.5 
Concomitant Medications ................................................................................................................................ 34 
REFERENCES .......................................................................................................................................................... 35 
3 
DOCUMENT VERSION CONTROL ............................................................................................................. 35 
APPENDIX A - PROGRAMMING SPECIFICATIONS FOR TABLES AND LISTINGS ............................... 36 
APPENDIX B – SAMPLE MMRM CODE ............................................................................................................. 38 
APPENDIX C – LOC III GRADING SYSTEM MMRM ANALYSIS ................................................................. 39 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 6 of 40 
 
 
1 Protocol Synopsis 
Title: A 12-Week, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Parallel-
Group, Phase 2 Trial to Evaluate the Efficacy and Safety of AQX-1125 (200 mg) in Male 
Subjects with Chronic Prostatitis/Chronic Pelvic Pain Syndrome 
Objectives:  
Primary Objective 
The primary objective of this study is to evaluate the effect of 12 weeks of treatment with AQX-
1125 (200 mg) administered orally once-daily compared to placebo on the change from Baseline 
(Visit 2) to Week 12 (Visit 4) in maximum daily pelvic pain (mean) in male subjects with non-
bacterial chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using a standardized 11-
point Numerical Rating Scale (NRS) pain score recorded daily by an electronic diary (eDiary). 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
 The effects of 12 weeks of treatment with AQX-1125 (200 mg) administered orally once-
daily compared to placebo on the change from Baseline (Visit 2) to Week 12 (Visit 4) for 
each of the following: 
o National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) pain 
subscale and all domains total score 
o Male sexual health as measured using the International Index of Erectile Function 
Questionnaire, Erectile Function Domain (IIEF-EF) 
o Average daily pelvic pain (eDiary), average and maximum pelvic pain (Paper-based 
NRS, in clinic), using the standardized 11-point NRS 
o 24-hour voiding frequency (eDiary)  
 Time course of effects: AQX-1125 (200 mg) compared to placebo on the change from 
Baseline (Visit 2) at Week 6 (Visit 3), Week 12 (Visit 4), and Week 16 (i.e. 4 weeks after 
end of treatment) for each of the pain and symptom scale endpoints 
 The overall response to treatment for AQX-1125 (200 mg) compared to placebo as 
measured by the subject’s Global Response Assessment (GRA), Patient’s Global 
Impression of Change scale (PGI-C) and Patient’s Global Impression of Severity scale 
(PGI-S) at Week 12 (Visit 4) 
 The proportion of subjects with ≥30% and ≥50% improvement in maximum daily pelvic 
pain (mean) using the standardized 11-point NRS recorded by the eDiary and the NIH-
CPSI pain subscale compared to placebo, at Weeks 6 (Visit 3) and 12 (Visit 4) 
 Responder analysis: response to treatment defined by any of the following: 
o Decrease in maximum daily pelvic pain from Baseline to Week 12 (eDiary) with no 
change in the amount or strength of concomitant analgesic medications 
o Decrease in maximum daily pelvic pain from Baseline to Week 12 (eDiary) with a 
decrease in the amount or strength of concomitant analgesic medications 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 7 of 40 
 
 Discontinuation of study medication due to treatment failure (% meeting treatment failure 
criteria and time to event) 
Safety Objectives 
The safety objectives of this study are to evaluate: 
 Safety and tolerability of AQX-1125 (200 mg) compared to placebo during the 12-week 
treatment period 
 Ocular safety based upon assessment of lenticular opacification using Lens Opacification 
Classification System (LOCS) III, best corrected visual acuity (BCVA) using the 
Logarithm of the Minimum Angle of Resolution (LogMAR) chart, intraocular pressure 
(IOP), corneal staining, and slit lamp examination 
Methodology [Study Design]: 
In this double-blind, placebo-controlled study, approximately 100 male subjects diagnosed with 
CP/CPPS will be randomized to either AQX-1125 (200 mg) or placebo in a 1:1 ratio across 
approximately 30 centers in North America. The study will consist of a screening period of up to 
3 weeks, a 12-week treatment period followed by a 4-week Off-Treatment Safety Follow-up 
period, and an Ophthalmic Safety Follow-up Visit 6 months post last dose, for a total study 
duration of about 41 weeks. There will also be a follow-up telephone call 3 months after the last 
dose.  
At Screening Visit 1, each subject will complete a set of questionnaires, and receive (and be 
trained to use) an eDiary. Subjects will record their average and maximum daily pelvic pain 
score, at approximately the same time each day (in the evening prior to the last dose of pain 
medication), as well as their daily use of analgesic pain medications. Baseline ophthalmic 
assessments, including lenticular opacification assessment using LOCS III, can be completed as 
a separate visit any time during the screening period (any time before Visit 2). 
At Baseline (Visit 2), all subjects will return to the clinic for review of eligibility and to complete 
the efficacy questionnaires and assessments to establish Baseline values. Average daily pelvic 
pain scores recorded in the eDiary within the 7 days prior to Baseline (Visit 2) will be part of the 
study entry criteria. If all entry criteria are met, the subject will be randomized (1:1) to receive a 
single daily oral dose of 2 tablets for 12 weeks as follows:  
 AQX-1125 200 mg dose group: 2 AQX-1125 100 mg tablets; or,  
 Placebo group: 2 placebo tablets 
All enrolled subjects will record the following in the eDiary (from Screening Visit 1 to Week 16 
[Off-Treatment Safety Follow-up Visit]): 
 Maximum daily pelvic pain: subjects will assess their maximum pelvic pain for that day on 
a scale of 0 to 10, with 0 indicating ‘no pelvic pain’ and 10 indicating ‘pelvic pain as bad as 
you can imagine’ 
 Average daily pelvic pain. Subjects will assess their average pelvic pain for that day on a 
scale of 0 to 10, with 0 indicating 'no pelvic pain' and 10 indicating 'pelvic pain as bad as 
you can imagine' 
 Analgesic medication taken each day 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 8 of 40 
 
 24-hour voiding frequency: voiding frequency will be measured over a 24-hour period, 
within a 3-day (72-hours) window before the next scheduled visit (Visit 2, 3, 4 and Off-
Treatment Safety Follow-up Visit) 
At Week 6 (Visit 3), and Week 12 (Visit 4), and Week 16 (Off-Treatment Safety Follow-up 
Visit) during the clinic visit, subjects will complete NIH-CPSI, paper-based 11-point NRS 
(average and maximum pelvic pain experienced over the last 24 hours), GRA, PHQ-9, PGI-C, 
IIEF, PGI-S, have vital signs assessed and return unused study drug (Week 6 and 12). Any 
adverse events (AEs) are to be recorded. 
Subject compliance with the eDiary will be monitored by trained study site personnel at each 
study visit. 
All subjects completing the 12 weeks of treatment (Visit 4) will be considered completers of 
treatment. Subjects who withdraw from the study during the treatment period should complete an 
Early Termination Visit. Subjects who discontinue the double-blind treatment for any reason will 
be encouraged to continue with all subsequent study-related visits and evaluations, with 
emphasis on obtaining pelvic pain data, analgesic medication data and voiding frequency data to 
assess efficacy endpoints. Subjects who complete the study or early terminate during the study 
will be asked to return for the Safety Follow-up Visit 4 weeks after discontinuing study drug, and 
the Ophthalmic Safety Follow-up Visit 6 months after the last dose. Subjects will also be 
contacted via telephone for the follow-up telephone call 3 months after their last dose. 
Number of Subjects: 
Approximately 100 male subjects at approximately 30 sites in North America. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria  
For inclusion into the screening period subjects must meet the following criteria: 
1. Provide written informed consent and the willingness and ability to comply with all 
aspects of the study requirements 
2. Males, ≥18 and ≤80 years of age at Screening Visit 1 
3. Have pain or discomfort in the pelvic region for at least 3 months in the last 6 months, in 
the absence of a urinary tract infection or other pelvic/urological cause, and have a 
physician diagnosis of CP/CPPS (NIH Prostatitis Category III) 
4. NIH-CPSI of ≥15 on the total score 
5. Subjects must agree to use a condom for sexual intercourse from Screening Visit 1 until 
at least 90 days after the last dose of study drug, unless they have been surgically 
sterilized (vasectomy) for a minimum of 6 months. True abstinence from sexual 
intercourse in accordance with the preferred and usual lifestyle of the subject is also 
acceptable  
6. Have an average daily pelvic pain score of ≥4 out of 10 on the 11-point NRS pain scale 
(mean of the average daily pelvic pain score recorded at each of the 7 days prior to 
Baseline [Visit 2]). A minimum of 5 daily records within 7 days prior to Baseline (Visit 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 9 of 40 
 
2) must be recorded 
7. Must be capable of voiding independently for 30 days prior to screening (to allow 
completion of 24-hour voiding diary) 
Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible for trial:  
1. Diagnosis of NIH Prostatitis Categories I (acute prostatitis) or II (chronic bacterial) 
prostatitis 
2. Diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) with symptoms of pain, 
pressure, or discomfort perceived to be related to the bladder, and associated lower 
urinary symptoms for >6 weeks in the absence of infection or other identifiable causes 
3. Relief of pelvic pain after voiding or have >15 voids per day  
4. Post-void residual volume >150 mL 
5. Have had an unresolved (positive bacterial urine culture) urinary tract infection within 8 
weeks (inclusive) prior to Screening Visit 1 (subjects can rescreen [up to 1 time] once 
infection clears) 
6. History of previous prostate or bladder intervention (i.e. prostate biopsy, cystoscopy, or 
indwelling urinary catheter) within 1 month of Screening Visit 1, history of microwave 
therapy, transurethral resection of the prostate, transurethral radiofrequency 
thermotherapy, transurethral incision of the prostate, transurethral needle ablation, 
transurethral laser vaporization of the prostate, Urolift®, Rezum, and other urological 
interventions (e.g., botulinum toxin) within 6 months of Screening Visit 1 
7. Unilateral testicular or scrotal pain as the sole symptom of CP/CPPS 
8. Ongoing, symptomatic urethral stricture disease 
9. Catastrophizing pain score of ≥30 as determined by the Pain Catastrophizing Scale (PCS) 
10. Current major depressive disorder (i.e. Patient Health Questionnaire-9 [PHQ-9] score 
≥10) 
11. Neurologic disease or disorder affecting the bladder, ability to void spontaneously, or 
directly contributing to urinary symptoms (e.g., multiple sclerosis, autonomic 
neuropathy) 
12. Severe, excruciating pain during rectal exam (i.e. an “inability to perform the exam”)  
13. History of chronic substance abuse, dependency or abuse of opioids, or other narcotics 
within the last 2 years  
14. Currently receiving, or expect to receive, any of the following prohibited medications or 
procedures: 
 Non-steroidal anti-inflammatory drug or other medication (e.g. alpha-blockers) for 
CP/CPPS, unless on a stable dose for ≥30 days prior to Screening Visit 1 
 Long-acting opioids: within 2 weeks prior to Baseline (Visit 2) or expected to take any 
long-acting opioids at any time during the study  
 Short-acting opioid or opioid-containing analgesics: more than 10 doses/month, or 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 10 of 40 
 
more than a single dose > 2 days per week, or any short-acting opioid within 3 days 
prior to randomization 
 Oral steroid therapy, immunosuppressants / immunomodulators (including daily 
phosphodiesterase Type 4 inhibitors) within 30 days prior to Screening Visit 1 and 
throughout the study 
 Have taken any investigational drug or device within 90 days prior to Screening Visit 
1, or have had previous exposure to AQX-1125 
15. Any prior history of pelvic cancer (e.g., colorectal, genitourinary) or treatment (radiation 
or chemotherapy) thereof 
16. Major surgery within 3 months prior to Screening Visit 1 
17. Have any other condition/disease which, in the opinion of the Investigator, could 
compromise subject safety or interfere with the subject’s participation in the study or in 
the evaluation of the study results. In case of any doubt, the Investigator shall consult the 
medical monitor. 
18. Known intolerance to micro-crystalline cellulose (Avicel® PH-102), mannitol or other 
ingredient of AQX-1125 tablets 
Test Product, Dose and Mode of Administration: 
Two AQX-1125 (activator of the Src homology 2-containing inositol-5'-phosphatase 1 protein) 
100 mg tablets will be administered orally once daily with a glass of water, around the same time 
of day, for 12 weeks. Tablets should be taken with food or eat a light meal no more than 4 hours 
prior to consumption. 
Reference Therapy, Dose and Duration of Administration: 
Matching placebo is identical in appearance to the test product and contains no active ingredient. 
Two placebo tablets will be administered orally once daily with a glass of water, around the 
same time of day, for 12 weeks. Tablets should be taken with food or eat a light meal no more 
than 4 hours prior to consumption. 
Duration of Treatment: 
Subjects will participate in a 12-week, double-blind treatment phase. After the treatment phase, 
there will be a 4-week post last dose Safety Follow-up, as well as a 6-month post last dose 
Ophthalmic Safety Follow-up. There will also be a 3-month post last dose Telephone Call 
Follow-up. 
Variables: 
Primary Endpoint 
The primary endpoint is the change from Baseline (Visit 2) to Week 12 (Visit 4) in the maximum 
daily pelvic pain (mean) using a standardized 11-point NRS pain score recorded daily by an 
eDiary. 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 11 of 40 
 
Secondary Endpoints 
The secondary endpoints are: 
 The change from Baseline to Week 12 for each of the following: 
o NIH-CPSI pain subscale and all domains total score 
o Male sexual health as measured using the IIEF-EF 
o Mean of average daily pelvic pain scores (eDiary), average and maximum pelvic pain 
(Paper-based NRS in clinic) 
o 24-hour voiding frequency (eDiary) 
 Time course of effects: AQX-1125 (200 mg once-daily) compared to placebo on the 
change from Baseline (Visit 2) to Week 6 (Visit 3), Week 12 (Visit 4), and Week 16 (i.e. 4 
weeks after end of treatment) for each of the following: 
o Mean of maximum daily pelvic pain score (eDiary)  
o NIH-CPSI pain subscale and all domains total score 
o IIEF-EF 
o Mean of average daily pelvic pain scores (eDiary), average and maximum pelvic pain 
(Paper-based NRS in clinic) 
o 24-hour voiding frequency (eDiary) 
 Response to treatment compared to placebo as measured by the GRA, PGI-C, and PGI-S at 
Week 12 (Visit 4) 
 A ≥30% and ≥50% improvement in maximum daily pelvic pain (using the 11-point NRS 
recorded by eDiary and the NIH-CPSI pain subscale) compared to placebo, at Week 6 
(Visit 3) and Week 12 (Visit 4) 
 Responder analysis: Response to treatment defined by any of the following: 
o Decrease in maximum daily pelvic pain from Baseline to Week 12 (eDiary) with no 
change in the amount or strength of concomitant analgesic medications 
o Decrease in maximum daily pelvic pain from Baseline to Week 12 (eDiary) with a 
decrease in the amount or strength of concomitant analgesic medications 
 Discontinuation of study medication due to treatment failure (% meeting treatment failure 
criteria and time to event) 
 
Safety Endpoints 
The safety endpoints are: 
 The frequency and severity of AEs will be reported for the treatment phase and will 
include: 
o Abnormal, clinically significant vital signs, laboratory tests, electrocardiogram (ECG), 
weight or findings on physical examinations 
o Ophthalmic safety based upon assessment of lenticular opacification using LOCS III, 
BCVA using the LogMar chart, IOP, corneal staining and slit lamp examination at 
Baseline, 12 weeks, and 6 months post last dose, and at Early Termination (ET). 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 12 of 40 
 
Statistical Methods: 
This study will investigate the comparative treatment effect of AQX-1125 versus placebo in 
subjects with CP/CPPS. The statistical analysis will use inferential methods (P values) and 
estimation (point estimates with confidence intervals) to evaluate the effect of AQX-1125 
compared to placebo. This study is powered to demonstrate a statistically significant effect of 
AQX-1125 versus placebo (P < 0.05) in the primary endpoint, if the treatment effect is 
sufficiently large. If a statistically significant result is not obtained but the estimated effect 
predicts a statistically significant effect in a larger, subsequent study comparing AQX-1125 to 
placebo, this study will be considered a success. 
Sample Size and Power 
Sample size was calculated using the 2-sample means statement in the POWER procedure in 
SAS. A sample size of 45 subjects per treatment group will provide 80% power to detect a 1.2-
point difference in the change from Baseline maximum pelvic pain score between AQX-1125 
and placebo assuming a between-subject standard deviation of 2.0 and a 2-sided 5% significance 
level.  
Assuming a 10% rate of discontinuation from study drug, the total number of subjects to be 
randomized is approximately 100. Subjects who discontinue will be included in the primary 
analysis, resulting in a slight decrease in power if the discontinuing subjects in the placebo group 
have no additional change after discontinuation of study drug while the discontinuing subjects in 
the AQX-1125 group have a loss of efficacy after discontinuing study drug. 
Analysis 
Subject pelvic pain as assessed by the 11-point NRS (eDiary) will be summarized at each week 
during the study. Analyses in the week prior to the Week 6 Visit, Week 12 Visit and Week 16 
Visit (Off-Treatment Safety Follow-Up) will be produced with mean, median, standard 
deviation, and quartiles for both pelvic pain score and the change from baseline in pelvic pain 
score, using the mean of the maximum observed value from each of the 7 days prior to each visit 
(Baseline, Week 6, Week 12 and Week 16). This will be reported for maximum daily pelvic pain 
score and similarly for average daily pelvic pain score. The proportion of subjects who respond 
to treatment at Week 6, Week 12 and at Week 16 will be summarized. Use of concomitant 
analgesic medication will be summarized with the percentage (%) of subjects taking each class 
of medication (permitted short-acting opioid-containing analgesics and non-opioid containing 
analgesics: e.g., acetaminophen) and the daily dose (mean, median, standard deviation, and 
quartiles, using subjects who took any such medication on at least 1 of the 7 days prior to the 
Baseline, Week 6, Week 12 or Week 16 Visit). 
Other secondary endpoints will be summarized at Baseline, Week 6, Week 12, and Week 16, 
including observed values at each timepoint and change from Baseline at post-baseline 
timepoints, with mean, median, standard deviation, and quartiles for continuous data, and counts 
and percentages for categorical and binary data. 
Comparison of AQX-1125 to placebo at Week 12 for the primary efficacy endpoint will use 
repeated measures analysis of variance to compare change from Baseline in maximum pain score 
(NRS score) (dependent variable) between treatment arms (AQX-1125 and placebo). Baseline 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 13 of 40 
 
maximum pain score (NRS score) will be included in the model as a covariate. Change from 
Baseline to Week 6 and Week 12 will be included in the analysis. A P value less than or equal to 
0.05 for the change from Baseline at Week 12 will be considered statistically significant. All 
randomized subjects will be included in the primary analysis. 
Comparison of AQX-1125 to placebo for proportion of subjects who are responders will be used 
to further understand the effect of AQX-1125 on pelvic pain. P values for the test of equal 
numbers of responders in each group will be reported, without adjustment for multiplicity, and 
used descriptively. 
Other secondary endpoints will be tested in an analogous procedure, with P values used for 
descriptive purposes rather than for statistical inference. 
Safety data will be summarized with no inferential analysis planned. AEs and treatment-
emergent AEs (TEAE) will be summarized by System Organ Class (SOC) and Preferred Term 
(PT) with counts by treatment group. Ophthalmological findings will be listed and summarized. 
Date of the Synopsis: 08 March 2018 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 14 of 40 
 
 
2 Statistical Methodology 
 
2.1 
General Considerations 
 
The objective of this double-blind Phase II study is to evaluate the efficacy and safety of 
AQX-1125 (200 mg) in male subjects with chronic prostatitis/chronic pelvic pain 
Syndrome (CP/CPPS). This study uses a randomized (1:1, AQX-1125: Placebo), double-
blind, placebo-controlled, parallel group design. Randomization will be conducted at 
Baseline (Visit 2), after verifying that the subject meets all inclusion criteria and has none 
of the exclusion criteria. Two tablets of AQX-1125 or placebo will be administered orally 
once daily for 12 weeks.  The study will consist of a screening period of up to 3-weeks a 
12-week treatment period followed by a 4-week off drug Safety Follow-up period, and an 
Ophthalmic Safety Follow-up Visit 6-months post last dose, for a total study duration of 
about 41 weeks. There will also be a follow-up telephone call 3 months after the last 
dose.  
 
All subjects screened into the study will be assigned a subject identifier number during 
screening that will be used on all subject documentation. The subject identifier number 
will contain the site number and the subject number assigned in numerical order at the 
screening visit. Subject numbers will be assigned in ascending order at each site starting 
with 01.  All data will be listed in subject data listings sorted by site and subject number 
unless otherwise noted.  Data tabulations will be prepared as described in the sections 
below. 
 
All statistical analyses will be performed using SAS Version 9.4 or higher. The following 
summary statistics will be reported for continuous data: number of subjects, mean, 
median, standard deviation, quartiles, minimum, and maximum.  Confidence intervals 
(CIs) will be provided where appropriate. For categorical data, the number and 
percentage of subjects within each treatment group will be reported.   
 
For weekly scores that are based on daily subject assessments, a subject’s score for a 
week will be the average (mean) of the daily scores across that week.  Baseline lab test 
results or vital sign results will be the last non-missing value before dosing. Change from 
baseline will be defined as the post-baseline visit value minus the baseline value unless 
otherwise specified. Assessments performed at the Early Termination visit will be 
summarized descriptively.  
 
2.2 
Subject Population 
2.2.1 Sample Size Justification   
Sample size was calculated using the 2-sample means statement in the POWER 
procedure in SAS. A sample size of 45 subjects per treatment group will provide 
80% power to detect a 1.2-point difference in the change from Baseline pain score 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 15 of 40 
 
between AQX-1125 and placebo assuming a between-subject standard deviation 
of 2.0 and a 2-sided 5% significance level.  
 
Assuming a 10% rate of discontinuation from study drug, the total number of 
subjects to be randomized is approximately 100. Subjects who discontinue will be 
included in the primary analysis, resulting in a slight decrease in power if the 
discontinuing subjects in the placebo group have no additional change after 
discontinuation of study drug while the discontinuing subjects in the AQX-1125 
group have a loss of efficacy after discontinuing study drug. 
 
2.2.2  Study Assessment Time Points 
All enrolled subjects will record the maximum and average daily pelvic pain in 
the eDiary from Screening Visit 1 to Week 16, as well as analgesic medication 
taken each day. Subjects will record 24-hour voiding frequency prior to scheduled 
visits at baseline, Week 6, Week 12 and Week 16. Visits are scheduled at the 
following timepoints: 
 Visit 1/Screening 
 Visit 1a/ Baseline ophthalmic assessments (at any time before Visit 2) 
 Visit 2/Baseline (Week 1)  
 Visit 3 (Week 6)  
 Visit 4 (Week 12)  
 Early Termination:  Subjects who withdraw from the study during the 
treatment period should complete an Early Termination Visit. Subjects who 
discontinue the double-blind treatment for any reason will be encouraged to 
continue with all subsequent study-related visits and a visit at Week 12 to 
assess efficacy endpoints. 
 Off Treatment (Week 16) 4-week off drug Safety Follow-up period 
 Ophthalmic Safety Follow-up Visit 6-months post last dose: Ophthalmic 
assessments and AE collection (ophthalmic related AEs only) 
 Follow-up telephone call 3 months after the last dose: AE collection 
(ophthalmic related AEs only) 
 Unscheduled Visits: Unscheduled visits may occur when subject needs to 
make a visit in between the scheduled visit dates due to an AE, difficulty 
complying with the study protocol requirements, or a significant change in 
their disease state. Unscheduled visits may be conducted at any time 
during the study and should include the same assessments as Week 16. 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 16 of 40 
 
 
2.2.3 Schedule of Events 
 
Event 
Screening Perioda 
Baseline
Treatment 
Period 
ETj 
Safety Follow-up 
Assessment 
Visit 1 
Baseline 
Ophthal. 
Visit 1a 
Visit 2 
Visit 3
Visit 4 
Off-
Treatment
Telephone 
callk 
Ophthalmick
Week 
 
 
1 
6 
12 
NA 
16 
25 
38 
Day (± window) 
-14 (±7) 
Before Visit 2 
1 
42 (±3) 84 (±3)
NA 
112 (±3) 
175 (±7) 
266 (±7) 
Informed consent 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
Demographicsb 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 m 
 
 
UPOINT classification 
 
 
 
 
 
 
 
 
 
NIH-CPSIc 
 
 
 
 
 
 
 
 
 
Paper-based 11-point NRSc,d 
 
 
 
 
 
 
 
 
 
PCSc 
 
 
 
 
 
 
 
 
 
PHQ-9 c 
 
 
  
 n 
 n 
 n 
 n 
 
 
GRAc 
 
 
 
 
 
 
 
 
 
PGI-Cc 
 
 
 
 
 
 
 
 
 
IIEF, PGI-Sc 
 
 
 
 
 
 
 
 
 
Ophthalmic assessmentse 
 
 
 
 
 
 
 m 
 
 
12-lead supine ECGf 
 
 
 
 
 
 
 m 
 
 
Vital signs (HR, BP, temperature) 
 
 
 
 
 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
Clinical chemistry,g hematology, urinalysis 
 
 
 
 
 
 
m 
 
 
Urine: bacterial culture & sensitivity, 
leukocyte esterase test 
 
 
 
 
 
 
 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 17 of 40 
 
Event 
Screening Perioda 
Baseline
Treatment 
Period 
ETj 
Safety Follow-up 
Assessment 
Visit 1 
Baseline 
Ophthal. 
Visit 1a 
Visit 2 
Visit 3
Visit 4 
Off-
Treatment
Telephone 
callk 
Ophthalmick
Week 
 
 
1 
6 
12 
NA 
16 
25 
38 
Day (± window) 
-14 (±7) 
Before Visit 2 
1 
42 (±3) 84 (±3)
NA 
112 (±3) 
175 (±7) 
266 (±7) 
24-hour voiding frequencyh 
 
 
 
 
 
 
 
 
 
AE collection 
 
 
 
 
 
 
 
l 
l 
Concomitant medications 
 
 
 
 
 
 
 
 
 
Study drug dispensingi 
 
 
 
 
 
 
 
 
 
Study drug compliance check 
 
 
 
 
 
 
 
 
 
Study drug accountability 
 
 
 
 
 
 
 
 
 
eDiary Issue/Train/Review/Collect 
I/T 
 
R 
R 
R 
R 
R/C 
 
 
Abbreviations: AE=adverse event; BCVA=best corrected visual acuity; BP=blood pressure; C=collect; ECG=electrocardiogram; eDiary=electronic diary; 
ET=Early Termination; GRA=Global Response Assessment; HR=heart rate; I=issue; IIEF =International Index of Erectile Function; IOP=intraocular 
pressure; LOCS= Lens Opacity Classification System; LogMAR=Logarithm of the Minimum Angle of Resolution; NA=not applicable; NIH-CPSI=National 
Institute of Health Chronic Prostatitis Syndrome Index; NRS=Numerical Rating Scale; PCS=Pain Catastrophizing Scale; PGI-C=Patient’s Global Impression 
of Change scale; PGI-S=Patient’s Global Impression of Severity scale; PHQ-9=Patient Health Questionnaire; R=review; T=train; UPOINT=Urinary, 
Psychosocial, Organ Specific, Infection, Neurologic/Systemic, Tenderness of Skeletal Muscles. 
a  Minimum screening period is 7 days, which includes the baseline ophthalmic assessment at Visit 1a. 
b  Demographics include age, birth year, sex, race and ethnicity. 
c  Questionnaires must be completed prior to other assessments. 
d  Paper-based 11-point NRS will be administered in-clinic during the study visit to assess the average and maximum daily pelvic pain. 
e  Ophthalmic assessments include BCVA using the LogMAR chart (i.e. after manifest refraction), IOP (preferably measured by Goldmann tonometry, before 
and after dilation with mydriatic agent) corneal staining, slit lamp examination, and lenticular opacification using LOCS III. Baseline ophthalmology 
assessment can be completed as a separate visit any time during the screening period (any time before Visit 2). Background incidence of cataracts in subjects 
noted prior to dosing should be recorded as medical history. Ophthalmic assessments at all post-Baseline Visits should occur within the specified Visit 
windows. 
f    Subjects will be resting supine for at least 5 minutes before the ECG recording. 
g   Clinical chemistry does not need to be fasting. 
h   Voiding frequency will be measured over a 24-hour period, within a 3-day (72 hours) window before the scheduled visits. 
I    The first dose of study drug at Baseline (Visit 2) will be administered in the clinic. At subsequent Visits, subjects are to refrain from taking study drug at 
home on the morning of the clinic visit day and should be dosed in the clinic. 
j     If a subject withdraws from the study, all assessments for the ET Visit should be conducted. 
k    Subjects who withdraw from the study anytime during the study will have a follow-up period of 6 months,    consisting  of an Off-Treatment Safety Follow-up 
Visit (4 weeks post last dose), telephone call follow-up (3 months post last dose) and ophthalmic assessment (6 months post last dose). 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 18 of 40 
 
l     Subjects will be asked for updates on new and ongoing (after the 28 days follow-up) ocular AEs only. 
m   Repeat at Off-Treatment Safety Follow-up is only needed if there are outstanding safety concerns from Week 12. 
N    Score will not be recorded in the database, assessment will be performed for patient safety/monitoring purposes only clinically significant findings will be 
reported as adverse events. 
 
NOTE: Unscheduled visits may be conducted at any time during the study and may include the same assessments as Week 12. 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 19 of 40 
 
 
 
2.2.4 Randomization/Unblinding 
2.2.4.1 
Randomization Methodology 
 
Approximately 100 male subjects with diagnosed CP/CPPS will be 
randomized to either AQX 1125 (200 mg) or placebo in a 1:1 ratio.   
 
A central, permuted block randomization scheme will be used with a 
selected blocking factor (block size) determined based on the proposed 
allocation ratio and number of subjects. The block size will be specified in  
the randomization plan.  
 
An Interactive Web Response System (IWRS) will be used for the 
randomization to either AQX-1125 (200 mg) or placebo and subsequent 
wallet assignments. Study staff will log in to the IWRS using unique 
credentials and input subject-specific screening and baseline information. 
In accordance with the randomization schedule, the IWRS will assign the 
randomization number and unique wallet numbers to the subject. Each 
subject must be given only the wallets assigned by IWRS. The study staff 
will document the wallet number in the Study Drug Accountability 
electronic Case Report Form (eCRF). Subjects are to be randomized in the 
order in which they qualify from the screening phase for inclusion in the 
study. The randomization plan will be executed in accordance with CTDS’ 
SOP DM016: Generation of Randomization Schemes/Unblinding. 
 
2.2.4.2 
Unblinding 
The investigators, study personnel, subjects, medical monitor, and clinical 
monitor will remain blinded throughout the study, unless safety concerns 
necessitate unblinding. 
 
If a medical emergency occurs and a decision regarding the subject’s 
clinical treatment requires knowledge of the treatment assignment, the 
study blind may be broken for the specific subject. Unless the medical 
emergency is deemed to be life-threatening, the medical monitor must 
first be consulted before unblinding. The Investigator would then utilize 
the IWRS for unblinding and the unblinding procedure will be provided 
in the eCRF Completion Guidelines. The date, time, and reason for 
unblinding must be documented in the source documents and on the 
applicable unblinding form in the IWRS. Investigators should note that 
the occurrence of a SAE should not routinely trigger immediate 
unblinding. If the medical monitor was not notified prior to breaking the 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 20 of 40 
 
blind, the investigator must notify the medical monitor of any and all 
blinds broken within 24 hours of each occurrence. 
 
 
2.2.5 Study Populations for Analysis 
The following are the analysis populations to be used: 
2.2.5.1 
Intent to Treat (ITT) Population 
The ITT Population will include all randomized subjects. In the event of 
study drug administration error, analyses on the ITT Population will be 
performed according to the treatment which the subject was randomized to 
receive.   
 
2.2.5.2 
Safety Population 
The Safety Population will include all subjects who received any amount 
of study drug. In the event of study drug administration error, analyses on 
the Safety Population will be performed according to the treatment the 
subject actually received. 
 
2.2.5.3 
Per-Protocol (PP) Population 
The PP Population will include all ITT subjects who do not have any 
major protocol deviations that possibly affect interpretation of the primary 
efficacy endpoint and have non-missing Baseline and Week 12 
assessments of maximum daily pelvic pain (i.e. the primary efficacy 
assessment). Determination of which subjects to be included in the PP 
population will be performed by a blinded review committee prior to 
database lock.  In the event of study drug administration error, the subject 
will be omitted from the PP population. 
 
2.2.6 Baseline Characteristics/Medical History 
 
Demographics – age (years), race, ethnicity and baseline height, weight 
BMI and baseline maximum daily pelvic pain will be summarized by 
treatment group and overall for the ITT, Safety, and PP Populations.  
 
Medical History will be coded using the MedDRA dictionary terms and 
will be summarized by SOC and PT by treatment group and overall for the 
ITT Population.  
  
2.2.7 Subject Disposition 
All subjects enrolled into the study that are issued a subject number will be 
accounted for in Subject Disposition.  Data will be tabulated by treatment group 
and overall and the numbers and percentages of subjects in each treatment group 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 21 of 40 
 
who are enrolled, randomized and treated, who comprise each of the analysis 
populations, who complete the study or discontinue from treatment or discontinue 
from the study prematurely along with the reason for discontinuation will be 
presented.  The number of subjects who were seen at each specified study visit 
will also be tabulated by treatment group and by site.  
 
Reasons for any early withdrawals and the last date of dosing completed prior to 
discontinuation will be provided in a listing. 
 
 
2.2.8 Protocol Deviations  
 
Protocol deviations (major and minor) will be defined prospectively prior to 
database lock by a review committee who is blinded to treatment assignment. 
Deviations will not be entered by the clinical sites into the EDC database.  
Instead, they will be tracked separately by the ProTrial’s clinical personnel. This 
process will be defined in detail in the ProTrial’s separate Protocol Deviation Plan 
document.  Major protocol deviations as well as those deviations that could 
possibly affect the interpretation of the primary endpoint (subset of major 
deviations) will be tabulated by treatment group and overall.  All deviations will 
be presented in listings.  All deviations will be classified and excluded from the 
PP analysis.    
 
 
2.2.9 Dose Regimen 
Two AQX-1125 100 mg tablets will be administered orally once daily, around the 
same time of day, with food or eat a light meal no more than 4 hours prior to 
consumption, for 12 weeks. Matching placebo is identical in appearance to the 
test product and contains no active ingredient and will be administered the same 
as AQX-1125. Tabulations of exposure to study medication are described in 
Section 2.2.15.1, Extent of Exposure.  Details of study medication use will be 
provided in a subject data listing. 
 
2.2.10 Methods for Handling Missing Data 
2.2.10.1 
Missing Daily Data in the Weekly Scores 
For endpoints which are the average of a daily score across a week (e.g., 
maximum daily pain and average daily pain), if the subject has 4 or more 
non-missing values in that week, the weekly mean score will be calculated 
as the average of the non-missing values, otherwise the weekly mean score 
will be set to missing for that week.  
 
2.2.10.2 
Imputation Methods 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 22 of 40 
 
The primary endpoint analysis method is a mixed model for repeated 
measures (MMRM) ANCOVA. This is an observed case approach to 
missing data and assumes the missing data is missing at random (MAR).  
 
Sensitivity analyses for the primary efficacy analysis will include 
imputing the missing data using two multiple imputation (MI) methods 
(described below). Any sensitivity analyses performed will be considered 
supportive analyis. 
  
 
 Multiple Imputation Assuming Missing at Random: Missing post-
baseline weekly maximum daily pelvic pain (mean) change from 
baseline scores at Weeks 6 and 12 will be imputed via MI assuming 
(MAR).  SAS Proc MI using the linear regression method will be the 
method for the imputation if the missing data pattern follows a 
monotonic pattern. If the data does not follow a monotonic pattern a 
sequential approach to imputing the variables to produce a monotone 
missing data pattern as described in Alut (2012) will be applied.  
 
A default random number generator of 345353 will be used and 100 
imputed datasets will be created. Each of the imputed datasets will be 
analyzed via the same model as the primary efficacy endpoint analysis 
(See Section 2.2.13.1). The range of the imputed pain values will be 
set between 0 and 10 via the SAS Proc MI Maximum and Minimum 
options. The results across the multiple imputed data sets will be 
combined using SAS Proc MIANALZYE. 
 
The following are the set of variables to be used in the MI model: 
o treatment group (placebo/AQX-1125) 
o age group (<65, 65-<75, ≥75 years) 
o race (White/Non-White) 
o baseline daily pelvic pain score 
o experienced a severe AE (yes/no) (CTCAE grade 3-5, severe, life-
threatening or death) 
o duration of exposure [last day-first day] +1 
 
For the ‘experienced a severe AE’ imputation variable, if a subject 
experiences a severe AE from baseline to Week 6 the value will be 
‘yes’ for the imputation of the Week 6 time-point, ‘no’ otherwise. 
Similarly, if a subject experiences a severe AE from Baseline to Week 
12 the value will be ‘yes’ for the imputation of the Week 12 time-
point, ‘no’ otherwise.  
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 23 of 40 
 
Note: if the MI model does not converge or produce estimates (i.e., 
due to over-specification) the set of imputation variables may be 
modified.  
 
 Multiple Imputation Assuming Missing Not at Random: For this 
imputation the missing weekly maximum daily pelvic pain (mean) 
change from baseline scores will be imputed at Weeks 6 and 12 
assuming the data follow a Missing Not at Random (MNAR) pattern.  
The imputation of weekly mean change from baseline pain scores in 
the AQX-1125 treatment group will be based on the distribution in the 
placebo group.  This method assumes that the trajectory of 
withdrawals from the AQX-1125 treatment arm follows the 
distribution of the placebo subjects. Placebo-based imputation will be 
implemented by the sequential modelling approach via PROC MI 
(O'Kelly & Ratitch., 2014). Missing change from baseline endpoint 
values will be imputed using the distribution of the non-missing 
placebo group values.  SAS Proc MI using the linear regression 
method will be the method for the imputation if the missing data 
pattern follows a monotonic pattern. If the data does not follow a 
monotonic pattern a sequential approach to imputing the variables to 
produce a monotone missing data pattern as described in Alut (2012) 
will be applied.  
 
A default random number generator of 345354 will be used and 100 
imputed datasets will be created.  Each of the imputed datasets will be 
analyzed via the same model as the primary efficacy endpoint analysis 
(See Section 2.2.13.1). The range of the imputed pain values will be 
set between 0 and 10 via the SAS Proc MI Maximum and Minimum 
options. The results across the multiple imputed data sets will be 
combined using SAS Proc MIANALZYE.  
 
The set of variables for the MI model is the same set as defined for the 
MAR MI imputation.    
 
Note: if the MI model does not converge or produce estimates (i.e., 
due to over-specification) the set of imputation variables may be 
modified.  
 
2.2.11 Safety Monitoring 
No safety monitoring committees are planned for the study.  
 
2.2.12 Interim Analysis 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 24 of 40 
 
There are no formal interim analyses planned for this study, however, there will 
be an interim database freeze/lock of the study data after all subjects have 
completed their Off-Treatment Safety Follow-up Visit (Week 16).   After this 
interim freeze/lock occurs, unblinding will occur and CTDS will produce the 
unblinded TLFs, except for the safety ophthalmic follow-up results.   Once the 
final data has been collected and cleaned, the database will be locked and the 
ophthalmic safety results will be produced using the final, locked data.   Blinded 
data review will occur periodically throughout the study (i.e. 50% of subjects who 
completed week 16, 75% of subjects who completed week 16) and any results that 
are produced will be clearly marked as “Blinded”.   
 
 
2.2.13 Efficacy Analyses 
 
The primary efficacy analysis population will be the ITT Population.  
 
2.2.13.1 
Primary Endpoint  
The primary endpoint is the change from Baseline (Visit 2) to Week 12 
(Visit 4) in the maximum daily pelvic pain (mean) using a standardized 
11-point numerical rating scale (NRS) pain score recorded daily by an 
eDiary. 
 
Average maximum pain scores will be summarized by week for each of 
the planned 12 weeks of treatment, for each treatment group. The results 
will be reported in a table and also graphically. 
 
The primary analysis will use data from week 6 and week 12, based on 
actual clinic visit dates. If a subject has at least 4 recorded maximum 
pelvic pain scores in the 7 days prior to a clinic visit, the mean of the 
available scores will be calculated to be that subject’s value in the primary 
efficacy analysis. These values will differ slightly from the weekly 
reported pain score, if a subject’s clinic visit is not on the exact target date. 
 
Comparison of AQX-1125 to placebo at Week 12 for the primary 
efficacy endpoint will use MMRM.  SAS PROC MIXED will be used 
with the observed change from baseline score at Week 6 and Week 12 as 
dependent variables. The model will include the baseline NRS score as a 
fixed effect covariate with fixed effect categorical factors for treatment 
group, visit and baseline×visit and treatment×visit interactions. The 
interactions will remain in the model regardless of significance. 
Treatment group comparisons at each visit (including the primary 
analysis endpoint at the Week 12 visit) will be estimated by least squares 
(LS) means differences with accompanying p-values and 95% CIs.  


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 25 of 40 
 
 
An unstructured covariance pattern will be used to estimate the variance–
covariance of the within-subject repeated measures. Sample SAS code for 
the primary efficacy endpoint analysis is provided in Appendix B – 
Sample MMRM Code.  
 
2.2.13.2 
Supplementary Analysis to the Primary Endpoint  
The following supplementary analysis will be provided to support the 
primary efficacy analysis.  
 
 
The primary efficacy analysis will be performed on the PP Population 
 
 
The primary efficacy analysis will be performed on the ITT Population 
based on MI MAR data imputation (see Section 2.2.10.2) 
 
 
The primary efficacy analysis will be performed on the ITT Population 
based on MI MNAR data imputation (see Section 2.2.10.2) 
 
 
The primary analysis will be repeated using each observed daily value 
of pelvic pain score, through day 84. For this analysis, weekly average 
pain score will not be used, but reported daily values will be to 
estimate daily change from baseline values. This analysis will be an 
MMRM on the PP Population using Observed Cases.  The model will 
include the baseline NRS score as a fixed effect covariate with fixed 
effect categorical factors for treatment group, visit and baseline×day 
and treatment×day interactions.  Here visit is a weekly level variable. 
Treatment group comparisons at each day will be estimated by least 
squares (LS) means differences with accompanying p-values and 95% 
CIs. Treatment group comparisons at each day  will be estimated by 
least squares (LS) means differences with accompanying p-values and 
95% CIs. The model will adjust for the multiple subject observations 
using a REPEATED statement in SAS Proc Mixed 
 
An unstructured covariance pattern will be used to estimate the 
variance–covariance of the within-subject repeated measures. If the 
model does not converge a different covariance structure (i.e., one 
with less parameters to estimate) will be applied.  
 
 
The weekly maximum daily pelvic pain (mean) scores and change 
from baseline values will be summarized by treatment group for each 
of the 12 weeks in the treatment period. This summary may differ 
slightly from the primary analysis, since the primary analysis uses the 
values at week 6 and week 12 from the 7 days prior to the actual clinic 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 26 of 40 
 
visit, while this analysis will use values from the weekly visits (days 1-
7, days 8-14, days 15-21, etc.). 
 
2.2.13.3 
Secondary Endpoints 
 
P values for secondary endpoints will be used for descriptive purposes 
rather than for statistical inference; therefore, no adjustments for 
multiplicity will be utilized. 
 
The following four change from Baseline to Week 12 endpoints will be 
analyzed in a manner similar to the primary efficacy analysis as described 
in Section 2.2.13.1: 
 
(1) NIH-CPSI pain subscale (pain, urinary symptoms and quality of life 
impact) and all domains total score 
 Total score (score range 0-43) 
 Pain: Total of items 1a, 1b, 1c, 2a, 2b, 3, 4 (score range 0-21) 
 Urinary Symptoms: total of items 5 and 6 (score range 0-10) 
 QoL Impact: total of items 7,8 and 9 (score range 0-12) 
 
NIH-CPSI data are collected on a paper form at each planned clinic 
visit. 
 
(2) Male sexual health as measured using the International Index of 
Erectile Function Questionnaire, Erectile Function domain (IIEF-EF): 
The IIEF-EF score is the sum of the ordinal responses to the 5 items 
 
IIEF-EF data are collected on a paper form at each planned clinic 
visit. 
 
(3) Mean of average daily pelvic pain scores (eDiary), average pelvic 
pain (in clinic), and maximum daily pelvic pain (in clinic).  
 
Average and maximum daily pelvic pain are collected on the eDiary, 
and also on a paper form at each planned clinic visit. Analysis of data 
collected on paper at the planned clinic visits will be used to confirm 
results from the analysis of data collected on the eDiary. 
 
(4) 24-hour voiding frequency 
For each of the scheduled assessment periods, the voiding frequency 
will be the last 24-hour period in which voiding is collected (i.e., if 
voiding is collected in more than one 24-hour period).  
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 27 of 40 
 
The following four-time course secondary endpoints will be assessed by 
MMRM model where the change from Baseline (Visit 2) to Week 6 (Visit 
3), Week 12 (Visit 4), and Week 16 (i.e. 4 weeks after end of treatment) 
is the dependent variable: 
(1) Mean of maximum daily pelvic pain score (eDiary) 
 
(2) NIH-CPSI pain subscale and all domains total score 
  
(3) IIEF-EF 
 
(4) Mean of average daily pelvic pain scores (eDiary), average and 
maximum pelvic pain (Paper-based NRS in clinic)  
 
The MMRM model to assess time course will have treatment as a factor, 
the corresponding baseline value as a covariate, a linear term for time (in 
weeks), and a time×treatment interaction effect term. The model will 
allow for a subject random intercept and slope over time with an 
unstructured correlation matrix. Sample SAS code for the time course 
MMRM is provided in Appendix B – Sample MMRM Code. 
 
For response to treatment as measured by the GRA and PGI-C at Week 
12 (Visit 4), the frequency distribution of each response scale will be 
presented by treatment group and assessed using a chi-square row mean 
score difference test.  
 
 The GRA response is a 7-point Likert scale (range: -3 to 3) with a 
score of -3 indicating “Markedly Worse”, a score of 0 indicating “No 
Change”, and a score of 3 indicating “Markedly Improved” to the 
question: As compared to when you started the study drug, how would 
you rate your Chronic Prostatitis / Chronic Pelvic Pain Syndrome 
symptoms now? 
 
 The PGI-C response is a 7-point Likert scale (range: 1 to 7) with a 
score of 1 indicating “Very much improved”, a score of 4 indicating 
“No change”, and a score of 7 indicating “Very much worse” to the 
item:  Choose the response that best describes the overall change 
your pelvic pain since you started the study. 
 
 The PGI-S response is a 5-point ordinal scale with a score of 1 being 
“None” and a score of 5 being “Very Severe” to the item: Choose the 
response that best described the severity of your chronic prostatitis / 
chronic pelvic pain symptoms over the past week. 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 28 of 40 
 
 
For response to treatment as measured by the PGI-S at Week 12 (Visit 4), 
the frequency distribution of each response scale will be presented by 
treatment group and the change from baseline will be assessed by an 
ANCOVA model with treatment as a factor and baseline PGI-S as a 
covariate. 
 
For the following two dichotomous secondary efficacy endpoints the rates 
for each treatment group and difference between the treatment groups will 
be presented with corresponding 95% CIs. A CMH test will be used to 
test for differences in rates between the treatment groups controlling for 
baseline pelvic pain. The baseline pelvic pain will be stratified into 2 
categories (4-7 and >7): 
(1) Treatment response as defined by meeting either of the following: 
 
Decrease in maximum daily pelvic pain (mean) from Baseline to 
Week 12 using a standardized 11-point NRS with no change in the 
amount or strength of concomitant analgesic medications (as 
defined in Section 2.2.14). 
 
Decrease in maximum daily pelvic pain from Baseline to Week 12 
using a standardized 11-point NRS with a decrease in the amount 
or strength of concomitant analgesic medications (as defined in 
Section 2.2.14). 
(2) A ≥30% and ≥50% improvement (decrease) in maximum daily pelvic 
pain (mean) (using the 11-point NRS recorded by eDiary and the 
NIH-CPSI pain subscale), at Weeks 6 (Visit 3) and 12 (Visit 4). 
 
For the Discontinuation of study medication due to treatment failure 
endpoint, only summary statistics will be provided for the percent 
meeting treatment failure criteria and the time to event (no inferential 
analyses will be performed). Time to discontinuation of study medication 
due to treatment failure will be summarized and presented graphically 
using Kaplan-Meier methods (i.e., SAS PROC LIFETEST stratifying on 
treatment group). 
 
The frequency distribution of the 5-category IIEF-EF score will be 
presented by treatment group for Week 12 as well as a shift table from 
Baseline. The 5 categories are no erectile dysfunction (score: 26-30), mild 
erectile dysfunction (score: 22-25), mild to moderate erectile dysfunction 
(score: 17-21), moderate erectile dysfunction (score: 11-16) and severe 
erectile dysfunction (score: 1-10). Responses to all items must be 
completed to calculate anIIEF-EF score.  Any response with missing 
values will be excluded from the analyses.   Treatment group difference 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 29 of 40 
 
with corresponding 95% CIs in the 5-category IIEF-EF will be assessed 
by a Cochran-Mantel-Haenszel (CMH) test using row mean scores 
controlling for Baseline IIEF-EF score. 
 
Data from both treatment arms will be used to calculate a meaningful 
change threshold (MCT), which reports a change in the primary endpoint 
(change in maximum daily pelvic pain) by anchoring to other outcomes 
(including PGI-S and/or PGI-C) to determine a change in maximum 
pelvic pain that provides a meaningful benefit to patients. The 
determination of the MCT will be made outside of the methods 
documented in this SAP prior to database lock. Once the MCT is 
determined, the proportion of subjects who have an improvement of at 
least the MCT will be summarized by treatment group and compared 
using a chi-square test as an exploratory analysis.   
 
2.2.14 Concomitant Analgesic Medication Change Definitions 
 
Concomitant analgesic medication use for each subject will be 
programmatically categorized from the eDiary data using the following 
definitions: 
 
(1) No change in the amount or strength of concomitant analgesic 
medications 
 For each concomitant analgesic medication the subject is taking at 
Baseline, the average daily dose change from Baseline to Week 12 
is within 15% of the average daily dose in the 7 days prior to 
Baseline and 
 No new concomitant analgesic medications are started at any time 
after baseline until week 12 and  
 No concomitant analgesic medications are discontinued at any time 
after baseline until week 12  
(2) Decrease in the amount or strength of concomitant analgesic 
medications 
 For at least one concomitant analgesic medication the subject is 
taking at Baseline, the average daily dose change from Baseline to 
Week 12 has decreased by at least 15% of the average daily dose 
in the 7 days prior to Baseline and 
 For all other concomitant analgesic medication the subject is 
taking at Baseline, the average daily dose change from Baseline to 
Week 12 does not increase by >15% of the average daily dose in 
the 7 days prior to Baseline and 
 No new concomitant analgesic medications are started at any time 
after baseline until week 12 unless a non-opioid analgesic 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 30 of 40 
 
medication is added and an opioid analgesic is discontinued (i.e., a 
non-opioid replaces an opioid analgesic medication as described 
below).    
(3) Increase in the amount or strength of concomitant analgesic 
medications 
  For at least one concomitant analgesic medication the subject is 
taking at Baseline, the average daily dose change from Baseline to 
Week 12 is >15% of the average daily dose in the 7 days prior to 
Baseline or 
 A new concomitant analgesic medication is started at any time 
after baseline until week 12, unless a non-opioid analgesic 
medication is added and an opioid analgesic is discontinued (i.e., a 
non-opioid replaces an opioid analgesic medication as described 
below).   
 
If any non-opioid analgesic is added but simultaneously (within two days) 
an opioid analgesic is permanently discontinued, this will not be 
considered an increase in the amount or strength of concomitant analgesic 
medications; instead, it will be considered a decrease. 
 
A separate blinded assessment of concomitant analgesic use will be 
provided following a manual review. For this manual review, a charter 
will be prepared describing the process. Individuals with knowledge and 
training will review concomitant analgesic data from each individual 
subject and classify each subject as having a decrease, no important 
change, or an increase in concomitant medications. This assessment will 
be used in a separate analysis supportive of the programmatic assessment. 
 
2.2.15 Safety Analyses 
 
Safety analyses will be based on the Safety Population and be presented 
by treatment groups. Only descriptive statistics will be presented and 
inferential statistical testing will not be performed.  
 
2.2.15.1 
Extent of Exposure and Compliance 
Extent of exposure to study medication will be tabulated by treatment 
group. Duration of exposure will be calculated as last day of exposure 
minus the first day of exposure +1. Exposure will be summarized by 
treatment group for the safety population. 
 
Compliance will be assessed by pill counts. The number of tablets 
dispensed and the number of tablets returned will be calculated. 
Compliance will be calculated by subtracting the number of returned 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 31 of 40 
 
tablets (number of tablets taken) from the number of tablets dispensed 
(minus extra tablets dispensed) and then dividing the difference by the 
number of tablets that should have been taken (two for each day on study). 
The result will be multiplied by 100%. Compliance will be calculated over 
the entire duration of exposure. 
 
2.2.15.2 
Adverse Events 
Counts and percentages of subjects who experienced any of the following 
will be presented by treatment group and overall: any AE, any drug related 
AE, discontinuations of study participation due to an AE, any serious 
adverse events (SAE), deaths, drug related SAEs, and treatment-emergent 
AE of special interest (TEAESI). Only those adverse events determined to 
be treatment emergent (TEAE) will be presented. Treatment emergent 
adverse events are those events with the date and time of AE onset being 
greater than the date and time of first dosing, and (other than TEAESIs) 
only those with an onset date within 28 days after the last date of dosing.  
 
Verbatim terms on the case report forms will be linked to preferred terms 
and related body systems using the MedDRA Coding Dictionary version 
20.0.  The number and percentage of subjects who experience treatment-
emergent adverse events will be tabulated by System Organ Class (SOC) 
and Preferred Term (PT) by treatment group and overall.  Adverse events 
will be counted only once for a subject within each Preferred Term and 
System Organ Class; thus, since a subject may have more than one 
Preferred Term within an SOC, percentages of PT may not sum to the 
percentage in the SOC.  If a subject reports an AE with a Preferred Term 
multiple times with differing severities, only the most severe is counted.  
If a subject reports an AE with a Preferred Term multiple times with 
differing relationships to study medication, only the one related to study 
drug is counted. Drug-related adverse events are defined as having a 
causality rating of being probable or possible. 
 
All reported AEs will be tabulated as described above.  For the overall AE 
table, number of adverse events will also be presented.  In addition, a 
tabulation of adverse events that occur at a frequency of 2% or greater in 
any active treatment group at the SOC or PT level will be prepared.   
 
AEs will also be tabulated by intensity/severity of the event (Grade 1 – 
mild/ Grade 2 – moderate/ Grade 3 – severe/ Grade 4 – life-threatening or 
disabling/ Grade 5 - death) and by Investigator’s assessment of 
relationship to study medication (Probable, Possible or Unlikely).  
Adverse events judged by the Investigator to be Serious Adverse Events 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 32 of 40 
 
(SAEs), SAEs resulting in death, AEs (regardless of seriousness) that 
require modification to study medication dosing (interruption or 
discontinuation) will also be tabulated by SOC and PT. 
 
2.2.15.2.1 
Serious Adverse Events 
The number and percentage of subjects experiencing a Serious 
Adverse Event (SAE) will be tabulated by SOC and PT by 
treatment group and overall.  SAEs will be counted only once for a 
subject within each PT and SOC.    
 
2.2.15.2.2 
Deaths 
A listing of subjects who die while on study will be prepared along 
with the adverse event associated with the cause of death. 
 
2.2.15.2.3 
Interruptions or Discontinuations of Study 
Medication Due to an AE 
A listing of subjects who have changes to their study medication 
dosing will be prepared.   
 
2.2.15.2.4 
Ocular Treatment Emergent AEs of Special Interest 
As defined in protocol Section 9.3.5.5 the following Ocular AEs 
will be treated as TEAESIs: 
 A Class II or Class III grading shift in LOCS III as defined 
in the Ophthalmology Manual compared to Baseline.  A 
class II or III grading shift will be programmatically 
derived from the fields captured on the eCRFs in 
accordance with the Rosiptor Ophthalmology Manual 
which is the following: 
 
o Class II: Increase in LOCS III grade of ≥ 0.9 (NO), 
≥ 1.0 (C), or ≥ 0.9 (P) 
o Class III: Increase in LOCS III grade of ≥ 1.2 (NO), 
≥ 1.5 (C), or ≥ 1.5 (P) 
 
 A reduction of 2 lines or more on the LogMAR chart in 
BCVA compared to Baseline 
 Ocular AEs without clear etiology 
 Ocular AEs considered possibly or probably related to 
study drug 
 
Ocular AEs with clear etiology will be reviewed on a case by case 
basis to determine if they should be treated as TEAESIs. Ocular 
TEAESIs will be assessed by an independent, blinded adjudicator. 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 33 of 40 
 
 
The number and percentage of subjects who experience a TEAESI 
will be tabulated by System Organ Class (SOC) and Preferred 
Term (PT) by treatment group and overall.   
 
2.2.15.2.5 
Ophthalmic Safety 
Ophthalmic safety will be summarized by treatment groups and 
overall at Baseline, Week 12, Week 16 and 6 months post last 
dose: assessment of lenticular opacification using LOCS III 
grading system, best corrected visual acuity (BCVA) using the 
LogMar chart (i.e., after manifest refraction), and Intraocular 
Pressure (IOP) before and after dilation.  Summaries will also be 
provided at early termination, although such summaries are 
acknowledged to not be a representative sample of the distribution. 
Number and percentage of subjects detected with corneal stain and 
abnormal slit lamp examination results will be presented at 
Baseline, Week 12 and 6 months post last dose. 
 
2.2.15.2.6 
Analysis of LOCS III  
Change from baseline in LOCS III score to each scheduled visit 
will be summarized by treatment group. Incidence of class events 
(Class I, Class II and Class III) will be summarized. Incidence of 
cumulative events (at least a Class I event, at least a Class II event 
and a Class III event) will be summarized and p-values will be 
provided for descriptive purposes, using a chi-square test.  The 
definition of class I, II and III events are described in the Rosiptor 
Ophthalmology Manual.   
 
The LOCS III grading system values will also be analyzed by 
means of a longitudinal MMRM model which accounts for the 
between-eye correlation.  The details of this MMRM is provided in 
Appendix C – LOC III Grading System MMRM Analysis. 
 
 
2.2.15.3 
Laboratory Data  
Shift 
tables 
will 
be 
presented 
showing 
the 
shift 
in 
(Normal/Low/High) from baseline to Week 12, off treatment 
follow-up and early termination visit by treatment group.  
 
 
2.2.15.4 
Vital Signs, 12-Lead ECG, physical examination and Other 
Observations Related to Safety   
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 34 of 40 
 
Vital signs include blood pressure and heart rate. Actual values and 
change from baseline will be tabulated by treatment group at 
baseline and each post-baseline.  
 
Shift tables will be provided for ECG data (Normal/Abnormal) 
from Screening Visit to Week 12, off treatment follow-up and 
early termination visit by treatment group. 
 
Physical Examination Findings will be presented in the listings but 
not tabulated. 
 
2.2.15.5 
Concomitant Medications 
 
Concomitant Medications will be coded per the WHO Drug Dictionary B3 
Global (version effective March 2017). Concomitant Medications will be 
tabulated by treatment group, Drug Class (pharmacological level, ATC3) 
and Drug Name (chemical substance level, ATC5).  These data will be 
provided in subject data listings along with the verbatim drug term and 
usage details.  
 
Use of concomitant analgesic medication will be summarized with the 
percentage (%) of subjects taking each class of medication using subjects 
who took any such medication on at least 1 of the 7 days prior to the 
Baseline, Week 6 or Week 12 Visit). 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 35 of 40 
 
 
References 
O'Kelly, M., & Ratitch, B. (2014). Clinical Trials with Missing Data: a Guide for Practitioners. 
Wiley. 
Alut, K. Multiple Imputation for Ordinal Variables: A Comparison of SUDAAN PROC IMPUTE 
and SAS® PROC MI, SESUG 2012, Paper SD-12, 2012. 
 
 
 
3 Document Version Control 
Revision History: 
 
REVISION 
RELEASE 
DATE 
AUTHOR 
SUMMARY OF CHANGES 
A
June 25, 2018
Jim MacDougall, PhD
Initial Release
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 36 of 40 
 
Appendix A - Programming Specifications for Tables and Listings 
 
The following specifications will be used in the production of tables and listings. 
 
1. Page Setup 
 
Unless otherwise noted, tables and listings will use landscape orientation.  Margins will be at 
least 1.5 inches on the bound side and at least 1 inch on the other three sides.   
The following header information should be included: 
  Upper left:  Sponsor name and protocol number 
  Center: CONFIDENTIAL 
  Upper right: Page number shown as Page n of N.  Page numbers should be sequential 
within a table or listing.   
 
The footer should include: 
  The name of the SAS program used to generate the output along with the run date/time 
and the words “by CTDS”.   
  For tables, the corresponding listing number(s). 
 For figures, the corresponding table number. 
    
2. Footnotes 
 
Unless otherwise specified, footnotes should appear on all pages within the table. 
 
3. Font  
 
Font will be 8-point Arial, or smaller if needed for space constraints.  If possible, small tables 
should appear on one page.  If tables continue on to multiple pages, there should be a page 
break after an assessment so that all the statistics for an assessment appear on the same page.  
 
4. Tables 
 
Table titles should reflect the content of the table.  Under the main title, in parentheses, the 
name of the analysis population being summarized should appear.   
 
4.1 Summary Statistics - Continuous Data 
 
Unless otherwise noted, the mean and median and confidence interval (CI) of a set of 
values should be printed out to one decimal place more than the original value.  The 
standard deviation should be printed out to 2 decimal places more than the original 
value.   The number of subjects on whom the parameter is assessed should appear.  
Minimum and maximum should be consistent with the original value.  P-values will be 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 37 of 40 
 
expressed as 4 decimal places.   Any p-values that get calculated as 0.00005 or less 
should be expressed as P <0.0001. 
 
4.2 
Summary Statistics - Categorical Data 
 
Numbers of subjects are reported as whole numbers.  Null counts are represented as 0.  
Table percentages should be reported to one decimal.  Null percentages will be 
suppressed (i.e., just showing the null count of 0). 
 
For all categories, the total number of subjects with data will be presented as N and the 
number of subjects with non-missing data will be used as the denominator for the 
calculation of the percentages, unless otherwise stated in a footnote.    
 
5. Subjects Included in Listings 
 
In general, subject data listings should include all subjects who signed the informed consent.  If 
a listing includes a subset of subjects who meet a certain condition (e.g., subjects with SAEs) 
then this should be clear from the title of the listing.  If there are no subjects who meet the 
condition (e.g. no subjects with SAEs) for either the tables or the listings, then a page marker 
should appear stating that no subjects met the criteria. 
 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 38 of 40 
 
Appendix B – Sample MMRM Code  
 
The following is sample SAS Proc Mixed code to be used for the primary endpoint analysis.  
 
**-----------------------------------------------------**; 
** usubjid: subject identifier                         **; 
** visit: visit identifier                             **; 
** trt: treatment identified                           **; 
** chg: change from baseline value                     **; 
** base: baseline value                                **; 
 
proc mixed data=xxxx; 
  class usubjid visit trt(ref='0'); 
  model chg = base visit trt base*visit trt*visit/s; 
  repeated /subject=usubjid type=un; 
  ** note: LS Mean analysis is primary analysis **; 
  lsmeans trt trt*visit / diff cl; 
  ods output LSMeans=LSMeans Diffs=diffs; 
  where visit >0; 
run; 
 
 
The following is sample SAS Proc Mixed code for the MMRM to assess time course  
 
**-----------------------------------------------------**; 
** usubjid: subject identifier                         **; 
** visit: visit identifier (numeric)                   **; 
** trt: treatment identified                           **; 
** chg: change from baseline value                     **; 
** base: baseline value                                **; 
 
proc mixed data=xxxx; 
  class usubjid trt(ref='0'); 
  model chg = base visit trt trt*visit/s; 
  random intercept visit /subject=usubjid type=un; 
  where visit >0; 
run; 
 
 
 
 
 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 39 of 40 
 
Appendix C – LOC III Grading System MMRM Analysis 
 
 
The analysis of the LOCS III lens opacification data will use the following model: 
Let yijk= LOCS III grade for the ith subject at the jth time point for the kth eye, 
i = 1,…,100; j = 1,…,4; k = 1,2;  
the visits corresponding to the values of j are:  
1= Week 1 (baseline) 
2=Week 12  
3=Week 16 
4=Week 38. 
 
Note: if the subject has an early termination visit, that value will be included in the week 
corresponding to the next scheduled visit (i.e., either Week 12, 16, or 38). 
 
Let tj = time (weeks) at the jth time point;  
tj =0 if j=1  
tj =12 if j=2  
tj =16 if j=3  
tj =38 if j=4. 
 
Let k = 1 for the right eye (OD), k= 2 for the left eye (OS). 
 
Let xi=1 if the ith subject is in the active treatment group, xi= 0 if in the placebo group. 
 
Let zil = value of the ith covariate for the lth subject at baseline, where i = 1 for age (years). 
 
Separately for each cataract type, the following MMRM will be fit: 
yijk =  + β1xi + β2tj + β3zi + γ1xitj + γ2zitj + eijk 
 
where:  

is the intercept parameter 
β1 
is the difference in mean LOCSIII grade at baseline between the active and placebo 
groups
β2 
is the rate of increase in LOCS III grade in the placebo group for each visit (Weeks 
12, 16, and 38)
β2+ γ1 
is the rate of increase in LOCS III grade in the active group for each visit (Weeks 12, 
16, and 38)
β3
are the effects of covariates on baseline LOCS III grade 
γ2 
are the effects of covariates on the rate of change of LOCSIII grade over time for 
each visit (Weeks 12, 16, and 38).
note: underlining indicates a vector.


 
FM DM015.1 
            Statistical Analysis Plan 
 
 
Rev: A 
AQX-1125-205 
 
 
            Page 40 of 40 
 
 
The primary parameter of interest is γ1, the difference in the rate of increase in LOCS III grade 
between the active group and placebo group for post-baseline each scheduled visit (i.e., Weeks 
12, 16, 38).  A contrast statement, testing for a trend across time will also be calculated.  
 
 
SAS PROC MIXED will be used to fit the model in based on the eye as the unit of analysis using 
the REPEATED option with a UN@UN correlation structure. This will enable control for 
correlation between-eyes and across time:  
(a) Between LOCS III grade for two eyes of the same person at the same time 
(b) Between LOCS III grade for the same eye over time 
(c) Between LOCS III grade for one eye (e.g., OD) at one time and the fellow eye (e.g., OS) 
at a different time. 
This analysis will be performed separately for each type of cataract (NO, C, P). 
 
Sample SAS code is provided below:  
 
**-----------------------------------------------------**; 
** usubjid: subject identifier                         **; 
** eye: eye identifier                                 **; 
** trt: treatment                                      **; 
** time: week of assessment                            **; 
** aval: LOCS III Grade                                **; 
 
proc mixed data=xxxx; 
  class usubjid eye(ref=1’) time(ref=’0’) trt(ref='0'); 
  model aval = trt time age  
               trt*time age*time /s; 
  repeated time eye/subject=usubjid type=un@un; 
   ** note: linear contrast statement for estimating the **; 
   **       trend when the visits are 0, 6, 12, 16, 38   **; 
   **       contrast constrained that sum of contrasts   **; 
   **       coefficients =0, squared sum =1               **; 
   estimate 'slope: trt-x-time'  
        time -0.163771768 -0.018196863 0.782465115 -0.600496483 
        trt*time -0.163771768 -0.018196863 0.782465115 -0.600496483 0 0 0 0  
    /e; 
run;