A Phase 2, Multicenter, Open Label Study to Evaluate the Efficacy and Safety of OK-432 Immunotherapy in Individuals With Lymphatic Malformations
Phase: PHASE2
Conditions: Lymphatic Malformations
Sponsor: Richard JH Smith

NCT03427619 
Protocol (May 2014) and Statistical Analysis Plan (7 April 2021) 
A Phase 2, Multicenter, Open Label Study to Evaluate the Efficacy and Safety of OK-432 Immunotherapy 
in Individuals With Lymphatic Malformations 

 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
   

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
 
 
 
St atistic al A n al ysis Pl a n  
 
 
Pr ot oc ol O K -4 3 2 -0 0 3 -O P E N  
Pr otara T hera pe utics , I nc. 
 
 
A M U L TI C E N T E R, O P E N -L A B E L  S T U D Y  T O E V A L U A T E  T H E E F FI C A C Y A N D 
S A F E T Y  O F O K -4 3 2 I M M U N O T H E R A P Y I N  I N DI VI D U A L S WI T H L Y M P H A TI C 
M A L F O R M A TI O N S  
 
 
P hase 2  E x pa nsi o n  
 
 
 
Pr ot oc ol  V ersi o n D ate d : M A Y 2 0 1 4  
 
 
 
 
 
 
Pre p are d 
 
 
 
 
 
 
 
Versi o n:  
Fi nal  
 
D ate:  
A pril 7 , 2 0 2 1 
 

  
O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
St atistic al A n al ysis Pl a n  
 
Pr ot oc ol O K -4 3 2 -0 0 3 -O P E N  
Pr otara T hera pe utics , I nc. 
 
 
A M U L TI C E N T E R, O P E N -L A B E L S T U D Y  T O E V A L U A T E T H E E F FI C A C Y A N D 
S A F E T Y O F O K -4 3 2 I M M U N O T H E R A P Y I N  I N DI VI D U A L S WI T H L Y M P H A TI C 
M A L F O R M A TI O N S  
 
 
P hase 2 E x pa nsi o n  
 
 
Pr ot oc ol V ersi o n D ate d :  M A Y 2 0 1 4  
 
 
T his Statistical A nal ysis Pla n has bee n re vie we d a n d a p pr o ve d b y:  
                   

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
3  
T A B L E O F C O N T E N T S  
LI S T O F A B B R E VI A TI O N  ................................................................................................................................... 5  
1  
I N T R O D U C TI O N ........................................................................................................................................... 6  
1. 1  
St u d y B ac k gr o u n d  ................................................................................................................................ 6  
1. 2  
Retr os pecti ve A nal ysis of O K -4 3 2 -0 0 3 -O P E N  .................................................................................... 6  
2  
S T U D Y O BJ E C TI V E S  ................................................................................................................................... 6  
2. 1  
Pri mar y Efficac y O bj ecti ve  .................................................................................................................. 6  
2. 2  
Sec o n dar y Efficac y O bj ecti ve  .............................................................................................................. 6  
2. 3  
Safet y O bj ecti ve  ................................................................................................................................... 7  
3  
S T U D Y O V E R VI E W  ..................................................................................................................................... 7  
3. 1  
St u d y Desi g n  ........................................................................................................................................ 7  
3. 2  
St u d y Pr oce d ures a n d Visit Str uct ure  ................................................................................................... 7  
4  
S T U D Y E N D P OI N T S  .................................................................................................................................. 1 0  
4. 1  
Pri mar y Efficac y E n d p oi nt(s)  ............................................................................................................. 1 0  
4. 2  
Sec o n dar y Efficac y E n d p oi nts  ............................................................................................................ 1 0  
4. 3  
Safet y E n d p oi nts  ................................................................................................................................. 1 0  
5  
A N A L Y SI S P O P U L A TI O N S  ....................................................................................................................... 1 1  
5. 1  
E nr olle d P o p ulati o n  ............................................................................................................................ 1 1  
5. 2  
Safet y P o p ulati o n  ................................................................................................................................ 1 1  
5. 3  
M o difie d I nte nt -t o-Treat P o p ulati o n  ................................................................................................... 1 1  
6  
S T U D Y S U BJ E C T S  ..................................................................................................................................... 1 1  
6. 1  
S u bj ect Dis p ositi o n  ............................................................................................................................. 1 1  
6. 2  
De m o gra p hic a n d B aseli ne C haracteristics  ........................................................................................ 1 2  
6. 3  
C o nc o mita nt Me dicati o ns  ................................................................................................................... 1 2  
6. 4  
Me dical a n d S ur gical Hist or y  ............................................................................................................. 1 2  
6. 5  
Pr ot oc ol De viati o ns a n d Vi olati o ns  .................................................................................................... 1 2  
6. 6  
St u d y Dr u g A d mi nistrati o n a n d E xte nt of E x p os ure  .......................................................................... 1 3  
7  
S T A TI S TI C A L M E T H O D S O F A N A L Y SI S  ............................................................................................... 1 3  
7. 1  
Ge neral C o nsi derati o ns  ....................................................................................................................... 1 3  
7. 1. 1  
H y p ot hesis Testi n g  ............................................................................................................... 1 3  
7. 1. 2  
Defi ni n g t he St u d y B aseli ne  ................................................................................................. 1 3  
7. 1. 3  
Deri vi n g Res p o nse Data  ....................................................................................................... 1 3  
7. 1. 4  
Ha n dli n g of M ulti ple O bser vati o ns  ...................................................................................... 1 4  
7. 1. 5  
Visit Ma p pi n g d ue t o C ha n ge i n Pr ot oc ol  ............................................................................ 1 4  
7. 1. 6  
Ha n dli n g of Missi n g or P artial Dates  ................................................................................... 1 4  
7. 1. 7  
Ha n dli n g of Missi n g Efficac y Data  ...................................................................................... 1 5  
7. 2  
Efficac y A nal yses  ............................................................................................................................... 1 5  
7. 2. 1  
A nal yses of Pri mar y E n d p oi nt(s)  ......................................................................................... 1 5  
7. 2. 1. 1  
Se nsiti vit y A nal ysis  ............................................................................................ 1 5  
7. 2. 2  
A nal yses of Sec o n dar y E n d p oi nts  ........................................................................................ 1 5  
7. 2. 2. 1  
Res p o nse Rate P ost -T hera p y as Assesse d b y I ma gi n g  ....................................... 1 5  
7. 2. 2. 2  
I n vesti gat or-e val uate d O verall Res p o nse  ........................................................... 1 6  
7. 2. 2. 3  
Re d ucti o n i n V ol u me P ost -T hera p y  ................................................................... 1 6  
7. 2. 3  
Ti me t o E ve nt A nal yses f or Cli nical I m pr o ve me nt  .............................................................. 1 7  
7. 2. 4  
Ot her A nal ysis  ...................................................................................................................... 1 7  
7. 3  
Safet y A nal yses  .................................................................................................................................. 1 7  
7. 3. 1  
A d verse E ve nts  ..................................................................................................................... 1 7  
7. 3. 1. 1  
Reacti o ns t o O K -4 3 2  .......................................................................................... 1 7  
7. 3. 1. 2  
Seri o us A d verse E ve nts  ...................................................................................... 1 9  
7. 3. 2  
Cli nical La b orat or y E val uati o ns  ........................................................................................... 1 9  
7. 3. 3  
Electr ocar di o gra m  ................................................................................................................ 2 0  
7. 3. 4  
P h ysical E xa mi nati o n  ........................................................................................................... 2 0  
7. 3. 5  
Vital Si g ns  ............................................................................................................................ 2 0  

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
4  
8  
S T A TI S TI C A L S O F T W A R E  ....................................................................................................................... 2 1  
 
LI S T O F T A B L E S  
T a ble 1 Sc he d ule of E ve nts  .................................................................................................................................... 9  
T a ble 2 Res p o nse Assess me nt Criteria  ................................................................................................................. 1 0  
T a ble 3 R ules f or Missi n g or P artial Dates  ........................................................................................................... 1 4  
 
 
 

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
5  
LI S T O F A B B R E VI A TI O N  
 
A E  
A d verse e ve nt  
A T C  
A nat o mic thera p e utic ch e mist r y 
B MI  
B o d y mass i n de x  
C R F  
C ase re p ort f or m  
CI  
C o nfi de nce i nter val  
C T  
C o m p ute d t o m o gra p h y 
E C G  
E lectr ocar di o gra m 
I C F 
Inf or me d c o ns e nt f or m  
I N D 
In v esti gati o nal ne w dr u g  
L M  
L y m p hatic malf or mati o ns  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y A cti vities  
m I T T 
M o difie d i nte nt -t o-treat 
M RI  
M a g n etic res o n a nce i ma gi n g  
P E  
P h ysical e x a mi nati o n  
P T  
Preferre d ter m  
S A E  
S eri o us a d verse e ve nts  
S A P  
S tatistical a nal ysis pla n 
S A S  
Statistical a nal ysis s oft ware  
S D  
S ta n dar d de viati o n 
S E  
Sta n dar d err or  
S O C  
S yste m or ga n class  
T E S A E  
Treat me nt -e mer ge nt s eri o us a d verse e ve nts  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
6  
1  
I N T R O D U C TI O N 
1. 1  
St u d y B ac k gr o u n d  
T he S p o ns or is de vel o pi n g its pr o p ose d T A R A -0 0 2 injecti o n pr o d uct f or i ntrac ystic 
a d mi nistrati o n f or t he treat me nt of l y m p hatic m alf or mati o ns ( L Ms) i n pe diatric a n d a d ult 
s u bjects. TA R A -0 0 2  is a l y o p hilize d bi ol o gical pr e parati o n f or i njecti o n c o ntai ni n g 
atte n uate d cells of Stre pt oc occ us p y o ge nes ( A gr o u p, t y pe 3) S u strai n treat e d wit h 
be nz yl pe nicilli n.  T he c h aracteristics of T A R A -0 0 2 are i nte n de d t o b e c o m p ara ble t o O K -4 3 2 
( ma n ufacture d b y C h u gai P har mace uticals) w hic h is c urre ntl y a p pr o ve d i n Ja pa n a n d T ai wa n 
f or use as tr eat me nt f or L Ms. T heref ore, n o ncli nical a n d cli nical st u dies wit h O K -4 3 2 
s u p p ort t he de vel o p me nt of T A R A-0 0 2.  
I n t he U S, a n I n vesti gati o nal Ne w Dr u g a p plicati o n (IN D) was o pe n e d b y 
 
at t he U ni versit y of I o w a  t o e val uate t he p ote ntial safet y a n d efficac y of O K-4 3 2 i n t he 
treat me nt of L Ms. U n der t his I N D, O K-4 3 2 was  c o m passi o natel y use d f or t he treat me nt of 
L Ms i n pe diatri c a n d a d ult s u bjects as a n alter nati ve t o s ur ger y. After  t he c o ncl usi o n of t he 
P hase 2 ra n d o mize d st u d y  ( O K-4 3 2 -0 0 2 -R A N D) , all ne w  s u bjects w h o prese nte d wit h a n 
L M a n d were eli gi ble f or treat me nt were treate d u n der a n o pe n -la bel pr ot o c ol f or c o nti n ue d 
access t o O K-4 3 2. T he m ultice nter , o pe n-la bel st u d y ( O K-4 3 2 -0 0 3 -O P E N)  e nr olle d patie nts 
bet wee n S e pte m b er 2 0 0 5 a n d N o ve m ber 2 0 1 7 .  
1. 2  
Retr os pecti ve A n al ysis of O K -4 3 2 -0 0 3 -O P E N  
T his d oc u me nt pr o vi des a detaile d des cri pti o n of t he statistical met h o ds a n d pr oce d ures t o be 
i m ple me nte d d uri n g t he  retr os pecti ve a nal ysis of  t he m ultice nter, o pe n -la bel st u d y t o 
e val uate t he effic ac y a n d safet y of O K -4 3 2 i m m u n ot hera p y i n i n di vi d ual s wit h l y m p h atic 
malf or mati o ns . T his S A P i ncl u des t he f ull dataset of s u bjects e nr olle d i n st u d y O K-4 3 2 -0 0 3 -
O P E N  bet wee n S e pt e m ber 2 0 0 5 a n d N o ve m ber 2 0 1 7 . 
2  
S T U D Y O B J E C TI V E S  
T he  o bjec ti ve of t his st u d y is t o pr o vi de  i m m u n osti m ula nt O K -4 3 2 t o s u bjects wit h 
macr oc y stic or mi x e d ( > 5 0 % macr oc ystic) L Ms a n d i n vesti gate  t he effi cac y a n d s afet y of  
O K -4 3 2 as a treat me nt o pti o n i n s u bjects wit h L Ms . 
2. 1  
Pri m ar y Effic ac y O bjecti ve  
T o  e val uate t he rate of cli nicall y s uccessf ul o utc o mes of  O K -4 3 2 i m m u n ot hera p y i n s u bjects 
wit h L Ms . 
2. 2  
Sec o n d ar y  Effic ac y O bjecti ve  
T o  f urt her e val uate t he res p o nse rate t o O K -4 3 2 i m m u n ot hera p y i n s u bjects wit h L Ms . 

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
7  
 
2. 3  
S afet y O bjecti ve  
T o e val uate t he s afet y a n d t olera bilit y of O K -4 3 2 i m m u n ot hera p y i n s u bjects wit h  L Ms.   
3  
S T U D Y O V E R VI E W  
3. 1  
St u d y Desi g n  
St u d y O K -4 3 2 -0 0 3 -O P E N  is a m ulti ce nter, o pe n-l a bel cli nical st u d y t o e val uate t he efficac y 
a n d safet y of O K -4 3 2 i m m u n ot hera p y i n s u bjects wit h L Ms. T he st u d y was c o n d ucte d acr oss  
1 4 ce nters acr oss t he U nite d States  bet wee n S e pte m ber 2 0 0 5 a n d N o ve m ber 2 0 1 7 . M ost 
eli gi ble s u bjects w ere b et wee n 6 m o nt hs a n d 1 8 years of a ge wit h a L M t hat was macr oc ystic 
or mi x e d ( > 5 0 % macr oc ystic) . C lassificati o n was deter mi ne d ra di o gra p hicall y b y c o m p ute d 
t o m o gra p h y ( C T) or ma g netic res o na n ce i ma gi n g ( M RI) sca ns b y meas uri n g t he v ol u me of 
all c ysts. Macr oc ystic L M s were d efi ne d as c ystic s paces ≥ 2. 0 ml ( 2 c m × 1 c m × 1c m) . L M 
wit h b ot h macr oc ystic a n d micr oc ystic  ( m ulti ple c ysts, eac h less t ha n 2 cc i n v ol u me) lesi o ns 
were d esi g n ate d mi x e d L M.  
S u bject s recei v e d O K-4 3 2 i m m u n ot hera p y s h ortl y after e nr oll me nt. Eac h s u bject recei ve d a 
series of f o ur-d ose i njecti o ns of O K -4 3 2  i m m u n ot hera p y, u nless a c o ntrai n dicati o n ar ose or a 
c o m plete res p o nse was o bser ve d pri or t o c o m pleti o n of t he i njecti o n series.  
3. 2  
St u d y Pr oce d ures a n d Visit Str uct ure  
T he  ma xi m u m d ose of O K -4 3 2 i njecte d per s u bject at eac h sessi o n was  0. 2 m g at a 
c o nce ntr ati o n of 0. 0 1 -0. 0 5 m g/ ml . T his c o nce ntr ati o n  was ac hie ve d b y diss ol vi n g 0. 1 m g vi al 
of O K -4 3 2 i n 1 0 ml of n or mal sali ne or 0. 1 m g of O K -4 3 2 diss ol ve d i n 5 ml n or mal sali ne . 
T he d ose was n ot b ase d o n lesi o n size.  
Eac h i njecti o n sessi o n w as  perf or me d b y pe diatri c ot olar y n g ol o gists, pe di atric s ur ge o ns, or 
ot her s ur gical s pe cialists wit h c o m para ble e x pertise.  I ntrac ystic fl ui d was as pirate d usi n g a 
2 5 -ga u ge  ( occasi o nall y l ar ger) i ntra ve n o us cat het er. If necess ar y, nee dle pl ace me nt was 
c o nfir me d b y ultras o n o gra p h y.  F o ll o wi n g as pirati o n, O K-4 3 2 was i nje cte d i nt o t he c yst  at t he 
a p pr o priate c o nce ntrati o n . F oll o wi n g i njecti o n, s u bjects were o bser ve d i n t he rec o v er y 
r o o m/ h os pital f or a p pr o xi matel y ~ 4 h o urs. I n t he a bse nce of s y m pt o ms t hat necessitate 
a d missi o n (i ncl u di n g b ut n ot li mite d t o se psis, s h oc k, air wa y c o m pr o mise, seiz ures), s u bjects 
will be disc har ge d.  
A  4 -d ose i njecti o n seri es of O K -4 3 2 , 6 t o 1 2  wee ks a part  was pl a n ne d f or all s u bjects . If a 
c o ntrai n dicati o n e xist e d, or a c o m plete res p o nse was  o bser ve d pri or t o c o m pleti o n of all 4 
i njecti o ns, su bject s were treate d wit h fe wer t h a n 4 i njecti o ns .  S u bject s ma y ha v e bee n 
treate d wit h m ore t h a n 4 i njecti o ns if m ulti ple L Ms were  tr eate d or if t here was a rec urre nce. 

 O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
8  
St u d y visits a n d pr o ce d ures are s u m marize d i n t he sc he d ule of e ve nts i n  Ta ble 1. 

  
O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
9  
T a ble 1  Sc he d ule of E ve nts  
E v al u ati o n  
Pre -
T her a p y  
Tre at me nt Peri o d 5  
P ost -tre at me nt Peri o d/ F oll o w u p 
V 1  
V 2 ; 
( 1st I nj.) 
V 3 ; 
2 w ee ks after 
First I nj.  
V 4 ; 
( 2n d  I nj.) 
V 5 ; 
( 3r d I nj.) 
V 6 ; 
( 4t h I nj.) 
V 7;  
1 -6 m o nt hs after 
Fi n al I nj.  
V 8 ; 
1 ye ar after Fi n al 
I nj. 
( O pti o n al) 
V 9/ St u d y E xit ; 
2 ye ars after Fi n al I nj.  
( O pti o n al) 
I nf or m e d C o nse nt 
x  
 
 
 
 
 
 
 
 
C o m plete Hist or y  
x  
 
 
 
 
 
x  
 
 
F oc use d Hist or y  
 
x  
x  
x  
x  
x  
 
x  
x  
Pe nicilli n Aller g y Testi n g  
x  
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Cli nical S ta gi n g1 
x  
 
 
 
 
 
 
 
x  
Vital Si g ns  
 
x  
x  
x  
x  
x  
x  
x  
 
La b orat or y A nal ysis 7  
x  
 
 
 
 
 
x  
 
 
Pre g na nc y Test 4  
x  
 
 
 
 
 
 
 
 
Me dical P h ot o gra p h y  
x  
 
 
 
 
 
x  
 
 
A E/ S A E  
 
x  
x  
x  
x  
x  
x  
x  
x  
M RI/ C T
6 
x  
 
 
 
 
 
x  
 
 
Ass ess me nt Q uesti o n naire 2 
 
x  
 
x  
x  
x  
 
 
 
Dr u g A d mi nistrati o n  
 
x  
 
x  
x  
x  
 
 
 
S u bject  Diaries 3  
 
x  
 
x  
x  
x  
 
 
 
V –  Visit, I nj. –  I njecti o n 
 
1  Cli nical sta gi n g base d o n m o difie d de Serr es classificati o n . 
2 A n assess me nt f or m wit h a ret ur n e n vel o pe was gi ve n t o patie nt/fa mil y t o fill o ut  3 -5 da ys a n d 2 -3 
wee ks  after eac h i njecti o n series.   
3 S u bjects d oc u me nt e d dail y te m perat ure, pai n, er yt he ma, e de ma, a n d si de effects f or 1 4 da ys after eac h 
i njecti o n sessi o n. 
4 I n fe males of c hil d-beari n g a ge.  
 
 
5A 4 -d ose i njecti o n series  was pla n ne d f or all s u bjects s pace d a p pr o xi matel y 6 -1 2 wee ks a part . If a 
c o ntrai n dicati o n e xiste d, or a c o m plete res p o nse was o bser ve d pri or t o c o m pleti o n of all 4 i njecti o ns, 
s u bjects wer e treate d wit h fe wer t ha n 4 i njecti o ns. S u bjects  ma y ha ve bee n treate d wit h  m ore t ha n  4 
i njecti o ns if m ulti ple L Ms were treate d or if t here was a rec urre nce. 
6 M RI/ C T ma y ha ve bee n perf or me d at a d diti o nal ti me p oi nts per I n vesti gat or’s discreti o n . 
7 La b orat or y a nal ysis was c o n d ucte d at c o nc urre nt e val uati o ns if it was c o m plete d greater t ha n 3 m o nt hs 
fr o m pre-treat me nt e xa mi nati o n. 
 

  
O K -4 3 2 -0 0 3 -O P E N  Statistical A nal ysis Pla n  
 
 
1 0  
4  
S T U D Y E N D P OI N T S  
4. 1  
Pri m ar y Effic ac y E n d p oi nt (s) 
T he p ri mar y effic ac y e n d p oi nt is t he pr o p orti o n of s u bjects wit h cli nical s uccess defi ne d as 
ha vi n g eit her a c o m plete or a s u bsta ntial  res p o nse t o t hera p y at 1 -6  m o nt hs  p ost -t hera p y as 
assesse d b y i ma gi n g ( M RI a n d/ or C T). T he p ost -t hera p y i ma gi n g was d o n e at 1-6 m o nt hs 
after t he f o urt h  or last i nj ecti o n series  (if fe wer t ha n f o ur). If s u bjects were treate d wit h m or e 
t ha n 4 i njecti o ns, p ost-t hera p y res p o nse f or t he pri mar y a nal ysis was e val uate d 1 -6  m o nt hs  
after t he 4 t h i njecti o n. 
Res p o nse t o t hera p y will be  gra de d  as perce nta ge re d ucti o n i n L M v ol u me fr o m pre-
treat me nt t o p ost-treat me nt as assesse d b y i ma gi n g . Ta bl e 2  descri bes t he criteria f or 
assess me nt of cli nical r es p o nse.  
T a ble 2  Res p o nse Assess me nt Criteri a  
C o m plete Res p o nse  
9 0 % – 1 0 0 % re d ucti o n i n v ol u me  
S u bsta ntial Res p o nse  
6 0 % –  8 9 % re d ucti o n i n v ol u me  
I nter me diate Res p o nse  
2 0 % – 5 9 % re d ucti o n i n v ol u me  
N o Res p o nse  
< 2 0 % re d ucti o n i n v ol u me  
 
4. 2  
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 i ncl u de:  
1.  T he pr o p orti o n of s u bjects w h o de m o nstrate d  c o m plete, s u bsta ntial, i nter me diate, or 
n o res p o nse 1 -6  m o nt hs  p ost -t hera p y.   
2.  T he pr o p orti o n of s u bjects w h ose i n vesti gat or-e v al uate d o verall res p o nse was 
rec ord e d as “ C li nical I m pr o ve me nt” or “ N o C ha n ge” . T he e val uati o n was perf or me d 
vis uall y at e ac h i njecti o n series a n d f oll o w u p visits fr o m sec o n d i njecti o n s eries 
o n war ds.  
3.  T he c ha n ge a n d perce nt c ha n ge fr o m b aseli ne i n lesi o n v ol u me fr o m t he i ma gi n g 
data, w here t he bas eli ne v ol u me is defi ne d as t he pre -t hera p y v ol u me. 
4. 3  
S afet y E n d p oi nts  
T he safet y e n d p oi nts i ncl u de :  
 Reacti o ns t o O K -4 3 2 i ncl u di n g:  

  
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o  S u bject  st u d y diaries d o c u me nt i n g dail y te m perat ure, pai n, er yt h e ma, e d e ma, 
a n d si de effects f or 1 4 da ys after eac h i njecti o n sessi o n . 
o  Reacti o ns re p ort e d t hr o u g h p ost -tr eat me nt q uesti o n naire  Case Re p ort F or m 
( C R F). 
o  I n v esti gat or-e v al uate d cli nical reacti o ns t o O K -4 3 2  re p orte d t hr o u g h p ost -
treat me nt Cli nical Res p o nse C R F . 
 I n ci de nce of seri o us a d verse e ve nts . 
 Cli nicall y si g nifica nt c ha n ges i n la b orat or y val u es  (c he mistr y, he mat ol o g y, ser ol o g y 
a n d uri nal ysis).  
 P h ysical e x a m.  
 Vital Si g ns.   
5  
A N A L Y SI S P O P U L A TI O N S  
5. 1  
E nr olle d P o p ul ati o n  
T he E nr ol le d p o p ulati o n i ncl u des all s u bjects t hat ha ve bee n e nr olle d i n t he st u d y. All 
s u bjects n ot desi g nat e d as Scree n Fail ures will be c o nsi dere d e nr olle d . 
5. 2  
S afet y  P o p ul ati o n  
T he Safet y p o p ulati o n i n cl u des all E nr olle d s u bjects t hat ha ve bee n treat e d wit h at least o ne 
i njecti o n of O K-4 3 2.   
5. 3  
M o difie d I nte nt -t o-Tre at  P o p ul ati o n  
T he M o difie d I nte nt -t o-Treat ( mI T T) p o p ulati o n  i ncl u des all E nr olle d s u bj ects t hat ha ve b ee n 
treate d wit h at least o ne i njecti o n of O K -4 3 2 a n d ha ve eit her p ost -t h era p y i ma gi n g 
assess me nt d ata or at least o ne i n vesti gat or assess me nt f or  o verall res p o nse  t hr o u g h o ut t he 
st u d y. Si nce t he  o pe n -la b el st u d y was c o n d ucte d s o t hat s u bjects ma y h a ve c o nti n ue d access 
t o O K-4 3 2  o n a c o m p assi o nate use basis a n d res p o nse data was n ot well d oc u me nte d f or 
e ver y o ne, t h e m o difie d I nte nt-t o-Treat p o p ulati o n ( mI T T) p o p ulati o n is defi ne d t o better 
assess t he res p o ns e rate b ase d o n t he o bser ve d dat a.  
6  
S T U D Y S U B J E C T S  
6. 1  
S u bject  Dis p ositi o n  
S u bject  dis p ositi o n i nf or mati o n, i ncl u di n g t he c o u nts a n d perce nta ges of s u bjects w h o 
c o m plete or disc o nti n ue fr o m t he st u d y, as well as reas o ns of disc o nti n uati o n, will be 
s u m marize d f or t he E nr olle d  p o p ulati o n .  

  
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6. 2  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
S u bject  de m o gra p hics will be s u m marize d f or t he  Safet y a n d mI T T p o p ulati o n s. T he 
s u m mar y will i ncl u de a ge, se x, race, et h nicit y, cli nical sta ge, lateralit y, l y m p hatic 
malf or mati o n t y p e, w het her t he s u bject h a d pri or s ur ger y, a n d wei g ht, hei g ht, a n d B MI at 
baseli ne.  A ge gr o u ps will be s u m marize d b y t he f oll o wi n g cat e g ories:  
 < 6 m o nt hs  
 6 m o nt hs t o < 1 8 years  
 6 m o nt hs t o < 2 years  
 2 t o < 6 years  
 6 t o < 1 2 years  
 1 2 t o < 1 8 years  
 1 8 t o < 6 5 years  
 ≥ 6 5 years  
6. 3  
C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt me dicati o ns i ncl u de all me dicati o ns ta ke n d uri n g t he c o n d u ct of t he st u d y (fr o m 
pre -treat me nt t hr o u g h p ost-treat me nt peri o d). Ne w c o nc o mita nt me dicati o ns i ncl u de all 
me dicati o ns starte d after recei vi n g t he first O K -4 3 2 treat me nt.  
T he W orl d Healt h Or ga niz ati o n Dr u g Dicti o nar y ( W H O-D D) will be use d t o cate g orize 
ver bati m descri pti o ns of n o n -st u d y me dicati o ns i nt o t he A nat o mic T hera pe utic C he mist r y 
( A T C) classificati o n s yst e m. Eac h ver bati m na me will be classifie d b y a nat o mical mai n 
gr o u p ( A T C le vel 1), t hera pe utic s u b gr o u p ( A T C le vel 2), p har m ac ol o gical s u b gr o u p ( A T C 
le vel 3), c he mical s u b gr o u p ( A TC le vel 4), preferre d ter m, a n d tr a de na m e (if a p pr o priate). 
N u m bers a n d perce nta ges of s u bjects wit h c o nc o mita nt a n d ne w c o nc o mit a nt me dicati o ns 
will be s u m mariz e d b y A T C classificati o n ( A T C l e vel 2 a n d le v el 4) f or t h e Safet y 
p o p ulati o n.   
6. 4  
Me dic al a n d S ur gic al Hist or y  
Me dical a n d s ur gic al hist or y a n d pri or treat me nts will be s u m marize d f or all s u bjects i n t he 
Safet y  p o p ulati o n. S u bject  le vel data will be prese nte d i n data listi n gs.   
6. 5  
Pr ot oc ol D e vi ati o ns a n d Vi ol ati o ns  
N o tra diti o nal pr ot oc ol d e viati o n data was  c ollect e d i n t his st u d y.   

  
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6. 6  
St u d y Dr u g A d mi nistr ati o n a n d E xte nt of E x p os ure  
St u d y dr u g a d mi nistrati o n a n d d osi n g i nf or mati o n will be prese nte d i n a listi n g . T he e xte nt of 
st u d y me dicati o n e x p os ure will be  s u m marize d f or t he Safet y P o p ulati o n. T he s u m mar y will 
i ncl u de t otal d ose a d mi nistere d  a n d n u m ber of i njecti o n sites  d uri n g eac h i njecti o n sessi o n 
al o n g wit h t he n u m ber of i njecti o ns a n d s u m of d oses ta ke n d uri n g t he f ull treat me nt peri o d.  
7  
S T A TI S TI C A L M E T H O D S O F A N A L Y SI S  
7. 1  
Ge ner al C o nsi der ati o n s 
E fficac y e n d p oi nts will be s u m marize d f or t he m I T T p o p ulati o n. Descri pti ve statistics as 
well as d ata listi n gs will be pr o vi de d. Safet y a nal ysis will be c o n d ucte d o n t he Safet y 
p o p ulati o n . T he s u m maries of t he cate g orical data will be calc ulate d b ase d o n  t he n u m ber of 
s u bjects wit h n o n -missi n g res p o nse dat a.  
C o nti n u o us varia bles will be s u m marize d b y fre q u e nc y, mea n, sta n d ar d de viati o n,  sta n dar d 
err or, me di a n, mi ni m u m, a n d ma xi m u m, a n d cate g orical vari a bles will be s u m marize d b y 
fre q ue n c y a n d p erce nta ge  i n c orres p o n di n g cate g ories.  
Mi ni m u m a n d ma xi m u m val ues will be r o u n de d t o t he precisi o n of t he ori gi nal val u e. Mea ns 
a n d me dia ns will be r o u n de d t o o ne deci mal place greater t ha n t he precisi o n of t he ori gi nal 
val ue. S Ds, S Es, a n d 9 5 % c o nfi de n ce i nter val s ( CIs) will be r o u n de d t o t w o deci mal places 
greater t ha n t he precisi o n of t he ori gi nal val ue. Perce nta ges f or s u m marizi n g cate g orical data 
will be r o u n de d t o t he nearest w h ole n u m ber . 
7. 1. 1  
H y p ot hesis Testi n g  
T here is n o pre -s pecifie d f or mal h y p ot hesis of effi cac y i n t he pr ot o c ol.  
7. 1. 2  
Defi ni n g t he St u d y B aseli ne  
I n ge neral, the baseli ne v al ue f or eac h v aria ble is defi ne d as t he v al ue rec or de d at t he last 
visit o n or bef ore t he first O K -4 3 2 i njecti o n is a d mi nistere d.  
7. 1. 3  
Deri vi n g Res p o nse D at a  
Res p o nse cate g ories as d efi ne d i n Secti o n 4  will be deri ve d b ase d o n c h a n ge i n le gi o n  
v ol u me  fr o m pre-tr eat me nt t o p ost-treat me nt, if a p plica ble . Ort h o g o nal meas ure me nts of L M 
siz e o n C T  or M RI  fi n di n gs will be use d t o calc ulate v ol u me/size. V ol u me will be deri ve d 
fr o m le n gt h × wi dt h × hei g ht if all t he t hree val ues are a v aila ble. If a n y of t he le n gt h, wi dt h, 
or hei g ht d ata are missi n g, t he v ol u me val ue as re p orte d will be use d t o deri ve t he res p o nse. 
If v ol u me data is n ot a vaila ble b ut t here is c ollect e d res p o nse dat a, t he n c oll ecte d res p o nse 
data will be use d.   

  
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7. 1. 4  
H a n dli n g of M ulti ple O bser v ati o ns  
F or m ulti ple o bser vati o ns f or t he sa me e n d p oi nts t hat are c ollecte d m ulti ple ti mes o n t he 
sa me da y a nd ti me, t he s a m ple t hat was dee me d t he re -t est will be use d f or data a nal ysis. F or 
m ulti ple rec or ds of s u bject diar y a n d q uesti o n nair e data, t he hi g hest se v erit y or te m p erat ur e 
will be use d t o c o nser vati vel y ca pt ure  s afet y d ata.    
O nl y dat a fr o m t he sc h e d ule d visits will be use d f or ta bles, b ut all visits, i ncl u di n g 
u nsc he d ule d visits will be prese nt e d i n listi n gs.  
F or o bser vati o ns fr o m m ulti ple ra di ol o gists, t he a vera ge of t he t w o val u es will be use d f or 
a nal ysis. F or m ultil oc ular v ol u me meas ure m e nts (i.e . res ults fr o m m ulti ple si des of t he sa me 
L M), t he val ues will be a d de d t o get her f or a nal ysis.  
7. 1. 5  
Visit M a p pi n g d ue t o C h a n ge i n Pr ot oc ol  
I nitiall y, t he P hase 2 e x pa nsi o n o pe n-la bel st u d y e nr olle d s u bjects fr o m Se pte m ber 2 0 0 5 
usi n g si milar visit str uct ures p o st-treat me nt as t he P hase 2 ra n d o mize d st u d y ( p ost -tr eat me nt 
visits occ urre d at ~ 2 wee ks , 2 4 -2 6 wee ks , 5 0-5 2 wee ks a n d 2 years  after treat me nt). T h e 
p ost -treat me nt efficac y assess me nt was perf or me d at ~ 2 wee ks after treat m e nt. H o we ver, t he 
pr ot oc ol was a me n d e d i n J a n uar y 2 0 1 1, w hic h e x pa n de d t he visit wi n d o w fr o m ~ 2 wee ks  
p ost -treat me nt t o 1-6 m o nt hs p ost -treat me nt i n or der t o all o w fle xi bilit y wit h visits after 
c o m pleti o n of t he i njecti o n series . A d diti o nall y, a n y visits after t h e 1 -6 m o nt hs p ost -
treat me nt was ma d e o pti o nal.  
F or t he p ur p os e of a n al ysis, t he ~ 2 wee ks p ost -treat me nt a n d t he 2 4-2 6 wee ks p ost -treat me nt 
visit will b ot h be ma p pe d t o t he 1 -6 m o nt hs p ost -treat me nt f or p atie nts w h o were e nr olle d 
pri or t o t he pr ot oc ol  a me n d me nt . F or t hese s u bjects w h o ma y h a ve m ulti ple rec or ds  of visits  
at t he 1-6 m o nt hs p ost -treat me nt, t he first r ec or d c orres p o n di n g t o t he ~ 2 wee ks p ost-
treat me nt will be use d i n ta ble s u m maries. B ot h  rec or ds will be pres e nte d i n t he listi n gs wit h 
ass ociate d visi t dates. 
7. 1. 6  
H a n dli n g of Missi n g or P a rti al D ates  
I n cases of i nc o m plete dates f or A Es, t he missi n g c o m p o ne nt(s) will be ass u me d as t he m ost 
c o nser vat i ve v al ue(s) p ossi ble. F or e x a m ple, t he i m p utati o n r ule is t o c o nser vati vel y ca pt ure 
A Es wit h missi n g start da tes as treat me nt-e mer ge nt A Es ( T E A Es) . Act ual data val ues, as 
t he y a p pear i n t he cli nical data base, will be s h o w n i n t he data listi n gs. R ules f or partial dat es 
are des cri be d i n  T a ble 3 .   
T a ble 3  R ules f or Missi n g or P arti al D ates   
P ar a meter  
Missi n g  
A d diti o n al C o n diti o ns  
I m p ut ati o n 
Start d ate f or A Es  
D o nl y  
M a n d Y sa me as M a n d Y of first 
i nj ecti o n 
Date of first i nj ecti o n 

  
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P ar a meter  
Missi n g  
A d diti o n al C o n diti o ns  
I m p ut ati o n 
M a n d/ or Y n ot sa m e as M a n d Y 
of first i nj ecti o n 
First da y of n o n -missi n g m o nt h  
D a n d M  
Y sa me as Y of first i nj ecti o n 
Date o f first i nj ecti o n 
Y n ot sa me as Y of first i nj ecti o n 
Use J a n 1 of n o n -missi n g year  
M, D a n d Y  
N o ne –  date c o m pletel y missi n g  
Date of first i nj ecti o n 
St o p date f or A Es  
D o nl y  
 
Last da y of n o n -missi n g m o nt h                                     
D a n d M  
 
Use Dec 3 1 of n o n -missi n g ye ar  
M, D a n d Y  
Decease d  
Date of deat h  
N ot decease d  
D ate of t he e n d of st u d y 
partici pati o n  
N otes: D = Da y, M = M o nt h, Y = Year  
Start a n d s t o p dates were n ot c ollecte d f or n o n-st u d y me dicati o ns a n d will n ot be i m p ute d. 
Deter mi nati o ns f or n e w c o nc o mita nt me dicati o ns will be  base d o n t he c ollecte d visit date.  
7. 1. 7  
H a n dli n g of Missi n g Effic ac y D at a  
I n ge neral, n o i m p utati o n of missi n g efficac y d ata will be perf or me d. T he efficac y data will 
be prese nt e d as o bser ve d.   
7. 2  
Effic ac y A n al yse s 
7. 2. 1  
A n al yses of Pri m ar y E n d p oi nt(s)  
T he pr o p orti o n of s u bjects wit h cli nical s uccess (a c o m plete or s u bsta ntial  res p o nse) at 1 -6  
m o nt hs p ost -t hera p y as assesse d b y i ma gi n g will be s u m marize d f or t he mI T T p o p ul ati o n.  
7. 2. 1. 1  
Se nsiti vit y  A n al ysis  
T he pri mar y a n al ysis will als o be re peate d f or a s u b gr o u p o f t he mI T T p o p ulati o n b y 
e x cl u di n g s u bjects wit h missi n g i nf or me d c o nse nt d oc u me ntati o n. N ote t hat t he i nf or me d 
c o nse nt f or m ( I C F) d o c u me ntati o n f or s o me E nr olle d  s u bjects were n ot retrie va ble fr o m 
st u d y sites f or t his le gac y st u d y. T heref ore, t his se nsitivit y a n al ysis will be perf or me d t o 
e val uate t he r o b ust ness of t he effi cac y res ults o n s u bjects t hat were e nr olle d t o t he st u d y wit h 
a vaila ble I C F d oc u me ntati o n.  
7. 2. 2  
A n al yses of Sec o n d ar y E n d p oi nts  
7. 2. 2. 1  
Res p o nse R ate P ost -T her a p y  as Assesse d b y I m a gi n g  
T he  pr o p orti o n of s u bjects w h o de m o nstrate d a c o m plete (9 0 % – 1 0 0 % re d u cti o n i n v ol u me ), 
s u bsta ntial ( 6 0 %–  8 9 % re d ucti o n i n v ol u me), i nter me diate ( 2 0 % – 5 9 % re d ucti o n i n v ol u me), 
or n o ( < 2 0 % re d ucti o n i n v ol u me) res p o nse 1 -6 m o nt hs p ost -t hera p y as ass esse d b y i magi n g  
will be s u m marize d f or t he mI T T p o p ulati o n. 

  
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T o e x pl ore h o w t he p ost -t hera p y res p o nse rates vary  i n t he p o p ulati o n b y v ari o us c o vari ates, 
the cate g ori es of res p o nse rates i n s u bjects will als o be s u m marize d b y t he f oll o wi n g 
c o variates: 
 A ge gr o u ps as d e fi ne d i n Secti o n 6. 2 , 
 Se x , 
 Race ( W hite/ N o n -W hite) , 
 Pri or S ur ger y ( Yes/ N o) , 
 L M t y pe ( macr oc ystic, mi x e d, micr oc ystic),  
 C li nical sta ge (cli nical sta ge ta bles will i ncl u de cli nical sta ge m o difier data f or 
me diasi nal i n v ol ve me nt a n d retr o p h ar y n geal i n v ol ve me nt),  
 N u m ber of i njecti o ns r ecei ve d.  
T he  pri mar y e n d p oi nt, pr o p orti o n of cli nical s uccess , will als o be s u m marize d b y t h e a b o ve 
c o variates.  
7. 2. 2. 2  
I n vesti g at or-e v al u ate d O ver all Res p o nse    
T he pr o p orti o n of s u bjects w h o e ver d e m o nstrate a Cli nical I m pr o ve m e nt a n d N o C ha n ge  as 
deter mi ne d b y a n i n vesti gat or j u d ge me nt  t hr o u g h o ut t he c o n d uct of t he st u d y will be 
s u m marize d f or t he mI T T p o p ulati o n . I n v esti gat or-e val u ate d O verall res p o nse (eit her 
Cli nical I m pr o ve m e nt or N o C ha n ge) will als o be s u m marize d b y visit (i ncl u di n g a n o v erall 
r o w t hat p o ole d data fr o m all visits ) f or t he m I T T p o p ulati o n. A si milar s u m mar y will be 
pr o d uce d f or o verall res p o nse  as deter mi ne d b y i n vesti gat or j u d ge me nt  b y t he c o vari ates as 
o utli ne d i n Secti o n 7. 2. 2. 1  f or t he mI T T p o p ulati o n.  
I n a d diti o n, t he pr o p orti o n of s u bjects w h o rec or de d “ Cli nical I m pr o ve me nt” o n t he P ost-
t hera p y Cli nical Res p o nse C R F c ollecte d fr o m t he sec o n d i njecti o n visit o n war ds will be 
p o ole d a n d s u m mariz e d ≥ 6 m o nt hs p ost -treat me nt. Onl y s u bjects w h o recei ve d 4 i njecti o ns 
or less will be i ncl u de d i n t his s u m mar y t o assess persiste nce of res p o ns e o n t he sa me L M. 
T he s u bjects w h o were tr eate d wit h  m ore t ha n 4 i njecti o ns  c o ul d ha ve ha d m ulti ple L Ms 
treate d s o e x cl u di n g t h e m e ns ures persiste n ce of res p o nse is meas ure d f or t he sa me L M i n a 
s u bject. F or t he s u b g r o u p of s u bjects wit h or wit h o ut cli nical success  1 -6 m o nt hs  p ost -
treat me nt, ≥ 6 m o nt hs p ost-treat me nt will be s u m marize d f or t he mI T T p o p ulati o n. 
7. 2. 2. 3  
Re d uc ti o n i n V ol u me P ost -T her a p y  
T he baseli ne lesi o n v ol u me, p ost -t hera p y v ol u me, c ha n ge fr o m baseli ne, a n d perce nt c ha n ge 
fr o m baseli ne will be s u m marize d n u mericall y f or t he m I T T p o p ulati o n.  A d diti o nall y, pre - 
a n d p ost -t hera p y v ol u me will be prese nte d i n a listi n g f or all s u bjects. 

  
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7. 2. 3  
Ti me t o E ve nt A n al yses f or Cli nic al I m pr o ve me nt  
T he ti me fr o m recei vi n g t he firs t O K-4 3 2  t o o bser vi n g t he first rec or d of “ Cli nical 
I m pr o v e me nt” o n t he Post -t hera p y Cli nical Res p o nse C R F d uri n g t h e treat me nt peri o d a n d 1 -
6 m o nt hs  p ost -treat me nt e val uati o n  will be c o m p ute d f or eac h s u bject i n t h e mI T T 
p o p ulati o n . If s u bjects di d n ot rec or d “ Cli nical I m pr o ve me nt” d uri n g t h ose s pecific treat me nt 
peri o ds, s u bjects will be ce ns ore d at t he last date a vaila ble a m o n g t he i n vesti gat or ass ess me nt 
date, vital si g ns, i njecti o n date, or ter mi nati o n dat e wit hi n t he s pecific p eri o d, w hic he ver is 
t he latest. A d diti o nall y, s u bjects w h o ha d m ore t h a n 4 i njecti o ns will be  ce ns ore d at t he 
f o urt h i njecti o n series if t he y h a ve n ot rec or de d Cli nical I m pr o ve me nt . T he Ka pla n -Mei er 
esti mates a n d t he 9 5 % CIs of t he s ur vi val f u ncti o ns of t he ti me t o o bser ve ‘ Clinical 
I m pr o v e me nt’ will be cal c ulate d.  
7. 2. 4  
Ot her A n al ysis  
F or  s u bjects wit h ≥6 m o nt hs of p ost treat me nt f oll o w u p, cli nical o utc o me at st u d y 
c o m pleti o n s uc h as n o rec urre n ce, micr oc ystic resi d ue/ resi d ual c yst, rec urre nce, s ur ger y, a n d 
n o res p o nse/c h a n ge will b e s u m marize d  f or t he m I T T p o p ul ati o n. 
7. 3  
S afet y A n al yses  
7. 3. 1  
A d verse E ve nts  
A d verse E v e nts ( A E) f or t his st u d y was defi n e d as a n y d e viati o n fr o m t he e x pecte d res p o nse 
t o O K-4 3 2. T he e x pecte d res p o nse i ncl u des fe ver a n d c hills us uall y be gi n ni n g si x h o urs after 
O K -4 3 2 i njecti o n a n d lat e r s u bsi di n g s p o nta n e o usl y. T he p ai n a n d fe ver are te m p orar y a n d 
us uall y s u bsi de wit h t he use of me dicati o ns s uc h as  T yl e n ol. T he t y pical l ocal reacti o ns t o t he 
i nitial O K-4 3 2 i njecti o n is re d ness a n d s welli n g. T his us uall y e v ol ves o ver a peri o d of wee k, 
lea vi n g a s u perficial scar at t he site of i njecti o n, w hic h last f or se veral wee ks. 
Details of c ollecti o n a n d re p orti n g of Reacti o ns t o O K -4 3 2 is pr o vi de i n Secti o n 7 . 3. 1. 1. At 
t he ti me of t he trial, o nl y seri o us A Es were c ollecte d per pr ot o c ol. Refer t o Secti o n 7 . 3. 1. 2 
f or seri o us A Es d ata a n al ysis. 
7. 3. 1. 1  
Re acti o ns t o O K -4 3 2  
T he c ollecti o n of reacti o ns data i n t his assess me nt i ncl u de d a n e v al uati o n of c o m m o nl y 
occ urri n g l oc al a n d s yste mic reacti o ns i ncl u di n g meas ure me nt of b o d y t e m perat ure i n t he 
f or m of S u bject  Diari es, P ost -treat me nt Q uesti o n naires, a n d P os t-t hera p y Cli nical Res p o nse 
i n t he C R F. S u bject  Diaries were c o m plete d fr o m t he da y of i njecti o n u p t o 1 4 da ys p ost 
i njecti o n a n d were assess e d b y visit, ti me p oi nt, a n d se verit y (f or l ocal r eacti o ns a n d si de 
effects). P ost -treat me nt Q uesti o n naires w ere c om plete d 2 4 h o urs p ost i njecti o n, 3 – 5 da ys 
p ost i njecti o n, a n d 2 – 3 wee ks p ost i njecti o n via a cli nic visit or safet y p h o n e call, a n d were 
assesse d b y visit, ti me p oi nt, a n d se ver it y (f or l o cal reacti o ns). P ost-t hera p y Cli nical 

  
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Res p o nse  C R Fs were c o m plete d f r o m t he sec o n d i njecti o n o n war ds o n t he da y of i njecti o n 
a n d i ncl u de d a n assess me nt of l ocal a n d s yste mic reacti o ns.  
A d diti o nall y, t he P ost -thera p y Cli nical Res p o nse C R F i ncl u de d a n assess me nt of He mat uria 
t o assess p ost-stre pt oc occal gl o mer ul o ne p hritis an d a n assess me nt of J o nes Criteria f or t he 
dia g n osis of a n i nitial attac k of R he u matic Fe v er.  
T he f oll o wi n g O K -4 3 2 reacti o n s u m maries will b e prese nt e d f or t he Safet y p o p ulati o n:  
- 
Reacti o ns re p ort e d t hr o u g h S u bject  Diar y b y reacti o n cate g or y, ver bati m ter ms, 
visit/ti me p oi nt, se verit y (f or l ocal r eacti o ns a n d si de effects) . 
- 
Te m perat ur e (c ollecte d via S u bject  Diar y) will be s u m marize d a n d t otal as (a) n u m ber 
a n d perce nt of s u bjects wit h at least 3 8° C ( 1 0 0. 4° F), a n d ( b ) n u m b er a n d p erce nt of 
s u bjects wit h at least 4 0° C ( 1 0 4° F). Fe ver will be defi ne d as a b o d y te m perat ure of at 
least 3 8° C. 
- 
Reacti o ns re p ort e d t hr o u g h q uesti o n nair e  ( P ost-Treat me nt Q uesti o n nair e C R F)  b y 
reacti o n cate g or y, v er bati m ter ms, visit/ti me p oi nt, sev erit y (f or l o cal r eacti o ns) . 
- 
I n v esti gat or-e v al uate d reacti o ns ( Cli nical Res p o nse C R F) t o O K -4 3 2 b y reacti o n 
cate g or y, v er bati m ter ms, visit.  
- 
J o nes Criteria f or t he Dia g n osis of a n I nitial Attac k of R he u matic Fe ver ( Cli nical 
Res p o nse C R F) b y maj or/ mi n or ma nifestat i o ns, visit/ti me p oi nt; Assess me nt of 
He mat uria t o assess p ost -stre pt oc occal gl o mer ul o n e p hritis. 
A listi n g will be pr o vi de d f or t he i nf or mati o n r e p orte d t hr o u g h t he s u bject st u d y diar y, 
q uesti o n naires,  a n d cli nic al res p o nse C R Fs .  
A d diti o nall y, t h e reacti o ns re p orte d t hr o u g h S u bj ect  Diar y, P ost -Treat me nt Q uesti o n naire 
C R F a n d Cli nical Res p o nse C R F will be s u m marize d f or t he s u b gr o u p of s u bjects wit h n o n -
missi n g i nf or me d c o nse nt dates si milar t o t he pri mar y effi cac y a nal ysis.  
Ti me t o E v e nt A n al ysis  
T he ti me fr o m first pai n t o res ol uti o n a n d ti me fr o m first fe ver t o res ol uti o n will be c o m p ute d 
f or eac h s u bject at eac h i njecti o n. T he first da y of pai n after a s pecific i njecti o n will be 
defi ne d as t he first diar y re p ort of pai n o n or after t he i njecti o n  da y. T he first da y of fe ver a n d 
t he ti me t o fe ver res ol uti o n will be defi ne d si milarl y usi n g te m perat ure c ollecte d i n t he diar y 
data.  If s u bjects di d n ot rec or d fe ver/ p ai n res ol uti o n d uri n g t he s p ecifie d ti me  peri o d (i.e. 
wit hi n 1 4 da ys after i njecti o n) , t he y will be ce ns ore d at t he last a vaila bl e date of diar y re p ort 
of fe ver/ pai n.  T he K a pla n -Meier esti mates a n d t he 9 5 % c o nfi d e nce i nter vals of t he s ur vi val 
f u ncti o ns of pai n a n d fe v er will be cal c ulate d a n d pl otte d b y  i njecti o n.  

  
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7. 3. 1. 2  
Seri o us A d verse E ve nts  
A Es  were  referre d t o as “ Seri o us A d verse E v e nts” ( S A Es) i n t he st u d y C R F. F or t he 
p ur p oses of t he retr os pecti ve a nal ysis, tr eat me nt -e mer ge nt seri o us a d v erse e ve nts ( T E S A Es) 
are defi ne d as S A Es t hat occ ur after t he first i njecti o n a n d wit hi n 3 5 da ys of t he fi nal 
i njecti o n. T E S A Es will be s u m marize d a n d liste d  f or t he Safet y p o p ulati o n a n d t he s u b gr o u p 
of s u bjects wit h n o n-missi n g i nf or me d c o nse nt dates . T he ver bati m ter m use d b y 
i n vesti gat ors will be retr os pecti vel y m a p pe d t o pr eferre d ter ms usi n g t he Me d D R A 
dicti o nar y. T E S A Es , T E S A Es t hat were d eter mi n e d b y t h e i n vesti gat or t o be relate d t o t he 
st u d y dr u g, a n d T E S A Es lea di n g t o st u d y disc o nti n uati o n will be s u m marize d b y S yste m 
Or ga n Class  ( S O C) a n d Preferre d Ter m  ( P T). 
7. 3. 2  
Cli nic al L a b or at or y E v al u ati o ns  
All he mat ol o g y, c h e mistr y,  uri nal ysis a n d s er ol o g y res ults will be s u m marize d f or t he Safet y 
p o p ulati o n , i ncl u di n g dat a fr o m t he sc h e d ule d ass ess me nts . La b orat or y v al ues c ollecte d fr o m 
u nsc he d ule d  visits will be pr o vi de d i n listi n gs o nl y.  La b orat or y assess me nts t hat are o utsi de 
of n or mal ra n ges a n d/ or wit h p ote ntial cli nical si g nifica nce will be c o nsi dere d a n a b n or mal 
val ue a n d fla g ge d i n t he listi n gs. N ote t hat d ue t o l ac k of a ce ntr al la bs n or mal ra n ges are 
differe nt acr oss sites. T h eref ore, s hift ta bles b ase d o n refere nce n or mal r a n ges  will be use d .   
Baseli ne v al ues, t he val u es at p ost -baseli ne visits, a n d c ha n ges fr o m t he bas eli ne val ues will 
be s u m mariz e d descri pti vel y f or all la b orat or y para meters wit h n u merical meas ures. 
A d diti o nall y, s hift ta bles will be ge n erat e d t o s u m marize t he n or mal a n d a b n or mal (a b n or mal 
hi g h a n d a b n or mal l o w) stat us c ha n ges fr o m baseli ne t o p ost -baseli ne visits. T he fre q u e nc y 
a n d perce nta ge of s u bjects wit h la b orat or y res ults a b o ve or bel o w t he n or m al ra n ge at eac h 
sc he d ule d ass ess me nt or a n y ti me d uri n g t he treat me nt will be s u m marize d.  
T he f oll o wi n g l a b tests will be s u m marize d: 

  
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Test C ate g or y  
C he mistr y  
He m at ol o g y  
Uri n al ysis  
 
Ala ni ne 
A mi n otra nsferase  
 
Al b u mi n  
 
Al kali ne P h os p hatase  
 
As partate 
A mi n otra nsferase  
 
Bilir u bi n  
 
C Reacti ve Pr otei n  
 
Calci u m  
 
Car b o n Di o xi de  
 
C hl ori de  
 
Creati ni ne  
 
Gl o b uli n  
 
Gl uc ose  
 
P otassi u m  
 
Pr otei n  
 
S o di u m  
 
Urea Nitr o ge n  
 
Bas o p hils  
 
E osi n o p hils  
 
Er y. Mea n C or p usc ular 
H G B C o nce ntrati o n  
 
Er y. Mea n C or p usc ular 
He m o gl o bi n  
 
Er y. Mea n C or p usc ular 
V ol u me  
 
Er yt hr oc yte Se di me ntati o n  
Rate  
 
Er yt hr oc ytes  
 
Er yt hr oc ytes Distri b uti o n 
Wi dt h  
 
He mat ocrit  
 
He m o gl o bi n  
 
Le u k oc ytes  
 
L y m p h oc ytes  
 
Mea n Platelet V ol u me  
 
M o n oc ytes  
 
Ne utr o p hils  
 
Ne utr o p hils Ba n d F or m  
 
Platelets  
 
 
Bacteria  
 
Bilir u bi n  
 
Casts  
 
C ol or  
 
Cr ystals  
 
E pit helial Cells  
 
Er yt hr oc ytes  
 
Gl uc ose  
 
Ket o nes  
 
Le u k oc yte Esterase  
 
Le u k oc ytes  
 
M uc us  
 
Nitrite  
 
Occ ult Bl o o d  
 
Pr otei n  
 
S pecific Gra vit y  
 
T ur bi dit y  
 
Ur o bili n o ge n  
 
V ol u me  
 
p H  
 
Ser ol o g y  
 
Stre pt ol ysi n O A nti b o d y  
7. 3. 3  
Electr oc a r di o gr a m  
Alt h o u g h Electr ocar di o gra m ( E C G) was n ot i ncl u de d i n t he a me n de d pr ot oc ol  after Ja n uar y 
2 0 1 1, s u bjects e nr olle d pri or t o t he pr ot oc ol a me n d me nt u n der we nt E C G meas ure me nts as 
part of a n earlier versi o n of t he pr ot oc ol  as des cri b e d i n Secti o n 7. 1. 5 . A vaila ble E C G ra w 
val ues a n d c h a n ge fr o m ba seli ne will be s u m mari ze d descri pti vel y at eac h visit  f or heart rat e , 
P wa ve a xis, P wa ve d urati o n, P R i nter val, Q R S d urati o n , Q T  dis persi o n, Q T i nter val wit h  
C orrecti o n met h o d, R wa ve a xis a n d  T wa ve a xis . S u bject le vel data will be pr o vi de d  i n a 
listi n g. 
7. 3. 4  
P h ysic al E x a mi n ati o n  
T he  res ults of p h ysical e x a mi nati o n i ncl u di n g t he f oc use d p h ysic al e xa m will be pr o vi de d i n 
a listi n g.  
7. 3. 5  
Vit al Si g ns  
V ital si g ns (te m perat ure, s yst olic a n d diast olic bl o o d press ure, h eart rate, a n d res pirati o n rat e) 
a n d wei g ht , a n d its c ha n ge fr o m baseli ne, will be s u m marize d descri pti vel y.  

  
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8  
S T A TI S TI C A L S O F T W A R E  
All a nal ys es will be perf or me d wit h S A S ®  versi o n 9. 4.