Conditions: Breast Cancer
Keywords: confirmed adenocarcinoma non-metastatic breast cancer estrogen receptor positive progesterone receptor positive non-steroidal aromatase aromatase inhibitor therapy postmenopausal woman adjuvant chemotherapy neoadjuvant chemotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3420
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether denosumab compared to placebo, will reduce the rate of first clinical fracture in women with non-metastatic breast cancer receiving (non-steroidal) aromatase inhibitor therapy.

Detailed description:
Participants will remain on treatment until the required number of events (where an event is defined as first clinical fracture) is reached and all participants have had the opportunity to receive a minimum of at least 2 doses of study drug, whichever occurs later. The primary analysis data cut-off date (PADCD) is defined as the time at which the required number of events is reached and all participants have had the opportunity to receive at least 2 doses of study drug. When the PADCD is reached, all participants will discontinue study drug.

Following the study PADCD, participants will be followed every 12 months starting from their last study visit until a maximum of 66 months after PADCD.

After approval of Amendment 4, willing and eligible participants randomized to placebo during the double-blind phase may participate in an open-label phase (OLP) and receive denosumab 60 mg Q6M for up to 36 months (maximum of 7 doses).

After approval of Amendment 6 in 2019 a zoledronic acid (ZA) substudy was added to the protocol. Willing and eligible participants who participated in the OLP of the study and completed open-label denosumab may opt in to this ZA substudy and either receive a single dose of ZA (Therapy Arm), or be managed according to the current standard of care for this patient population (Control Arm).

Arms:
arm 1: Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy. arm 2: Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy. arm 3: Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive a single 5 mg intravenous dose of zoledronic acid 8 months after the last open-label dose of denosumab. arm 4: Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive standard of care 8 months after the last open-label dose of denosumab.

Interventions: intervention 1: Placebo intervention 2: Denosumab intervention 3: Non-steroidal aromatase inhibitor therapy intervention 4: Zoledronic Acid intervention 5: Standard of Care
Intervention descriptions: intervention 1: None intervention 2: Administered as a subcutaneous injection intervention 3: An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting intervention 4: 5 mg zoledronic acid administered at a constant infusion rate intervention 5: Standard of care (SoC) as recommended by the treating physician, depending on individual factors such as bone density, lifestyle recommendations by the Investigator such as diet, physical activities and sun exposure, as well as local treatment standards.

Protocol document:
Prot_000.pdf: 
Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 of 1 0 4 
C O N FI D E N TI A L 
 
 
A R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, M ulti- C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s Wit h N o n- M et a st ati c 
Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y 
D e n o s u m a b 
A m g e n Pr ot o c ol N u m b er 2 0 0 5 0 2 0 9 
A B C S G Pr ot o c ol N u m b er A B C S G 1 8 
E u dr a C T #: 2 0 0 5- 0 0 5 2 7 5 -1 5  
N C T 0 0 5 5 6 3 7 4 
 
Cli ni c al St u d y S p o n s or:  
A m g e n Li mit e d  
2 4 0 C a m bri d g e S ci e n c e P ar k  
Milt o n R o a d  
C a m bri d g e C B 4 0 W D  
P h o n e:  4 4 ( 0) 1 2 2 3 4 2 0 3 0 5  
F a x: 4 4 ( 0) 1 2 2 3 4 2 3 0 4 9  
 
K e y S p o n s or C o nt a ct:  
Gl o b al Cli ni c al Tri al M a n a g er  
A m g e n Li mit e d  
U nit e d Ki n g d o m  
P h o n e:
E m ail: 
 
K e y A B C S G C o nt a ct : 
A u stri a n Br e a st a n d C ol or e ct al C a n c er St u d y Gr o u p  
N u s s d orf er Pl at z 8/ 1 2 + 1 3    
A -1 1 9 0 Wi e n  
A u stri a  
P h o n e:
F a x:
 
D at e:  
1 3 M ar c h 2 0 0 6  FI N A L  
2 7 A pril 2 0 0 6 S u p er s e di n g V er si o n  
1 2 J u n e 2 0 0 6 A m e n d m e nt 1  
0 6 A pril  2 0 1 0 A m e n d m e nt 2  
1 5  A u g u st  2 0 1 2  A m e n d m e nt 3  
0 2 N o v e m b er  2 0 1 2 S u p er s e di n g A m e n d m e nt 3  
2 7  N o v e m b er 2 0 1 2 S u p er s e di n g 2 A m e n d m e nt 3  
2 5 J a n u ar y 2 0 1 3 S u p er s e di n g 3 A m e n d m e nt 3  
2 5  J a n u ar y 2 0 1 6 A m e n d m e nt 4  
2 2  F e br u ar y 2 0 1 6 S u p er s e di n g A m e n d m e nt 4  
0 1 A pril 2 0 1 9  A m e n d m e nt 5  
1 5  J ul y 2 0 1 9 A m e n d m e nt 6  ( a d d e d z ol e dr o ni c a ci d  
s u b st u d y)  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 of 1 0 4 
C O N FI D E N TI A L 
 
 
C o nfi d e nti alit y N oti c e 
T hi s d o c u m e nt c o nt ai n s c o nfi d e nti al i nf or m ati o n of A m g e n I n c .  Thi s d o c u m e nt m u st n ot b e 
di s cl o s e d t o a n y o n e ot h er t h a n t h e st u d y st aff a n d m e m b er s of t h e i n d e p e n d e nt et hi c s c o m mitt e e.   
T h e i nf or m ati o n i n t hi s d o c u m e nt c a n n ot b e u s e d f or a n y p ur p o s e ot h er t h a n t h e e v al u ati o n or 
c o n d u ct of t h e cli ni c al i n v e sti g ati o n wit h o ut t h e pri or writt e n c o n s e nt of A m g e n I n c.  
If y o u h a v e q u e sti o n s r e g ar di n g h o w t hi s d o c u m e nt m a y b e u s e d or s h ar e d, c o nt a ct y o ur l o c al 
A m g e n r e pr e s e nt ati v e or t h e k e y s p o n s or c o nt a ct li st e d a b o v e.   F or all ot h er st u d y-r el at e d 
q u e sti o n s, c o nti n u e t o c o nt a ct t h e K e y S p o n s or C o nt a ct.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 of 1 0 4 
C O N FI D E N TI A L 
 
 
I n v e sti g at or’ s A gr e e m e nt 
I h a v e r e a d t h e att a c h e d pr ot o c ol e ntitl e d “ A R a n d o mi z e d, D o u bl e- Blin d, 
Pl a c e b o- C o ntr oll e d, M ulti- C e nt er P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of 
D e n o s u m a b i n S u bj e ct s wit h N o n- M et a st ati c Br e a st C a n c er r e c ei vi n g Ar o m at a s e 
I n hi bit or T h er a p y” d at e d 1 5  J ul y 2 0 1 9, a n d a gr e e t o a bi d e b y all pr o vi si o n s s et f ort h 
t h er ein.  
I a gr e e t o c o m pl y wit h t h e I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n Tri p artit e 
G ui d eli n e o n G o o d Cli ni c al Pr a cti c e a n d a p pli c a bl e E ur o p e a n U ni o n a n d F D A 
r e g ul ati o n s/ g ui d eli n e s s et f ort h i n 2 1 C F R P art s 1 1, 5 0, 5 4, 5 6 a n d 3 1 2. 
I a gr e e t o e n s ur e t h at Fi na n ci al Di s cl o s ur e St at e m e nt s will b e c o m pl et e d b y: 
 
m e (i n cl u di n g, if a p pli c a bl e, m y s p o u s e [ or l e g al p art n er] a n d d e p e n d e nt c hil dr e n) 
 
m y s u bi n v e sti g at or s (i n cl u di n g, if a p pli c a bl e, t h eir s p o u s e s [ or l e g al p art n er s] a n d 
d e p e n d e nt c hil dr e n)  
b ef or e st u d y i niti ati o n, d uri n g t h e st u d y if t h er e ar e c h a n g e s t h at aff e ct m y fi n a n ci al 
di s cl o s ur e st at u s, a n d aft er t h e st u d y i s c o m pl et e d. 
I a gr e e t o e n s ur e t h at t h e c o nfi d e nti al i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt will n ot b e 
u s e d f or a n y p ur p o s e ot h er t h a n t h e e v al u ati o n or c o n d u ct of t h e cli ni c al i n v e sti g ati o n 
wit h o ut t h e pri or writt e n c o n s e nt of A m g e n I n c.  
 
 
 
Si g n at ur e  
 
 
N a m e of Pri n ci p al I n v e sti g at or  
 
D at e ( D D M o nt h Y Y Y Y)  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 of 1 0 4 
C O N FI D E N TI A L 
 
 
Pr ot o c ol S y n o p si s 
Titl e:   A R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, M ulti- C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h N o n- M et a st ati c Br e a st C a n c er 
R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y 
St u d y P h a s e:   P h a s e 3 
I n di c ati o n:  Tr e at m e nt of t h er a p y-i n d u c e d b o n e l o s s t o r e d u c e o c c urr e n c e of fr a ct ur e s i n p ati e nt s 
u n d er g oi n g e str o g e n d e pri v ati o n t h er a p y. 
Pri m ar y O bj e cti v e:    
T o d et er mi n e w h et h er d e n o s u m a b c o m p ar e d t o pl a c e b o will r e d u c e t h e r at e of fir st ( o n- st u d y) 
cli ni c al fr a ct ur e (i e, cli ni c all y e vi d e nt fr a ct ur e wit h a s s o ci at e d s y m pt o m s) i n w o m e n wit h 
n o n - m et a st ati c br e a st c a n c er r e c ei vi n g n o n- st er oi d al ar o m at a s e i n hi bit or t h er a p y ( AI T). 
S e c o n d ar y O bj e cti v e( s):    
T o a s s e s s t h e eff e ct of d e n o s u m a b c o m p ar e d t o pl a c e b o o n t h e f oll o wi n g: 
Fr a ct ur e-r el at e d s e c o n d ar y e n d p oi nt s: 
  
B o n e mi n er al d e n sit y ( B M D) at l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k i n a s u b gr o u p of 
s u bj e ct s at pr e- s el e ct e d sit e s  
  I n ci d e n c e of n e w v ert e br al fr a ct ur e s ( b ot h cli ni c al a n d m or p h o m etri c [i e, a fr a ct ur e i n t h e 
v ert e br al c ol u m n t h at i s n ot cli ni c all y e vi d e nt a n d t h at i s a s y m pt o m ati c]) 
  I n ci d e n c e of n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s ( b ot h cli ni c al a n d 
m or p h o m etri c) 
Di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s: 
  
Di s e a s e-fr e e s ur vi v al ( D F S)  
  
B o n e m et a st a si s-fr e e s ur vi v al ( B M F S) 
  
O v er all s ur vi v al ( O S) 
  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of d e n o s u m a b i n t hi s p o p ul ati o n 
E x pl or at or y O bj e cti v e( s):    
H y p ot h e s e s:    
Cli ni c al Effi c a c y H y p ot h e si s:  
D e n o s u m a b, w h e n a d mi ni st er e d s u b c ut a n e o u sl y ( S C) at a d o s e of 6 0 m g e v er y 6 m o nt h s ( Q 6 M), 
will b e c o n si d er e d effi c a ci o u s i n br e a st c a n c er s u bj e ct s r e c ei vi n g AI T if t h e r at e of fir st cli ni c al 
fr a ct ur e s i n d e n o s u m a b-tr e at e d s u bj e ct s i s l o w er t h a n t h at i n pl a c e b o-tr e at e d s u bj e ct s.  It i s 
a nti ci p at e d t h at d e n o s u m a b will r e d u c e t h e r at e b y 3 0 % c o m p ar e d wit h pl a c e b o (i e,  t h e tr u e 
h a z ar d r ati o of d e n o s u m a b c o m p ar e d wit h pl a c e b o i s 0. 7 0 ). 
Cli ni c al S af et y H y p ot h e si s:  
D e n o s u m a b, w h e n a d mi ni st er e d S C at a d o s e of 6 0 m g Q 6 M, will b e w ell t ol er at e d i n br e a st 
c a n c er s u bj e ct s r e c ei vi n g AI T . 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 of 1 0 4 
C O N FI D E N TI A L 
 
 
St u d y D e si g n:   
T hi s i s a m ulti- c e nt er p h a s e 3, r a n d o mi z e d, d o u bl e- bli n d, pl a c e b o- c o ntr oll e d st u d y t o d et er mi n e 
t h e tr e at m e nt eff e ct of d e n o s u m a b i n s u bj e ct s wit h br e a st c a n c er tr e at e d wit h a n a p pr o v e d 
n o n - st er oi d al ar o m at a s e i n hi bit or ( AI), ( eg,  a n a str a z ol e).  A p pr o xi m at el y 3 4 0 0  s u bj e ct s will b e 
r a n d o mi z e d i n a 1: 1 r ati o t o r e c ei v e eit h er d e n o s u m a b a d mi ni st er e d at a d o s e of 6 0 m g or 
pl a c e b o S C Q 6 M i n a bli n d e d m a n n er.  S u bj e ct s will b e r e cr uit e d o v er a p pr o xi m at el y 8 2  m o nt h s.  
T h e r a n d o mi z ati o n s c h e d ul e will b e str atifi e d b y: t y p e of h o s pit al ( pr e- s el e ct e d c e nt er s or ot h er 
c e nt er s), pri or AI u s a g e ( Y/ N) a n d t ot al l u m b ar s pi n e B M D s c or e at b a s eli n e ( T- s c or e < – 1. 0 v s 
 - 1. 0).  
S u bj e ct s will r e m ai n o n i n v e sti g ati o n al pr o d u ct (I P) u ntil t h e pri m ar y a n al y si s d at a c ut- off d at e 
( P A D C D) i s r e a c h e d, w hi c h i s d efi n e d a s t h e ti m e at w hi c h t h e r e q uir e d n u m b er of e v e nt s ( w h er e 
a n e v e nt i s d efi n e d a s fir st cli ni c al fr a ct ur e) i s r e a c h e d a n d all s u bj e ct s h a d t h e o p p ort u nit y t o 
r e c ei v e at l e a st 2 d o s e s of I P, w hi c h e v er o c c ur s l at er.  W h e n t h e P A D C D d at e i s r e a c h e d, all 
s u bj e ct s will di s c o nti n u e I P.  
F or all s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or t o 
t h e P A D C D w a s a y e arl y vi sit ( e g, m o nt h 1 2, 2 4, et c) a n d r a di ol o gi c al a s s e s s m e nt s w er e 
p erf or m e d, t hi s vi sit will b e c o n si d er e d a n e n d of tr e at m e nt ( E O T) vi sit ( c orr e s p o n di n g c a s e r e p ort 
f or m [ C R F] will h a v e t o b e c o m pl et e d).  F or t h o s e s u bj e ct s, t h e n e xt vi sit will b e r e g ar d e d a s a 
l o n g-t er m f oll o w- u p ( L T F U) vi sit, at w hi c h a n a nti b o d y s a m pl e will b e t a k e n.  T h o s e s u bj e ct s, f or 
w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e n ot p erf or m e d, will n e e d t o att e n d t h e n e xt s c h e d ul e d 
6 m o nt h s vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s ( v ert e br al x-r a y s, d u al X-r a y a b s or pti o m etr y 
[ D X A]) will t a k e pl a c e a n d a n a nti b o d y s a m pl e will b e t a k e n.  F or t h e s e s u bj e ct s t hi s vi sit will b e 
c o n si d er e d a s E O T vi sit.  
It i s hi g hl y r e c o m m e n d e d t h at all s u bj e ct s s h o ul d r e c ei v e at l e a st 5 0 0 m g el e m e nt al c al ci u m a n d 
at l e a st 4 0 0 I U vit a mi n D d ail y t hr o u g h o ut tr e at m e nt wit h I P.  If a s u bj e ct h a s gr e at er t h a n 
1 0 %  l o s s of B M D at t h e t ot al hi p or l u m b ar s pi n e o v er a n y 1- y e ar p eri o d, t h e n a n i nf or m e d 
di s c u s si o n b et w e e n t h e i n v e sti g at or a n d t h e s u bj e ct r e g ar di n g alt er n ati v e t h er a pi e s a n d 
a p pr o pri at e tr e at m e nt i s r e q uir e d.    
T h e n u m b er of pri m ar y e n d p oi nt e v e nt s o b s er v e d will dri v e t h e ti mi n g of t h e pri m ar y a n d fi n al 
a n al y s e s.  T h e a ct u al ti mi n g of t h e pri m ar y a n al y si s will d e p e n d o n t h e s u bj e ct e nr oll m e nt r at e 
a n d t h e r at e at w hi c h cli ni c al fr a ct ur e s ar e o b s er v e d.   
All s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or t o t h e 
P A D C D w a s a 6 m o nt h s vi sit ( e g, m o nt h 6, 1 8, et c), will h a v e t o att e n d t h e n e xt r e g ul arl y 
s c h e d ul e d y e arl y st u d y vi sit ( e g,  m o nt h 1 2) wit hi n 6 m o nt h s aft er P A D C D at t h e l at e st a n d 
p erf or m all c orr e s p o n di n g  a s s e s s m e nt s, i n cl u di n g a nti b o d y s a m pli n g. 
D at a o n fr a ct ur e s o c c urri n g b et w e e n t h e l a st vi sit pri or t o P A D C D a n d P A D C D h a v e t o b e 
c oll e ct e d vi a t el e p h o n e or p h y si c al vi sit s wit hi n 6 m o nt h s aft er P A D C D at t h e l at e st. 
S u bj e ct s w h o wit h dr a w fr o m I P pri or t o t h e o b s er v e d P A D C D will c o nti n u e t o att e n d Q 6 M st u d y 
vi sit s f or a s s e s s m e nt of t h e pri m ar y a n d s e c o n d ar y e n d- p oi nt a n d s af et y. 
S u bj e ct s c o m pl eti n g or di s c o nti n ui n g AI T  will h a v e t h e o p p ort u nit y t o r e m ai n o n I P f or at l e a st 
2 d o s e s of I P aft er t h eir l a st s c h e d ul e d st u d y vi sit d uri n g w hi c h t h e y w er e still o n AI T .  F oll o wi n g 
t h e st u d y P A D C D, s u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S e v er y 1 2 m o nt h s ( Q1 2 M) b y 
cli ni c vi sit s or t el e p h o n e c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O T vi sit) u ntil 
a m a xi m u m of eit h er 1 8 or 6 6 m o nt h s aft er t h e P A D C D, d e p e n di n g o n a n i nt eri m a n al y si s at 
P A D C D ( s e e S e cti o n s 7. 1 6  a n d 1 0. 5 ).  B a s e d o n t h e D at a M o nit ori n g C o m mitt e e ( D M C) 
r e c o m m e n d ati o n t h at i nt eri m f utilit y a n al y si s of D F S di d n ot i n di c at e f utilit y, it w a s d e ci d e d t o 
f oll o w s u bj e ct s u ntil a m a xi m u m of a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D.  F oll o wi n g r e g ul at or y 
a n d I n stit uti o n al R e vi e w B o ar d / I n d e p e n d e nt Et hi c s C o m mitt e e (I R B/I E C) a p pr o v al of Pr ot o c ol 
A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d ( s e e S e cti o n 3. 1 ). 
D u e t o t h e st ati sti c all y si g nifi c a nt tr e at m e nt eff e ct i n t h e pri m ar y e n d p oi nt a n d fr a ct ur e-r el at e d 
s e c o n d ar y e n d p oi nt s b et w e e n t h e d e n o s u m a b ar m a n d t h e pl a c e b o ar m, w hi c h w er e 
d e m o n str at e d at t h e pri m ar y a n al y si s ( G n a nt et al.; L a n c et 2 0 1 5  [ s e e S e cti o n 2. 3 ]), willi n g a n d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 of 1 0 4 
C O N FI D E N TI A L 
eli gi bl e s u bj e ct s r a n d o mi z e d t o pl a c e b o d uri n g t h e d o u bl e- bli n d p h a s e m a y p arti ci p at e i n a n  
o p e n -l a b el p h a s e ( O L P) a n d r e c ei v e d e n o s u m a b 6 0 m g Q 6 M f or u p t o 3 6 m o nt h s ( m a xi m u m of 
7 d o s e s), a s r e c o m m e n d e d b y t h e D M C.  
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 4, t h e o p p ort u nit y t o st art 
o p e n -l a b el d e n o s u m a b will o p e n f or a 1 2 - m o nt h p eri o d.  S u bj e ct s w h o c o n s e nt a n d f ulfil t h e 
eli gi bilit y crit eri a will r e c ei v e d e n o s u m a b 6 0 m g Q 6 M f or u p t o 3 6 m o nt h s ( a m a xi m u m of 
7 d o s e s), a s r e c o m m e n d e d b y t h e D M C.  S u bj e ct s w h o d o n ot f ulfil t h e eli gi bilit y crit eri a or d o n ot 
c o n s e nt will c o m pl et e L T F U a s s e s s m e nt s o nl y ( A p p e n di x A ). 
S u bj e ct s w h o d o n ot r e c ei v e o p e n -l a b el d e n o s u m a b will b e f oll o w e d o n c e a y e ar ( Q 1 2 M st u d y 
vi sit) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s f or: 

D F S, B M F S, a n d O S

Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g s eri o u s a d v er s e e v e nt [ S A E ] r e p orti n g of s u s p e ct e d
at y pi c al f e m or al fr a ct ur e c a s e s)

C o n c o mit a nt b o n e aff e cti n g m e di c ati o n
o
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b)
o
Gl u c o c orti c oi d s
o
A nti e pil e pti c dr u g s
o
A nti d e pr e s s a nt s
o
I n s uli n

A nti- c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y)

S u p pl e m e nt s ( vit a mi n D a n d c al ci u m)
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will att e n d cli ni c vi sit s Q 6 M f or: 

A d mi ni str ati o n of d e n o s u m a b ( 6 0 m g S C)

C oll e cti o n of s eri o u s a n d n o n- s eri o u s a d v er s e e v e nt s [( S) A E s] of s p e ci al i nt er e st ( or al
e v e nt s) a n d S A E s

Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al fr a ct ur e
c a s e s) ( Q 1 2 M o nl y)

D F S, B M F S, a n d O S ( Q 1 2 M o nl y)

C o n c o mit a nt b o n e aff e cti n g m e di c ati o n ( Q 1 2 M o nl y)
o
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b)
o
Gl u c o c orti c oi d s
o
A nti e pil e pti c dr u g s
o
A nti d e pr e s s a nt s
o
I n s uli n

A nti- c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y) ( Q 1 2 M o nl y)

S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) ( Q 1 2 M o nl y)
I n a d diti o n, f or all s u bj e ct s, B M D d at a will b e c oll e ct e d at a n y ti m e a D X A s c a n i s p erf or m e d f or 
B M D a n al y si s a s st a n d ar d of c ar e ( S O C) fr o m P A D C D t o e n d of st u d y ( E O S); t he s e d at a will b e 
c oll e ct e d i n t h e C R F. 
I n t h e e v e nt a s eri o u s or n o n- s eri o u s a d v er s e e v e nt of s p e ci al i nt er e st ( or al e v e nt) or ot h er S A E i s 
i d e ntifi e d o ut si d e t h e s u bj e ct s’ s c h e d ul e d vi sit s, t h e st a n d ar d g ui d a n c e i n S e cti o n 9  s h o ul d b e 
f oll o w e d. 
A ti m e- dri v e n a n al y si s f or effi c a c y of t h e s e c o n d ar y e n d p oi nt D F S will t a k e pl a c e a p pr o xi m at el y 
1 8 m o nt h s aft er P A D C D, pri or t o a n y u n bli n di n g of s u bj e ct s at t h e i n v e sti g at or/ s u bj e ct l e v el.  
At t h e e n d of t h e m ai n  st u d y (L T F U  a n d O L P), a fi n al a n al y si s will o c c ur l o o ki n g at t h e s e c o n d ar y 
di s e a s e o ut c o m e-r el at e d e n d p oi nt s ( O S a n d B M F S) a s w ell a s a n e x pl or at or y a n al y si s of  
 
A p pr o ve d


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 of 1 0 4 
C O N FI D E N TI A L 
 
 
.  D at a c oll e ct e d d uri n g t h e Z A s u b st u d y will b e c e n s or e d at 
t h e E n d of O p e n-l a b el Tr e at m e nt Vi sit or t h e E O S Vi sit (L T F U  a n d O L P), w hi c h e v er o c c ur s 
l at er, f or t h e fi n al a n al y si s. 
A  st u d y s c h e m a  at t h e e n d of t h e pr ot o c ol s y n o p si s s e cti o n d e s cri b e s t h e o v er all m ai n 
st u d y d e si g n. 
Z ol e dr o ni c A ci d ( Z A) S u b st u d y: 
A s u b st u d y h a s b e e n a d d e d i n A p p e n di x G t o e v al u at e s u bj e ct s c o m pl eti n g o p e n-l a b el 
d e n o s u m a b tr e at m e nt, t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e m a n a g e d a c c or di n g 
t o c urr e nt st a n d ar d of c ar e ( S O C) f or t h e p ati e nt p o p ul ati o n. 
S u bj e ct s e nr oll e d i n t h e m ai n st u d y w h o r e c ei v e d d e n o s u m a b d uri n g t h e o p e n l a b el p h a s e 
a n d ar e d e e m e d eli gi bl e p er t h e i n cl u si o n a n d e x cl u si o n crit eri a, m a y c h o o s e t o p arti ci p at e 
i n t hi s s u b st u d y.  S u bj e ct s t h at ar e n ot i n cl u d e d i n t h e s u b st u d y will e n d st u d y a s pl a n n e d.  
Pr ot o c ol- d efi n e d d e n o s u m a b a d mi ni str ati o n will c o m pl et e at e n d of t h e o p e n-l a b el p eri o d 
n o m att er if s u bj e ct s p arti ci p at e i n t h e s u b st u d y or n ot. 
S u bj e ct s e nr oll e d i n t h e s u b st u d y will b e r a n d o mi z e d t o eit h er r e c ei v e a si n gl e d o s e of Z A 
( T h er a p y Ar m) or will b e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or t hi s p ati e nt p o p ul ati o n 
( C o ntr ol Ar m).  D a y 1 f or b ot h ar m s i s 8 m o nt h s ( ± 4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  F oll o w u p will c o nti n u e 
f or a t ot al of 1 8 m o nt h s aft er d a y 1. 
Pri m ar y E n d p oi nt s:  
  
T h e ti m e t o t h e fir st cli ni c al fr a ct ur e 
S e c o n d ar y E n d p oi nt s: 
Fr a ct ur e-r el at e d s e c o n d ar y e n d p oi nt s:    
  
T h e p er c e nt c h a n g e i n t ot al l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k B M D fr o m b a s eli n e t o 
3 6 m o nt h s ( at pr e- s el e ct e d sit e s) 
  
S u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e s ( m or p h o m etri c v ert e br al fr a ct ur e s i d e ntifi e d fr o m 
o n st u d y x-r a y s a n d cli ni c al v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y s) at m o nt h 3 6  
  
S u bj e ct i n ci d e n c e of a n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s ( m or p h o m etri c 
v ert e br al fr a ct ur e s i d e ntifi e d fr o m o n st u d y x-r a y s a n d cli ni c al v ert e br al fr a ct ur e s c o nfir m e d b y 
x-r a y s) at m o nt h 3 6 
Di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s: 
  
Di s e a s e-fr e e s ur vi v al d et er mi n e d b y t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st o b s er v ati o n of 
di s e a s e r e c urr e n c e or d e at h fr o m a n y c a u s e 
  
B o n e m et a st a si s-fr e e s ur vi v al d et er mi n e d b y t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st 
o b s er v ati o n of b o n e m et a st a si s or d e at h fr o m a n y c a u s e 
  
O v er all s ur vi v al d et er mi n e d b y t h e ti m e fr o m r a n d o mi z ati o n t o d e at h fr o m a n y c a u s e  
S af et y E n d p oi nt s: 
  
S u bj e ct i n ci d e n c e of tr e at m e nt- e m er g e nt a d v er s e e v e nt s 
  
Cli ni c all y si g nifi c a nt c h a n g e s i n l a b or at or y v al u e s 
  
S u bj e ct i n ci d e n c e of a nti- d e n o s u m a b a nti b o d y ( bi n di n g a n d n e utr ali zi n g) f or m ati o n 
S a m pl e Si z e:    
A p pr o xi m at el y 3 4 0 0  s u bj e ct s will b e e nr oll e d i n t hi s st u d y ( 1 7 0 0 i n e a c h ar m)  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 of 1 0 4 
C O N FI D E N TI A L 
 
 
S u m m ar y of S u bj e ct Eli gi bilit y Crit eri a ( d o u bl e- bli n d p h a s e):    
I n cl u si o n crit eri a: 
  
Hi st ol o gi c all y or c yt ol o gi c all y c o nfir m e d a d e n o c ar ci n o m a of t h e br e a st  
  
F e m al e s u bj e ct s wit h n o n- m et a st ati c di s e a s e w h o ar e e str o g e n r e c e pt or a n d/ or pr o g e st er o n e 
r e c e pt or p o siti v e, a n d w h o h a v e c o m pl et e d t h eir tr e at m e nt p at h w a y ( s ur g er y, c h e m ot h er a p y) 
  
S u bj e ct s w h o ar e c urr e ntl y o n, or will i niti at e a n a p pr o v e d n o n- st er oi d al ar o m at a s e i n hi bit or 
t h er a p y ( eg,  a n a str a z ol e) i n t h e a dj u v a nt s etti n g  
  
P o st m e n o p a u s al w o m a n1 ,2 , d efi n e d a s a w o m a n f ulfilli n g a n y 1 of t h e f oll o wi n g crit eri a: 
o  
H a vi n g u n d er g o n e a bil at er al o o p h or e ct o m y;  
o  
A g e  6 0 y e ar s; 
o  
A g e d < 6 0  y e ar s m e eti n g t h e f oll o wi n g r e q uir e m e nt s:  
-  
F olli cl e- sti m ul ati n g h or m o n e a n d e str a di ol i n t h e p o st m e n o p a u s al r a n g e 
-  
A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n.  S u bj e ct s w h o h a v e 
u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st. 
  
E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) p erf or m a n c e s c or e of 0 or 1 
  
B ef or e a n y  st u d y- s p e cifi c pr o c e d ur e i s p erf or m e d, a si g n e d a n d d at e d writt e n i nf or m e d 
c o n s e nt m u st b e o bt ai n e d 
E x cl u si o n crit eri a: 
  
Ar o m at a s e i n hi bit or t h er a p y f or m or e t h a n 2 4 m o nt h s 
  
Pri or or c o n c urr e nt tr e at m e nt wit h S el e cti v e E str o g e n R e c e pt or M o d ul at or s ( e g, t a m o xif e n) 
  
E vi d e n c e of m et a st ati c di s e a s e 
  
C urr e nt or pri or i ntr a v e n o u s bi s p h o s p h o n at e a d mi ni str ati o n 
  
Or al bi s p h o s p h o n at e tr e at m e nt: 
o  
Gr e at er t h a n or e q u al t o 3 y e ar s c o nti n u o u sl y 
o  
Gr e at er t h a n 3 m o nt h s b ut l e s s t h a n 3 y e ar s u nl e s s s u bj e ct h a s h a d a w a s h o ut p eri o d of 
at l e a st 1 y e ar 
o  
A n y u s e d uri n g t h e 3- m o nt h p eri o d pri or t o r a n d o mi z ati o n  
  
K n o w n li v er or r e n al d efi ci e n c y a s d et er mi n e d b y t h e i n v e sti g at or a n d i n di c at e d b y t h e 
f oll o wi n g crit eri a: 
o  
A s p art at e a mi n otr a n sf er a s e  2. 5 x u p p er li mit of n or m al ( U L N)  
o  
Al a ni n e tr a n s a mi n a s e  2. 5 x U L N 
o  
S er u m cr e ati ni n e  2 x U L N  
  
Pri or a d mi ni str ati o n of d e n o s u m a b ( A M G 1 6 2) 
  
R e c urr e n c e of t h e pri m ar y m ali g n a n c y ( eg,  d uri n g t h e all o w e d i nt er v al of pr etr e at m e nt wit h a n 
ar o m at a s e i n hi bit or) 
  
Di a g n o si s of a n y s e c o n d n o n- br e a st m ali g n a n c y wit hi n t h e l a st 5 y e ar s, e x c e pt f or a d e q u at el y 
tr e at e d b a s al c ell or s q u a m o u s c ell s ki n c a n c er, or f or i n sit u c ar ci n o m a of t h e c er vi x ut eri 
  
K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf r e p ort or c h art r e vi e w 
o  
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a, or ot h er a cti v e m et a b oli c 
b o n e di s e a s e 
                                                
1   F or s u bj e ct s pr e vi o u sl y tr e at e d wit h a l ut ei ni zi n g h or m o n e-r el e a si n g h or m o n e a nt a g o ni st, t h e 
l a st d o s e m u st h a v e b e e n 4 m o nt h s pri or t o r a n d o mi z ati o n a n d f olli cl e- sti m ul ati n g h or m o n e a n d 
e str a di ol m u st b e i n t h e p o st m e n o p a u s al r a n g e. 
2   S u bj e ct s w h o h a v e r e c ei v e d a dj u v a nt or n e o a dj u v a nt c h e m ot h er a p y m u st h a v e m et 1 of t h e 
crit eri a f or p o st m e n o p a u s al st at u s pri or t o t h at c h e m ot h er a p y.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 of 1 0 4 
C O N FI D E N TI A L 
 
 
o  
H y p er c al c e mi a or h y p o c al c e mi a: a s d efi n e d b y c al ci u m o ut si d e t h e n or m al r a n g e ( A 
si n gl e v al u e o ut si d e t h e n or m al r a n g e d o e s n ot n e c e s s aril y c o n stit ut e h y p er c al c e mi a or 
h y p o c al c e mi a, b ut s h o ul d b e ‘ c orr e ct e d’ b ef or e i n cl u di n g t h e s u bj e ct.  S u bj e ct s wit h a 
k n o w n hi st or y of h y p er c al c e mi a or h y p o c al c e mi a c a n n ot b e i n cl u d e d.) 
o  
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s pri or t o 
r a n d o mi z ati o n 
o  
K n o w n H u m a n I m m u n o d efi ci e n c y Vir u s i nf e cti o n  
o  
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s 
  
A n y m aj or m e di c al or p s y c hi atri c di s or d er t h at, i n t h e o pi ni o n of t h e i n v e sti g at or, mi g ht 
pr e v e nt t h e s u bj e ct fr o m c o m pl eti n g t h e st u d y or i nt erf er e wit h t h e i nt er pr et ati o n of t h e st u d y 
r e s ult s 
  
T hirt y d a y s or l e s s si n c e r e c ei vi n g a n i n v e sti g ati o n al pr o d u ct or d e vi c e i n a n ot h er cli ni c al 
st u d y 
  
K n o w n s e n siti vit y t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d d uri n g t h e st u d y 
( eg,  m a m m ali a n- d eri v e d pr o d u ct s, c al ci u m or vit a mi n D) 
  
S u bj e ct s w h o ar e pr e g n a nt, br e a stf e e di n g, or pl a n t o b e c o m e pr e g n a nt d uri n g t h e c o ur s e of 
t h e st u d y.  All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y t e st wit hi n 
7 d a y s b ef or e r a n d o mi z ati o n. 
  
A n y ki n d of di s or d er t h at c o m pr o mi s e s t h e a bilit y t o gi v e writt e n i nf or m e d c o n s e nt a n d/ or 
c o m pl y wit h st u d y pr o c e d ur e s 
S u bj e ct s r a n d o mi z e d t o pl a c e b o d uri n g t h e d o u bl e- bli n d p h a s e m a y b e eli gi bl e t o r e c ei v e 
d e n o s u m a b i n t h e O L P .  Pl e a s e r ef er t o S e cti o n s 4. 3  a n d  4. 4  f or eli gi bilit y crit eri a f or r e c ei vi n g 
d e n o s u m a b i n t h e O L P . 
I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n D o u bl e- bli n d P h a s e a n d i n t h e O L P:  
D e n o s u m a b 6 0 m g a d mi ni st er e d S C e v er y 6 m o nt h s 
C o ntr ol Gr o u p ( d o u bl e- bli n d p h a s e):  
M at c hi n g pl a c e b o a d mi ni st er e d S C e v er y 6 m o nt h s 
Pr o c e d ur e s: 
Bli n d e d Tr e at m e nt P h a s e 
Writt e n i nf or m e d c o n s e nt m u st b e o bt ai n e d fr o m all s u bj e ct s pri or t o s cr e e ni n g f or eli gi bilit y.  
S cr e e ni n g a s s e s s m e nt s will i n cl u d e a m e di c al a n d m e di c ati o n hi st or y, p h y si c al e x a mi n ati o n 
( E C O G p erf or m a n c e st at u s), w ei g ht, h ei g ht a n d vit al si g n s (t e m p er at ur e, p ul s e, bl o o d pr e s s ur e), 
l at er al s pi n e r a di o gr a p h s, b o n e s c a n, D X A a n d c oll e cti o n of bl o o d f or h e m at ol o g y, c h e mi str y, 
pr e g n a n c y t e st (if a p pli c a bl e) a n d d e n o s u m a b a nti b o d y a n al y si s.   
Eli gi bl e s u bj e ct s will b e r a n d o mi z e d i nt o 1 of t h e 2 tr e at m e nt gr o u p s wit hi n 3 5 d a y s of s cr e e ni n g .  
Fir st a d mi ni str ati o n of I P ( d a y 1) m u st t a k e pl a c e wit hi n 8 d a y s of r a n d o mi z ati o n.  D uri n g t hi s vi sit 
t h e b a s eli n e r el at e d a s s e s s m e nt s will b e c o m pl et e d.  Aft er t h e i niti al d o s e of I P i s a d mi ni st er e d, 
s u bj e ct s will r et ur n f or st u d y vi sit s a n d r e c ei v e I P e v er y 6 m o nt h s.  T h e tr e at m e nt p h a s e will e n d 
w h e n t h e P A D C D i s r e a c h e d ( s e e Gl o s s ar y ).  At t h e e n d of t h e tr e at m e nt p h a s e all s u bj e ct s will 
di s c o nti n u e I P.  
F or all s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or t o 
t h e P A D C D w a s a y e arl y vi sit ( e g, m o nt h 1 2, 2 4, et c) a n d r a di ol o gi c al a s s e s s m e nt s w er e 
p erf or m e d, t hi s vi sit will b e c o n si d er e d a n E O T vi sit ( c orr e s p o n di n g C R F will h a v e t o b e 
c o m pl et e d).  F or t h o s e s u bj e ct s, t h e n e xt vi sit will b e r e g ar d e d a s L T F U vi sit, at w hi c h a n a nti b o d y 
s a m pl e will b e t a k e n.  T h o s e s u bj e ct s, f or w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e n ot 
p erf or m e d, will n e e d t o att e n d t h e n e xt s c h e d ul e d 6 m o nt h s vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s 
( v ert e br al x-r a y s, D X A) will t a k e pl a c e a n d a n a nti b o d y s a m pl e will b e t a k e n.  F or t h e s e s u bj e ct s 
t hi s vi sit will b e c o n si d er e d a s E O T vi sit. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
All s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or t o t h e 
P A D C D w a s a 6 m o nt h s vi sit ( e g, m o nt h 6, 1 8, et c), will h a v e t o att e n d t h e n e xt r e g ul arl y 
s c h e d ul e d y e arl y st u d y vi sit ( e g,  Q 1 2 M V) wit hi n 6 m o nt h s aft er P A D C D at t h e l at e st a n d p erf or m 
all c orr e s p o n di n g  a s s e s s m e nt s, i n cl u di n g a nti b o d y s a m pli n g. 
D at a o n fr a ct ur e s o c c urri n g b et w e e n t h e l a st vi sit pri or t o P A D C D a n d P A D C D h a v e t o b e 
c oll e ct e d vi a t el e p h o n e or p h y si c al vi sit s wit hi n 6 m o nt h s aft er P A D C D at t h e l at e st.  
S u bj e ct s w h o wit h dr a w e arl y fr o m i n v e sti g ati o n al pr o d u ct will c o nti n u e o n st u d y, wit h o ut 
i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n a c c or di n g t o t h e S c h e d ul e of A s s e s s m e nt s (A p p e n di x A ).  
S u bj e ct s c o m pl eti n g or di s c o nti n ui n g  AI T  will h a v e t h e o p p ort u nit y t o r e m ai n o n I P f or at l e a st 
2 d o s e s of I P aft er t h eir l a st s c h e d ul e d st u d y vi sit d uri n g w hi c h t h e y w er e still o n AI T .  
T h e f oll o wi n g pr o c e d ur e s will b e p erf or m e d p er t h e s c h e d ul e o utli n e d i n A p p e n di x A :  p h y si c al 
e x a m, w ei g ht a n d vit al si g n s, l at er al s pi n e r a di o gr a p h s, D X A s c a n s, bl o o d dr a w f or h e m at ol o g y, 
a n d s er u m c h e mi str y.  Cli ni c al a n d m or p h o m etri c fr a ct ur e e v e nt s will b e r e c or d e d t hr o u g h o ut t h e 
st u d y a s d e s cri b e d i n S e cti o n 7. 7 .  A d v er s e e v e nt s a n d c o n c o mit a nt m e di c ati o n s will b e r e c or d e d 
t hr o u g h 3 0 d a y s aft er t h e l a st d o s e of i n v e sti g ati o n al pr o d u ct.  D e n o s u m a b a nti b o d y l e v el will b e 
a s s e s s e d at s cr e e ni n g a n d t h e E n d of Tr e at m e nt vi sit.   
O p e n -l a b el P h a s e 
S u bj e ct s r a n d o mi z e d t o pl a c e b o d uri n g t h e d o u bl e- bli n d p h a s e m a y r e c ei v e d e n o s u m a b i n t h e 
O L P.  T h e o p p ort u nit y t o st art o p e n-l a b el d e n o s u m a b will b e o p e n f or 1 2 m o nt h s f oll o wi n g 
Pr ot o c ol A m e n d m e nt 4 r e g ul at or y a n d I R B/I E C a p pr o v al.   
S u bj e ct s c urr e ntl y t a ki n g a n a p pr o v e d n o n- st er oi d al AI ( e g, a n a str a z ol e ), or w h o h a v e c o m pl et e d 
or di s c o nti n u e d AI T  wit hi n 1 2 m o nt h s pri or t o p arti ci p ati o n i n t h e O L P will b e eli gi bl e t o r e c ei v e u p 
t o 3 6 m o nt h s ( m a xi m u m of 7 d o s e s) of d e n o s u m a b.  F or d et ail s of eli gi bilit y s e e S e cti o n s 4. 3  
a n d  4. 4 . 
I nf or m e d c o n s e nt m u st b e o bt ai n e d b ef or e u n bli n di n g t o c o nfir m eli gi bilit y.  Pl e a s e r ef er t o 
A p p e n di x A  ( S c h e d ul e of A s s e s s m e nt s) f or a d et ail e d li st of O L P pr o c e d ur e s.  
L o n g -t er m F oll o w-u p  
F oll o wi n g t h e st u d y P A D C D, all s u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S e v er y 
1 2  m o nt h s b y cli ni c vi sit s or t el e p h o n e c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s 
E O T vi sit) u ntil a p pr o xi m at el y 6 6 m o nt h s aft er t h e P A D C D.  
F oll o wi n g r e g ul at or y a p pr o v al of Pr ot o c ol A m e n d m e nt 4 f urt h er d at a will b e a s s e s s e d.   
S u bj e ct s w h o d o n ot r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d o n c e a y e ar ( Q 1 2 M st u d y 
vi sit) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s f or: 
  
D F S, B M F S, a n d O S  
  
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al fr a ct ur e 
c a s e s) 
  
C o n c o mit a nt b o n e aff e cti n g m e di c ati o n: 
o  
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b) 
o  
Gl u c o c orti c oi d s 
o  
A nti e pil e pti c dr u g s 
o  
A nti d e pr e s s a nt s 
o  
I n s uli n 
  
A nti- c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y) 
  
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will att e n d cli ni c vi sit s Q 6 M f or: 
  
A d mi ni str ati o n of d e n o s u m a b ( 6 0 m g S C) 
  
C oll e cti o n of ( S) A E s of s p e ci al i nt er e st ( or al e v e nt s) a n d S A E s 
  
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al fr a ct ur e 
c a s e s) ( Q 1 2 M o nl y) 
  
D F S, B M F S, a n d O S ( Q 1 2 M o nl y) 
  
C o n c o mit a nt b o n e aff e cti n g m e di c ati o n ( Q 1 2 M): 
o  
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b)  
o  
Gl u c o c orti c oi d s 
o  
A nti e pil e pti c dr u g s 
o  
A nti d e pr e s s a nt s 
o  
I n s uli n 
  
A nti- c a n c er r el at e d t h er a p y ( e g c h e m ot h er a p y or e n d o cri n e t h er a p y) ( Q 1 2 M o nl y) 
  
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) ( Q 1 2 M o nl y) 
I n a d diti o n, f or all s u bj e ct s, B M D d at a will b e c oll e ct e d at a n y ti m e a D X A s c a n i s p erf or m e d f or 
B M D a n al y si s a s st a n d ar d of c ar e fr o m P A D C D t o e n d of st u d y; t he s e d at a will b e c oll e ct e d i n t h e 
C R F.  
I n t h e e v e nt a s eri o u s or n o n- s eri o u s a d v er s e e v e nt of s p e ci al i nt er e st ( or al e v e nt) or ot h er S A E i s 
i d e ntifi e d o ut si d e t h e s u bj e ct s’ s c h e d ul e d vi sit s, t h e st a n d ar d g ui d a n c e i n S e cti o n 9  s h o ul d b e 
f oll o w e d. 
St ati sti c al C o n si d er ati o n s: 
T hi s st u d y i s d e si g n e d t o c o m p ar e t h e tr e at m e nt eff e ct of d e n o s u m a b wit h pl a c e b o i n t h e r at e of 
cli ni c al fr a ct ur e i n w o m e n wit h br e a st c a n c er r e c ei vi n g AI T . 
A p pr o xi m at el y 3 4 0 0  s u bj e ct s will b e r a n d o mi z e d i n a 1: 1 r ati o t o r e c ei v e d e n o s u m a b or pl a c e b o.  
T h e r a n d o mi z ati o n will b e str atifi e d b y t y p e of h o s pit al, pri or AI u s a g e a n d t ot al l u m b ar s pi n e B M D 
s c or e ( T- s c or e < - 1. 0 v s  - 1. 0).  T h e tr e at m e nt p h a s e will e n d w h e n a p pr o xi m at el y 2 4 7  s u bj e ct s 
h a v e e x p eri e n c e d t h eir fir st cli ni c al fr a ct ur e a n d all s u bj e ct s h a v e h a d t h e o p p ort u nit y t o r e c ei v e at 
l e a st 2 d o s e s of I P w h e n t h e pri m ar y a n al y si s will b e c o n d u ct e d. 
T h e pri m ar y a n al y si s of t h e ti m e t o fir st o n- st u d y cli ni c al fr a ct ur e will u s e a C o x m o d el ( C o x, 1 9 7 2 ) 
i n cl u di n g tr e at m e nt gr o u p s a s t h e i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e r a n d o mi z ati o n 
str atifi c ati o n f a ct or s.  T h e s e c o n d ar y e n d p oi nt s s u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e s a n d 
s u bj e ct i n ci d e n c e of n e w or w or s e ni n g pr e- e xi sti n g v ert e br al fr a ct ur e s will u s e l o gi sti c r e gr e s si o n 
m o d el s i n cl u di n g tr e at m e nt gr o u p s a s t h e i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e 
r a n d o mi z ati o n str atifi c ati o n f a ct or s.  A n al y si s of t h e p er c e nt c h a n g e i n l u m b ar s pi n e, t ot al hi p a n d 
f e m or al n e c k fr o m b a s eli n e t o m o nt h 3 6 at pr e- s el e ct e d sit e s will b e a n al y z e d u si n g a mi x e d 
eff e ct m o d el i n cl u di n g tr e at m e nt gr o u p s a s t h e i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e 
r a n d o mi z ati o n str atifi c ati o n f a ct or s.  A ti m e- dri v e n a n al y si s f or effi c a c y of t h e s e c o n d ar y e n d p oi nt 
D F S will t a k e pl a c e a p pr o xi m at el y 1 8 m o nt h s aft er P A D C D, b ef or e u n bli n di n g of s u bj e ct s at t h e 
i n v e sti g at or/ s u bj e ct l e v el h a s o c c urr e d. 
At t h e e n d of t h e m ai n  st u d y (L T F U  a n d O L P), a fi n al a n al y si s will o c c ur l o o ki n g at t h e s e c o n d ar y 
di s e a s e o ut c o m e-r el at e d e n d p oi nt s ( O S a n d B M F S) a s w ell a s a n e x pl or at or y a n al y si s 
 
 f or t h e m ai n st u d y.  
 
 
  O nl y d at a c oll e ct e d u p t o t h e E O S vi sit ( e n d of O L tr e at m e nt vi sit or 
t h eir l a st s c h e d ul e d L T F U vi sit) will b e i n cl u d e d i n t h e fi n al a n al y si s.  A n y d at a c oll e ct e d 
fr o m t h e Z A s u b st u d y will b e e x cl u d e d. 
T h e pri m ar y a n d s e c o n d ar y n ull h y p ot h e si s ( p er c e nt c h a n g e i n B M D e n d p oi nt s, i n ci d e n c e of n e w 
v ert e br al fr a ct ur e s at m o nt h 3 6 a n d i n ci d e n c e of n e w or w or s e ni n g pr e- e xi sti n g v ert e br al fr a ct ur e s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
at m o nt h 3 6) will b e t e st e d u si n g t h e hi er ar c hi c al a n al y si s str at e g y a n d t h e H o c h b er g pr o c e d ur e 
t o c o ntr ol t h e o v er all si g nifi c a n c e l e v el of 0. 0 5.  
S af et y will b e c h ar a ct eri z e d b y e v al u at e d i n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s, a n d t o xi cit y 
gr a d e s hift i n l a b v al u e s .  Th e n u m b er a n d p er c e nt a g e of s u bj e ct s w h o d e v el o p bi n di n g a n d 
n e utr ali zi n g a nti- d e n o s u m a b a nti b o di e s will b e t a b ul at e d b y st u d y vi sit. 
S p o n s or/ Li c e n s e e:   A m g e n I n c  
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
D o u bl e- bli n d P h a s e - St u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
O p e n-l a b el P h a s e - St u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
St u d y Gl o s s ar y 
A b br e vi ati o n/ A cr o n y m  
D efi niti o n  
A B C S G  
A u stri a n Br e a st a n d C ol or e ct al C a n c er St u d y Gr o u p  
A E  
A d v er s e E v e nt  
AI T  
ar o m at a s e i n hi bit or  t h er a p y 
A T A C  
Ari mi d e x, T a m o xif e n Al o n e or i n C o m bi n ati o n 
BI G  
Br e a st I nt er n ati o n al Gr o u p  
B M D  
b o n e mi n er al d e n sit y  
B M F S  
B o n e m et a st a s e s -fr e e s ur vi v al 
CI  
c o nfi d e n c e i nt er v al  
C R F  
C a s e R e p ort F or m  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s  
C T X  
C -t er mi n al t el o p e pti d e 
D M C  
D at a M o nit ori n g  C o m mitt e e  
D F S  
Di s e a s e -fr e e s ur vi v al 
D X A  
D u al X -R a y A b s or pti o m etr y  
E C O G  
E a st er n C o o p er ati v e O n c ol o g y Gr o u p  
E O S  
e n d of st u d y  
E O T  
E n d of tr e at m e nt  
E R  
e str o g e n r e c e pt or  
F A S  
f ull a n al y si s s et 
F S H  
F olli cl e -sti m ul ati n g h or m o n e  
G C P  
G o o d Cli ni c al Pr a cti c e  
H E R -2  
H u m a n E pi d er m al gr o wt h f a ct or R e c e pt or 2  
I C F 
i nf or m e d c o n s e nt f or m 
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n  
I E C 
In d e p e n d e nt E t hi c s C o m mitt e e  
I P 
I n v e sti g ati o n al p r o d u ct 
I R B 
In stit uti o n al R e vi e w B o ar d  
I V 
i ntr a v e n o u s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
A b br e vi ati o n/ A cr o n y m  
D efi niti o n  
I V R S 
i nt er a cti v e v oi c e r e s p o n s e s y st e m 
L T F U  
L o n g -t er m f oll o w-u p  
M  
m o nt h ( s) 
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
O L  
o p e n -l a b el 
O L P  
o p e n -l a b el p h a s e  
O N J  
o st e o n e cr o si s of t h e ja w  
O S  
O v er all s ur vi v al  
P A D C D  
p ri m ar y a n al y si s d at a c ut -off d at e  
P F S  
pr efill e d s yri n g e  
P g R  
pr o g e st er o n e r e c e pt or  
PI N  
p er s o n al i d e ntifi c ati o n n u m b er  
Q 6 M  
e v er y 6 m o nt h s  
Q 1 2 M  
e v er y 1 2 m o nt h s  
R A N K /L  
r e c e pt or a cti v at or f or n u cl e ar f a ct or k a p p a B li g a n d  
S A E  
S eri o u s A d v er s e E v e nt  
( S) A E 
s eri o u s a n d n o n -s eri o u s a d v er s e  e v e nt  
S E R M  
S el e cti v e E str o g e n R e c e pt or M o d ul at or  
S C  
S u b c ut a n e o u s  
S m P C  
s u m m ar y of pr o d u ct c h ar a ct eri sti c s  
U L N  
u p p er li mit of n or m al p er l a b or at or y r ef er e n c e r a n g e  
Z A  
z ol e dr o ni c a ci d  
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
St u d y T er m  
D efi niti o n  
Cli ni c al fr a ct ur e  
cli ni c all y e vi d e nt fr a ct ur e wit h a s s o ci at e d s y m pt o m s 
D at e of r a n d o mi z ati o n  
d at e s u bj e ct i s r a n d o mi z e d; e nr oll m e nt d at e  
D a y 1  i n d o u bl e-bli n d p h a s e 
a n d O L P  
fir st d a y i n v e sti g ati o n al pr o d u ct i s a d mi ni st er e d 
D a y 1 i n Z A s u b st u d y  
D efi n e d a s 8  m o nt h s (  4  w e e k s) aft er t h e l a st  O L P 
d e n o s u m a b d o s e  
F or tr e at m e nt ar m:   fir st d a y Z A i s a d mi ni st er e d  
F or c o ntr ol ar m ( S O C tr e at m e nt):  S O C d a y  1 vi sit  
E n d of O p e n -L a b el Tr e at m e nt  
la st a d mi ni str ati o n of o p e n -l a b el p h a s e d e n o s u m a b  f or e a c h 
s u bj e ct  
E n d of O p e n -L a b el Tr e at m e nt 
Vi sit  
t h e l a st a s s e s s m e nt of t h e pr ot o c ol s p e cifi e d o p e n-l a b el 
tr e at m e nt f or a s u bj e ct.  If n ot eli gi bl e f or Z A s u b st u d y  or 
willi n g t o t a k e p art i n t hi s s u b st u d y, s u bj e ct s wi ll 
c o m pl et e a n e n d of O L  tr e at m e nt vi sit 3 0 t o 4 5 d a y s aft er 
t h e l a st d o s e of O L d e n o s u m a b e it h er b y cli ni c vi sit or 
t el e p h o n e c o nt a ct. 
E n d  of  st u d y ( E O S)  
t h e d at e w h e n t h e l a st s u bj e ct c o m pl et e s t h e l a st s c h e d ul e d 
vi sit  
E n d of St u d y vi sit  
a s u bj e ct’ s l a st f or m al vi sit or l a st f or m al c o nt a ct or a n 
u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m 
st u d y  
E n d of St u d y ( E O S) of Z A 
s u b st u d y  
T h e d at e w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
s u b st u d y  c o m pl et e s t h e l a st f or m al vi sit or a n 
u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m 
t h e Z A s u b st u d y  
E n d of Tr e at m e nt i n 
d o u bl e -bli n d p h a s e  
l a st a d mi ni str ati o n of d o u bl e -bli n d i n v e sti g ati o n al pr o d u ct f or 
e a c h s u bj e ct  
E n d of Tr e at m e nt vi sit  i n d o u bl e 
bli n d p h a s e  
t h e vi sit at w hi c h t h e s u bj e ct  r e c ei v e s t h e l a st d o s e of I P; f or 
all s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6  m o nt h s  
( + 4 5 d a y s ti m e wi n d o w) pri or t o t h e P A D C D w a s a y e arl y 
vi sit ( e g, m o nt h s 1 2, 2 4, et c)  a n d r a di ol o gi c al a s s e s s m e nt s 
w er e p erf or m e d , t hi s vi sit will b e c o n si d er e d a n E O T  vi sit .  
T h o s e s u bj e ct s, f or w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e 
n ot  p erf or m e d, will n e e d t o att e n d  t h e n e xt s c h e d ul e d 
6  m o nt h s vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s ( v ert e br al 
x -r a y s, D X A) will t a k e pl a c e a n d a n a nti b o d y s a m pl e will b e 
t a k e n.  F or t h e s e s u bj e ct s t hi s vi sit will b e c o n si d er e d a s  E O T  
vi sit.  F or t h o s e w h o s e l a st r e g ul ar stu d y vi sit wit hi n 6 m o nt h s 
( + 4 5  d a y s ti m e wi n d o w) pri or t o t h e P A D C D w a s a 6  m o nt h s 
vi sit ( e g, m o nt h 6, 1 8, et c), t h e n e xt r e g ul arl y s c h e d ul e d 
y e arl y st u d y vi sit ( e g,  Q 1 2 M) wit hi n 6 m o nt h s aft er P A D C D  
will b e c o n si d er e d a n  E O T  vi sit  
E nr oll m e nt d at e  
d at e of r a n d o mi z ati o n  
Fi n al a n al y si s  
a n al y si s p erf or m e d aft e r l o n g-t er m f oll o w u p, a n d O L P ,  
I nt eri m A n al y si s 
A n i nt eri m a n al y si s f or f utilit y f or t h e s e c o n d ar y e n d p oi nt D F S 
will b e p erf or m e d aft er P A D C D b y a n i n d e p e n d e nt st ati sti ci a n  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
St u d y T er m  
D efi niti o n  
L o n g -T er m  F oll o w -U p ( L T F U) 
vi sit  
all Q 1 2 M vi sit s t h at ar e att e n d e d aft er  E O T  vi sit  
M or p h o m etri c fr a ct ur e  
a fr a ct ur e i n t h e v ert e br al c ol u m n t h at i s n ot cli ni c all y e vi d e nt 
a n d t h at i s a s y m pt o m ati c  
Pri m ar y a n al y si s  
a n al y si s at Pri m ar y A n al y si s D at a C ut -off D at e ( P A D C D) 
S O C  
st a n d ar d of c ar e  
S cr e e ni n g p eri o d  
b e gi n s wit h si g n e d i nf or m e d c o n s e nt a n d e n d s o n d a y 
i n v e sti g ati o n al pr o d u ct i s a d mi ni st er e d 
Pri m ar y A n al y si s D at a C ut -off 
D at e ( P A D C D)  
t h e d at e w h e n a p pr o xi m at el y 2 4 7 s u bj e ct s h a v e e x p eri e n c e d 
t h eir fir st cli ni c al fr a ct ur e a n d all s u bj e ct s h a v e eit h er 
wit h dr a w n or h a d t h e o p p ort u nit y t o r e c ei v e at l e a st 2 d o s e s 
of  I P. 
Z A s u b st u d y Tr e at m e nt  
S u bj e ct s  r a n d o mi z e d t o tr e at m e nt ar m will r e c ei v e a 
si n gl e d o s e Z A.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
T A B L E O F C O N T E N T S 
Pr ot o c ol S y n o p si s ............................................................................................................. 4 
D o u bl e- bli n d P h a s e - St u d y D e si g n a n d Tr e at m e nt S c h e m a .......................................... 1 3  
O p e n-l a b el P h a s e - St u d y D e si g n a n d Tr e at m e nt S c h e m a ............................................ 1 4  
St u d y Gl o s s ar y ................................................................................................................ 1 5  
1.  
O B J E C TI V E S ......................................................................................................... 2 3  
1. 1  
Pri m ar y ....................................................................................................... 2 3  
1. 2  
S e c o n d ar y .................................................................................................. 2 3  
1. 3  
E x pl or at or y ................................................................................................. 2 3  
2.  
B A C K G R O U N D A N D R A TI O N A L E ........................................................................ 2 3  
2. 1  
Di s e a s e ....................................................................................................... 2 3  
2. 2  
D e n o s u m a b B a c k gr o u n d ............................................................................ 2 4  
2. 3  
R ati o n al e .................................................................................................... 2 5  
2. 4  
H y p ot h e s e s ................................................................................................. 2 7  
2. 4. 1  
Cli ni c al Effi c a c y H y p ot h e si s ........................................................ 2 7  
2. 5  
Cli ni c al S af et y H y p ot h e si s .......................................................................... 2 7  
3.  
E X P E RI M E N T A L P L A N ......................................................................................... 2 7  
3. 1  
St u d y D e si g n .............................................................................................. 2 7  
3. 2  
N u m b er of C e nt er s ..................................................................................... 3 1  
3. 3  
N u m b er of S u bj e ct s .................................................................................... 3 1  
3. 4  
E sti m at e d St u d y D ur ati o n ........................................................................... 3 2  
3. 4. 1  
St u d y D ur ati o n f or P arti ci p a nt s ................................................... 3 2  
3. 4. 2  
E n d of Tr e at m e nt ........................................................................ 3 2  
3. 4. 3  
L o n g -t er m F oll o w-u p  ................................................................... 3 2  
3. 4. 4  
E n d of O p e n-l a b el Tr e at m e nt ..................................................... 3 3  
3. 4. 5  
E n d of St u d y ( D o u bl e- bli n d P h a s e a n d E n d of Z A 
S u b st u d y) ................................................................................... 3 3  
4.  
S U B J E C T E LI GI BI LI T Y  .......................................................................................... 3 3  
4. 1  
I n cl u si o n Crit eri a f or D o u bl e- bli n d P h a s e ................................................... 3 3  
4. 2  
E x cl u si o n Crit eri a f or D o u bl e- bli n d P h a s e .................................................. 3 4  
4. 3  
I n cl u si o n Crit eri a t o R e c ei v e O p e n-l a b el P h a s e D e n o s u m a b ..................... 3 5  
4. 4  
E x cl u si o n Crit eri a t o R e c ei v e O p e n-l a b el P h a s e D e n o s u m a b ................... 3 5  
5.  
S U B J E C T E N R O L L M E N T ..................................................................................... 3 6  
5. 1  
S cr e e ni n g ................................................................................................... 3 6  
5. 2  
Tr e at m e nt A s si g n m e nt ( Bli n d e d Tr e at m e nt P h a s e) ................................... 3 6  
5. 3  
R a n d o mi z ati o n ............................................................................................ 3 7  
5. 4  
O p e n-l a b el P h a s e ....................................................................................... 3 7  
5. 5  
U n bli n di n g Pr o c e d ur e s ............................................................................... 3 8  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
6.  
T R E A T M E N T P R O C E D U R E S ............................................................................... 3 8  
6. 1  
Bli n d e d Tr e at m e nt P h a s e ........................................................................... 3 8  
6. 1. 1  
I n v e sti g ati o n al Pr o d u ct D o s a g e, A d mi ni str ati o n, a n d 
S c h e d ul e .................................................................................... 3 8  
6. 1. 2  
Mi s s e d D o s e ............................................................................... 3 8  
6. 1. 3  
D o s e E s c al ati o n a n d St o p pi n g R ul e s ......................................... 3 8  
6. 1. 4  
D o s a g e A dj u st m e nt s .................................................................. 3 9  
6. 1. 5  
S u p pl e m e nt s ............................................................................... 3 9  
6. 1. 6  
C o n c o mit a nt T h er a p y ................................................................. 3 9  
6. 1. 6. 1  
Bli n d e d Tr e at m e nt P h a s e C o n c o mit a nt 
T h er a p y  .................................................................... 3 9  
6. 1. 6. 2  
O p e n-l a b el C o n c o mit a nt T h er a p y/ 
L o n g -t er m F oll o w u p ................................................ 3 9  
6. 1. 7  
Pr o hi bit e d T h er a p y D uri n g Bli n d e d P h a s e ................................. 4 0  
6. 2  
O p e n-l a b el P h a s e ....................................................................................... 4 0  
6. 2. 1  
Mi s s e d D o s e D uri n g O L P ........................................................... 4 0  
6. 2. 2  
D o s e E s c al ati o n a n d St o p pi n g R ul e s ......................................... 4 1  
6. 2. 3  
D o s a g e A dj u st m e nt s .................................................................. 4 1  
6. 2. 4  
S u p pl e m e nt s ............................................................................... 4 1  
6. 2. 5  
Pr o hi bit e d T h er a p y D uri n g O p e n-l a b el P h a s e ............................ 4 1  
7.  
S T U D Y P R O C E D U R E S ......................................................................................... 4 1  
7. 1  
S cr e e ni n g Vi sit ............................................................................................ 4 1  
7. 2  
St u d y D a y 1 ................................................................................................ 4 1  
7. 3  
Tr e at m e nt P h a s e Vi sit s .............................................................................. 4 1  
7. 4  
M e di c al Hi st or y ........................................................................................... 4 2  
7. 5  
M e di c ati o n Hi st or y ...................................................................................... 4 2  
7. 6  
P h y si c al E x a mi n ati o n ................................................................................. 4 2  
7. 7  
Cli ni c al Fr a ct ur e A s s e s s m e nt ..................................................................... 4 2  
7. 7. 1  
A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n- l a b el 
P h a s e ......................................................................................... 4 3  
7. 8  
L at er al S pi n e X-r a y ..................................................................................... 4 3  
7. 9  
D u al E n er g y X-r a y A b s or pti o m etr y ( D X A) A s s e s s m e nt .............................. 4 4  
7. 9. 1  
S cr e e ni n g D X A ........................................................................... 4 4  
7. 9. 2  
O n - St u d y D X A ............................................................................ 4 4  
7. 1 0  
B o n e S c a n .................................................................................................. 4 5  
7. 1 1  
L a b or at or y A s s e s s m e nt s ............................................................................ 4 5  
7. 1 2  
Bl o o d a n d S er u m A s s e s s m e nt s ................................................................. 4 5  
7. 1 3  
A d v er s e E v e nt s .......................................................................................... 4 6  
7. 1 4  
E arl y Wit h dr a w al Fr o m Tr e at m e nt .............................................................. 4 7  
7. 1 5  
E n d of Tr e at m e nt ........................................................................................ 4 7  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
7. 1 6  
E n d of O p e n-l a b el Tr e at m e nt ..................................................................... 4 8  
7. 1 7  
L o n g -t er m F oll o w-u p  ................................................................................... 4 8  
7. 1 8  
E n d of St u d y ............................................................................................... 4 8  
8.  
R E M O V A L A N D R E P L A C E M E N T O F S U B J E C T S ............................................... 4 9  
8. 1  
R e m o v al of S u bj e ct s ................................................................................... 4 9  
8. 2  
R e pl a c e m e nt of S u bj e ct s ............................................................................ 5 0  
9.  
A D V E R S E E V E N T R E P O R TI N G ........................................................................... 5 0  
9. 1  
D efi niti o n s ................................................................................................... 5 0  
9. 1. 1  
A d v er s e E v e nt s .......................................................................... 5 0  
9. 1. 2  
S eri o u s A d v er s e E v e n t s ............................................................. 5 0  
9. 2  
R e p orti n g Pr o c e d u r e s f or All A d v er s e E v e nt s D uri n g t h e 
D o u bl e- bli n d P h a s e .................................................................................... 5 1  
9. 3  
S eri o u s A d v er s e E v e nt R e p orti n g Pr o c e d ur e s D uri n g t h e 
D o u bl e- bli n d P h a s e .................................................................................... 5 2  
9. 3. 1  
A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s 
A d v er s e E v e nt R e p orti n g D uri n g t h e O p e n- l a b el 
P h a s e ......................................................................................... 5 3  
9. 3. 1. 1  
A d v er s e E v e nt s of S p e ci al I nt er e st 
R e p orti n g ................................................................. 5 3  
9. 3. 1. 2  
S eri o u s A d v er s e E v e nt R e p orti n g ............................ 5 3  
1 0.  S T A TI S TI C A L C O N SI D E R A TI O N S  ....................................................................... 5 4  
1 0. 1  
St u d y D e si g n .............................................................................................. 5 4  
1 0. 2  
St u d y E n d p oi nt s, S u b s et s, a n d C o v ari at e s ................................................ 5 5  
1 0. 2. 1  
Pri m ar y E n d p oi nt ........................................................................ 5 5  
1 0. 2. 2  
S e c o n d ar y E n d p oi nt s ................................................................. 5 5  
1 0. 2. 3  
S af et y E n d p oi nt s ........................................................................ 5 5  
1 0. 2. 4  
E x pl or at or y E n d p oi nt s ................................................................ 5 5  
1 0. 2. 5  
S u b s et s ....................................................................................... 5 6  
1 0. 2. 6  
C o v ari at e s .................................................................................. 5 6  
1 0. 3  
S a m pl e Si z e C o n si d er ati o n s ...................................................................... 5 6  
1 0. 4  
A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s ................................ 5 7  
1 0. 5  
I nt eri m A n al y si s, E arl y St o p pi n g G ui d eli n e s, a n d Ti m e- p oi nt s of 
A n al y s e s ..................................................................................................... 5 8  
1 0. 6  
Pl a n n e d M et h o d s of A n al y si s ..................................................................... 5 9  
1 0. 6. 1  
G e n er al A p pr o a c h/ C o n si d er ati o n s ............................................. 5 9  
1 0. 6. 2  
A n al y si s of K e y St u d y E n d p oi nt s ................................................ 6 1  
1 0. 6. 2. 1  
Effi c a c y A n al y si s ...................................................... 6 1  
1 0. 6 . 2. 2 
S af et y A n al y s e s ....................................................... 6 2  
1 0. 6. 2. 3  
A nti- d e n o s u m a b A nti b o di e s ..................................... 6 3  
1 0. 6. 2. 4  
E x pl or at or y A n al y s e s ............................................... 6 3  
1 1.  I N V E S TI G A TI O N A L P R O D U C T ............................................................................ 6 4  
1 1. 1  
D e n o s u m a b ................................................................................................ 6 4  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 1. 2  
A c c e s s t o Tr e at m e nt A s si g n m e nt s ............................................................. 6 5  
1 1. 2. 1  
Bli n d e d p h a s e ............................................................................. 6 5  
1 1. 2. 2  
O p e n-l a b el P h a s e ....................................................................... 6 5  
1 1. 3  
C o m pli a n c e i n I n v e sti g ati o n al Pr o d u ct A d mi ni str ati o n ................................ 6 5  
1 2.  R E G U L A T O R Y O B LI G A TI O N S ............................................................................. 6 6  
1 2. 1  
I nf or m e d C o n s e nt ....................................................................................... 6 6  
1 2 . 2 
I n d e p e n d e nt Et hi c s C o m mitt e e/I n stit uti o n al R e vi e w B o ar d ........................ 6 6  
1 2. 3  
Pr e st u d y D o c u m e nt ati o n R e q uir e m e nt s ..................................................... 6 7  
1 2. 4  
S u bj e ct C o nfi d e nti alit y ................................................................................ 6 7  
1 2. 5  
I n v e sti g at or Si g n at or y O bli g ati o n s .............................................................. 6 8  
1 3.  A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S ................................................... 6 8  
1 3. 1  
Pr ot o c ol A m e n d m e nt s a n d St u d y T er mi n ati o n ........................................... 6 8  
1 3. 2  
St u d y D o c u m e nt ati o n a n d Ar c hi v e ............................................................. 6 8  
1 3. 3  
St u d y M o nit ori n g a n d D at a C oll e cti o n ........................................................ 6 9  
1 3. 4  
L a n g u a g e .................................................................................................... 7 1  
1 3. 5  
P u bli c ati o n P oli c y ....................................................................................... 7 1  
1 3. 6  
C o m p e n s ati o n ............................................................................................ 7 2  
1 4.  R E F E R E N C E S ....................................................................................................... 7 3  
1 5.  A P P E N DI C E S ........................................................................................................ 7 5  
Li st of T a bl e s  
T a bl e 1.  S er u m a n d Bl o o d S a m pl e A n al yt e Li sti n g ........................................................ 4 6  
T a bl e 3.  S a m pl e Si z e s ................................................................................................. 1 0 0  
T a bl e 4.  S c h e d ul e of A s s e s s m e nt s f or Z A S u b st u d y ................................................... 1 0 2  
Li st of A p p e n di c e s  
A p p e n di x A.  S c h e d ul e of A s s e s s m e nt s f or Bli n d e d a n d O p e n- l a b el 
Tr e at m e nt P h a s e s .................................................................................... 7 6  
A p p e n di x B.  A d v er s e E v e nt A s s e s s m e nt s ..................................................................... 7 9  
A p p e n di x C.  P h ar m a c y G ui d e ........................................................................................ 8 0  
A p p e n di x D.  Pr e g n a n c y N otifi c ati o n W or k s h e et ............................................................ 8 6  
A p p e n di x E.  Cl a s sifi c ati o n E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G ) 
P erf or m a n c e S c al e .................................................................................. 8 7  
A p p e n di x F.  S eri o u s A d v er s e E v e nt F or m ..................................................................... 8 8  
A p p e n di x G.  Z ol e dr o ni c A ci d S u b st u d y .......................................................................... 9 0  
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
1.  
O B J E C TI V E S 
1. 1   
Pri m ar y 
T o d e t er mi n e w h et h er d e n o s u m a b c o m p ar e d t o pl a c e b o will r e d u c e t h e r at e of fir st 
( o n- st u d y) cli ni c al fr a ct ur e (i e, cli ni c all y e vi d e nt fr a ct ur e wit h a s s o ci at e d s y m pt o m s) i n 
w o m e n wit h n o n- m et a st ati c br e a st c a n c er r e c ei vi n g n o n- st er oi d al ar o m at a s e i n hi bit or 
t h er a p y ( AI T).  
1. 2   
S e c o n d ar y 
T o a s s e s s t h e eff e ct of d e n o s u m a b c o m p ar e d t o pl a c e b o o n: 
Fr a ct ur e-r el at e d s e c o n d ar y e n d p oi nt s: 
 
B o n e mi n er al d e n sit y ( B M D) at l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k i n a 
s u b gr o u p of s u bj e ct s at pr e- s el e ct e d sit e s  
 
I n ci d e n c e of n e w v ert e br al fr a ct ur e s ( b ot h cli ni c al a n d m or p h o m etri c [i e, a fr a ct ur e i n 
t h e v ert e br al c ol u m n t h at i s n ot cli ni c all y e vi d e nt a n d t h at i s a s y m pt o m ati c]) 
 
I n ci d e n c e of n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s ( b ot h cli ni c al a n d 
m or p h o m etri c) 
Di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s:  
 
Di s e a s e-fr e e s ur vi v al ( D F S) 
 
B o n e m et a st a si s-fr e e s ur vi v al ( B M F S) 
 
O v er all s ur vi v al ( O S) 
T o a s s e s s t h e s af et y a n d t ol er a bilit y of d e n o s u m a b i n t hi s p o p ul ati o n. 
1. 3   
E x pl or at or y 
2.  
B A C K G R O U N D A N D R A TI O N A L E 
2. 1   
Di s e a s e 
Br e a st c a n c er i s a c o m m o n m ali g n a n c y i n w o m e n, wit h a n i n ci d e n c e r at e of o v er 
2 1 0, 0 0 0 c a s e s p er y e ar a n d pr e v al e n c e r at e i n e x c e s s of 2 milli o n i n t h e U S al o n e 
(J e m al et  al,  2 0 0 3 ).  E n d o cri n e t h er a p y i s r e c o m m e n d e d f or n e arl y all w o m e n wit h br e a st 
c a n c er t h at e x pr e s s e s e str o g e n r e c e pt or ( E R) or pr o g e st er o n e r e c e pt or ( P g R) ( E R + or 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
E R -/ Pg R +).  Ar o m at a s e i n hi bit or t h er a p y i n hi bit s p eri p h er al e str o g e n s y nt h e si s 
(T hij s s e n a n d Bl a n k e n st ei n, 1 9 8 9; L a k e a n d  H u di s 2 0 0 2 ).  Tr e at m e nt of a d v a n c e d 
E R +  or E R-/ Pg R + br e a st c a n c er wit h ar o m at a s e i n hi bit or s d e m o n str at e d i m pr o v e m e nt s 
i n t h e o bj e cti v e r e s p o n s e r at e a n d ti m e t o pr o gr e s si o n (D o m b er n o w s k y et  al,  1 9 9 8;   
N a b h olt z et al, 2 0 0 0; M o uri d s e n et al, 2 0 0 1 ).  Tr e at m e nt wit h ar o m at a s e i n hi bit or s i n t h e 
a dj u v a nt s etti n g f or p o st m e n o p a u s al w o m e n wit h E R + or E R- / Pg R + t u m or s h a s 
d e m o n str at e d i m pr o v e m e nt s i n O S , pr o gr e s si o n-fr e e s ur vi v al a n d i n ci d e n c e of br e a st 
c a n c er i n t h e c o ntr al at er al br e a st f or w o m e n wit h E R + or E R- / Pg R + br e a st c a n c er  
(G o s s et al, 2 0 0 3 ). 
D e s pit e t h e s e i m pr o v e m e nt s, t h er e i s gr o wi n g a w ar e n e s s of ri s k of b o n e l o s s i n d u c e d b y 
a dj u v a nt tr e at m e nt wit h ar o m at a s e i n hi bit or s i n p o st m e n o p a u s al w o m e n wit h e arl y st a g e 
br e a st c a n c er t h at ar e E R + or E R- / Pg R + p o siti v e ( A T A C tri ali st s gr o u p, 2 0 0 5; 
J a k e s z et  al,  2 0 0 5; BI G 1- 9 8 C oll a b or ati v e Gr o u p, 2 0 0 5). 
A n a n al y si s of Ari mi d e x, T a m o xif e n Al o n e or i n C o m bi n ati o n ( A T A C) d at a s h o w e d a n 
i n cr e a s e i n t h e i n ci d e n c e of s y m pt o m ati c ( cli ni c al) fr a ct ur e s ( b ot h v ert e br al a n d n o n 
v ert e br al), n ot r el at e d t o di s e a s e pr o gr e s si o n f or t h e w o m e n tr e at e d wit h a n a str o z ol e, a n 
ar o m at a s e i n hi bit or, a s c o m p ar e d t o t a m o xif e n.  Si mil arl y, t h e Br e a st I nt er n ati o n al Gr o u p 
( BI G) 1- 9 8 C oll a b or ati v e gr o u p d e m o n str at e d t h at fr a ct ur e s w er e si g nifi c a ntl y m or e 
fr e q u e nt i n t h e l etr o z ol e gr ou p t h a n i n t h e t a m o xif e n gr o u p ( 5. 7 % v s. 4. 0 %, P < 0. 0 0 1).  
D eri v ati o n of t h e d at a s u g g e st e d a n o c c urr e n c e of a p pr o xi m at el y 2 0 fr a ct ur e s p er 
1 0 0 0  s u bj e ct- y e ar s (l etr o z ol e gr o u p). 
2. 2   
D e n o s u m a b B a c k gr o u n d 
P ert ur b ati o n s i n t h e b al a n c e b et w e e n b o n e f or m ati o n a n d r e s or pti o n c a n l e a d t o 
g e n er ali z e d o st e o p or o si s (r e s ulti n g fr o m e str o g e n d efi ci e n c y a n d a gi n g) or l o c al b o n e 
l y si s (r e s ulti n g fr o m r h e u m at oi d art hriti s a n d b o n e m et a st a s e s).  T h e R A N K- R A N K 
li g a n d ( R A N K/ L) s y st e m h a s b e e n i d e ntifi e d a s a n e s s e nti al m e di at or of o st e o cl a st 
f or m ati o n, f u n cti o n, a n d s ur vi v al (T eit el b a u m et  al,  2 0 0 3 ).  R A N K/ L bi n d s R A N K o n 
o st e o cl a st s or o st e o cl a st pr e c ur s or s t o sti m ul at e or pr o m ot e diff er e nti ati o n i nt o 
o st e o cl a st s a n d a cti v at e m at ur e o st e o cl a st s t o r e s or b b o n e.  T h er ef or e, R A N K/ L i s a 
t h er a p e uti c t ar g et f or di s e a s e s a s s o ci at e d wit h i n cr e a s e d b o n e r e s or pti o n. 
D e n o s u m a b i s a f ull y h u m a n m o n o cl o n al I g G 2 a nti b o d y t o R A N K/ L t h at bi n d s wit h hi g h 
affi nit y ( K d  3 x 1 0-1 2  M) a n d s p e cifi cit y t o t h e s ol u bl e a n d c ell m e m br a n e-b o u n d f or m s of 
h u m a n R A N K/ L.  D e n o s u m a b i s hi g hl y s p e cifi c b e c a u s e it bi n d s o nl y t o R A N K/ L a n d n ot 
t o ot h er m e m b er s of t h e T N F f a mil y, i n cl u di n g T N F, T N F, T N F-r el at e d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
a p o pt o si s-i n d u ci n g li g a n d, or C D 4 0 li g a n d ( Elli ott et  al, 2 0 0 6 ).  D e n o s u m a b bi n di n g 
pr e v e nt s t h e a cti v ati o n of R A N K a n d i n hi bit s t h e f or m ati o n, a cti v ati o n, a n d s ur vi v al of 
o st e o cl a st s.  A s a c o n s e q u e n c e, b o n e r e s or pti o n a n d c a n c er-i n d u c e d b o n e d e str u cti o n 
ar e r e d u c e d.   
R ef er t o t h e l at e st v er si o n of t h e i n v e sti g at or br o c h ur e f or a d diti o n al a n d u p d at e d 
i nf or m ati o n o n d e n o s u m a b b a c k gr o u n d, cli ni c al e x p eri e n c e, a n d s af et y i nf or m ati o n. 
2. 3   
R ati o n al e 
I n t h e A T A C st u d y aft er 5 y e ar s of f oll o w- u p, d e s pit e a n i m pr o v e d D F S, a r etr o s p e cti v e 
a n al y si s s h o w e d a n i n cr e a s e i n t h e i n ci d e n c e of cli ni c al fr a ct ur e s ( v ert e br al a n d n o n 
v ert e br al n ot r el at e d t o di s e a s e pr o gr e s si o n) f or t h e w o m e n tr e at e d wit h a n a str o z ol e, a n 
ar o m at a s e i n hi bit or, a s c o m p ar e d t o t h o s e tr e at e d wit h t a m o xif e n, a n o n- st er oi d al 
a nti - e str o g e n t h at h a s p arti al- e str o g e n- a g o ni st a cti vit y (A T A C tri ali st s gr o u p, 2 0 0 5 ).  F or 
t h e a n a str o z ol e tr e at e d gr o u p, fr a ct ur e r at e s w er e 2 2. 6 p er 1 0 0 0 w o m e n- y e ar s a n d  
1 5. 6 p er 1 0 0 0 w o m e n - y e ar s f or t h e t a m o xif e n tr e at e d gr o u p  
( h a z ar d r ati o 1. 4 4, 9 5 % C.I. 1. 2 1-1. 6 8, p  < 0. 0 0 1). 
E str o g e n sti m ul at e s t h e o st e o bl a st t o pr o d u c e o st e o pr ot e g eri n a n d i n hi bit s t h e 
pr o d u cti o n of R A N K/ L .  In t h e a b s e n c e of e str o g e n, t h e r e d u c e d l e v el s of 
o st e o pr ot e g eri n r e s ult i n i n cr e a s e d b o n e r e s or pti o n d u e t o u n o p p o s e d a cti o n s of 
R A N K / L.  D e n o s u m a b i n hi bit s R A N K/ L, r e s ulti n g i n t h e i n hi biti o n of b o n e r e s or pti o n.   
T o d at e, t h er e ar e n o a p pr o v e d tr e at m e nt s t o pr e v e nt b o n e l o s s i n t hi s at -ri s k p o p ul ati o n 
a n d n o tri al s h a v e b e e n p u bli s h e d u si n g bi s p h o s p h o n at e s f or t h e s p e cifi c tr e at m e nt or  
pr e v e nti o n of b o n e l o s s t h at o c c ur s d uri n g or aft er tr e at m e nt wit h ar o m at a s e i n hi bit or s.  
O n g oi n g st u di e s ar e i n v e sti g ati n g t h e r ol e of bi s p h o s p h o n at e s f or t hi s p arti c ul ar 
i n di c ati o n.  T w o l ar g e 5- y e ar tri al s ( Z- F a st i n t h e U S a n d Z O- F A S T i n E ur o p e) ar e 
i n v e sti g ati n g i m m e di at e a n d d el a y e d tr e at m e nt wit h z ol e dr o ni c a ci d ( 4 m g vi a 1 5- mi n ut e 
i nf u si o n e v er y 6 m o nt h s) i n m or e t h a n 1 5 0 0 p o st- m e n o p a u s al w o m e n r e c ei vi n g a dj u v a nt 
t h er a p y wit h t h e ar o m at a s e i n hi bit or l etr o z ol e f or e arl y st a g e h or m o n e r e c e pt or p o siti v e 
br e a st c a n c er ( Br uf s k y et al, 2 0 0 4 ).  T h e pri m ar y e n d-p oi nt i n t hi s tri al i s l u m b ar B M D at 
1 2  m o nt h s.    
A s t h e u s e of AI T b e c o m e s m or e pr e v al e nt, it will b e c o m e i n cr e a si n gl y i m p ort a nt t o 
i d e ntif y eff e cti v e tr e at m e nt s t o pr e v e nt a n d tr e at b o n e l o s s i n w o m e n w h o ar e 
u n d er g oi n g a dj u v a nt tr e at m e nt wit h ar o m at a s e i n hi bit or s.  F or t h e o n c ol o g y cli ni c al 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
c o m m u nit y it will b e i m p ort a nt t o e st a bli s h w hi c h tr e at m e nt s will b e eff e cti v e i n r e d u ci n g 
cli ni c al fr a ct ur e s a s d e s cri b e d i n t h e A T A C st u d y.  
B e c a u s e of it s pr ofil e a s a f a st- a cti n g, p ot e nti all y r e v er si bl e a n d p ot e nt i n hi bit or of 
o st e o cl a sti c b o n e r e s or pti o n, d e n o s u m a b m a y b e a n eff e cti v e a n d c o n v e ni e nt t h er a p y 
f or o st e o p or o si s a s s o ci at e d wit h h or m o n e a bl ati o n t h er a p y, i n cl u di n g AI T.  If s u c c e s sf ul, 
t hi s st u d y will s h o w t h at d e n o s u m a b r e d u c e s t h e r at e of cli ni c al fr a ct ur e i n t h e p o p ul ati o n 
of s u bj e ct s o n AI T .  
T h e pi v ot al 2 0 0 3 0 2 1 6 – tri al ( d e n o s u m a b v er s u s pl a c e b o i n t h e tr e at m e nt of w o m e n wit h 
p o st m e n o p a u s al o st e o p or o si s) s h o w e d a cli ni c al fr a ct ur e r e d u cti o n b y 3 0 % b y 
d e n o s u m a b c o m p ar e d t o pl a c e b o.  B a s e d u p o n t h e r e vi e w of t h e s e fr a ct ur e d at a i n t h e 
2 0 0 3 0 2 1 6 tri al ( C u m mi n g s et al, 2 0 0 9 ) a n d t a ki n g i nt o a c c o u nt t h at ar o m at a s e i n hi biti o n 
i n cr e a s e s b o n e t ur n o v er (E a st ell et al, 2 0 0 6 ), a h a z ar d r ati o w a s c al c ul at e d  f or t h e 
2 0 0 5 0 2 0 9 –  tri al a n d a fr a ct ur e ri s k r e d u cti o n of 3 0 % b y d e n o s u m a b c o m p ar e d t o 
pl a c e b o ( or h a z ar d r ati o = 0. 7 0) i s m or e li k el y t o r efl e ct t h e cli ni c al fr a ct ur e ri s k f or t hi s 
p o st m e n o p a u s al a dj u v a nt br e a st c a n c er p o p ul ati o n tr e at e d wit h ar o m at a s e i n hi biti o n.  
T h e A u stri a n Br e a st a n d C ol or e ct al C a n c er St u d y Gr o u p ( A B C S G) 1 8 pri m ar y a n al y si s 
s h o w e d t h at a dj u v a nt d e n o s u m a b 6 0 m g , a d mi ni st er e d t wi c e y e arl y, r e d u c e s t h e ri s k of 
cli ni c al fr a ct ur e s, i n cl u di n g n e w v ert e br al fr a ct ur e s a n d  n e w or w or s e ni n g v ert e br al 
fr a ct ur e s, i n p o st m e n o p a u s al w o m e n wit h br e a st c a n c er w h o ar e r e c ei vi n g AI T a n d  al s o 
i n cr e a s e s B M D at t h e l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k.   T h er e w er e n o n e w 
s af et y fi n di n g s i n t h e st u d y a n d t h e s af et y pr ofil e w a s si mil ar t o t h at pr e vi o u sl y o b s er v e d 
wit h Pr oli a . 
S u b c ut a n e o u s d e n o s u m a b 6 0 m g e v er y 6 m o nt h s si g nifi c a ntl y d el a y e d t h e ti m e t o fir st 
cli ni c al fr a ct ur e ( H R = 0. 5 0, 9 5 % c o nfi d e n c e i nt er v al [ CI ] 0.3 9 - 0.6 5, p  < 0 . 0 0 1).  T hi s 
r e d u cti o n i n fr a ct ur e s b et w e e n d e n o s u m a b a n d pl a c e b o ar m s ( o v er all 9 2 v s 1 7 6, 
r e s p e cti v el y) w a s si mil ar i n all s u bj e ct s u b gr o u p s, i n cl u di n g s u bj e ct s wit h n or m al b o n e 
h e alt h at b a s eli n e ( T- s c or e ≥ - 1, n = 1 8 7 2, H R = 0. 4 4, 9 5 % CI 0 .3 1 - 0.6 4, p  < 0. 0 0 1) a n d 
o st e o p e ni c s u bj e ct s ( T- s c or e < - 1 , n = 1 5 4 8, H R = 0. 5 7, 9 5 % CI 0 .4 0 - 0.8 2, p  = 0. 0 0 2).  
D e n o s u m a b al s o si g nifi c a ntl y i n cr e a s e d B M D of l u m b ar s pi n e ( 1 0. 0 2 %), t ot al hi p 
( 7.9 2 %) , a n d f e m or al n e c k ( 6. 5 1 %) at 3 6 m o nt h s c o m p ar e d wit h t h e pl a c e b o gr o u p ( all 
a dj u st e d p- v al u e s < 0. 0 0 1).  D e n o s u m a b tr e at m e nt al s o si g nifi c a ntl y r e d u c e d t h e 
i n ci d e n c e of n e w v ert e br al fr a ct ur e s at 3 6 m o nt h s, wit h 2 7 fr a ct ur e s i n 8 3 5 p ati e nt s i n t h e 
d e n o s u m a b gr o u p c o m p ar e d wit h 4 9 fr a ct ur e s i n 8 0 9 p ati e nt s i n t h e pl a c e b o gr o u p 
( o d d s r ati o 0. 5 3 [ 9 5 % CI 0. 3 3 - 0. 8 5], p- v alu e  = 0. 0 0 9) a n d t h e i n ci d e n c e of n e w or 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
w or s e ni n g v ert e br al fr a ct ur e s at 3 6 m o nt h s ( 3 1 of 8 3 5 p ati e nt s i n t h e d e n o s u m a b gr o u p 
c o m p ar e d wit h 5 5 of 8 0 9 p ati e nt s i n t h e pl a c e b o gr o u p; o d d s r ati o  
0. 5 4 [ 9 5 % CI 0. 3 4 - 0. 8 4], p = 0. 0 0 7).  T h er e w er e n o diff er e n c e s b et w e e n t h e 
d e n o s u m a b a n d pl a c e b o gr o u p s wit h r e s p e ct t o s u bj e ct i n ci d e n c e of  a d v er s e e v e nt s 
( 1 3 6 6 [ 8 0 %] v s 1 3 3 4 [ 7 9 %]), or s eri o u s a d v er s e e v e nt s ( S A E s) ( 5 2 1 v s 5 1 1; 3 0 % i n 
e a c h gr o u p).  D e s pit e pr o a cti v e a dj u di c ati o n of e v er y p ot e nti al o st e o n e cr o si s of t h e j a w 
( O N J) b y a n i nt er n ati o n al e x p ert p a n el, n o O N J c a s e w a s o b s er v e d.  N o at y pi c al f e m or al 
fr a ct ur e s w er e i d e ntifi e d. 
F or t h e s e p o st m e n o p a u s al br e a st c a n c er p ati e nt s wit h m o d e st ri s k of di s e a s e 
r e c urr e n c e, eff e cti v el y pr e v e nti n g t h e m o st s eri o u s si d e eff e ct of t h eir ar o m at a s e 
i n hi bit or tr e at m e nt i s hi g hl y b e n efi ci al (G n a nt et al.; L a n c et 2 0 1 5 ). 
B a s e d o n t h e r e s ult s of t h e A B C S G 1 8 pri m ar y a n al y si s, t h e D at a M o nit ori n g C o m mitt e e 
( D M C) r e c o m m e n de d  off eri n g d e n o s u m a b 6 0 m g f or u p t o 3 6 m o nt h s ( m a xi m u m of 
7 d o s e s) t o s u bj e ct s, w h o aft er u n bli n di n g, w er e s h o w n t o b e i n t h e pl a c e b o ar m.  
2. 4   
H y p ot h e s e s 
2. 4. 1   
Cli ni c al Effi c a c y H y p ot h e si s 
D e n o s u m a b, w h e n a d mi ni st er e d S C at a d o s e of 6 0 m g e v er y 6 m o nt h s, will b e 
c o n si d er e d effi c a ci o u s i n br e a st c a n c er s u bj e ct s r e c ei vi n g AI T if t h e r at e of fir st cli ni c al 
fr a ct ur e s ( v ert e br al a n d n o n- v ert e br al – c o n si st e nt wit h A T A C) i n d e n o s u m a b-tr e at e d 
s u bj e ct s i s l o w er t h a n t h at i n pl a c e b o- tr e at e d s u bj e ct s.  It i s a nti ci p at e d t h at d e n o s u m a b 
will r e d u c e t h e r at e b y 3 0 % c o m p ar e d wit h pl a c e b o (i e,  t h e tr u e h a z ar d r ati o of 
d e n o s u m a b c o m p ar e d wit h pl a c e b o i s 0. 7 0 ).  
2. 5   
Cli ni c al S af et y H y p ot h e si s 
D e n o s u m a b, w h e n a d mi ni st er e d S C at a d o s e of 6 0 m g e v er y 6 m o nt h s will b e w ell 
t ol er at e d i n br e a st c a n c er s u bj e ct s r e c ei vi n g AI T. 
3.  
E X P E RI M E N T A L P L A N 
3. 1   
St u d y D e si g n 
T hi s i s a m ulti- c e nt er  p h a s e 3, r a n d o mi z e d, d o u bl e-bli n d, pl a c e b o - c o ntr oll e d st u d y t o 
d et er mi n e t h e tr e at m e nt eff e ct of d e n o s u m a b i n s u bj e ct s wit h br e a st c a n c er tr e at e d wit h 
a n a p pr o v e d n o n- st er oi d al ar o m at a s e i n hi bit or , eg,  a n a str o z ol e.  A p pr o xi m at el y 
3 4 0 0  s u bj e ct s will b e r a n d o mi z e d i n a 1: 1 r ati o t o r e c ei v e eit h er d e n o s u m a b 
a d mi ni st er e d at a d o s e of 6 0 m g or pl a c e b o S C e v er y 6 m o nt h s ( Q 6 M) i n a bli n d e d 
m a n n er.  S u bj e ct s will b e r e cr uit e d o v er a p pr o xi m at el y 8 2  m o nt h s.  Th e r a n d o mi z ati o n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
s c h e d ul e will b e str atifi e d b y: t y p e of h o s pit al ( m aj or a c a d e mi c c e nt er s or ot h er c e nt er s), 
pri or AI u s a g e ( Y/ N) a n d t ot al l u m b ar s pi n e B M D s c or e at b a s eli n e  
( T- s c or e < -1. 0  v s   - 1. 0). 
S u bj e ct s will r e m ai n o n i n v e sti g ati o n al pr o d u ct (I P) u ntil t h e r e q uir e d n u m b er of e v e nt s 
( w h er e a n e v e nt i s d efi n e d a s fir st cli ni c al fr a ct ur e) i s r e a c h e d a n d all s u bj e ct s h a d t h e 
o p p ort u nit y t o r e c ei v e a mi ni m u m of at l e a st 2 d o s e s of I P, w hi c h e v er o c c ur s l at er.  Th e 
pri m ar y a n al y si s d at a c ut- off  d at e ( P A DC D) i s d efi n e d a s t h e ti m e at w hi c h t h e r e q uir e d 
n u m b er of e v e nt s i s r e a c h e d a n d all s u bj e ct s h a v e h a d t h e o p p ort u nit y t o r e c ei v e at l e a st 
2 d o s e s of I P.  Wh e n t h e P A D C D i s r e a c h e d, all s u bj e ct s will di s c o nti n u e I P.  
F or all s u bj e ct s w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) 
pri or t o t h e P A D C D w a s a y e arl y vi sit ( e g, m o nt h 1 2, 2 4, et c) a n d r a di ol o gi c al 
a s s e s s m e nt s w er e p erf or m e d, t hi s vi sit will b e c o n si d er e d a n E O T vi sit ( c orr e s p o n di n g 
c a s e r e p ort f or m [ C R F ] will h a v e t o b e c o m pl et e d).  F or t h o s e s u bj e ct s, t h e n e xt vi sit will 
b e r e g ar d e d a s l o n g-t er m f oll o w-u p ( L T F U ) vi sit, at w hi c h a n a nti b o d y s a m pl e will b e 
t a k e n.  T h o s e s u bj e ct s, f or w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e n ot p erf or m e d, will 
n e e d t o att e n d t h e n e xt s c h e d ul e d 6 m o nt h s vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s 
( v ert e br al x-r a y s, d u al X -r a y a b s or pti o m etr y [ D X A]) will t a k e pl a c e a n d a n a nti b o d y 
s a m pl e will b e t a k e n.  F or t h e s e s u bj e ct s t hi s vi sit will b e c o n si d er e d a s E O T vi sit.  
All s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or 
t o t h e P A D C D w a s a 6 m o nt h s vi sit ( e g, m o nt h 6, 1 8, et c), will h a v e t o att e n d t h e n e xt 
r e g ul arl y s c h e d ul e d y e arl y st u d y vi sit ( e g, m o nt h 1 2) wit hi n 6 m o nt h s aft er P A D C D at t h e 
l at e st a n d p erf or m all c orr e s p o n di n g a s s e s s m e nt s, i n cl u di n g a nti b o d y s a m pli n g. 
D at a o n fr a ct ur e s o c c urri n g b et w e e n t h e l a st vi sit pri or t o P A D C D a n d P A D C D h a v e t o 
b e c oll e ct e d vi a t el e p h o n e or p h y si c al vi sit s wit hi n si x m o nt h s aft er P A D C D at t h e l at e st. 
S u bj e ct s w h o wit h dr a w fr o m I P pri or t o t h e o b s er v e d P A D C D will c o nti n u e t o att e n d Q 6 M 
st u d y vi sit s f or a s s e s s m e nt of t h e pri m ar y a n d s e c o n d ar y e n d- p oi nt a n d s af et y.  
S u bj e ct s c o m pl eti n g or di s c o nti n ui n g AI T will h a v e t h e o p p ort u nit y t o r e m ai n o n I P f or at 
l e a st 2 d o s e s of I P aft er t h eir l a st s c h e d ul e d st u d y vi sit d uri n g w hi c h t h e y w er e still o n 
AI T.   F oll o wi n g t h e st u d y P A D C D , s u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S 
e v er y 1 2 m o nt h s ( Q 1 2 M) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s st arti n g fr o m t h eir l a st 
st u d y vi sit ( c o n si d er e d a s E O T vi sit) u ntil a m a xi m u m of eit h er 1 8 or 6 6 m o nt h s aft er t h e 
P A D C D, d e p e n di n g o n a n i nt eri m a n al y si s at P A D C D ( s e e S e cti o n s 7. 1 6  a n d 1 0. 5 ).  
B a s e d o n t h e D M C r e c o m m e n d ati o n t h at i nt eri m f utilit y a n al y si s of D F S di d n ot i n di c at e 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
f utilit y, it w a s d e ci d e d t o f oll o w s u bj e ct s u ntil a m a xi m u m of a p pr o xi m at el y 6 6 m o nt h s 
aft er P A D C D.  F oll o wi n g r e g ul at or y a n d I n stit uti o n al R e vi e w B o ar d / I n d e p e n d e nt Et hi c s 
C o m mitt e e (I R B/I E C) a p pr o v al of Pr ot o c ol A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d. 
O p e n -l a b el P h a s e  
D u e t o t h e st ati sti c all y si g nifi c a nt diff er e n c e s i n t h e pri m ar y e n d p oi nt a n d fr a ct ur e-r el at e d 
s e c o n d ar y e n d p oi nt s b et w e e n t h e d e n o s u m a b ar m a n d t h e pl a c e b o ar m d e m o n str at e d 
at t h e pri m ar y a n al y si s  (G n a nt et al.; L a n c et 2 0 1 5 ), willi n g a n d eli gi bl e s u bj e ct s 
r a n d o mi z e d t o pl a c e b o d uri n g t h e d o u bl e-bli n d p h a s e m a y p arti ci p at e i n a n o p e n -l a b el 
p h a s e ( O L P ) a n d r e c ei v e d e n o s u m a b 6 0 m g Q 6 M f or u p t o 3 6 m o nt h s ( m a xi m u m of 
7  d o s e s), a s r e c o m m e n d e d b y t h e D M C.  
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of A m e n d m e nt 4, t h e o p p ort u nit y t o st art 
o p e n -l a b el d e n o s u m a b will o p e n f or a 1 2 - m o nt h p eri o d.  S u bj e ct s w h o c o n s e nt a n d f ulfil 
t h e eli gi bilit y crit eri a will r e c ei v e d e n o s u m a b i n t h e O L P f or u p t o 3 6 m o nt h s ( a m a xi m u m 
of 7 d o s e s).  S u bj e ct s w h o d o n ot f ulfil t h e eli gi bilit y crit eri a or d o n ot c o n s e nt will 
c o m pl et e L T F U a s s e s s m e nt s o nl y ( A p p e n di x A ). 
S u bj e ct s w h o d o n ot r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d o n c e a y e ar ( Q 1 2 M 
st u d y vi sit) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s f or: 
 
D F S, B M F S, a n d O S  
 
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e c a s e s) 
 
C o n c o mit a nt b o n e aff e cti n g m e di c ati o n 
o  
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b) 
o  
Gl u c o c orti c oi d s 
o  
A nti e pil e pti c dr u g s 
o  
A nti d e pr e s sa nt s  
o  I n s uli n 
 
A nti- c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y) 
 
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) 
S u bj e ct s w h o r e c ei v e o p e n -l a b el d e n o s u m a b will att e n d cli ni c vi sit s Q 6 M  f or:  
 
A d mi ni str ati o n of d e n o s u m a b ( 6 0 m g S C) 
 
C oll e cti o n of s eri o u s a n d n o n- s eri o u s a d v er s e e v e nt s  [( S) A E s] of s p e ci al 
i nt er e st ( or al e v e nt s) a n d S A E s 
 
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e c a s e s) ( Q 1 2 M o nl y) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
D F S, B M F S, a n d O S ( Q 1 2 M o nl y) 
 
C o n c o mit a nt b o n e aff e cti n g m e di c ati o n ( Q 1 2 M o nl y) 
o  
B o n e t ar g et e d t h er a p y ( e g, bi s p h o s p h o n at e or d e n o s u m a b)   
o  
Gl u c o c orti c oi d s 
o  
A nti e pil e pti c dr u g s 
o  
A nti d e pr e s sa nt s  
o  I n s uli n 
 
A nti- c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y) ( Q 1 2 M 
o nl y) 
 
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) ( Q 1 2 M o nl y) 
I n a d diti o n, f or all s u bj e ct s, B M D d at a will b e c oll e ct e d at a n y ti m e a D X A s c a n i s 
p erf or m e d f or B M D a n al y si s a s st a n d ar d of c ar e fr o m P A D C D t o e n d of st u d y ( E O S), 
t h e s e d at a will b e c oll e ct e d i n t h e C R F.  
Z ol e dr o ni c A ci d ( Z A) S u b st u d y: 
A s u b st u d y h a s b e e n a d d e d i n A p p e n di x G  t o e v al u at e s u bj e ct s c o m pl eti n g 
o p e n -l a b el d e n o s u m a b tr e at m e nt, t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e 
m a n a g e d a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or t h e p ati e nt p o p ul ati o n.  
S u bj e ct s e nr oll e d i n t h e m ai n st u d y w h o r e c ei v e d d e n o s u m a b d uri n g t h e o p e n 
l a b el p h a s e a n d ar e d e e m e d eli gi bl e p er t h e i n cl u si o n a n d e x cl u si o n crit eri a, m a y 
c h o o s e t o p arti ci p at e i n t hi s s u b st u d y.  S u bj e ct s t h at ar e n ot i n cl u d e d i n t h e 
s u b st u d y will e n d st u d y a s pl a n n e d.  Pr ot o c ol- d efi n e d d e n o s u m a b a d mi ni str ati o n 
will c o m pl et e at e n d of t h e o p e n -l a b el p eri o d n o m att er if s u bj e ct s p arti ci p at e i n 
t h e s u b st u d y or n ot. 
S u bj e ct s e nr oll e d i n t h e s u b st u d y will b e r a n d o mi z e d t o eit h er r e c ei v e a si n gl e 
d o s e of Z A ( T h er a p y Ar m) or will b e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or 
t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  D a y 1 f or b ot h ar m s i s 8 m o nt h s ( ± 4 w e e k s) 
fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n 
t hi s vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1. 
I n t h e e v e nt an  a d v er s e e v e nt of s p e ci al i nt er e st (r e n al t o xi cit y, cli ni c all y r el e v a nt 
h y p er/ h y p o c al c e mi a a n d or al e v e nt) or ot h er S A E i s i d e ntifi e d o ut si d e t h e s u bj e ct s’ 
s c h e d ul e d vi sit s, t h e st a n d ar d g ui d a n c e i n S e cti o n 9  s h o ul d b e f oll o w e d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
It i s hi g hl y r e c o m m e n d e d t h at all s u bj e ct s s h o ul d r e c ei v e d ail y s u p pl e m e nt s of at l e a st 
5 0 0  m g el e m e nt al c al ci u m a n d at l e a st 4 0 0 I. U. vit a mi n D.   
D o u bl e- bli n d e d P h a s e  
F or a s u bj e ct wit h > 1 0 % l o s s of B M D at t h e t ot al hi p or l u m b ar s pi n e o v er a n y 1- y e ar 
p eri o d, a n i nf or m e d di s c u s si o n will t a k e pl a c e b et w e e n t h e i n v e sti g at or a n d t h e s u bj e ct 
r e g ardi n g alt er n ati v e t h er a pi e s a n d a p pr o pri at e tr e at m e nt.  If t h e s el e ct e d tr e at m e nt 
o pti o n d o e s n ot i n cl u d e  c o m m er ci all y a v ail a bl e d e n o s u m a b (i e, X G E V A or Pr oli a), I V 
bi s p h o s p h o n at e s or or all y a d mi ni st er e d bi s p h o s p h o n at e t h er a p y l a sti n g l o n g er t h a n 
3 0  d a y s, w hi c h i s e x cl u si o n ar y (l e a di n g t o e arl y E O T), t h e s u bj e ct will r e m ai n i n t h e 
st u d y.   
T h e n u m b er of pri m ar y e n d p oi nt e v e nt s o b s er v e d will dri v e t h e ti mi n g of t h e pri m ar y a n d 
fi n al a n al y s e s (r ef er t o S e cti o n 1 0. 5  f or d et ail s).  T h e a ct u al ti mi n g of t h e pri m ar y 
a n al y si s will d e p e n d o n t h e r at e of r e cr uit m e nt i nt o t h e st u d y a n d t h e r at e at w hi c h 
cli ni c al fr a ct ur e s ar e o b s er v e d.   
A st u d y s c h e m a at t h e  e n d of t h e pr ot o c ol s y n o p si s s e cti o n d e s cri b e s t h e o v er all m ai n 
st u d y d e si g n. 
T h e st u d y e n d p oi nt s ar e d efi n e d i n S e cti o n 1 0. 2 . 
3. 2   
N u m b er of C e nt er s 
A B C S G will c o n d u ct t h e st u d y.  A n et w or k of a p pr o xi m at el y 6 0  t o 8 0 c e nt er s i s 
a nti ci p at e d t o p arti ci p at e.  Sit e s t h at d o n ot e nr oll s u bj e ct s wit hi n 6 m o nt h s of sit e 
i niti ati o n m a y b e cl o s e d.   
3. 3   
N u m b er of S u bj e ct s 
P arti ci p a nt s e nr oll e d i n t hi s cli ni c al i n v e sti g ati o n s h all b e r ef err e d t o a s “ s u bj e ct s”.  
A p pr o xi m at el y 3 4 0 0  s u bj e ct s will b e e nr oll e d i nt o t h e st u d y.  Eli gi bl e s u bj e ct s will b e 
r a n d o mi z e d t o 1 of t h e 2 tr e at m e nt gr o u p s. 
B a s e d o n e x p eri e n c e of dr o p o ut r at e s i n pr e vi o u s st u di e s it i s a nti ci p at e d t h at 
a p pr o xi m at el y 2 2 % of p ati e nt s o v er 3 y e ar s ar e e x p e ct e d t o di s c o nti n u e tr e at m e nt.  
H o w e v er, d u e t o t h e n at ur e of st a n d ar d m e di c al pr a cti c e it i s a nti ci p at e d t h at e v e n w h e n 
s u bj e ct s di s c o nti n u e tr e at m e nt, al m o st 1 0 0 % of t h e m will b e f oll o w e d u p wit hi n t h e st u d y 
f or t h e o c c urr e n c e of t h e pri m ar y e n d-p oi nt .  Ref er t o S e cti o n 1 0. 3  f or d et ail s o n t h e 
r ati o n al e f or t h e n u m b er of s u bj e ct s. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
3. 4   
E sti m at e d St u d y D ur ati o n 
T h e a ct u al ti mi n g of a n al y s e s will b e d et er mi n e d b y t h e P A D C D.  St u d y d ur ati o n i s 
e sti m at e d t o b e 1 6 9  m o nt h s, w hi c h i n cl u d e s a n e nr oll m e nt p eri o d of a p pr o xi m at el y 
8 2  m o nt h s, a n e n d of t h e t r e at m e nt p h a s e (i e, t h e P A D C D) of a p pr o xi m at el y 2 1  m o nt h s 
a n d a p pr o xi m at el y 6 6  m o nt h s f oll o wi n g t h e P A D C D f or a 5 y e ar l o n g-t er m f oll o w-u p  
i n cl u di n g a n O L P ( 1 2 m o nt h s  u n bli n di n g o pti o n a n d a m a xi m u m of 3 6  m o nt h s of 
tr e at m e nt) ( s e e S e cti o n s 7. 1 6  a n d 1 0. 5 ).   
3. 4. 1   
St u d y D ur ati o n f or P arti ci p a nt s 
St u d y d ur ati o n f or i n di vi d u al s u bj e ct s will v ar y d e p e n di n g o n t h e P A D C D.  B a s e d o n t h e 
e sti m at e d r e cr uit m e nt p eri o d a n d e x p e ct e d o c c urr e n c e of cli ni c al fr a ct ur e s, t h e l a st 
s u bj e ct r a n d o mi z e d will p arti ci p at e i n t h e tr e at m e nt p h a s e u ntil t h e y h a v e h a d t h e 
o p p ort u nit y t o r e c ei v e at l e a st 2 d o s e s of I P b ef or e t h e st u d y tr e at m e nt p h a s e e n d s. 
F oll o wi n g t h e st u d y P A D C D, s u bj e ct s will b e f oll o w e d- u p Q 1 2 M b y cli ni c vi sit s or 
t el e p h o n e c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O T vi sit) f or a 
m a xi m u m of a p pr o xi m at el y 6 6 m o nt h s aft er t h e P A D C D. 
S u bj e ct s w h o r e c ei v e o p e n -la b el d e n o s u m a b will b e f oll o w e d -u p u ntil c o m pl eti o n of 
3 6  m o nt h s of tr e at m e nt or a p pr o xi m at el y 6 6 m o nt h s aft er  P A D C D, w hi c h e v er i s l o n g er.  
T h e e x p e ct e d ti m e o n st u d y i s u p t o a p pr o xi m at el y 1 6 9 m o nt h s. 
3. 4. 2   
E n d of Tr e at m e nt 
T h e E n d of Tr e at m e nt i s d efi n e d f or e a c h s u bj e ct a s t h e p oi nt i n ti m e w h e n t h e l a st d o s e 
of bli n d e d i n v e sti g ati o n al pr o d u ct i s a d mi ni st er e d. 
3. 4. 3  
L o n g -t er m F oll o w-u p  
S u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S Q 1 2 M b y cli ni c vi sit s or t el e p h o n e 
c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O T  vi sit) f or a p pr o xi m at el y 
6 6  m o nt h s aft er t h e P A D C D ( s e e S e cti o n s 7. 1 6  a n d  1 0. 5 ).  F oll o wi n g r e g ul at or y a n d 
I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d (s e e  
S e cti o n 3. 1 ).   
S u bj e ct s w h o d o n ot r e c ei v e o p e n -l a b el d e n o s u m a b will b e f oll o w e d f or D F S, B M F S, a n d 
O S o n c e a y e ar ( Q 1 2 M st u d y vi sit) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s u ntil 
a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D .  A d diti o n all y, f urt h er d at a will b e a s s e s s e d ( s e e  
S e cti o n 3. 1 ). 
S u bj e ct s w h o r e c ei v e o p e n -l a b el d e n o s u m a b will h a v e Q 6 M o n - sit e vi sit s f or 
a d mi ni str ati o n of d e n o s u m a b  ( 6 0 m g S C Q 6M)  a n d m o nit ori n g of S A E s a n d ( S) A E s of 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
s p e ci al i nt er e st a n d will b e f oll o w e d Q 1 2 M f or D F S, B M F S, a n d O S u ntil eit h er 
a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D or c o m pl eti o n of tr e at m e nt, w hi c h e v er i s l o n g er.   
A d diti o n all y, f urt h er d at a will b e a s s e s s e d ( s e e S e cti o n 3. 1 ). 
3. 4. 4   
E n d of O p e n-la b el Tr e at m e nt 
T h e e n d of o p e n -la b el tr e at m e nt i s d efi n e d f or e a c h s u bj e ct a s t h e p oi nt i n ti m e t h e l a st 
d o s e of d e n o s u m a b i s a d mi ni st er e d. 
3. 4. 5   
E n d of St u dy ( D o u bl e-bli n d P h a s e a n d E n d of Z A S u b st u d y) 
T h e e n d of t h e st u d y will o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit 
or l a st f or m al c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e 
st u d y.  T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h e Z A s u b st u d y.  
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w-u p , c o n s e nt 
wit h dr a w al) a n d p er pr ot o c ol E O S. 
At E n d of S t u d y, t h e e n d of st u d y  C R F h a s t o b e c o m pl et e d f or e a c h s u bj e ct. 
4.  
S U B J E C T E LI GI BI LI T Y 
I n v e sti g at or s will b e e x p e ct e d t o m ai nt ai n a s cr e e ni n g l o g of all p ot e nti al st u d y 
c a n di d at e s t h at i n cl u d e s li mit e d i nf or m ati o n a b o ut t h e p ot e nti al c a n di d at e ( a g e), d at e, 
a n d o ut c o m e of t h e s cr e e ni n g pr o c e s s ( e g,  e nr oll e d i nt o st u d y, r e a s o n f or i n eli gi bilit y, or 
r ef u s e d t o p arti ci p at e). 
4. 1  
I n cl u si o n Crit eri a f or D o u bl e- bli n d P h a s e 
4. 1. 1  
Hi st ol o gi c all y or c yt ol o gi c all y c o nfir m e d a d e n o c ar ci n o m a of t h e br e a st  
4. 1. 2  
F e m al e s u bj e ct s wit h n o n- m et a st ati c di s e a s e w h o ar e E R a n d/ or P g R p o siti v e, 
a n d w h o h a v e c o m pl et e d t h eir tr e at m e nt p at h w a y ( s ur g er y, c h e m ot h er a p y)  
4. 1. 3  S u bj e ct s w h o ar e c urr e ntl y o n, or will i niti at e a n a p pr o v e d n o n- st er oi d al 
ar o m at a s e i n hi bit or t h er a p y ( e g, a n a str a z ol e) i n t h e a dj u v a nt s etti n g  
4. 1. 4  
P o st m e n o p a u s al w o m a n1 ,2 , d efi n e d a s a w o m a n f ulfilli n g a n y o n e of t h e f oll o wi n g 
crit eri a: 
 
H a vi n g u n d er g o n e a bil at er al o o p h or e ct o m y;  
 
A g e  6 0 y e ar s;  
 
A g e d < 6 0 y e ar s m e eti n g t h e f oll o wi n g r e q uir e m e nt s:  
                                                
1   F or s u bj e ct s pr e vi o u sl y tr e at e d wit h a l ut ei ni zi n g h or m o n e-r el e a si n g h or m o n e a nt a g o ni st, t h e l a st d o s e 
m u st h a v e b e e n 4 m o nt h s pri or t o r a n d o mi z ati o n, a n d F S H a n d e str a di ol m u st b e i n t h e p o st m e n o p a u s al 
r a n g e. 
2   S u bj e ct s w h o h a v e r e c ei v e d a dj u v a nt or n e o a dj u v a nt c h e m ot h er a p y m u st h a v e m et 1 of t h e a b o v e crit eri a 
f or p o st m e n o p a u s al st at u s pri or t o t h at c h e m ot h er a p y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
F olli cl e- sti m ul ati n g h or m o n e ( F S H) a n d e str a di ol i n t h e p o st m e n o p a u s al 
r a n g e;  
 
A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n. S u bj e ct s 
w h o h a v e u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st.  
4. 1. 5  
E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) p erf or m a n c e s c or e of 0 or 1  
( s e e A p p e n di x E ) 
4. 1. 6  
B ef or e a n y st u d y- s p e cifi c pr o c e d ur e i s p erf or m e d, a si g n e d a n d d at e d writt e n 
i nf or m e d c o n s e nt m u st b e o bt ai n e d ( s e e S e cti o n 1 2. 1 )  
4. 2   
E x cl u si o n Crit eri a f or D o u bl e- bli n d P h a s e 
4. 2. 1  
Ar o m at a s e i n hi bit or t h er a p y f or m or e t h a n 2 4 m o nt h s 
4. 2. 2  
Pri or or c o n c urr e nt tr e at m e nt wit h S el e cti v e E str o g e n R e c e pt or M o d ul at or s 
( S E R M s) ( e g, t a m o xif e n) 
4. 2. 3  
E vi d e n c e of m et a st ati c di s e a s e 
4. 2. 4  
C urr e nt or pri or I V bi s p h o s p h o n at e a d mi ni str ati o n 
4. 2. 5  
Or al bi s p h o s p h o n at e tr e at m e nt: 
 
Gr e at er t h a n or e q u al t o 3 y e ar s c o nti n u o u sl y 
 
Gr e at er t h a n 3 m o nt h s b ut l e s s t h a n 3 y e ar s u nl e s s s u bj e ct h a s h a d a 
w a s h o ut p eri o d of at l e a st 1 y e ar pri or t o r a n d o mi z ati o n 
 
A n y u s e d uri n g t h e 3- m o nt h p eri o d pri or t o r a n d o mi z ati o n 
4. 2. 6  
Pri or a d mi ni str ati o n of d e n o s u m a b ( A M G 1 6 2)  
4. 2. 7  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d i n di c at e d b y 
t h e f oll o wi n g crit eri a: 
 
A s p art at e  a mi n otr a n sf er a s e ≥ 2. 5 x u p p er li mit of n or m al ( U L N) 
 
Al a ni n e tr a n s a mi n a s e ≥ 2. 5 x U L N  
 
S er u m cr e ati ni n e ≥ 2 x U L N 
4. 2. 8  
R e c urr e n c e of t h e pri m ar y m ali g n a n c y ( eg,  d uri n g t h e all o w e d i nt er v al of 
pr etr e at m e nt wit h AI) 
4. 2. 9  
Di a g n o si s of a n y s e c o n d n o n- br e a st m ali g n a n c y wit hi n t h e l a st 5 y e ar s, e x c e pt 
f or a d e q u at el y tr e at e d b a s al c ell or s q u a m o u s c ell s ki n c a n c er, or f or i n sit u 
c ar ci n o m a of t h e c er vi x ut eri 
4. 2. 1 0  K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf r e p ort or 
c h art r e vi e w 
 
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a or ot h er 
a cti v e m et a b oli c b o n e di s e a s e  
 
H y p er c al c e mi a or h y p o c al c e mi a: a s d efi n e d b y c al ci u m o ut si d e t h e n or m al 
r a n g e ( A si n gl e v al u e o ut si d e t h e n or m al r a n g e d o e s n ot n e c e s s aril y 
c o n stit ut e h y p er c al c e mi a or h y p o c al c e mi a, b ut s h o ul d b e ‘ c orr e ct e d’ b ef or e 
i n cl u di n g t h e s u bj e ct.  S u bj e ct s wit h a k n o w n hi st or y of h y p er c al c e mi a or 
h y p o c al c e mi a c a n n ot b e i n cl u d e d) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s pri or t o 
r a n d o mi z ati o n 
 
K n o w n h u m a n i m m u n o d efi ci e n c y vir u s i nf e cti o n 
 
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s  
4. 2. 1 1  A n y m aj or m e di c al or p s y c hi atri c di s or d er t h at, i n t h e o pi ni o n of t h e i n v e sti g at or, 
mi g ht pr e v e nt t h e s u bj e ct fr o m c o m pl eti n g t h e st u d y or i nt erf er e wit h t h e 
i nt er pr et ati o n of t h e st u d y r e s ult s 
4. 2. 1 2  T hirt y d a y s or l e s s si n c e r e c ei vi n g a n i n v e sti g ati o n al pr o d u ct or d e vi c e i n a n ot h er 
cli ni c al st u d y 
4. 2. 1 3  K n o w n s e n siti vit y t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d d uri n g t h e st u d y 
( e g, m a m m ali a n d eri v e d pr o d u ct s, c al ci u m or vit a mi n D) 
4. 2. 1 4  S u bj e ct s w h o ar e pr e g n a nt, br e a stf e e di n g, or pl a n t o b e c o m e pr e g n a nt d uri n g 
t h e c o ur s e of t h e st u d y.  All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a 
n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s b ef or e r a n d o mi z ati o n 
4. 2. 1 5  A n y ki n d of di s or d er t h at c o m pr o mi s e s t h e a bilit y t o gi v e writt e n i nf or m e d c o n s e nt 
a n d/ or c o m pl y wit h st u d y pr o c e d ur e s 
4. 3  
I n cl u si o n Crit eri a t o R e c ei v e O p e n- l a b el P h a s e D e n o s u m a b  
4. 3. 1  
O bt ai n si g n e d a n d d at e d writt e n i nf or m e d c o n s e nt pri or t o p erf or mi n g a n y 
s t u d y- s p e cifi c pr o c e d ur e ( se e S e cti o n 1 2. 1 ) 
4. 3. 2  
S u bj e ct s c urr e ntl y t a ki n g a n a p pr o v e d n o n - st er oi d al AI T ( e g, a n a str a z ol e) or wh o  
h a v e c o m pl et e d or di s c o nti n u e d AI T wit hi n 1 2 m o nt h s  pri or t o p arti ci p ati o n i n t h e 
O L P   
4. 3. 3  
R a n d o mi z e d t o pl a c e b o ar m d uri n g t h e d o u bl e - bli n d p h a s e ( a s d et er mi n e d b y 
u n bli n di n g pr o c e d ur e s) 
4. 4   
E x cl u si o n Crit eri a t o R e c ei v e O p e n- l a b el P h a s e  De n o s u m a b  
4. 4. 1  
C urr e nt or pri or I V bi s p h o s p h o n at e a d mi ni str ati o n  
4. 4. 2  
S u bj e ct s me eti n g t h e f oll o wi n g crit eri a f or or al bi s p h o s p h o n at e tr e at m e nt: 
  
Gr e at er t h a n or e q u al t o 3 y e ar s c o nti n u o u sl y 
  
Gr e at er t h a n 3 m o nt h s b ut l e s s t h a n 3 y e ar s u nl e s s s u bj e ct h a s h a d a 
w a s h o ut p eri o d of at l e a st 1 y e ar pri or t o p arti ci p ati o n i n t h e O L P 
  
A n y u s e d uri n g t h e 3- m o nt h p eri o d pri or t o p arti ci p ati o n i n t h e O L P 
4. 4. 3  
Pri or or c o n c urr e nt tr e at m e nt wit h S E R M s ( e g, t a m o xif e n) 
4. 4. 4  
S u bj e ct s wh o  en d e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct (I P) pr e m at ur el y i n t h e 
d o u bl e - bli n d p h a s e  
4. 4. 5  
Tr e at m e nt wit h c o m m er ci al d e n o s u m a b ( Pr oli a or X g e v a) pri or t o p arti ci p ati o n 
i n t h e O L P 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
5.  
S U B J E C T E N R O L L M E N T 
B ef or e s u bj e ct s m a y b e e nt er e d i nt o t h e st u d y, A B C S G a n d A m g e n r e q uir e a c o p y of t h e 
writt e n I n d e p e n d e nt Et hi c s C o m mitt e e  (I E C) a p pr o v al of t h e pr ot o c ol, i nf or m e d c o n s e nt 
f or m (I C F), a n d all ot h er s u bj e ct i nf or m ati o n a n d/ or r e cr uit m e nt m at eri al, if a p pli c a bl e 
( s e e S e cti o n 1 2. 3 ).  All s u bj e ct s or l e g all y a c c e pt a bl e r e pr e s e nt ati v e s m u st p er s o n all y 
si g n a n d d at e t h e c o n s e nt f or m b ef or e e nr oll m e nt. 
T h e e nr oll m e nt d at e i s d efi n e d a s t h e d at e t h e s u bj e ct i s r a n d o mi z e d ( i e, t h e d at e t h e 
sit e c all s t h e i nt er a cti v e v oi c e r e s p o n s e s y st e m (I V R S) t o c o m pl et e t h e r a n d o mi z ati o n 
pr o c e s s).  
5. 1   
S cr e e ni n g 
All s u bj e ct s w h o e nt er i nt o t h e s cr e e ni n g p eri o d f or t h e st u d y ( d efi n e d a s t h e p oi nt at 
w hi c h t h e s u bj e ct si g n s t h e i nf or m e d c o n s e nt) will r e c ei v e a u ni q u e 9- di git s u bj e ct 
i d e ntifi c ati o n n u m b er b ef or e a n y st u d y pr o c e d ur e s ar e p erf or m e d.  T h e s u bj e ct 
i d e ntifi c ati o n n u m b er will b e pr o vi d e d b y t h e I V R S.  T hi s n u m b er will b e u s e d t o i d e ntif y 
t h e s u bj e ct t hr o u g h o ut t h e cli ni c al st u d y a n d m u st b e u s e d o n all st u d y d o c u m e nt ati o n 
r el at e d t o t h at s u bj e ct.  T h e s u bj e ct i d e ntifi c ati o n n u m b er m u st r e m ai n c o n st a nt 
t hr o u g h o ut t h e e ntir e cli ni c al st u dy; it m u st n ot b e c h a n g e d at t h e ti m e of r e s cr e e ni n g, 
e nr oll m e nt, or r a n d o mi z ati o n.  T hi s n u m b er will n ot n e c e s s aril y b e t h e s a m e a s t h e 
r a n d o mi z ati o n n u m b er a s si g n e d f or t h e st u d y. 
T h e s u bj e ct i d e ntifi c ati o n n u m b er will c o n si st of 9 di git s.  T h e fir st 3 di git s will r e pr e s e nt a 
pr ot o c ol i d e ntifi er (i e,  0 1 8) a n d will b e i d e nti c al f or all sit e s.  T h e n e xt 3 di git s will 
r e pr e s e nt t h e sit e n u m b er ( eg,  0 0 1, 0 0 2, 0 0 3) a n d will b e i d e nti c al f or all s u bj e ct s at a 
p arti c ul ar sit e.  T h e l a st 3 di git s will r e pr e s e nt t h e s u bj e ct i d e ntifi c ati o n a n d will b e 
a s si g n e d i n s e q u e nti al or d er, p er sit e, a s s u bj e ct s ar e s cr e e n e d ( e g,  0 0 1, 0 0 2, 0 0 3).  
T h er ef or e, t h e fir st s u bj e ct t o e nt er s cr e e ni n g at sit e 0 0 1 will r e c ei v e t h e n u m b er 
; t h e s e c o n d s u bj e ct at t hi s sit e will r e c ei v e t h e n u m b er 
, et c.  T hi s 
n u m b er will n ot b e t h e s a m e a s t h e r a n d o mi z ati o n n u m b er a s si g n e d f or t h e st u d y. 
R ef er t o S e cti o n 7  a n d  A p p e n di x A  f or s cr e e ni n g pr o c e d ur e s a n d m e di c al hi st or y d et ail s.  
S u bj e ct s m a y b e r e- s cr e e n e d 1 ti m e.  If a s u bj e ct f ail s t o m e et all e ntr y crit eri a aft er 
2 att e m pt s, t h e s u bj e ct will n ot b e e nr oll e d i nt o t h e st u d y.  
5. 2   
Tr e at m e nt A s si g n m e nt ( Bli n d e d Tr e at m e nt P h a s e) 
A s u bj e ct w h o gi v e s writt e n i nf or m e d c o n s e nt a n d w h o s ati sfi e s all t h e i n cl u si o n a n d 
e x cl u si o n crit eri a m a y b e r a n d o mi z e d i nt o t h e st u d y.  Q u e sti o n s r e g ar di n g s u bj e ct 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
eli gi bilit y s h o ul d b e di s c u s s e d ( a n d d o c u m e nt e d) wit h A m g e n or t h e A B C S G pr oj e ct 
m a n a g er b ef or e r a n d o mi z ati o n.   
A s u bj e ct will b e r a n d o mi z e d t o r e c ei v e eit h er d e n o s u m a b or pl a c e b o b y c alli n g t h e I V R S 
aft er c o m pl eti o n of all s cr e e ni n g a s s e s s m e nt s a n d m e eti n g all eli gi bilit y crit eri a .  
A d mi ni str ati o n of I P m u st o c c ur wit hi n 8 d a y s aft er r a n d o mi z ati o n.  
O n c e a s u bj e ct i s r e a d y f or h er i niti al or o n- st u d y s c h e d ul e d d o s e, t h e sit e p er s o n n el will 
c all t h e I V R S v e n d or t o o bt ai n a b o x n u m b er a s si g n m e nt.  T h e b o x n u m b er will b e 
u ni q u e t o e a c h s u bj e ct a n d m u st b e r e c or d e d i n t h e C R F a n d i n t h e a c c o u nt a b ilit y 
r e c or d s.  Pl e a s e r ef er t o s p e cifi c i n str u cti o n s pr o vi d e d b y t h e I V R S v e n d or f or a d diti o n al 
i nf or m ati o n. 
5. 3   
R a n d o mi z ati o n 
A s u bj e ct will b e a s si g n e d b y a n I V R S t o 1 of 2 tr e at m e nt gr o u p s ( d e n o s u m a b or 
pl a c e b o), i n a 1: 1 r ati o, wit h t h e a s si g n m e nt b al a n c e d wit h r e s p e ct t o str atifi c ati o n f a ct or s 
at t h e ti m e of st u d y e ntr y.  T h e r a n d o mi z ati o n s c h e d ul e will u s e r a n d o ml y p er m ut e d 
bl o c k s, a n d will b e str atifi e d b y t y p e of h o s pit al ( m aj or a c a d e mi c c e nt er s or ot h er 
c e nt er s), pri or AI u s a g e ( Y e s or N o) a n d t ot al l u m b ar s pi n e B M D s c or e at b a s eli n e 
( T- s c or e < - 1. 0 or  - 1. 0).  A s u bj e ct will b e c o n si d er e d r a n d o mi z e d o n c e a 
r a n d o mi z ati o n n u m b er i s a s si g n e d.  A s u bj e ct m a y o nl y b e r a n d o mi z e d o n c e a n d e a c h 
r a n d o mi z ati o n n u m b er m a y o nl y b e a s si g n e d t o 1 s u bj e ct.  T h e r a n d o mi z ati o n li st will b e 
g e n er at e d a n d m ai nt ai n e d b y a n A m g e n r e pr e s e nt ati v e n ot i n v ol v e d i n t h e c o n d u ct of 
t h e st u d y. 
T h e r a n d o mi z e d a s si g n m e nt f or i n v e sti g ati o n al pr o d u ct will r e m ai n bli n d e d t o t h e 
s u bj e ct, c e nt er p er s o n n el, a n d all A m g e n/ A B C S G st u d y p er s o n n el a n d d e si g n e e s 
i n v ol v e d wit h t h e c o n d u ct of t h e st u d y, wit h t h e e x c e pti o n of t h o s e cir c u m st a n c e s w h er e 
t h e i n v e sti g at or d e e m s it n e c e s s ar y t o br e a k t h e bli n d i n or d er t o pr o vi d e a p pr o pri at e 
m e di c al tr e at m e nt f or t h e s u bj e ct.  R ef er t o S e cti o n 1 0. 4  f or d et ail s o n w h e n a n d h o w t h e 
r a n d o mi z ati o n c o d e m a y b e br o k e n. 
5. 4   
O p e n-l a b el P h a s e 
T h e o p p ort u nit y t o st art o p e n -l a b el d e n o s u m a b will b e o p e n f or 1 2 m o nt h s f oll o wi n g 
Pr ot o c ol A m e n d m e nt  4 r e g ul at or y a n d I R B/I E C a p pr o v al.  
Aft er si g ni n g of t h e I C F, u n bli n di n g of s u bj e ct s c o n si d er e d eli gi bl e f or tr e at m e nt wit h 
d e n o s u m a b c a n o c c ur.  T h e fir st d o s e of d e n o s u m a b m u st b e a d mi ni st er e d wit hi n 8 d a y s 
of u n bli n di n g .  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
5. 5   
U n bli n di n g Pr o c e d ur e s 
U n bli n di n g of willi n g s u bj e ct s t h o u g ht t o b e eli gi bl e t o r e c ei v e d e n o s u m a b i n t h e O L P will 
b e d o n e b y a ut h ori z e d sit e p er s o n n el u si n g t h e u n bli n di n g ( c o d e br e a k) c all wit h t h e 
I V R S c all c e nt er. 
6.  
T R E A T M E N T P R O C E D U R E S 
D e n o s u m a b a n d pl a c e b o will b e c o n si d er e d t h e o nl y i n v e sti g ati o n al pr o d u ct s i n t hi s 
st u d y.  It i s hi g hl y r e c o m m e n d e d t h at all s u bj e ct s r e c ei v e d ail y c al ci u m a n d vit a mi n D.  
T h e s e m e di c ati o n s will b e r ef err e d t o a s s u p pl e m e nt s. 
6. 1   
Bli n d e d Tr e at m e nt P ha s e  
6. 1. 1  
I n v e sti g ati o n al Pr o d u ct D o s a g e, A d mi ni str ati o n, a n d S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e 6 0 m g of d e n o s u m a b or pl a c e b o e v er y 
6 m o nt h s.  S u bj e ct s will r e m ai n o n st u d y tr e at m e nt u ntil t h e r e q uir e d n u m b er of e v e nt s i s 
r e a c h e d a n d u ntil  t h e y h a v e h a d t h e o p p ort u nit y t o r e c ei v e a mi ni m u m of at 
l e a st 2 d o s e s of I P, w hi c h e v er o c c ur s l at er.  D e n o s u m a b a n d pl a c e b o will b e 
a d mi ni st er e d a s a S C i nj e cti o n.  
All d o s e s s h o ul d b e a d mi ni st er e d b y a li c e n s e d h e alt h c ar e pr of e s si o n al aft er all ot h er 
st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d.  T h e fir st d o s e of i n v e sti g ati o n al pr o d u ct 
m u st b e a d mi ni st er e d wit hi n 8 d a y s aft er r a n d o mi z ati o n.  
T h er e h a v e b e e n n o r e p ort s of o v er d o s e wit h t hi s pr o d u ct.  It i s p o s si bl e t h at a n 
o v er d o s e m a y r e s ult i n h y p o c al c e mi a.   H y p o c al c e mi a, if s e v er e, s h o ul d b e m a n a g e d b y 
or al or p ar e nt al c al ci u m r e pl a c e m e nt, a s cli ni c all y i n di c at e d.   
R ef er t o t h e p h ar m a c y g ui d e ( A p p e n di x C ) f or d et ail e d i nf or m ati o n o n t h e a d mi ni str ati o n 
of d e n o s u m a b.   
6. 1. 2   
Mi s s e d D o s e 
If a s u bj e ct mi s s e s a s c h e d ul e d S C i nj e cti o n, t h e n t h e y s h o ul d r et ur n t o t h e cli ni c a s 
s o o n a s p o s si bl e f or i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n ( pr ef er a bl y n o l at er t h a n 
4 5  d a y s aft er t h eir s c h e d ul e d d o s e).  If m or e t h a n 4 5 d a y s h a v e el a p s e d si n c e t h e 
s c h e d ul e d I P d o s e, t h e I P d o s e will b e c o n si d er e d a mi s s e d d o s e.  T h e n e xt d o s e i s t o 
b e gi v e n o n t h e n e xt s c h e d ul e d vi sit d at e ( b a s e d o n st u d y d a y 1).  
6. 1. 3   
D o s e E s c al ati o n a n d St o p pi n g R ul e s 
T h er e ar e n o pl a n n e d d o s e e s c al ati o n s i n t hi s st u d y.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
A d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct will b e wit h h el d f or a n y s u bj e ct w h o e x p eri e n c e s 
a gr a d e 3 or 4 a d v er s e e v e nt (r ef er t o C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s 
[ C T C A E] V er si o n 3. 0; s e e A p p e n di x B  f or li n k) r e p ort e d b y t h e i n v e sti g at or t o b e r el at e d 
t o i n v e sti g ati o n al pr o d u ct.  R e- e x p o s ur e t o i n v e sti gati o n al pr o d u ct m a y o c c ur o nl y w h e n 
t h e e v e nt r e s ol v e s t o gr a d e 1 or b ett er a n d if t h e i n v e sti g at or a n d s p o n s or a gr e e s u bj e ct 
s af et y will n ot b e c o m pr o mi s e d. 
S u bj e ct s will c o nti n u e t o r e c ei v e i n v e sti g ati o n al pr o d u ct u ntil o n e of t h e f oll o wi n g o c c ur s:  
t h e P A D C D d at e i s r e a c h e d ( s e e Gl o s s ar y ), t h e i n v e sti g at or or A m g e n r e c o m m e n d s 
di s c o nti n u ati o n, t h e s u bj e ct d e ci d e s t o di s c o nti n u e f or a n y r e a s o n, or t h e s u bj e ct 
d e v el o p s m et a st a s e s.  F or a d et ail e d li st of E O T r e a s o n s s e e S e cti o n 8 .  A S c h e m a  i n 
t h e pr ot o c ol s y n o p si s d e s cri b e s t h e d o si n g s c h e d ul e. 
6. 1. 4   
D o s a g e A dj u st m e nt s 
T h er e will b e n o d o s e a dj u st m e nt s of t h e i n v e sti g ati o n al pr o d u ct i n t hi s st u d y. 
6. 1. 5   
S u p pl e m e nt s 
It i s hi g hl y r e c o m m e n d e d t h at all s u bj e ct s r e c ei v e d ail y s u p pl e m e nt s of at l e a st 5 0 0 m g 
of el e m e nt al c al ci u m a n d at l e a st 4 0 0 I U vit a mi n D t hr o u g h o ut i n v e sti g ati o n al pr o d u ct 
a d mi ni str ati o n.  C al ci u m a n d vit a mi n D d o s a g e s m a y v ar y d u e t o diff er e n c e s i n 
a v ail a bilit y.  ( C al citri ol i s n ot all o w e d – s e e S e cti o n 6. 1. 7 ). 
S u p pl e m e nt s will b e r e c or d e d o n a C R F. 
6. 1. 6   
C o n c o mit a nt T h er a p y 
6. 1. 6. 1   
Bli n d e d Tr e at m e nt Ph a s e  C o n c o mit a nt T h er a p y 
T hr o u g h o ut t h e st u d y, i n v e sti g at or s m a y pr e s cri b e a n y c o n c o mit a nt m e di c ati o n s or 
tr e at m e nt s d e e m e d n e c e s s ar y t o pr o vi d e a d e q u at e s u p p orti v e c ar e e x c e pt f or t h o s e 
li st e d i n S e cti o n 6. 1. 7 .  All c o n c o mit a nt m e di c ati o n s, i n cl u di n g o v er-t h e- c o u nt er pr o d u ct s, 
a d mi ni st er e d fr o m e nr ol m e nt t hr o u g h 3 0 d a y s aft er t h e l a st d o s e of i n v e sti g ati o n al 
pr o d u ct, m u st b e r e c or d e d i n t h e C R F.  I n a d diti o n, t h e d o s e a d mi ni st er e d will b e 
r e c or d e d i n t h e C R F f or vit a mi n D s u p pl e m e nt s, c al ci u m s u p pl e m e nt s, a n d ar o m at a s e 
i n hi bit or t h er a p y.  
6. 1. 6. 2   
O p e n-l a b el C o n c o mit a nt T h er a p y/ L o n g-t er m F oll o w u p 
T hr o u g h o ut t h e  O L P, i n v e sti g at or s m a y pr e s cri b e a n y c o n c o mit a nt m e di c ati o n s or 
tr e at m e nt s d e e m e d n e c e s s ar y t o pr o vi d e a d e q u at e s u p p orti v e c ar e e x c e pt f or t h o s e 
li st e d i n S e cti o n 6. 2. 5 .  C o n c o mit a nt t h er a pi e s b ei n g t a k e n f or t h e di s e a s e u n d er st u d y 
( e g, c h e m ot h er a p y, e n d o cri n e t h er a p y) a n d b o n e aff e cti n g m e di c ati o n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
( e g, bi s p h o s p h o n at e s, gl u c o c orti c oi d s, a nti e pil e pti c dr u g s, a nti d e pr e s s a nt s, a n d i n s uli n ) 
will b e r e c or d e d i n t h e C R F t hr o u g h t h e e n d of t h e st u d y f or all s u bj e ct s .   
I n a d diti o n, c o nfir m ati o n of w h et h er a s u bj e ct i s t a ki n g c al ci u m a n d vit a mi n D 
s u p pl e m e nt s will b e r e c or d e d i n t h e C R F. 
6. 1. 7   
Pr o hi bit e d T h er a p y D uri n g Bli n d e d P h a s e 
Bi s p h o s p h o n at e s (I V or o v er 3 0 d a y s or al) or c o m m er ci all y a v ail a bl e d e n o s u m a b (i e, 
X G E V A  or Pr oli a) ar e n ot t o b e a d mi ni st er e d d uri n g t h e tr e at m e nt p h a s e.  S u bj e ct s 
w h o b e gi n a bi s p h o s p h o n at e r e gi m e n (I V or o v er 3 0 d a y s or al) or c o m m er ci all y a v ail a bl e 
d e n o s u m a b d uri n g t h e tr e at m e nt p h a s e will b e wit h dr a w n fr o m i n v e sti g ati o n al pr o d u ct 
( e arl y E O T).   
T h e f oll o wi n g m e di c ati o n s s h o ul d n ot b e a d mi ni st er e d d uri n g t h e tr e at m e nt p h a s e : 
fl u ori d e (f or o st e o p or o si s), str o nti u m r a n el at e, s y st e mi c e str o g e n, s el e cti v e e str o g e n 
r e c e pt or m o d ul at or s ( eg,  r al o xif e n e), ti b ol o n e, c al cit o ni n, a n a b oli c st er oi d s, p ar at h yr oi d 
h or m o n e ( or a d eri v ati v e), c al citri ol, t a m o xif e n a n d a n y ot h er m e di c ati o n t h at i s k n o w n or 
s u s p e ct e d t o h a v e a cti vit y o n b o n e m et a b oli s m ( e x c e pt c al ci u m a n d vit a mi n D).   
U s e of a n y ot h er i n v e sti g ati o n al pr o d u ct i s n ot p er mitt e d u ntil P A D C D . 
6. 2   
O p e n-l a b el P h a s e 
Willi n g a n d  eli gi bl e su bj e ct s will r e c ei v e d e n o s u m a b 6 0 m g Q 6 M S C f or u p t o 3 6  m o nt h s 
( m a xi m u m of 7 d o s e s).    
S u bj e ct s will r e m ai n o n d e n o s u m a b 6 0 m g Q 6 M u ntil t h e y c o m pl et e 3 6 m o nt h s ( 7 d o s e s) 
of tr e at m e nt , t h e i n v e sti g at or or A m g e n r e c o m m e n d s di s c o nti n u ati o n, or t h e s u bj e ct 
d e ci d e s t o di s c o nti n u e f or a n y r e a s o n ( s e e S e cti o n 8. 1 ).  S e e al s o D e n o s u m a b D o s a g e, 
A d mi ni str ati o n, a n d S c h e d ul e. 
All d o s e s s h o ul d b e a d mi ni st er e d b y a li c e n s e d h e alt h c ar e pr of e s si o n al.   
T h er e h a v e b e e n n o r e p ort s of o v er d o s e wit h t hi s pr o d u ct.  It i s p o s si bl e t h at a n 
o v er d o s e m a y r e s ult i n h y p o c al c e mi a.  H y p o c al c e mi a, if s e v er e, s h o ul d b e m a n a g e d b y 
or al or p ar e nt er al c al ci u m r e pl a c e m e nt, a s cli ni c all y i n di c at e d.   
R ef er t o t h e p h ar m a c y g ui d e ( A p p e n di x C ) f or d et ail e d i nf or m ati o n o n t h e a d mi ni str ati o n 
of d e n o s u m a b.   
6. 2. 1   
Mi s s e d D o s e D uri n g O L P 
Pl e a s e s e e S e cti o n 6. 1. 2  f or g ui d a n c e o n mi s s e d d o s e s. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
6. 2. 2   
D o s e E s c al ati o n a n d St o p pi n g R ul e s 
Pl e a s e s e e S e cti o n 6. 1. 3  f or g ui d a n c e o n d o s e e s c al ati o n a n d st o p pi n g r ul e s. 
6. 2. 3   
D o s a g e A dj u st m e nt s 
T h er e will b e n o d o s e a dj u st m e nt s of d e n o s u m a b. 
6. 2. 4   
S u p pl e m e nt s 
Pl e a s e s e e S e cti o n 6. 1. 5 . 
6. 2. 5   
Pr o hi bit e d T h er a p y D uri n g O p e n-l a b el Ph a s e  
F or s u bj e ct s r e c ei vi n g d e n o s u m a b i n t h e O L P, b i s p h o s p h o n at e s (I V or o v er 3 0 d a y s 
or al) ar e n ot t o b e a d mi ni st er e d d uri n g t h e tr e at m e nt p h a s e.  S u bj e ct s w h o b e gi n a 
bi s p h o s p h o n at e r e gi m e n (I V or o v er 3 0 d a y s or al) d uri n g t h e tr e at m e nt p h a s e will b e 
wit h dr a w n fr o m d e n o s u m a b.   
F or a d diti o n al i nf or m ati o n, r ef er t o t h e P R O LI A  pr e s cri bi n g i nf or m ati o n. 
7.  
S T U D Y P R O C E D U R E S 
St u d y a s s e s s m e nt s will b e p erf or m e d o nl y aft er writt e n i nf or m e d c o n s e nt i s o bt ai n e d.  
T h e s c h e d ul e of a s s e s s m e nt s i s pr o vi d e d i n A p p e n di x A . 
7. 1   
S cr e e ni n g Vi sit 
Wit h t h e f oll o wi n g e x c e pti o n s, a ll s cr e e ni n g pr o c e d ur e s m u st b e c o m pl et e d  3 5  d a y s 
b ef or e t h e d a y of r a n d o mi z ati o n.  
F or eli gi bilit y p ur p o s e s, all s u bj e ct s m u st h a v e a b o n e s c a n t h at h a s b e e n p erf or m e d 
wit hi n 6 m o nt h s of r a n d o mi z ati o n .   
D X A a n d X-r a y s s h o ul d i d e all y b e p erf or m e d wit hi n t h e 3 5 d a y s cr e e ni n g wi n d o w .  
H o w e v er, if n e c e s s ar y, D X A a n d/ or X-r a y a s s e s s m e nt s m u st h a v e b e e n p erf or m e d 
wit hi n 1 2 0  d a y s of r a n d o mi z ati o n. 
7. 2   
St u d y D a y 1 
E nr oll m e nt d at e i s d efi n e d a s t h e d at e of r a n d o mi z ati o n.  St u d y d a y 1 i s d efi n e d a s t h e 
d a y t h at t h e i niti al d o s e of i n v e sti g ati o n al pr o d u ct i s a d mi ni st er e d t o t h e s u bj e ct.  T h e 
i niti al d o s e of i n v e sti g ati o n al pr o d u ct will b e a d mi ni st er e d wit hi n 8 d a y s aft er 
r a n d o mi z ati o n.  
7. 3   
Tr e at m ent P h a s e Vi sit s 
Tr e at m e nt p h a s e vi sit s will o c c ur e v er y 6 m o nt h s (  4 5 d a y s) fr o m st u d y d a y 1. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
If a s u bj e ct’ s vi sit i s d el a y e d, t h eir s u b s e q u e nt vi sit d at e s h o ul d n ot b e s hift e d, b ut r e v ert 
b a c k t o t h e ori gi n al s c h e d ul e. 
7. 4   
M e di c al Hi st or y 
T h e s u bj e ct’ s m e di c al hi st or y will b e o bt ai n e d pri or t o e nr oll m e nt a n d r e c or d e d o n t h e 
C R F.  D et ail e d hi st or y of t h e s u bj e ct’ s br e a st c a n c er will b e o bt ai n e d.   
7. 5   
M e di c ati o n Hi st or y 
I nf or m ati o n o n all m e di c ati o n s, s ur gi c al pr o c e d ur e s, a n d r a di ot h er a p y, 
i n cl u di n g i ntr a- o p er ati v e r a di ot h er a p y, s p e cifi c all y u s e d t o tr e at t h e s u bj e ct’ s c a n c er pri or 
t o st u d y d a y 1 will b e r e c or d e d o n t h e C R F .   
I n a d diti o n, i nf or m ati o n o n all k n o w n pr e vi o u s bi s p h o s p h o n at e u s e will b e r e c or d e d o n 
t h e C R F .  
7. 6   
P h y si c al E x a mi n ati o n 
E a c h p h y si c al e x a mi n ati o n vi sit will i n cl u d e a s s e s s m e nt of E C O G p erf or m a n c e st at u s, 
h ei g ht ( d uri n g s cr e e ni n g o nl y), w ei g ht, a n d vit al si g n s (t e m p er at ur e, p ul s e , a n d bl o o d 
pr e s s ur e).  R ef er t o A p p e n di x E  f or E C O G p erf or m a n c e st at u s crit eri a.  R e s ult s fr o m a 
p h y si c al e x a mi n ati o n p erf or m e d a s st a n d ar d of c ar e wit hi n t h e 3 0- d a y p eri o d pri or t o 
si g ni n g t h e I C F m a y b e u s e d a s s cr e e ni n g d at a f or t hi s st u d y. 
7. 7   
Cli ni c al Fr a ct ur e A ss e s s m e nt  
At e a c h st u d y vi sit t h e i n v e sti g at or will a s s e s s if t h e s u bj e ct h a s a n y r el e v a nt s y m pt o m s 
of cli ni c al fr a ct ur e s.  If n e w s y m pt o m s ar e r e p ort e d, t h e i n v e sti g at or will u s e cli ni c al 
j u d g m e nt t o d et er mi n e if t h e s e s y m pt o m s w arr a nt f urt h er i n v e sti g ati o n a n d w h et h er a 
di a g n o sti c x-r a y s h o ul d b e p erf or m e d.  All cli ni c al fr a ct ur e s, e x c e pt t h o s e of t h e s k ull, 
f a c e, fi n g er s, a n d t o e s, w hi c h ar e t y pi c all y n ot a s s o ci at e d wit h o st e o p or o si s, will b e 
i n cl u d e d i n t h e a n al y si s of cli ni c al fr a ct ur e s. 
A q u alifi e d m e m b er of t h e st u d y sit e will c o nt a ct t h e s u bj e ct vi a t el e p h o n e a p pr o xi m at el y 
e v er y 1 2 w e e k s aft er t h e st u d y vi sit t o c h e c k if t h er e h a v e b e e n a n y cli ni c al fr a ct ur e s i n 
or d er t o ai d e v e nt tr a c ki n g.  T h e s e t el e p h o n e c o nt a ct s will b e gi n at a ti m e p oi nt cl o s er t o 
t h e r e q uir e d n u m b er of e v e nt s t h at d efi n e t h e e n d of t h e st u d y.  I n c a s e a cli ni c al fr a ct ur e 
i s r e p ort e d, t h e p ati e nt s h o ul d att e n d a n u n s c h e d ul e d vi sit.   
T h e C R F will c a pt ur e s u bj e ct r e p ort s of p ai n a n d/ or ot h er s y m pt o m s i n di c ati v e of fr a ct ur e 
or d et eri or ati o n of m o bilit y.  T h e i n v e sti g at or will b e a s k e d t o c o nfir m if i n hi s/ h er o pi ni o n 
t h e s y m pt o m l o c alit y i s li n k e d t o t h e fr a ct ur e. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
T h e Bli n d e d R e vi e w C o m mitt e e will r e vi e w r a di o gr a p h s a n d r e p ort s of t h o s e s u bj e ct s f or 
w h o m t h e l o c al i n v e sti g at or c a n n ot e a sil y c o nfir m a cli ni c al fr a ct ur e a n d f or c a s e s w h er e 
t h e li n k b et w e e n s y m pt o m l o c alit y a n d fr a ct ur e i s a m bi g u o u s.  D et ail s of t h e pr o c e s s e s 
f oll o w e d b y t h e Bli n d e d R e vi e w C o m mitt e e will b e i n cl u d e d i n a s e p ar at e c h art er. 
If t h e s u bj e ct r e p ort s s y m pt o m s b et w e e n st u d y vi sit s t h at w o ul d s u g g e st a cli ni c al 
fr a ct ur e t h e n t h e s a m e pr o c e d ur e s a s d e s cri b e d a b o v e s h o ul d b e f oll o w e d. 
A c o p y of a n y r a di o gr a p h s or r a di ol o gi st r e p ort s m u st b e i n cl u d e d i n t h e s u bj e ct’ s st u d y 
r e c or d s.  For t h e p ur p o s e of t h e st u d y, all cli ni c al fr a ct ur e s m u st b e c o nfir m e d b y x -r a y. 
7. 7. 1   
A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n- l a b el P h a s e   
C li ni c al fr a ct ur e s i d e ntifi e d b y t h e sit e will b e r e c or d e d o n t h e C R F  f or all s u bj e ct s.   
7. 8   
L at er al S pi n e X-r a y 
X-r a y s of t h e l at er al t h or a ci c a n d l u m b ar s pi n e will b e a c q uir e d a c c or di n g t o s e p ar at e 
i n str u cti o n s p er t h e s c h e d ul e o utli n e d i n A p p e n di x A .  Sit e s will b e pr e- q u alifi e d to 
c o n d u ct t h e s e x-r a y s b a s e d o n pr e- d efi n e d crit eri a .  An y sit e t h at d o e s n ot m e et t h e 
pr e- q u alifi c ati o n crit eri a will s e n d t h eir s u bj e ct s t o t h e n e ar e st q u alifi e d c e nt er f or 
o n - st u d y v ert e br al x-r a y s.  As s e s s m e nt of v ert e br al fr a ct ur e s will b e p erf or m e d b y a n 
e x p ert r a di ol o gi st at t h e c e ntr al i m a gi n g c e nt er u si n g a s e mi q u a ntit ati v e gr a di n g s c al e 
(G e n a nt et  al , 1 9 9 3): Gr a d e 1, 2 0 % t o 2 5 % r e d u cti o n i n v ert e br al h ei g ht ( a nt eri or, 
mi d dl e, or p o st eri or); Gr a d e 2, 2 5 % t o 4 0 % r e d u cti o n i n h ei g ht; Gr a d e 3, gr e at er t h a n 
4 0 % r e d u cti o n i n h ei g ht. 
Pr e v al e nt v ert e br al fr a ct ur e s will b e a s s e s s e d a n d r e c or d e d at b a s eli n e .  F or 
a s s e s s m e nt of i n ci d e nt v ert e br al fr a ct ur e, x-r a y s will b e r e vi e w e d bli n d e d t o tr e at m e nt 
b ut n ot t o s e q u e n c e .  T h e s e mi q u a ntit ati v e s c al e will b e u s e d.  F or t h e st u d y a n e w 
v ert e br al fr a ct ur e i s d efi n e d a s a fr a ct ur e i n a pr e vi o u sl y u n d ef or m e d v ert e br a e.  
V ert e br al fr a ct ur e s will i n cl u d e n e w c o m pr e s si o n fr a ct ur e s, d efi n e d a s t h o s e 
c o m pr e s si o n fr a ct ur e s h a vi n g a d e cr e a s e i n t ot al a nt eri or or p o st eri or h ei g ht of at l e a st 
2 5 % fr o m b a s eli n e .  N e w v ert e br al fr a ct ur e s will b e cl a s sifi e d a s eit h er cli ni c al or 
m or p h o m etri c d e p e n di n g o n w h et h er or n ot i n t h e i n v e sti g at or’ s o pi ni o n t h e s y m pt o m 
l o c alit y c a n b e li n k e d t o t h e fr a ct ur e.  W or s e ni n g of pr e- e xi sti n g fr a ct ur e s will al s o b e 
a s s e s s e d.  W or s e ni n g i s d efi n e d a s a n i n cr e a s e i n fr a ct ur e s e v erit y of at l e a st 1 gr a d e 
o n t h e s e mi q u a ntit ati v e s c al e.  
If a s u bj e ct h a s a c ut e b a c k p ai n at a ti m e p oi nt ot h er t h a n w h e n a s c h e d ul e d s pi n al x-r a y 
i s o bt ai n e d, a n d o c c urr e n c e of a v ert e br al fr a ct ur e i s s u s p e ct e d, t h e i n v e sti g at or s h o ul d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
o bt ai n a l at er al s pi n al x -r a y t o c o nfir m t h e pr e s e n c e of cli ni c al fr a ct ur e a s d e s cri b e d i n 
S e cti o n 7. 7 .  A c o p y of a n y r a di o gr a p h s or r a di ol o gi st r e p ort s m u st b e i n cl u d e d i n t h e 
s u bj e ct’ s st u d y r e c or d s. 
7. 9   
D u al E n er g y X-r a y A b s or pti o m etr y ( D X A) A s s e s s m e nt 
All s u bj e ct s will b e r e q uir e d t o u n d er g o b o n e d e n sit o m etr y a s s e s s m e nt s of t h e l u m b ar 
s pi n e a n d pr o xi m al f e m ur p erf or m e d b y D X A p er t h e s c h e d ul e o utli n e d i n A p p e n di x A .   
T h e s a m e D X A m a c hi n e m u st b e u s e d f or all st u d y pr o c e d ur e s f or a p arti c ul ar s u bj e ct.  
T h e l eft si d e s h o ul d b e u s e d f or t h e pr o xi m al f e m ur s c a n s, u nl e s s pr o hi bit e d, e g,  hi p 
i m pl a nt.   
L u m b ar s pi n e s c a n s m u st i n cl u d e L 1 t hr o u g h L 4.  V ert e br a e t h at ar e u n e v al u a bl e 
( e g, cl e arl y fr a ct ur e d, o s sifi c ati o n) will b e e x cl u d e d fr o m t h e l u m b ar s pi n e D X A a n al y si s. 
D et ail e d i n str u cti o n s f or s c a n a c q ui siti o n will b e i n a s e p ar at e m a n u al. 
7. 9. 1   
S cr e e ni n g D X A 
D e n sit o m etr y m e a s ur e m e nt s of b ot h t h e l u m b ar s pi n e a n d t h e pr o xi m al f e m ur m u st b e 
p erf or m e d at s cr e e ni n g.  T h e l u m b ar s pi n e D X A s h o ul d b e a n al y z e d b y t h e l o c al D X A 
t e c h ni ci a n t o d et er mi n e t h e str atifi c ati o n f a ct or b a s e d o n t h e s u bj e ct’ s l u m b ar T- s c or e.  
At b a s eli n e, at l e a st 2 l u m b ar v ert e br a e s h o ul d b e e v al u a bl e. 
7. 9. 2  
O n - St u d y D X A 
All o n- st u d y b o n e d e n sit o m etr y a s s e s s m e nt s will b e m e a s ur e d at t h e l u m b ar s pi n e a n d 
pr o xi m al f e m ur. 
F or a s u bj e ct wit h > 1 0 % l o s s of B M D at t h e t ot al hi p or l u m b ar s pi n e o v er a n y 1 - y e ar 
p eri o d, a n i nf or m e d di s c u s si o n will t a k e pl a c e b et w e e n t h e i n v e sti g at or a n d t h e s u bj e ct 
r e g ar di n g alt er n ati v e t h er api e s a n d a p pr o pri at e tr e at m e nt.  If t h e s el e ct e d tr e at m e nt 
o pti o n d o e s n ot i n cl u d e c o m m er ci all y a v ail a bl e d e n o s u m a b (i e, X G E V A  or Pr oli a) or 
bi s p h o s p h o n at e s, w hi c h i s e x cl u si o n ar y, t h e s u bj e ct will r e m ai n i n t h e st u d y.  T h o s e 
s u bj e ct s f or w h o m I V tr e at m e nt wit h bi s p h o s p h o n at e s or or all y a d mi ni st er e d 
bi s p h o s p h o n at e t h er a p y l a sti n g l o n g er t h a n 3 0 d a y s will b e c o n si d er e d t h e b e st o pti o n 
will b e r e m o v e d fr o m I P tr e at m e nt.  
T h e a n al y si s f or t h e s e c o n d ar y o bj e cti v e ( p er c e nt c h a n g e i n l u m b ar s pi n e, t ot al hi p a n d  
f e m or al n e c k B M D fr o m b a s eli n e t o m o nt h s 1 2, 2 4, a n d 3 6) will o nl y i n cl u d e t h e d at a 
c oll e ct e d fr o m pr e- s el e ct e d sit e s.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
7. 1 0   
B o n e Sc a n  
A b o n e s c a n i s r e q uir e d at s cr e e ni n g t o r ul e o ut m et a st a s e s.  If t h e D X A a n d b o n e s c a n 
ar e p erf or m e d o n t h e s a m e d a y, t h e n t h e D X A s c a n m u st b e p erf or m e d fir st.  T h e 
r a di o a cti v e n u cl e oti d e u s e d i n t h e b o n e s c a n c a n i nt erf er e wit h t h e B M D m e a s ur e m e nt.  
If t h e b o n e s c a n i s p erf or m e d fir st, t h e n at l e a st 7 2 h o ur s m u st el a p s e b ef or e t h e D X A 
s c a n i s p erf or m e d. 
7. 1 1  
L a b o r at or y A s s e s s m e nt s 
All o n- st u d y bl o o d s a m pl e s will b e pr o c e s s e d a n d s e nt t o t h e l o c al l a b or at or y wit h t h e 
e x c e pti o n of t h e d e n o s u m a b a nti b o d y s a m pl e s.   
S p e cifi c i n str u cti o n will b e pr o vi d e d o n h o w t h e d e n o s u m a b a nti b o d y s a m pl e s s h o ul d b e 
h a n dl e d a n d st or e d. 
7. 1 2   
Bl o o d a n d S er u m A s s e s s m e nt s 
All bl o o d s a m pl e s will b e o bt ai n e d b y v e ni p u n ct ur e b ef or e i n v e sti g ati o n al pr o d u ct 
a d mi ni str ati o n.  T h e t ot al v ol u m e of bl o o d dr a w n fr o m a s u bj e ct t hr o u g h o ut t h e st u d y 
( b a s e d o n a n a v er a g e tr e at m e nt p eri o d of 4 8  m o nt h s) will b e a p pr o xi m at el y 2 0 0 m L, 
i n cl u di n g s cr e e ni n g. 
D e n o s u m a b a nti b o d y l e v el will b e a s s e s s e d at s cr e e ni n g a n d t h e E n d of Tr e at m e nt vi sit 
d uri n g t h e d o u bl e- bli n d p h a s e.    
Bl o o d will b e o bt ai n e d f or t h e f oll o wi n g a s s e s s m e nt s at t h e ti m e p oi nt s o utli n e d i n  
A p p e n di x A .  T a bl e 1  o utli n e s t h e s p e cifi c a n al yt e s f or e a c h a s s e s s m e nt.   
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
T a bl e  1.  S er u m a n d Bl o o d S a m pl e A n al yt e Li sti n g  
S er u m C h e mi str y  
H e m at ol o g y  
Ot h er  
S o di u m  
R e d bl o o d c ell s  
D e n o s u m a b a nti b o d y a s s a y  ( o nl y 
d o u bl e bli n d st u d y)  
P ot a s si u m  
H e m o gl o bi n  
 
C al ci u m  
H e m at o crit  
 
Bl o o d Ur e a Nitr o g e n/ Ur e a  
Pl at el et s  
 
Cr e ati ni n e  
W hit e bl o o d c ell s  
 
T ot al bilir u bi n  
 
 
Al k ali n e p h o s p h at a s e  
 
 
Al a ni n e tr a n s a mi n a s e   
 
 
A s p ar at e a mi n otr a n sf er a s e  
 
 
L D H  
 
 
G a m m a G T  
 
 
Al b u mi n  
 
 
 
7. 1 3   
A d v er s e E v e nt s 
Bli n d e d Tr e at m e nt P h a s e 
S u bj e ct s will b e e v al u at e d f or a d v er s e e v e nt s at e a c h cli ni c vi sit fr o m si g ni n g i nf or m e d 
c o n s e nt t hr o u g h 3 0 d a y s aft er t h eir l a st d o s e of i n v e sti g ati o n al pr o d u ct d uri n g t h e 
bli n d e d p h a s e .  A d v er s e e v e nt s will b e r e c or d e d in t h e C R F .     
Fr a ct ur e s a n d t h eir a s s o ci at e d s y m pt o m s will n ot b e r e p ort e d a s a d v er s e e v e nt s .  
C li ni c al fr a ct ur e s a n d v ert e br al fr a ct ur e s ( m or p h om etri c or cli ni c al) will b e c o n si d er e d a s 
a n e n d - p oi nt a n d r e c or d e d o n a s p e cifi c C R F p a g e.  Thi s C R F will al s o c a pt ur e s u bj e ct 
r e p ort s of p ai n or ot h er s y m pt o m s i n di c ati v e of fr a ct ur e or d et eri or ati o n of m o bilit y.   
H o w e v er, if t h e n at ur e of a fr a ct ur e or it s a s s o ci at e d s y m pt o m s c a n b e cl a s sifi e d a s a 
s eri o u s a d v er s e e v e nt ( s e e S e cti o n 9. 1. 2 ), t h e n t h e s e s h o ul d b e r e c or d e d o n a S eri o us 
A d v er s e E v e nt R e p ort f or m ( s e e A p p e n di x F ) a n d f a x e d t o t h e l o c al A m g e n S af et y 
S p e ci ali st wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of t h e e v e nt.  ( S e e S e cti o n 9. 3 ). 
O p e n- l a b el p h a s e / L o n g-t er m F oll o w-u p  
D uri n g t h e O L P/ L T F U, 
 
will b e d o c u m e nt e d i n t h e C R F o nl y f or s u bj e ct s r e c ei vi n g d e n o s u m a b. 
Cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e (f e m ur 
mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, f e m ur di st al) a s s o ci at e d wit h mi ni m al tr a u m a 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
will b e cl a s sifi e d a s a n S A E f or all s u bj e ct s ( s e e S e cti o n 9. 1. 2 ), a n d s h o ul d b e r e c or d e d 
o n a S eri o u s A d v er s e E v e nt R e p ort f or m ( s e e A p p e n di x F ) a n d f a x e d t o t h e l o c al A m g e n 
S af et y S p e ci ali st wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of t h e e v e nt 
( se e  S e cti o n 9. 3 ). 
7. 1 4   
E arl y Wit h dr a w al Fr o m Tr e at m e nt 
S u bj e ct s w h o di s c o nti n u e e arl y fr o m tr e at m e nt will c o nti n u e t o att e n d t h e st u d y vi sit s 
e v er y 6 m o nt h s ( wit h o ut i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n) u ntil t h e st u d y P A D C D i s 
r e a c h e d. 
At t h e s e vi sit s t h e i n v e sti g at or will a s s e s s t h e s u bj e ct f or cli ni c al fr a ct ur e s a s d e s cri b e d 
i n S e cti o n 7. 7 .  DX A a n d v ert e br al x-r a y s will b e p erf or m e d p er t h e s c h e d ul e i n   
A p p e n di x A .  I m p ort a nt pr ot o c ol d e vi ati o n s will o nl y b e r e p ort e d t hr o u g h 3 0 d a y s aft er 
t h e l a st a d mi ni str ati o n of I P. 
S u bj e ct s w h o wit h dr a w fr o m d e n o s u m a b d uri n g t h e O L P will h a v e f oll o w- u p s ur vi v al d at a 
c oll e ct e d e v er y 1 2 m o nt h s f or u p t o a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D .  
7. 1 5   
E n d of Tr e at m e nt 
S u bj e ct s will u n d er g o E O T a s s e s s m e nt s a s d e s cri b e d i n A p p e n di x A  a s f oll o w s: 
F or all s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wit hi n 6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) 
pri or t o t h e P A D C D w a s a y e arl y vi sit ( e g, m o nt h 1 2, 2 4, et c), a n d r a di ol o gi c al 
a s s e s s m e nt s w er e p erf or m e d, t hi s vi sit will b e c o n si d er e d a n E O T vi sit.  T h o s e s u bj e ct s, 
f or w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e n ot p erf or m e d, will n e e d t o att e n d  t h e n e xt 
s c h e d ul e d 6 m o nt h s vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s ( v ert e br al x-r a y s, D X A) will 
t a k e pl a c e a n d a n a nti b o d y s a m pl e will b e t a k e n.  F or t h e s e s u bj e ct s t hi s vi sit will b e 
c o n si d er e d a s E O T vi sit.  F or t h o s e s u bj e ct s w h o s e l a st r e g ul ar st u d y vi sit wit hi n 
6 m o nt h s ( + 4 5 d a y s ti m e wi n d o w) pri or t o t h e P A D C D w a s a 6 m o nt h s vi sit ( e g, 
m o nt h 6, 1 8 , et c), t h e n e xt r e g ul arl y s c h e d ul e d y e arl y st u d y vi sit (e g,  Q 1 2 M) wit hi n 
6 m o nt h s aft er P A D C D will b e c o n si d er e d a n e n d of tr e at m e nt  vi sit.  D at a o n fr a ct ur e s 
o c c urri n g b et w e e n t h e l a st vi sit pri or t o P A D C D a n d P A D C D h a v e t o b e c oll e ct e d vi a 
t el e p h o n e or p h y si c al vi sit s wit hi n si x m o nt h s aft er P A D C D at t h e l at e st. 
S u bj e ct s w h o wit h dr a w fr o m I P pri or t o t h e P A D C D will c o nti n u e t o att e n d Q 6 M st u d y 
vi sit s f or a s s e s s m e nt of t h e pri m ar y a n d s e c o n d ar y e n d- p oi nt a n d s af et y.  S u bj e ct s 
c o m pl eti n g or di s c o nti n ui n g A I T will h a v e t h e o p p ort u nit y t o r e m ai n o n I P f or at l e a st 
2 d o s e s of I P aft er t h eir l a st s c h e d ul e d st u d y vi sit d uri n g w hi c h t h e y w er e still o n AI T.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
S u bj e ct s w h o wit h dr a w f ull c o n s e nt will h a v e n o f urt h er st u d y a s s e s s m e nt s fr o m t h at 
d at e f or w ar d.  
7. 1 6   
E n d of O pe n -l a b el Tr e at m e nt 
S u bj e ct s will c o m pl et e a n e n d of o p e n-l a b el tr e at m e nt vi sit 3 0 t o 4 5 d a y s aft er t h e l a st 
d o s e of o p e n-l a b el d e n o s u m a b eit h er b y cli ni c vi sit or t el e p h o n e c o nt a ct; a s s e s s m e nt s 
will b e p erf or m e d a s d e s cri b e d i n A p p e n di x A . 
S u bj e ct s w h o wit h dr a w fr o m o p e n-l a b el d e n o s u m a b e arl y ( s e e S e cti o n 8. 1 ) will h a v e 
f oll o w-u p d at a c oll e ct e d e v er y 1 2 m o nt h s f oll o wi n g t h eir r e g ul ar f oll o w-u p  s c h e d ul e f or 
u p t o a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D.  
7. 1 7  
L o n g -t er m F oll o w-u p  
S u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S Q 1 2 M b y cli ni c vi sit s or t el e p h o n e 
c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O T vi sit) f or a p pr o xi m at el y 
6 6  m o nt h s aft er t h e P A D C D.  F oll o wi n g r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol 
A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d ( s e e S e cti o n 3. 1 ). 
S u bj e ct s w h o d o n ot r e c ei v e o p e n -l a b el d e n o s u m a b will b e f oll o w e d f or D F S, B M F S, a n d 
O S o n c e a y e ar ( Q 1 2 M st u d y vi sit) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s u ntil 
a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D.  A d diti o n all y, f urt h er d at a will b e a s s e s s e d ( s e e  
S e cti o n 3. 1 ). 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will h a v e Q 6 M o n- sit e vi sit s f or 
a d mi ni str ati o n of d e n o s u m a b ( 6 0 m g S C Q 6 M) a n d ( S) A E m o nit ori n g a n d will b e 
f oll o w e d Q 1 2 M o nl y f or D F S, B M F S, a n d O S u ntil eit h er a p pr o xi m at el y 6 6 m o nt h s aft er 
P A D C D or c o m pl eti o n of tr e at m e nt, w hi c h e v er i s l o n g er.  A d diti o n all y, f urt h er d at a will b e 
a s s e s s e d ( s e e S e cti o n 3. 1 ). 
7. 1 8   
E n d of St u d y 
T h e p ati e nt i n di vi d u al E O S i s d efi n e d a s t h e l a st f or m al vi sit or c o nt a ct f or a s u bj e ct or a n 
u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m st u d y .   
E n d of S t u d y r e a s o n s i n cl u d e t hr e e e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w-u p , c o n s e nt 
wit h dr a w al) a n d p er pr ot o c ol E O S.  At t h e en d of st u d y, t h e E O S C R F h a s t o b e 
c o m pl et e d f or e a c h s u bj e ct. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
8.  
R E M O V A L A N D R E P L A C E M E N T O F S U B J E C T S 
8. 1   
R e m o v al of S u bj e ct s 
S u bj e ct s h a v e t h e ri g ht t o wit h dr a w f ull y or p arti all y fr o m t h e st u d y at a n y ti m e a n d f or 
a n y r e a s o n wit h o ut pr ej u di c e t o h er f ut ur e m e di c al c ar e b y t h e p h y si ci a n or at t h e 
i n stit uti o n. 
Wit h dr a w al of f ull c o n s e nt f or a st u d y m e a n s t h at t h e s u bj e ct d o e s n ot wi s h t o r e c ei v e 
f urt h er i n v e sti g ati o n al tr e at m e nt a n d d o e s n ot wi s h t o or i s u n a bl e t o c o nti n u e f urt h er 
st u d y p arti ci p ati o n.  A n y s u bj e ct m a y wit h dr a w f ull c o n s e nt t o p arti ci p at e i n t h e st u d y at 
a n y ti m e d uri n g t h e st u d y.  T h e i n v e sti g at or will di s c u s s wit h t h e s u bj e ct t h e m o st 
a p pr o pri at e w a y t o wit h dr a w t o e n s ur e t h e s u bj e ct’ s h e alt h.   
Wit h dr a w al of p arti al c o n s e nt m e a n s t h at t h e s u bj e ct d o e s n ot wi s h t o t a k e 
i n v e sti g ati o n al pr o d u ct a n y l o n g er b ut i s still willi n g t o c oll a b or at e i n pr o vi di n g f urt h er 
d at a b y c o nti n ui n g o n st u d y ( e g,  p arti ci p at e i n all s u b s e q u e nt st u d y vi sit s or pr o c e d ur e s).  
S u bj e ct s m a y d e cli n e t o c o nti n u e r e c ei vi n g i n v e sti g ati o n al pr o d u ct at a n y ti m e d uri n g t h e 
st u d y.  T h e s e s u bj e ct s, a s w ell a s t h o s e w h o h a v e st o p p e d r e c ei vi n g i n v e sti g ati o n al 
pr o d u ct f or ot h er r e a s o n s ( e g,  i n v e sti g at or or s p o n s or c o n c er n) s h o ul d c o nti n u e o n t h e 
s c h e d ul e of st u d y o b s er v ati o n s a s o utli n e d i n A p p e n di x A . 
R e a s o n s f or r e m o v al fr o m i n v e sti g ati o n al pr o d u ct/ d e n o s u m a b d uri n g t h e bli n d e d p h a s e 
a n d t h e O L P ( s e e S e cti o n s 6. 1. 3  a n d 7. 1 5 ): 
 
e n d of st u d y  
 
c o m pl et e d i n v e sti g ati o n al pr o d u ct/ d e n o s u m a b 
 
pr ot o c ol d e vi ati o n 
 
n o n c o m pli a n c e 
 
a d v er s e e v e nt 
 
di s e a s e pr o gr e s si o n1  
 
r e q uir e m e nt s f or alt er n ati v e t h er a p y 
 
a d mi ni str ati v e d e ci si o n 
                                                
1  Di s e a s e pr o gr e s si o n i s d efi n e d a s f oll o w s: 
  
di st a nt m et a st a s e s i n cl u di n g s u pr a cl a vi c ul ar l y m p h n o d e s ( o nl y fr o m br e a st c a n c er). E O T 
d e ci si o n r el at e d t o i nfr a cl a vi c ul ar l y m p h n o d e s h a s t o b e di s c u s s e d wit h D M C. 
  i n v a si v e l o c al-r e c urr e n c e ( E O T d e ci si o n t o b e di s c u s s e d wit h D M C) 
  
D CI S i p sil at er al E O T d e ci si o n t o b e di s c u s s e d wit h D M C) 
Ot h er di s e a s e o ut c o m e-r el at e d e v e nt s r el e v a nt f or t h e s e c o n d ar y e n d p oi nt s, b ut n ot d efi n e d a s 
di s e a s e pr o gr e s si o n ar e: 
  i n v a si v e c o ntr al at er al br e a st c ar ci n o m a 
  
s e c o n d pri m ar y i n v a si v e n o n- br e a st c ar ci n o m a 
  
D CI S c o ntr al at er al 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
s u bj e ct r e q u e st 
 
pr e g n a n c y or br e a stf e e di n g 
 
ot h er  
8. 2   
R e pl a c e m e nt of S u bj e ct s 
S u bj e ct s will n ot b e r e pl a c e d. 
9.   
A D V E R S E E V E N T R E P O R TI N G 
9. 1   
D efi niti o n s 
9. 1. 1   
A d v er s e E v e nt s 
A n a d v er s e e v e nt i s d efi n e d i n t h e I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n (I C H) 
G ui d eli n e f or G o o d Cli ni c al Pr a cti c e a s “ a n y u nt o w ar d m e di c al o c c urr e n c e i n a p ati e nt or 
cli ni c al i n v e sti g ati o n s u bj e ct a d mi ni st er e d a p h ar m a c e uti c al pr o d u ct a n d t h at d o e s n ot 
n e c e s s aril y h a v e a c a u s al r el ati o n s hi p wit h t hi s tr e at m e nt.” (I C H E 6: 1. 2) 
T hi s d efi niti o n of a d v er s e e v e nt s i s br o a d e n e d i n t hi s st u d y t o i n cl u d e a n y s u c h 
o c c urr e n c e ( e g, si g n, s y m pt o m, or di a g n o si s) or w or s e ni n g of a pr e- e x i sti n g m e di c al 
c o n diti o n fr o m t h e ti m e t h at a s u bj e ct h a s si g n e d i nf or m e d c o n s e nt t o t h e ti m e of 
i niti ati o n of i n v e sti g ati o n al pr o d u ct. 
W or s e ni n g of a pr e- e xi sti n g m e di c al c o n diti o n ( e g, c a n c er, di a b et e s, mi gr ai n e 
h e a d a c h e s, g o ut) s h o ul d b e c o n si d er e d a n a d v er s e e v e nt if t h er e i s eit h er a n i n cr e a s e i n 
s e v erit y, fr e q u e n c y, or d ur ati o n of t h e c o n diti o n or a n a s s o ci ati o n wit h si g nifi c a ntl y w or s e 
o ut c o m e s.   
I nt er v e nti o n s f or pr etr e at m e nt c o n diti o n s ( e g, el e cti v e c o s m eti c s ur g er y) or m e di c al 
pr o c e d ur e s t h at w er e pl a n n e d b ef or e st u d y e nr oll m e nt ar e n ot c o n si d er e d a d v er s e 
e v e nt s. 
T h e i n v e sti g at or i s r e s p o n si bl e f or r e vi e wi n g l a b or at or y t e st r e s ult s a n d d et er mi ni n g 
w h et h er a n a b n or m al v al u e i n a n i n di vi d u al st u d y s u bj e ct r e pr e s e nt s a c h a n g e fr o m 
v al u e s b ef or e t h e st u d y.  I n g e n er al, a b n or m al l a b or at or y fi n di n g s wit h o ut cli ni c al 
si g nifi c a n c e ( b a s e d o n t h e i n v e sti g at or' s j u d g m e nt) s h o ul d n ot b e r e c or d e d a s a d v er s e 
e v e nt s; h o w e v er, l a b or at or y v al u e c h a n g e s r e q uiri n g t h er a p y or a dj u st m e nt i n pri or 
t h er a p y ar e c o n si d er e d a d v er s e e v e nt s. 
9. 1. 2   
S eri o u s A d v er s e E v e nt s 
A s eri o u s a d v er s e e v e nt i s d efi n e d b y r e g ul at or y a ut h oriti e s a s o n e t h at 
 
i s f at al 
 
i s lif e t hr e at e ni n g ( pl a c e s t h e s u bj e ct at i m m e di at e ri s k of d e at h) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
r e q uir e s i n- p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n 
 
r e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y 
 
i s a c o n g e nit al a n o m al y/ birt h d ef e ct 
 
ot h er si g nifi c a nt m e di c al h a z ar d 
A h o s pit ali z ati o n m e eti n g t h e r e g ul at or y d efi niti o n f or “ s eri o u s” i s a n y i n p ati e nt h o s pit al 
a d mi s si o n t h at i n cl u d e s a mi ni m u m of a n o v er ni g ht st a y i n a h e alt h c ar e f a cilit y e x cl u di n g 
h o s pit ali z ati o n s f or a nti ci p at e d pr ot o c ol- s p e cifi e d pr o c e d ur e s.  H o w e v er, pr ol o n g ati o n of 
h o s pit ali z ati o n or r e- a d mi s si o n aft er a s u bj e ct h a s b e e n di s c h ar g e d w o ul d b e c o n si d er e d 
a S A E. 
A n y a d v er s e e v e nt t h at d o e s n ot m e et o n e of t h e d efi niti o n s of s eri o u s ( e g,  e m er g e n c y 
r o o m vi sit, o ut p ati e nt s ur g er y, or r e q uir e s ur g e nt i n v e sti g ati o n) m a y b e c o n si d er e d b y t h e 
i n v e sti g at or t o m e et t h e “ ot h er si g nifi c a nt m e di c al h a z ar d” crit eri o n f or cl a s sifi c ati o n a s a 
S A E .  E x a m pl e s i n cl u d e all er gi c br o n c h o s p a s m, c o n v ul si o n s, a n d bl o o d d y s cr a si a s. 
9. 2   
R e p orti n g Pr o c e d ur e s f or All A d v er s e E v e nt s D uri n g t h e 
D o u bl e -bli n d  Ph a s e  
T h e i n v e sti g at or i s r e s p o n si bl e f or e n s uri n g t h at all a d v er s e e v e nt s ( a s d efi n e d i n 
S e cti o n 9. 1 ) o b s er v e d b y t h e i n v e sti g at or or r e p ort e d b y s u bj e ct s aft er t h e si g ni n g of t h e 
i nf or m e d c o n s e nt t hr o u g h 3 0 d a y s aft er th e  l a st d o s e of i n v e sti g ati o n al pr o d u ct 
a d mi ni str ati o n ar e r e p ort e d u si n g t h e a p pli c a bl e C R F.  A d v er s e e v e nt s t h at o c c ur b ef or e 
r a n d o mi z ati o n a n d ar e d e e m e d b y t h e i n v e sti g at or t o b e u nr el at e d t o st u d y s cr e e ni n g d o  
n ot h a v e t o b e r e c or d e d i n t h e C R F.  
T h e f oll o wi n g a d v er s e e v e nt attri b ut e s m u st b e a s si g n e d b y t h e i n v e sti g at or:  a d v er s e 
e v e nt di a g n o si s or s y n dr o m e( s) (if k n o w n, si g n s or s y m pt o m s if n ot k n o w n); e v e nt 
d e s cri pti o n ( wit h d et ail a p pr o pri at e t o t h e e v e nt); d at e s of o n s et a n d r e s ol uti o n; s e v erit y; 
a s s e s s m e nt of r el at e d n e s s t o i n v e sti g ati o n al pr o d u ct ; a n d a cti o n t a k e n.  T h e i n v e sti g at or 
m a y b e a s k e d t o pr o vi d e f oll o w- u p i nf or m ati o n, di s c h ar g e s u m m ari e s, a n d e xtr a ct s fr o m 
m e di c al r e c or d s or C R F s. 
If a p pli c a bl e, t h e r el ati o n s hi p of t h e a d v er s e e v e nt t o t h e i n v e sti g ati o n al pr o d u ct will b e 
a s s e s s e d b y m e a n s of t h e q u e sti o n:  “I s t h er e a r e a s o n a bl e p o s si bilit y t h at t h e e v e nt 
m a y h a v e b e e n c a u s e d b y t h e i n v e sti g ati o n al pr o d u ct ?”  T h e i n v e sti g at or s h o ul d r e s p o n d 
t o t hi s q u e sti o n wit h eit h er Y e s or N o. 
If t h e a d v er s e e v e nt o c c urr e d b ef or e i niti ati o n of i n v e sti g ati o n al pr o d u ct, t h e r el ati o n s hi p 
of t h e a d v er s e e v e nt t o st u d y s cr e e ni n g i s t o b e a s s e s s e d b y m e a n s of t h e q u e sti o n:  “I s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
t h er e a r e a s o n a bl e p o s si bilit y t h at t h e e v e nt m a y h a v e o c c urr e d b e c a u s e of st u d y 
s cr e e ni n g ?”  T h e i n v e sti g at or s h o ul d r e s p o n d t o t hi s q u e sti o n wit h eit h er Y e s or N o.  If 
t h e a n s w er i s Y e s, r e c or d w h at p art of t h e st u d y s cr e e ni n g i s s u s p e ct e d. 
T h e s e v erit y gr a di n g s c al e u s e d i n t hi s st u d y i s d e s cri b e d i n A p p e n di x B . 
M e di c all y si g nifi c a nt a d v er s e e v e nt s c o n si d er e d r el at e d t o t h e i n v e sti g ati o n al pr o d u ct  b y 
t h e i n v e sti g at or or t h e s p o n s or will b e f oll o w e d u ntil r e s ol v e d or c o n si d er e d st a bl e. 
It will b e l eft t o t h e i n v e sti g at or’ s cli ni c al j u d g m e nt t o d et er mi n e w h et h er a n a d v er s e 
e v e nt i s r el at e d a n d of s uffi ci e nt s e v erit y t o r e q uir e t h e s u bj e ct’ s r e m o v al fr o m tr e at m e nt.  
A s u bj e ct m a y al s o v ol u nt aril y wit h dr a w fr o m tr e at m e nt d u e t o w h at h e or s h e p er c ei v e s 
a s a n i nt ol er a bl e a d v er s e e v e nt.  If eit h er of t h e s e sit u ati o n s ari s e s, t h e s u bj e ct s h o ul d 
b e str o n gl y e n c o ur a g e d t o att e n d all f urt h er s c h e d ul e d st u d y vi sit s  a n d b e u n d er m e di c al 
s u p er vi si o n u ntil s y m pt o m s c e a s e or t h e c o n diti o n b e c o m e s st a bl e. 
9. 3   
S eri o u s A d v er s e E v e nt R e p orti n g Pr o c e d ur e s D uri n g t h e 
D o u bl e -bli n d  Ph a s e  
T h e i n v e sti g at or i s r e s p o n si bl e f or e n s uri n g t h at all s eri o u s a d v er s e e v e nt s o b s er v e d b y 
t h e i n v e sti g at or or r e p ort e d b y t h e s u bj e ct t h at o c c ur aft er si g ni n g of t h e i nf or m e d 
c o n s e nt t hr o u g h 3 0 d a y s aft er t h e l a st d o s e of i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n ar e 
r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d a n d ar e s u b mitt e d t o A m g e n.  R e p orti n g of 
s eri o u s a d v er s e e v e nt s t h at o c c ur m or e t h a n 3 0 d a y s aft er t h e e n d of i n v e sti g ati o n al 
pr o d u ct u ntil e n d of st u d y i s at t h e i n v e sti g at or’ s di s cr eti o n.  T h e s eri o u s a d v er s e e v e nt s 
m u st b e s u b mitt e d t o A m g e n wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of t h e e v e nt. 
N e w i nf or m ati o n r el ati n g t o a pr e vi o u sl y r e p ort e d s eri o u s a d v er s e e v e nt m u st b e 
s u b mitt e d t o A m g e n.  All n e w i nf or m ati o n f or s eri o u s a d v er s e e v e nt s m u st b e s e nt t o 
A m g e n wit hi n 2 4 h o ur s of r e c ei pt.  T h e i n v e sti g at or m a y b e a s k e d t o pr o vi d e a d diti o n al 
f oll o w- u p i nf or m ati o n, w hi c h m a y i n cl u d e a di s c h ar g e s u m m ar y or e xtr a ct s fr o m t h e 
m e di c al r e c or d.  I nf or m ati o n pr o vi d e d a b o ut t h e s eri o u s a d v er s e e v e nt s m u st b e 
c o n si st e nt wit h t h at r e c or d e d o n t h e a p pli c a bl e C R F ( e g, A d v er s e E v e nt S u m m ar y C R F). 
If a s u bj e ct i s p er m a n e ntl y wit h dr a w n fr o m t h e st u d y b e c a u s e of a s eri o u s a d v er s e 
e v e nt, t hi s i nf or m ati o n m u st b e i n cl u d e d i n t h e i niti al or f oll o w- u p S A E r e p ort f or m. 
T o c o m pl y wit h w orl d wi d e r e p orti n g r e g ul ati o n s f or s eri o u s a d v er s e e v e nt s , t h e tr e at m e nt 
a s si g n m e nt of s u bj e ct s w h o d e v el o p s eri o u s, u n e x p e ct e d, a n d r el at e d a d v er s e e v e nt s 
m a y b e u n bli n d e d b y A m g e n b ef or e s u b mi s si o n t o r e g ul at or y a ut h oriti e s.  I n v e sti g at or s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
will r e c ei v e n otifi c ati o n of r el at e d s eri o u s a d v er s e e v e nt s r e p ort s s e nt t o r e g ul at or y 
a ut h oriti e s i n a c c or d a n c e wit h l o c al r e q uir e m e nt s.   
A m g e n will r e p ort s eri o u s a d v er s e e v e nt s  a n d/ or s u s p e ct e d u n e x p e ct e d s eri o u s a d v er s e 
r e a cti o n s a s r e q uir e d t o r e g ul at or y a ut h oriti e s, i n v e sti g at or s/i n stit uti o n s, a n d I R B s/ E C s i n 
c o m pli a n c e wit h all r e p orti n g r e q uir e m e nt s a c c or di n g t o l o c al r e g ul ati o n s a n d G C P .  
T h e i n v e sti g at or s h o ul d n otif y t h e a p pr o pri at e I R B/ E C of s eri o u s a d v er s e e v e nt s 
o c c urri n g at t h e sit e a n d ot h er a d v er s e e v e nt r e p ort s r e c ei v e d fr o m A m g e n, i n 
a c c or d a n c e wit h l o c al pr o c e d ur e s a n d st at ut e s. 
A n y pr o c e d ur e pl a n n e d pri or t o t h e si g ni n g of t h e i nf or m e d c o n s e nt r e s ulti n g i n a n 
u nf or e s e e n w or s e ni n g of t h e u n d erl yi n g pr e- e xi sti n g c o n diti o n will n ot b e c o n si d er e d a 
s eri o u s a d v er s e e v e nt .  
9. 3. 1   
A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s A d v er s e E v e nt 
R e p orti n g D uri n g t h e O p e n-l a b el P h a s e  
9. 3. 1. 1   
A d v er s e E v e nt s of S p e ci al I nt er e st R e p orti n g 
 
o b s er v e d b y t h e i n v e sti g at or or r e p ort e d b y t h e s u bj e ct aft er si g ni n g t h e I C F f or t h e O L P 
t hr o u g h 3 0 d a y s aft er t h e l a st d o s e of d e n o s u m a b f or s u bj e ct s t h at r e c ei v e d e n o s u m a b 
i n t h e O L P will b e d o c u m e nt e d i n t h e C R F.  
 
 
  
9. 3. 1. 2   
S eri o u s A d v er s e E v e nt R e p orti n g 
F or s u bj e ct s p arti ci p ati n g i n t h e O L P a n d w h o r e c ei v e d e n o s u m a b, t h e i n v e sti g at or i s 
r e s p o n si bl e f or e n s uri n g t h at all S A E s o b s er v e d b y t h e i n v e sti g at or or r e p ort e d b y t h e 
s u bj e ct t h at o c c ur aft er si g ni n g of t h e I C F f or t h e O L P t hr o u g h 3 0 d a y s aft er t h e l a st 
d o s e of d e n o s u m a b i n t h e O L P ar e r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d a n d ar e 
s u b mitt e d t o A m g e n ( s e e A p p e n di x F - Cli ni c al Tri al S eri o u s A d v er s e E v e nt r e p ort f or m) 
a n d  r e c or d e d in t h e a p pli c a bl e C R F .   
I n a d diti o n a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur 
s u btr o c h a nt eri c, f e m ur di st al) a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s sifi e d a s a n 
S A E f or A L L s u bj e ct s, a n d s h o ul d b e r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d a n d 
s u b mitt e d t o A m g e n ( s e e A p p e n di x F - Cli ni c al Tri al S eri o u s A d v er s e E v e nt r e p ort f or m) 
a n d r e c or d e d i n t h e a p pli c a bl e fr a ct ur e r e c or di n g C R F.   S A E r e p orti n g p eri o d f or 
s u s p e ct e d at y pi c al f e m or al fr a ct ur e will b e u ntil e n d of st u d y . 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 0.   
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 0. 1   
St u d y D e si g n 
T hi s i s a m ulti- c e nt er, p h a s e 3, r a n d o mi z e d, d o u bl e- bli n d, pl a c e b o - c o ntr oll e d st u d y t o 
d et er mi n e t h e tr e at m e nt eff e ct of d e n o s u m a b i n s u bj e ct s wit h br e a st c a n c er r e c ei vi n g 
ar o m at a s e i n hi bit or t h er a p y.  A p pr o xi m at el y 3 4 0 0 s u bj e ct s will b e r a n d o mi z e d i n a 
1: 1  r ati o t o r e c ei v e eit h er d e n o s u m a b 6 0 m g or pl a c e b o S C Q 6 M i n a bli n d e d m a n n er.  
T h e r a n d o mi z ati o n s c h e d ul e will b e str atifi e d b y: t y p e of h o s pit al ( m aj or a c a d e mi c 
c e nt er s or ot h er c e nt er s), pri or AI u s a g e ( Y or N) a n d t ot al l u m b ar s pi n e B M D s c or e at 
b a s eli n e ( T- s c or e < - 1. 0 or  - 1. 0).  S u bj e ct s will b e r e cr uit e d o v er a n  8 2 - m o nt h p eri o d.  
S u bj e ct s will r e m ai n o n i n v e sti g ati o n al pr o d u ct u ntil t h e r e q uir e d n u m b er of e v e nt s i s 
r e a c h e d a n d u ntil  t h e y h a v e h a d t h e o p p ort u nit y t o r e c ei v e a mi ni m u m of at l e a st 
2 d o s e s of I P, w hi c h e v er o c c ur s l at er.  T h e P A D C D i s d efi n e d a s: 
 
t h e ti m e at w hi c h t h e r e q uir e d n u m b er of e v e nt s (fir st cli ni c al fr a ct ur e) i s r e a c h e d 
a n d,   
 
all s u bj e ct s h a v e h a d t h e o p p ort u nit y t o r e c ei v e at l e a st 2 d o s e s of I P  
T h e pri m ar y o bj e cti v e i s t o d et er mi n e w h et h er d e n o s u m a b c o m p ar e d t o pl a c e b o will 
r e d u c e t h e r at e of fir st cli ni c al fr a ct ur e i n w o m e n wit h n o n- m et a st ati c br e a st c a n c er 
r e c ei vi n g ar o m at a s e i n hi bit or t h er a p y.  T h e s e c o n d ar y o bj e cti v e s ar e t o a s s e s s t h e eff e ct 
of d e n o s u m a b c o m p ar e d t o pl a c e b o o n B M D at l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k 
i n a s u b gr o u p of s u bj e ct s at pr e- s el e ct e d sit e s; t h e i n ci d e n c e of n e w v ert e br al fr a ct ur e s 
( b ot h m or p h o m etri c a n d cli ni c al); t h e i n ci d e n c e of n e w or w or s e ni n g of pr e- e xi sti n g 
v ert e br al fr a ct ur e s ( b ot h m or p h o m etri c a n d cli ni c al); di s e a s e fr e e s ur vi v al; 
b o n e  m et a st a si s-fr e e s ur vi v al; o v er all s ur vi v al; a n d t o a s s e s s t h e s af et y a n d t ol er a bilit y 
of d e n o s u m a b i n t hi s p o p ul ati o n.  
 
T h e effi c a c y cli ni c al h y p ot h e si s i s t h at d e n o s u m a b, w h e n a d mi ni st er e d s u b c ut a n e o u sl y 
at a d o s e of 6 0 m g e v er y 6 m o nt h s, will b e c o n si d er e d effi c a ci o u s i n s u bj e ct s wit h 
n o n - m et a st ati c br e a st c a n c er r e c ei vi n g AI T if t h e r at e of fir st cli ni c al fr a ct ur e i n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
d e n o s u m a b- tr e at e d s u bj e ct s i s l o w er t h a n t h at i n pl a c e b o-tr e at e d s u bj e ct s.  It i s 
a nti ci p at e d t h at d e n o s u m a b will r e d u c e t h e r at e b y 3 0 % c o m p ar e d wit h pl a c e b o (i e,  t h e 
tr u e h a z ar d r ati o of d e n o s u m a b c o m p ar e d wit h pl a c e b o i s 0. 7 0).  T h e s af et y cli ni c al 
h y p ot h e si s i s t h at d e n o s u m a b, w h e n a d mi ni st er e d S C at a d o s e of 6 0 m g e v er y 
6 m o nt h s, will b e w ell t ol er at e d i n br e a st c a n c er s u bj e ct s r e c ei vi n g A I T.  
1 0. 2   
St u d y E n d p oi nt s, S u b s et s, a n d C o v ari at e s 
1 0. 2. 1   
Pri m ar y E n d p oi nt 
T h e ti m e t o t h e fir st cli ni c al fr a ct ur e.  T h e p o w er of t h e st u d y t o d et e ct diff er e n c e s i n t hi s 
e n d p oi nt i s d e s cri b e d i n S e cti o n 1 0. 3 . 
1 0. 2. 2   
S e c o n d ar y E n d p oi nt s 
Fr a ct ur e-r el at e d s e c o n d ar y e n d p oi nt s: 
 
T h e p er c e nt c h a n g e i n t ot al l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k B M D fr o m 
b a s eli n e t o 3 6 m o nt h s ( at pr e- s el e ct e d sit e s) 
 
S u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e s ( m or p h o m etri c fr a ct ur e s i d e ntifi e d fr o m 
o n st u d y x-r a y s a n d cli ni c al v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y s) at m o nt h 3 6  
 
S u bj e ct i n ci d e n c e of a n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s 
( m or p h o m etri c v ert e br al fr a ct ur e s i d e ntifi e d fr o m o n st u d y x-r a y s a n d cli ni c al 
v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y s) at m o nt h 3 6 
Di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s:  
 
D F S d et er mi n e d b y t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st o b s er v ati o n of di s e a s e 
r e c urr e n c e or d e at h fr o m a n y c a u s e 
 
B M F S d et er mi n e d b y t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st o b s er v ati o n of b o n e 
m et a st a si s or d e at h fr o m a n y c a u s e 
 
O S d et er mi n e d b y t h e ti m e fr o m r a n do m i z ati o n t o d e at h fr o m a n y c a u s e 
1 0. 2. 3   
S af et y E n d p oi nt s 
 
S u bj e ct i n ci d e n c e of tr e at m e nt- e m er g e nt a d v er s e e v e nt s 
 
Cli ni c all y si g nifi c a nt c h a n g e s i n l a b or at or y v al u e s 
 
S u bj e ct i n ci d e n c e of a nti- d e n o s u m a b a nti b o d y ( bi n di n g a n d n e utr ali zi n g) f or m ati o n 
1 0. 2. 4   
E x pl or at or y E n d poi nt s  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 0. 2. 5   
S u b s et s 
T h e pri n ci p al a n al y si s f or t h e pri m ar y e n d p oi nt will b e c o n d u ct e d o n t h e f ull a n al y si s s et 
( F A S); a n al y si s of t h e p er- pr ot o c ol p o p ul ati o n will b e c o n si d er e d s u p p orti v e.  T h e F A S i s 
d efi n e d a s all s u bj e ct s w h o ar e r a n d o mi z e d.  T h e p er - pr ot o c ol p o p ul ati o n i s d efi n e d a s 
all r a n d o mi z e d s u bj e ct s, wit h t h e c orr e ct di a g n o si s, n o i m p ort a nt pr ot o c ol vi ol ati o n s, a n d 
w h o r e c ei v e d at l e a st 1 d o s e of i n v e sti g ati o n al pr o d u ct .  Im p ort a nt pr ot o c ol vi ol ati o n s will 
b e d efi n e d i n t h e st ati sti c al a n al y si s pl a n.  T h e s af et y a n al y si s s et will c o n si st of all 
s u bj e ct s w h o w er e r a n d o mi z e d a n d r e c ei v e d at l e a st 1 d o s e of i n v e sti g ati o n al dr u g.   
1 0. 2. 6   
C o v ari at e s 
T h e r el ati o n s hi p of t h e f oll o wi n g c o v ari at e s t o t h e pri m ar y a n d s e c o n d ar y effi c a c y 
e n d p oi nt will b e e x pl or e d:  
 
T y p e of h o s pit al ( gr o u p e d a s m aj or a c a d e mi c c e nt er s or ot h er c e nt er s) 
 
Pri or AI u s a g e ( Y or N) 
 
T ot al l u m b ar s pi n e B M D s c or e at b a s eli n e  ( T- s c or e l e s s t h a n - 1. 0 or  -1. 0)  
 
A g e ( A g e will pri m aril y b e c o n si d er e d a s a c o nti n u o u s v ari a bl e h o w e v er, if 
a p pr o pri at e, t h e a g e m a y b e c at e g ori z e d s o t h at a n e q u al n u m b er of s u bj e ct s ar e i n 
e a c h c at e g or y) 
 
T h e f o ll o wi n g c o v ari at e s ar e s p e cifi c t o t h e e n d p oi nt s D F S, B M F S, a n d O S:  
 
Br e a st t u m or si z e 
 
L y m p h n o d e st at u s  
 
Hi st o p at h ol o gi c gr a di n g of t h e br e a st t u m or a n d t u m or t y p e 
 
Br e a st c a n c er t h er a p y 
 
H or m o n e r e c e pt or ( E R/ P g R) st at u s / E n d o cri n e t h er a p y 
 
H u m a n E pi d er m al gr o wt h f a ct or R e c e pt or 2 (H E R - 2) st at u s / H E R- 2 t ar g et e d t h er a p y 
 
Ot h er c o v ari at e s r e p ort e d i n lit er at ur e a s i m p ort a nt or fr o m ot h er o n g oi n g A m g e n 
st u di e s will b e c o n si d er e d i n t h e a n al y si s if c o n si d er e d a p pr o pri at e at t h e ti m e of 
a n al y si s. 
1 0. 3   
S a m pl e Si z e C o n si d er ati o n s 
A p pr o xi m at el y 3 4 0 0  s u bj e ct s will b e e nr oll e d i nt o t hi s tri al ( 1 7 0 0 p er tr e at m e nt gr o u p), 
w hi c h will c o n cl u d e o n c e a p pr o xi m at el y 2 4 7 s u bj e ct s h a v e e x p eri e n c e d a cli ni c al 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
fr a ct ur e.  T hi s a s s u m e s b a s e d o n c urr e nt r e cr uit m e nt a n d r e cr uit m e nt pr oj e cti o n s t h at 
t h er e will b e a n 8 2 - m o nt h a c cr u al p eri o d a n d o n a dr o p- o ut r at e of 3. 6 % p er y e ar.  
A p pr o xi m at el y 2 4 7 s u bj e ct s m u st e x p eri e n c e a cli ni c al fr a ct ur e f or t hi s st u d y t o h a v e 
8 0 % p o w er t o d et e ct a fr a ct ur e r ati o of 0. 7 0 ( d e n o s u m a b v s. c o ntr ol) wit h a t w o- si d e d 
si g nifi c a n c e l e v el o f 0. 0 5.  A h a z ar d r ati o of 0. 7 0 i n di c at e s t h at t h e fr a ct ur e r at e i n t h e 
d e n o s u m a b gr o u p i s 3 0 % l e s s t h a n i n t h e c o ntr ol gr o u p ( i e, 1. 3 9 % p er y e ar). 
T h e i n ci d e n c e of cli ni c al fr a ct ur e i n t h e A T A C tri al ( J a k e s z et al, 2 0 0 5 ) w a s 2 2. 6 p er 
1 0 0 0 s u bj e ct- y e ar s.  Fr o m t hi s t h e fr a ct ur e r at e i n t h e c o ntr ol gr o u p h a s b e e n e sti m at e d 
at 2. 4 3 % p er y e ar.   I n st u d y 2 0 0 5 0 2 0 9, t h e o b s er v e d t ot al fr a ct ur e r at e of b ot h ar m s 
c o m bi n e d aft er 6 1 m o nt h s i s 1. 7 % p er y e ar.  A s s u mi n g a h a z ar d r ati o of 0. 7 0, t h e 
fr a ct ur e r at e i n t h e c o ntr ol gr o u p i s e x p e ct e d t o b e a b o ut 2. 0 % p er y e ar.  A c c or di n g t o 
t hi s fr a ct ur e r at e, 2 4 7 fr a ct ur e s will b e r e a c h e d aft er 1 0 3  m o nt h s.  All s u bj e ct s will b e 
f oll o w e d u ntil t h e y h a v e h a d t h e o p p ort u nit y t o r e c ei v e at l e a st 2 d o s e s of I P.  
All cli ni c al fr a ct ur e s, e x c e pt t h o s e of t h e s k ull, f a c e, fi n g er s, a n d t o e s, w hi c h ar e t y pi c all y 
n ot a s s o ci at e d wit h o st e o p or o si s, will b e i n cl u d e d i n t h e a n al y si s of cli ni c al fr a ct ur e s. 
T h e k e y s e c o n d ar y e n d p oi nt a n al y si s i s a c o m p ari s o n of t h e p er c e nt c h a n g e of l u m b ar 
s pi n e B M D b et w e e n t h e d e n o s u m a b tr e at m e nt a n d pl a c e b o gr o u p s.  I n a s u b s et of t h e 
A T A C d at a ( E a st ell a n d A d a m s, 2 0 0 2 ) a 1. 8 % diff er e n c e w a s o b s er v e d b et w e e n t h e 
c h a n g e fr o m b a s eli n e t o 1 2 m o nt h s i n t h e t a m o xif e n a n d a n a str o z ol e gr o u p s.  T o h a v e 
9 0 % p o w er t o d et e ct a 1. 8 % diff er e n c e ( S D = 3. 9 %) b et w e e n d e n o s u m a b a n d pl a c e b o 
i n t h e p er c e nt a g e of c h a n g e of B M D f or l u m b ar s pi n e at 1 2 m o nt h s wit h a t w o- si d e d 
si g nifi c a n c e l e v el of 0. 0 5, it will b e n e c e s s ar y t o h a v e B M D d at a fr o m 1 0 2 s u bj e ct s p er 
tr e at m e nt ar m. 
1 0. 4   
A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s 
T hi s i s a d o u bl e- bli n d st u d y.  S u bj e ct tr e at m e nt a s si g n m e nt s will r e m ai n bli n d e d t o 
i n v e sti g at or, s u bj e ct s a n d A m g e n i n or d er t o r e d u c e bi a s.  T h e e xt er n al D M C will h a v e 
a c c e s s t o s u bj e ct tr e at m e nt a s si g n m e nt s.  T o mi ni mi z e t h e p ot e nti al i ntr o d u cti o n of bi a s, 
t h e s e i n di vi d u al s will n ot h a v e a n y dir e ct c o nt a ct wit h t h e st u d y sit e p er s o n n el or 
s u bj e ct s.  
T h e i d e ntit y of i n v e sti g ati o n al pr o d u ct a s si g n e d t o s u bj e ct s or t o i n di vi d u al b o x e s of 
i n v e sti g ati o n al pr o d u ct will b e c o nt ai n e d i n t h e I V R S.  A ut h ori z e d sit e st aff will b e 
pr o vi d e d wit h a u ni q u e P er s o n al I d e ntifi c ati o n N u m b er ( PI N) t o a c c e s s t h e I V R S t o 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
o bt ai n u n bli n di n g i nf or m ati o n.  T hi s PI N i s u ni q u e t o t h e i n di vi d u al a n d m u st n ot b e 
s h ar e d. 
A s u bj e ct’ s tr e at m e nt a s si g n m e nt s h o ul d o nl y b e u n bli n d e d w h e n k n o wl e d g e of t h e 
tr e at m e nt i s e s s e nti al f or t h e f urt h er m a n a g e m e nt of t h e s u bj e ct.  U n bli n di n g at t h e st u d y 
sit e f or a n y ot h er r e a s o n will b e c o n si d er e d a pr ot o c ol d e vi ati o n .  Th e pri n ci p al 
i n v e sti g at or i s str o n gl y e n c o ur a g e d t o c o nt a ct t h e A m g e n St u d y M a n a g er b ef or e 
u n bli n di n g a n y s u bj e ct’ s tr e at m e nt a s si g n m e nt, b ut m u st d o s o wit hi n 1 w or ki n g d a y aft er 
t h e e v e nt a n d m u st d o c u m e nt t h e u n bli n di n g i n t h e s u bj e ct’ s C R F . 
S u bj e ct s eli gi bl e t o r e c ei v e d e n o s u m a b i n t h e O L P will b e u n bli n d e d a s d et ail e d i n 
S e cti o n 5 . 
1 0. 5   
I nt eri m A n al y si s, E arl y St o p pi n g G ui d eli n e s, a n d Ti m e- p oi nt s of 
A n al y s e s 
A n e xt er n al D M C will b e f or m e d wit h m e m b er s c o n si sti n g of i n di vi d u al s c h o s e n f or t h eir 
e x p erti s e i n o n c ol o g y a n d b o n e di s e a s e.  S el e ct e d A B C S G a n d A m g e n st aff m a y s er v e 
a s li ai s o n s t o t h e e xt er n al D M C, b ut will n ot b e v oti n g m e m b er s, a n d will n ot b e 
u n bli n d e d  t o t h e r e s ult s.  T h e D M C will h a v e a c c e s s t o s u bj e ct’ s i n di vi d u al tr e at m e nt 
a s si g n m e nt s .  To mi ni mi z e t h e p ot e nti al i ntr o d u cti o n of bi a s, t h e s e i n di vi d u al s will n ot 
h a v e a n y dir e ct c o nt a ct wit h t h e st u d y sit e p er s o n n el or s u bj e ct s.  M e m b er s of t hi s 
e xt er n al D M C will i n cl u d e, at a mi ni m u m, p h y si ci a n s e xt er n al t o A m g e n a n d a p pr o pri at e 
st ati sti c al r e pr e s e nt ati o n e xt er n al t o A m g e n.  T h e D M C will m e et a p pr o xi m at el y a n n u all y.  
R e c or d s of all m e eti n g s will b e ar c hi v e d.  T h e D M C will c o m m u ni c at e m aj or s af et y 
c o n c er n s a n d r e c o m m e n d ati o n s r e g ar di n g st u d y m o difi c ati o n or t er mi n ati o n t o A m g e n 
s e ni or m a n a g e m e nt.  D et ail s r e g ar di n g t h e D M C will b e pr o vi d e d i n a s e p ar at e D M C 
C h art er. 
T hi s D M C will r e vi e w u n bli n d e d s af et y d at a .  Saf et y a n al y s e s pr o vi d e d t o t h e D M C will 
b e d e s cri pti v e i n n at ur e. 
T h er e will b e n o i nt eri m a n al y si s b a s e d o n t h e pri m ar y e n d p oi nt.  A n i nt eri m a n al y si s f or 
f utilit y f or t h e s e c o n d ar y e n d p oi nt D F S w a s p erf or m e d aft er P A D C D b y a n i n d e p e n d e nt 
st ati sti ci a n.  T hi s i nt eri m a n al y si s u s e d a n i nf or m al f utilit y b o u n d.  St u d y t er mi n ati o n m a y 
b e  r e c o m m e n d e d b y t h e D M C if t h e o b s er v e d h a z ar d r ati o e x c e e de d  t h e h a z ar d r ati o f or 
f utilit y ( 0. 8 5).  F oll o wi n g r e vi e w of t h e i nt eri m D F S a n al y si s r e s ult s, t h e D M C d et er mi n e d 
t h at t h e h a z ar d r ati o di d n ot i n di c at e f utilit y a n d t h at t h e st u d y s h o ul d c o nti n u e f urt h er f or 
a p pr o xi m at el y 6 6 m o nt h s.   I n a d diti o n, t h e D M C r e c o m m e n d e d t h at a ti m e- dri v e n 
a n al y si s f or effi c a c y of  t h e s e c o n d ar y e n d p oi nt D F S s h o ul d b e p erf or m e d at 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
a p pr o xi m at el y 1 8 m o nt h s aft er P A D C D,  b ef or e a n y i n v e sti g at or/ s u bj e ct l e v el u n bli n di n g 
o c c urr e d f or e ntr y i nt o t h e O L P. 
T h e pri m ar y a n al y si s will t a k e pl a c e aft er P A D C D w h e n all s u bj e ct s att e n d e d t h eir l a st 
st u d y vi sit ( c o n si d er e d a s E O T vi sit).  T h e pri m ar y a n al y si s i n cl u d e s t h e pri m ar y 
e n d p oi nt a n d t h e fir st t hr e e s e c o n d ar y e n d p oi nt s c o n c er ni n g t h e c h a n g e s i n B M D a n d 
v ert e br al fr a ct ur e s. 
A fi n al e x pl or at or y  
 a n al y si s a s w ell a s t h e m ai n a n al y s e s f or effi c a c y of t h e 
s e c o n d ar y e n d p oi nt s B M F S a n d O S will b e  p erf or m e d at t h e e n d of t h e m a i n st u d y.  
A d diti o n all y, 
 
 will b e e v al u at e d i n a fi n al 
e x pl or at or y a n al y si s at t hi s ti m e p oi nt.  O nl y d at a c oll e ct e d u p t o t h e E O S vi sit ( e n d of 
O L  tr e at m e nt vi sit or t h eir l a st s c h e d ul e d L T F U vi sit) will b e i n cl u d e d i n t h e fi n al 
a n al y si s.  A n y d at a c oll e ct e d fr o m t h e Z A s u b st u d y will b e e x cl u d e d.  
1 0. 6   
Pl a n n e d M et h o d s of A n al y si s 
1 0. 6. 1   
G e n er al A p pr o a c h/ C o n si d er ati o n s 
T h e pri n ci p al a n al y si s f or t h e effi c a c y e n d p oi nt s will b e c o n d u ct e d o n t h e F A S a n d t h e 
p er pr ot o c ol p o p ul ati o n a p pr o a c h will b e c o n si d er e d s u p p orti v e.  S af et y a n al y s e s will b e 
c o n d u ct e d o n t h e s af et y a n al y si s s et.   
W h er e t h e pr ot o c ol s p e cifi e s m ulti pl e b a s eli n e m e a s ur e m e nt s t o b e t a k e n, t h e m e a n of 
t h e b a s eli n e r e c or d s will b e u s e d f or c o m p ut ati o n of c h a n g e fr o m b a s eli n e e n d p oi nt s.  
Ot h er wi s e, b a s eli n e will b e t a k e n a s t h e o b s er v ati o n r e c or d e d j u st pri or t o fir st d o s e of 
i n v e sti g ati o n al pr o d u ct.   
F or ti m e t o e v e nt v ari a bl e s, K a pl a n- M ei er c ur v e s ( K a pl a n a n d M ei er, 1 9 5 8 ) will b e 
e sti m at e d a n d gr a p hi c all y di s pl a y e d.  T h e h a z ar d r ati o a n d it s c orr e s p o n di n g 9 5 % CI will 
b e e sti m at e d u si n g C o x M o d el .  
C o nti n u o u s v ari a bl e s will b e s u m m ari z e d d e s cri pti v el y u si n g m e a n, st a n d ar d d e vi ati o n, 
mi ni m u m, a n d m a xi m u m .  Me di a n a n d ot h er s el e ct e d p er c e ntil e s will b e s u b stit ut e d f or 
m e a n a n d st a n d ar d d e vi ati o n f or p ar a m et er s e x hi biti n g a l a c k of n or m alit y. 
Fr e q u e n ci e s a n d p er c e nt a g e s will b e pr e s e nt e d f or c at e g ori c al v a ri a bl e s. 
T h e pri m ar y a n al y si s f or fr a ct ur e-r el at e d e n d p oi nt s will t a k e pl a c e w h e n f or all s u bj e ct s , 
d at a o n cli ni c al fr a ct ur e s o c c urri n g pri or t o P A D C D h a v e b e e n c oll e ct e d vi a t el e p h o n e or 
p h y si c al vi sit s wit hi n si x m o nt h s aft er P A D C D at t h e l at e st.  T h e a n al y si s of D F S will b e 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
p erf or m e d at a p pr o xi m at el y 1 8 m o nt h s aft er P A D C D (f oll o wi n g D M C r e vi e w of t h e D F S 
i nt eri m a n al y si s).  A n al y si s of t h e di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s B M F S 
a n d O S will b e p erf or m e d at t h e e n d of t h e st u d y. 
T h e pri m ar y a n d s e c o n d ar y n ull h y p ot h e s e s will b e t e st e d u si n g t h e hi er ar c hi c al a n al y si s 
str at e g y a n d t h e H o c h b er g pr o c e d ur e t o c o ntr ol t h e o v er all si g nifi c a n c e l e v el of 0. 0 5.   
T h e D F S a n al y si s at a p pr o xi m at el y 1 8 m o nt h s aft er P A D C D will b e c o n si d er e d t h e m ai n 
D F S a n al y si s f or t h e hi er ar c hi c al t e sti n g str at e g y, wit h  t h e f
 
.   
T h e pri m ar y n ull h y p ot h e si s will b e t e st e d fir st at a si g nifi c a n c e l e v el of 0. 0 5.  If t h e 
pri m ar y h y p ot h e si s i s r ej e ct e d, t h e s e c o n d ar y n ull h y p ot h e s e s will b e t e st e d i n a 
st e p wi s e f a s hi o n o v er 6 st e p s at a si g nifi c a n c e l e v el of 0. 0 5.   I n c a s e a n y o n e of t h e 
h y p ot h e s e s i s n ot r ej e ct e d at a pr e vi o u s st e p , all s u b s e q u e nt e n d p oi nt s will b e a n al y s e d 
i n a d e s cri pti v e m a n n er o nl y.  S o m e st e p s i n v ol v e si n gl e n ull h y p ot h e si s a n d s o m e 
i n v ol v e m ulti pl e n ull h y p ot h e s e s.  If t h er e ar e m ulti pl e n ull h y p ot h e s e s, t h e H o c h b er g 
pr o c e d ur e will b e u s e d t o c o ntr ol f or m ulti pli cit y a n d t h e t e sti n g will pr o c e e d t o t h e n e xt 
st e p o nl y if all n ull h y p ot h e s e s ar e r ej e ct e d.  T h e s e st e p s will i n v ol v e t h e s e c o n d ar y n ull 
h y p ot h e s e s f or t h e f oll o wi n g e n d p oi nt s: 
Fr a ct ur e-r el at e d s e c o n d ar y e n d p oi nt s:  
A.  P er c e nt c h a n g e i n t ot al l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k B M D fr o m b a s eli n e 
t o m o nt h 3 6 ( at pr e - s el e ct e d sit e s) 
B.  S u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e s ( m or p h o m etri c v ert e br al fr a ct ur e s 
i d e ntifi e d fr o m st u d y x-r a y s a n d cli ni c al v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y) at 
m o nt h 3 6  
C.  S u bj e ct i n ci d e n c e of a n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s 
( m or p h o m etri c v ert e br al fr a ct ur e s i d e ntifi e d fr o m o n st u d y x-r a y s a n d cli ni c al 
v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y s) at m o nt h 3 6 
Di s e a s e o ut c o m e-r el at e d s e c o n d ar y e n d p oi nt s:  
D.  Di s e a s e-fr e e s ur vi v al i s d efi n e d a s a n y e vi d e n c e of di s e a s e r e c urr e n c e or d e at h fr o m 
a n y c a u s e 
E.  B o n e m et a st a si s-fr e e s ur vi v al d et er mi n e d b y t h e ti m e t o fir st o c c urr e n c e of b o n e 
m et a st a si s ( eit h er s y m pt o m ati c or a s y m pt o m ati c) or d e at h fr o m a n y c a u s e  
F.  
O v er all s ur vi v al 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
St ati sti c al a n al y si s pr o c e d ur e s a n d t e c h ni q u e s will b e r e vi e w e d i n t h e li g ht of c urr e nt 
pr a cti c e a n d n e w t e c h ni q u e s, pri or t o br e a ki n g tr e at m e nt bli n d, a n d if a p pr o pri at e 
alt er n ati v e n e w er t e c h ni c al pr o c e d ur e s will b e a d o pt e d.  
1 0. 6. 2   
A n al y si s of K e y St u d y E n d p oint s  
1 0. 6. 2. 1   
Effi c a c y A n al y si s 
Pri m ar y E n d p oi nt 
T h e ti m e t o fir st o n- st u d y cli ni c al fr a ct ur e will b e d efi n e d a s t h e n u m b er of d a y s fr o m 
r a n d o mi z ati o n t o t h e d at e of t h e x-r a y c o nfir mi n g t h e cli ni c al fr a ct ur e.  S u bj e ct s w h o di e 
or wit h dr a w wit h o ut e x p eri e n ci n g a cli ni c al fr a ct ur e will b e c e n s or e d at t h e d at e of l a st 
c o nt a ct or st u d y t er mi n ati o n w hi c h e v er i s e arli er.  O nl y cli ni c al fr a ct ur e s w hi c h o c c ur 
pri or t o P A D C D will b e i n cl u d e d i n t h e a n al y si s f or t h e pri m ar y e n d p oi nt.  T h e pri m ar y 
a n al y si s will u s e a C o x m o d el ( C o x, 1 9 7 2 ) i n cl u di n g tr e at m e nt gr o u p s a s t h e 
i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e r a n d o mi z ati o n str atifi c ati o n f a ct or s.  
 
  S u m m ar y st ati sti c s will i ncl u d e t h e h a z ar d r ati o of d e n o s u m a b c o m p ar e d 
wit h pl a c e b o a n d 9 5 % CI; e sti m at e d fr a ct ur e r at e s at 3 6 m o nt h s a n d 9 5 % CI u si n g 
K a pl a n- M ai er m et h o d; cr u d e i n ci d e n c e s at t h e E n d of St u d y a n d 9 5 % CI; diff er e n c e s 
b et w e e n fr a ct ur e r at e s a n d 9 5 % CI. 
S e n siti vit y a n al y s e s will b e p erf or m e d u si n g t h e pri m ar y a n al y si s m et h o d.  T h e fir st 
s e n siti vit y a n al y si s will c o n si d er t h e s u bj e ct s w h o wit h dr a w fr o m t h e tri al d u e t o a 
> 1 0 %  l o s s of B M D i n t h e l u m b ar s pi n e o v er a n y 1- y e ar p eri o d a s h a vi n g h a d a cli ni c al 
fr a ct ur e at t h e ti m e of wit h dr a w al.  T hi s will a s s e s s if st u d y m o nit ori n g h a s r e s ult e d i n 
i nf or m ati v e c e n s ori n g of s u bj e ct s wit hi n t h e tri al.  A s e c o n d s e n siti vit y a n al y si s will b e 
c o n d u ct e d o n t h e p er pr ot o c ol p o p ul ati o n t o a s s e s s t h e eff e ct of n o n- pr ot o c ol c o m pli a nt 
s u bj e ct s.  T h e pri m ar y a n al y si s will c o n si d er all a v ail a bl e s u bj e ct d at a r e g ar dl e s s of t h e 
s u bj e ct s ti m e si n c e l a st tr e at m e nt wit h st u d y dr u g, a t hir d s e n siti vit y a n al y si s will 
c o n si d er t h e i nfl u e n c e of s u bj e ct e x p eri e n c e s u b s e q u e nt t o di s c o nti n u ati o n fr o m st u d y 
tr e at m e nt.  If a n y of t h e s e n siti vit y a n al y s e s c a u s e c o nfli cti n g r e s ult s t o t h e pri m ar y 
a n al y si s t h e n si mil ar s e n siti vit y a n al y s e s will b e c o n d u ct e d f or t h e s e c o n d ar y r el at e d t o 
B M D a n d fr a ct ur e. 
S e c o n d ar y E n d p oi nt s 
T h e pr e s e n c e or a b s e n c e of a n e w v ert e br al fr a ct ur e ( m or p h o m etri c v ert e br al fr a ct ur e s 
i d e ntifi e d fr o m o n st u d y x-r a y s a n d cli ni c al v ert e br al fr a ct ur e s c o nfir m e d b y x-r a y s) will 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
b e n ot e d at 3 6  m o nt h s ( o v er a 3 6 m o nt h e v al u ati o n p eri o d).  T h e pri m ar y a n al y si s of t hi s 
e n d p oi nt will u s e l o gi st i c r e gr e s si o n m o d el s i n cl u di n g tr e at m e nt gr o u p s a s t h e 
i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e r a n d o mi z ati o n str atifi c ati o n f a ct or s.  
 
. 
T h e p er c e nt c h a n g e i n l u m b ar s pi n e, t ot al hi p a n d f e m or al n e c k B M D fr o m b a s eli n e t o 
3 6  m o nt h s will b e c al c ul at e d f or s u bj e ct s at pr e- s el e ct e d sit e s.  T h e pri m ar y a n al y si s of 
t h e s e e n d p oi nt s will e m pl o y a mi x e d eff e ct s m o d el (L o n gf or d, 1 9 9 3 ) i n cl u di n g tr e at m e nt 
gr o u p s a s t h e i n d e p e n d e nt v ari a bl e a n d str atifi e d b y t h e r a n d o mi z ati o n str atifi c ati o n 
f a ct or s.  
. 
Di s e a s e-fr e e s ur vi v al i s d efi n e d a s ti m e t o a n y e vi d e n c e of l o c al or di st a nt m et a st a s e s , 
c o ntr a-l at er al br e a st c a n c er, s e c o n d ar y c ar ci n o m a, or d e at h fr o m a n y c a u s e.   B o n e 
m et a st a s e s-fr e e s ur vi v al i s d et er mi n e d b y t h e ti m e t o fir st o c c urr e n c e of b o n e 
m et a st a s e s ( eit h er s y m pt o m ati c or a s y m pt o m ati c) or d e at h fr o m a n y c a u s e.   T h e s e 
e n d p oi nt s a n d O S  will b e a n al y z e d u si n g t h e s a m e m et h o d s a s u s e d i n t h e a n al y si s of 
t h e pri m ar y e n d p oi nt.  
.   
1 0. 6. 2. 2   
S af et y A n al y s e s 
S af et y d at a will b e s u m m ari z e d f or all s u bj e ct s w h o r e c ei v e at l e a st 1 d o s e of 
i n v e sti g ati o n al pr o d u ct s.  All A E s  will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or 
R e g ul at or y A cti viti e s ( M e d D R A) .  An y a d v er s e e v e nt s will b e a n al y z e d a s tr e at m e nt 
e m er g e nt if t h e i n di c at or of “ Di d e v e nt st art b ef or e t h e fir st d o s e of i n v e sti g ati o n al 
pr o d u ct” i s c h e c k e d a s “ N o” o n A d v er s e E v e nt s S u m m ar y C R F p a g e s.  T h e a n al y si s of 
a d v er s e e v e nt s will b e d e s cri pti v e.  T h e s u bj e ct i n ci d e n c e r at e s of tr e at m e nt- e m er g e nt 
a d v er s e e v e nt s r e p ort e d d uri n g t h e st u d y p eri o d will b e t a b ul at e d b y s y st e m or g a n cl a s s 
a n d pr ef err e d t er m.  A d diti o n al s u m m ar y t a bl e s will b e pr o vi d e d s e p ar at el y f or s eri o u s 
a d v er s e e v e nt s, C T C A E gr a d e 3, 4, or 5 A E s , a d v er s e e v e nt s l e a di n g t o i n v e sti g ati o n al 
pr o d u ct di s c o nti n u ati o n, a n d a d v er s e e v e nt s l e a di n g t o st u d y wit h dr a w al.  N arr ati v e s of 
d e at h s a n d s eri o u s a d v er s e e v e nt s will al s o b e pr o vi d e d .  All i n v e sti g ati o n al pr o d u ct 
r el at e d a d v er s e e v e nt s, S A E s , C T C A E gr a d e 3, 4 or 5 a d v er s e e v e nt s, a n d a d v er s e 
e v e nt s l e a di n g t o st u d y wit h dr a w al will b e s u m m ari z e d i n t h e s a m e m a n n er a s 
tr e at m e nt- e m er g e nt a d v er s e e v e nt s.  All a d v er s e e v e nt s, C T C A E gr a d e 3, 4, or 5 
a d v er s e e v e nt s, s eri o u s a d v er s e e v e nt s, all i n v e sti g ati o n al pr o d u ct r el at e d a d v er s e 
e v e nt s, i n v e sti g ati o n al pr o d u ct r el at e d C T C A E gr a d e 3, 4, or 5 A E s , a n d i n v e sti g ati o n al 
pr o d u ct r el at e d s eri o u s a d v er s e e v e nt s will al s o b e s u m m ari z e d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
T h e s u bj e ct i n ci d e n c e r at e s of 
 
 r e p ort e d d uri n g t h e O L P will b e t a b ul at e d s e p ar at el y b y 
s y st e m or g a n cl a s s a n d pr ef err e d t er m.   
L a b or at or y p ar a m et er s will b e s u m m ari z e d o v er ti m e u si n g d e s cri pti v e st ati sti c s f or 
r e c or d e d v al u e s a n d c h a n g e fr o m b a s eli n e a n d s hift s t a bl e s, i n w hi c h t h e i n ci d e n c e of 
s hift of t o xi cit y gr a d e ( C T C A E v er si o n 3. 0) i n r e c or d e d v al u e s fr o m b a s eli n e t o “ w or st” 
o n - st u d y v al u e i s di s pl a y e d.  Gr a p hi c al r e pr e s e nt ati o n s of a g gr e g at e d at a m a y al s o b e 
pr e s e nt e d f or p ar a m et er s of i nt er e st s. 
I n ci d e n c e of f at al a d v er s e e v e nt s will b e s u m m ari z e d f or all e nr oll e d s u bj e ct s. 
1 0. 6. 2. 3   
A nti-d e n o s u m a b A nti b o di e s  
T h e i n ci d e n c e a n d p er c e nt a g e s of s u bj e ct s w h o d e v el o p bi n di n g a n d n e utr ali zi n g 
a nti - d e n o s u m a b a nti b o di e s at a n y ti m e will b e t a b ul at e d b y tr e at m e nt gr o u p a n d vi sit. 
1 0. 6. 2. 4   
E x pl or at or y A n al y s e s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 1.   
I N V E S TI G A TI O N A L P R O D U C T 
1 1. 1   
D e n o s u m a b 
Bli n d e d p h a s e 
D e n o s u m a b m a y b e pr o vi d e d a s eit h er of t h e 2 f oll o wi n g f or m ul ati o n s:  1) a s a st eril e, 
cl e ar, c ol orl e s s  t o sli g htl y y ell o w, pr e s er v ati v e fr e e li q ui d i n bli n d e d-l a b el gl a s s vi al s;  
2) a s a pr efill e d s yri n g e ( P F S) a s a st eril e, si n gl e u s e, pr e s er v ati v e fr e e s ol uti o n f or 
s u b c ut a n e o u s i nj e cti o n.  T h e vi al f or m ul ati o n i s 6 0 m g d e n o s u m a b p er m L of  
 m M 
S o di u m A c et at e, 
% s or bit ol, wit h a p H of  
.  T h e P F S f or m ul ati o n c o nt ai n s 6 0 m g/ m L 
d e n o s u m a b,  
 m M a c et at e (  m g/ m L),  
% ( 
 m g/ m L) s or bit ol a n d  
% 
( 
 m g/ m L) p ol y s orb at e 2 0 at a p H of  
.  T h e P F S i s fill e d t o a t ar g et d eli v er a bl e 
v ol u m e of  
 m L.  Pl a c e b o will b e s u p pli e d i n m at c h e d c o nt ai n er s a n d t h e f or m ul ati o n 
will b e i d e nti c al t o d e n o s u m a b wit h t h e e x c e pti o n of t h e pr ot ei n c o nt e nt.  
T h e b o x n u m b er of i n v e sti g ati o n al pr o d u ct i s t o b e r e c or d e d o n e a c h s u bj e ct’ s 
i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n C R F.   
U ni q u e b o x e s will b e a s si g n e d f or e a c h d o s e t h e s u bj e ct will r e c ei v e w hil e o n st u d y.  T o 
o bt ai n b o x n u m b er a s si g n m e nt f or a s c h e d ul e d o s e, sit e p er s o n n el s h o ul d  c all t h e I V R S. 
R ef er t o S e cti o n s 1 0. 4  a n d 1 1. 2  f or c o n diti o n s a n d r e q uir e m e nt s f or u n bli n di n g.  
I n v e sti g ati o n al pr o d u ct d et ail s f or d e n o s u m a b i n cl u di n g l a b eli n g, st or a g e, pr e p ar ati o n, 
et c., ar e pr o vi d e d i n t h e P h ar m a c y G ui d e, A p p e n di x C . 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
O p e n- l a b el p h a s e 
D e n o s u m a b will b e pr o vi d e d a s a P F S a s a st eril e, si n gl e u s e, pr e s er v ati v e fr e e s ol uti o n 
f or s u b c ut a n e o u s i nj e cti o n.  T h e P F S f or m ul ati o n c o nt ai n s 6 0 m g/ m L d e n o s u m a b, 
 m M a c et at e (  m g/ m L),  
%  
 m g/ m L) s or bit ol a n d  
% ( 
 m g/ m L) 
p ol y s or b at e 2 0 at a p H of 
.  T h e P F S i s fill e d t o a t ar g et d eli v er a bl e v ol u m e of 1. 0 m L. 
B o x e s s h o ul d b e s el e ct e d fr o m t h e A m g e n s u p pli e d st o c k. 
Pr o d u ct d et ail s f or d e n o s u m a b i n cl u di n g l a b eli n g, st or a g e, pr e p ar ati o n, et c ar e pr o vi d e d 
i n t h e P h ar m a c y G ui d e. 
1 1. 2   
A c c e s s t o Tr e at m e nt A s si g n m e nt s 
1 1. 2. 1   
Bli n d e d p h a s e 
T h e i d e ntit y of i n v e sti g ati o n al pr o d u ct a s si g n e d t o s u bj e ct n u m b er s or t o i n di vi d u al b o x e s 
of i n v e sti g ati o n al pr o d u ct will b e a v ail a bl e f or e m er g e n c y sit u ati o n s t hr o u g h a n I V R S.  
A ut h ori z e d sit e st aff will b e pr o vi d e d wit h a u ni q u e P er s o n al I d e ntifi c ati o n N u m b er ( PI N) 
t o a c c e s s t h e I V R S t o o bt ai n u n bli n di n g i nf or m atio n.  T hi s PI N i s u ni q u e t o t h e i n di vi d u al 
a n d m u st n ot b e s h ar e d.  
A s u bj e ct’ s tr e at m e nt a s si g n m e nt s h o ul d o nl y b e u n bli n d e d w h e n k n o wl e d g e of t h e 
tr e at m e nt i s e s s e nti al f or t h e f urt h er m a n a g e m e nt of t h e s u bj e ct.  U n bli n di n g at t h e st u d y 
sit e f or a n y ot h er r e a s o n will b e c o n si d er e d a pr ot o c ol d e vi ati o n. 
T h e pri n ci p al i n v e sti g at or i s str o n gl y e n c o ur a g e d t o c o nt a ct t h e A m g e n st u d y m a n a g er 
b ef or e u n bli n di n g a n y s u bj e ct’ s tr e at m e nt a s si g n m e nt, b ut m u st d o s o wit hi n 1 w or ki n g 
d a y aft er t h e e v e nt a n d m u st d o c u m e n t t h e u n bli n di n g i n t h e s u bj e ct’ s C R F.   
1 1. 2. 2   
O p e n-l a b el P h a s e 
T h e o p p ort u nit y t o st art wit h o p e n -l a b el d e n o s u m a b will b e o p e n f or 12 m o nt h s f oll o wi n g 
Pr ot o c ol A m e n d m e nt 4 r e g ul at or y a n d I R B/I E C a p pr o v al, w hi c h will b e aft er t h e di s e a s e 
o ut c o m e-r el at e d e n d p oi nt a n al y si s p erf or m e d a p pr o xi m at el y 1 8 m o nt h s aft er  P A D C D. 
Aft er t h e I C F i s si g n e d, u n bli n di n g of s u bj e ct s t h o u g ht eli gi bl e f or d e n o s u m a b tr e at m e nt 
i n t h e O L P c a n o c c ur, a n d t h e fir st d o s e of d e n o s u m a b s h all b e a d mi ni st er e d wit hi n 
8 d a y s of u n bli n di n g.   
1 1. 3   
C o mpli a n c e i n I n v e sti g ati o n al Pr o d u ct A d mi ni str ati o n  
W h e n i n v e sti g ati o n al pr o d u ct i s di s p e n s e d f or a d mi ni str ati o n t o t h e s u bj e ct d uri n g a 
st u d y, t h e i n v e sti g at or or r e s p o n si bl e p er s o n will d et er mi n e t h e l e v el of c o m pli a n c e wit h 
t h e a d mi ni str ati o n of t h e i n v e sti g ati o n al pr o d u ct.  T h e s u bj e ct’ s i n v e sti g ati o n al pr o d u ct 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 6 of 1 0 4 
C O N FI D E N TI A L 
 
 
c o m pli a n c e ( e g,  a m o u nt u s e d) will b e r e c or d e d o n t h e i n v e sti g ati o n al pr o d u ct 
a d mi ni str ati o n c a s e r e p ort f or m. 
1 2.   
R E G U L A T O R Y O B LI G A TI O N S 
1 2. 1   
I nf or m e d C o n s e nt 
T h e writt e n i nf or m e d c o n s e nt d o c u m e nt s h o ul d b e pr e p ar e d i n t h e l a n g u a g e( s) of t h e 
p ot e nti al p ati e nt p o p ul ati o n.  A m g e n will di s c u s s u p d at e s wit h A B C S G a n d aft er a n 
a gr e e m e nt A m g e n will pr o vi d e t h e t e m pl at e t o A B C S G w h o will di s s e mi n at e t h e 
i nf or m ati o n t o t h e i n v e sti g at or s.   
B ef or e a s u bj e ct’ s p arti ci p ati o n i n t h e cli ni c al st u d y, t h e i n v e sti g at or i s r e s p o n si bl e f or 
o bt ai ni n g writt e n i nf or m e d c o n s e nt fr o m t h e s u bj e ct or l e g all y a c c e pt a bl e r e pr e s e nt ati v e 
aft er a d e q u at e e x pl a n ati o n of t h e ai m s, m et h o d s, a nti ci p at e d b e n efit s, a n d p ot e nti al 
h a z ar d s of t h e st u d y a n d b ef or e a n y pr ot o c ol- s p e cifi c s cr e e ni n g pr o c e d ur e s or a n y 
i n v e sti g ati o n al pr o d u ct s ar e a d mi ni st er e d.  A l e g all y a c c e pt a bl e r e pr e s e nt ati v e i s a n 
i n di vi d u al or ot h er b o d y a ut h ori z e d u n d er a p pli c a bl e l a w t o c o n s e nt o n b e h alf of a 
pr o s p e cti v e s u bj e ct, t o t h e s u bj e ct’ s p arti ci p ati o n i n t h e cli ni c al st u d y. 
T h e a c q ui siti o n of i nf or m e d c o n s e nt a n d t h e s u bj e ct’ s a gr e e m e nt or r ef u s al of hi s/ h er 
n otifi c ati o n of t h e pri m ar y c ar e p h y si ci a n  s h o ul d b e d o c u m e nt e d i n t h e s u bj e ct’ s m e di c al 
r e c or d s, a n d t h e i nf or m e d c o n s e nt f or m s h o ul d b e si g n e d a n d p er s o n all y d at e d b y t h e 
s u bj e ct or a l e g all y a c c e pt a bl e r e pr e s e nt ati v e a n d b y t h e p er s o n w h o c o n d u ct e d t h e 
i nf or m e d c o n s e nt di s c u s si o n ( n ot n e c e s s aril y a n i n v e sti g at or).  T h e ori gi n al si g n e d 
i nf or m e d c o n s e nt f or m s h o ul d b e r et ai n e d i n a c c or d a n c e wit h i n stit uti o n al p oli c y, a n d a 
c o p y of t h e si g n e d c o n s e nt f or m s h o ul d b e pr o vi d e d t o t h e s u bj e ct or l e g all y a c c e pt a bl e 
r e pr e s e nt ati v e. 
If a p ot e nti al s u bj e ct i s illit er at e or vi s u all y i m p air e d a n d d o e s n ot h a v e a l e g all y 
a c c e pt a bl e r e pr e s e nt ati v e, t h e i n v e sti g at or m u st pr o vi d e a n i m p arti al wit n e s s t o r e a d t h e 
i nf or m e d c o n s e nt f or m t o t h e s u bj e ct a n d m u st all o w f or q u e sti o n s.  T h er e aft er, b ot h t h e 
s u bj e ct or l e g all y a c c e pt a bl e r e pr e s e nt ati v e a n d t h e wit n e s s m u st si g n t h e i nf or m e d 
c o n s e nt f or m t o att e st t h at i nf or m e d c o n s e nt w a s fr e el y gi v e n a n d u n d er st o o d. 
1 2. 2  
I n d e p e n d e nt Et hi c s C o m mitt e e/I n stit uti o n al R e vi e w B o ar d 
A c o p y of t h e pr ot o c ol, pr o p o s e d i nf or m e d c o n s e nt f or m, ot h er writt e n s u bj e ct 
i nf or m ati o n, a n d a n y pr o p o s e d a d v erti si n g m at eri al m u st b e s u b mitt e d t o t h e I E C f or 
writt e n a p pr o v al.  F or e a c h p arti ci p ati n g sit e, A B C S G m u st r e c ei v e a c o p y of t h e writt e n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
a p pr o v al of t h e pr ot o c ol a n d i nf or m e d c o n s e nt f or m b ef or e r e cr uit m e nt of s u bj e ct s i nt o 
t h e st u d y a n d s hi p m e nt of i n v e sti g ati o n al pr o d u ct. 
T h e i n v e sti g at or m u st s u b mit a n d, w h er e n e c e s s ar y, o bt ai n a p pr o v al fr o m t h e I E C f or all 
s u b s e q u e nt pr ot o c ol a m e n d m e nt s a n d c h a n g e s t o t h e i nf or m e d c o n s e nt d o c u m e nt.  T h e 
i n v e sti g at or s h o ul d n otif y t h e I E C of d e vi ati o n s fr o m t h e pr ot o c ol or s eri o u s a d v er s e 
e v e nt s o c c urri n g at t h e sit e a n d ot h er a d v er s e e v e nt r e p ort s r e c ei v e d fr o m A m g e n, i n 
a c c or d a n c e wit h l o c al pr o c e d ur e s. 
T h e i n v e sti g at or will b e r e s p o n si bl e f or o bt ai ni n g a n n u al I E C r e n e w al t hr o u g h o ut t h e 
d ur ati o n of t h e st u d y a s a p pli c a bl e.  C o pi e s of t h e i n v e sti g at or’ s r e p ort s a n d t h e I E C 
c o nti n u a n c e of a p pr o v al m u st b e fil e d i n t h e st u d y fil e s. 
1 2. 3   
Pr e st u d y D o c u m e nt ati o n R e q uir e m e nt s 
T h e i n v e sti g at or i s r e s p o n si bl e f or f or w ar di n g t h e f oll o wi n g d o c u m e nt s t o A m g e n f or 
r e vi e w b ef or e i n v e sti g ati o n al pr o d u ct i s s hi p p e d: 
 
Si g n e d a n d d at e d pr ot o c ol si g n at ur e p a g e (I n v e sti g at or’ s A gr e e m e nt) 
 
C o p y of a p pr o v e d i nf or m e d c o n s e nt f or m a n d s u bj e ct i nf or m ati o n s h e et 
 
C o p y of t h e I E C a p pr o v al of t h e pr ot o c ol, c o n s e nt f or m, a n d s u bj e ct i nf or m ati o n 
s h e et 
 
U p -t o- d at e c urri c ul a vit a e of pri n ci p al i n v e sti g at or a n d all c o/ s u bi n v e sti g at or s 
 
I E C c o m p o siti o n a n d/ or writt e n st at e m e nt t h at I E C i s i n c o m pli a n c e wit h r e g ul ati o n s 
 
C urr e nt s u bj e ct/i n v e sti g at or i n d e m nit y i n s ur a n c e 
 
Si g n e d st u d y c o ntr a ct 
 
C o m pl et e d Fi n a n ci al Di s cl o s ur e F or m 
 
Ot h er c o u ntr y- s p e cifi c f or m s, a s d efi n e d i n t h e c o u ntr y- s p e cifi c r e q uir e m e nt s  
1 2. 4   
S u bj e ct C o nfi d e nti alit y 
T h e i n v e sti g at or m u st e n s ur e t h at t h e s u bj e ct’ s c o nfi d e nti alit y i s m ai nt ai n e d.  O n t h e 
c a s e r e p ort f or m s or ot h er d o c u m e nt s s u b mitt e d t o A m g e n/ A B C S G, s u bj e ct s s h o ul d b e 
i d e ntifi e d b y t h e s u bj e ct st u d y n u m b er o nl y.  D o c u m e nt s t h at ar e n ot f or s u b mi s si o n t o 
A m g e n/ A B C S G ( e g,  si g n e d i nf or m e d c o n s e nt f or m s) s h o ul d b e k e pt i n stri ct c o nfi d e n c e 
b y t h e i n v e sti g at or. 
I n c o m pli a n c e wit h l o c al r e g ul at or y r e q uir e m e nt s an d I C H G C P G ui d eli n e s, it i s r e q uir e d 
t h at t h e i n v e sti g at or a n d i n stit uti o n p er mit a ut h ori z e d r e pr e s e nt ati v e s of t h e c o m p a n y, of 
t h e r e g ul at or y a g e n c y( s), a n d t h e I E C dir e ct a c c e s s t o r e vi e w t h e s u bj e ct’ s ori gi n al 
m e di c al r e c or d s f or v erifi c ati o n of st u d y-r el at e d pr o c e d ur e s a n d d at a.  Dir e ct a c c e s s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
i n cl u d e s e x a mi ni n g, a n al y zi n g, v erif yi n g, a n d r e pr o d u ci n g a n y r e c or d s a n d r e p ort s t h at 
ar e i m p ort a nt t o t h e e v al u ati o n of t h e st u d y.  T h e i n v e sti g at or i s o bli g at e d t o i nf or m a n d 
o bt ai n t h e c o n s e nt of t h e s u bj e ct t o p er mit n a m e d r e pr e s e nt ati v e s t o h a v e a c c e s s t o h er 
st u d y-r el at e d r e c or d s wit h o ut vi ol ati n g t h e c o nfi d e nti alit y of t h e s u bj e ct. 
1 2. 5  
I n v e sti g at or Si g n at or y O bli g ati o n s 
E a c h cli ni c al st u d y r e p ort s h o ul d b e si g n e d b y t h e i n v e sti g at or or, i n t h e c a s e of 
m ulti c e nt er st u di e s, t h e c o or di n ati n g i n v e sti g at or. 
T h e c o or di n ati n g i n v e sti g at or, i d e ntifi e d b y A m g e n, will eit h er b e: 
 
a r e c o g ni z e d e x p ert i n t h e t h er a p e uti c ar e a 
 
a n i n v e sti g at or w h o pr o vi d e d si g nifi c a nt c o ntri b uti o n s t o eit h er t h e d e si g n or 
i nt er pr et ati o n of t h e st u d y 
 
a n i n v e sti g at or c o ntri b uti n g a hi g h n u m b er of eli gi bl e s u bj e ct s 
1 3.   
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S 
1 3. 1   
Pr ot o c ol A m e n d m e nt s a n d St u d y T er mi n ati o n 
Pr ot o c ol a m e n d m e nt s, e x c e pt w h er e n e c e s s ar y t o eli mi n at e a n i m m e di at e h a z ar d t o 
s u bj e ct s, m u st b e m a d e o nl y wit h t h e pri or a p pr o v al of A m g e n.  A gr e e m e nt fr o m t h e 
i n v e sti g at or m u st b e o bt ai n e d f or all pr ot o c ol a m e n d m e nt s.  T h e I E C m u st b e i nf or m e d 
of all a m e n d m e nt s a n d gi v e a p pr o v al.  A B C S G m u st s e n d a c o p y of t h e a p pr o v al l ett er 
fr o m t h e I E C t o A m g e n. 
B ot h A m g e n a n d t h e i n v e sti g at or r e s er v e t h e ri g ht t o t er mi n at e t h e st u d y a c c or di n g t o 
t h e st u d y c o ntr a ct.  T h e i n v e sti g at or s h o ul d n otif y t h e I E C i n writi n g of t h e st u d y’ s 
c o m pl eti o n or e arl y t er mi n ati o n a n d s e n d a c o p y of t h e n otifi c ati o n t o A m g e n. 
S u bj e ct s m a y b e eli gi bl e f or c o nti n u e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct b y 
e xt e n si o n pr ot o c ol or a s pr o vi d e d f or b y t h e l o c al c o u ntr y’ s r e g ul at or y m e c h a ni s m.  
H o w e v er, A m g e n r e s er v e s t h e u nil at er al ri g ht, at it s s ol e di s cr eti o n, t o d et er mi n e 
w h et h er t o s u p pl y t h e i n v e sti g ati o n al pr o d u ct, a n d b y w h at m e c h a ni s m, aft er t er mi n ati o n 
of t h e tri al a n d b ef or e it i s a v ail a bl e c o m m er ci all y.  
1 3. 2   
St u d y D o c u m e nt ati o n a n d Ar c hi v e 
T h e i n v e sti g at or s h o ul d m ai nt ai n a li st of a p pr o pri at el y q u alifi e d p er s o n s t o w h o m h e/ s h e 
h a s d el e g at e d st u d y d uti e s.  All p er s o n s a ut h ori z e d t o m a k e e ntri e s a n d/ or c orr e cti o n s 
o n c a s e r e p ort f or m s will b e i n cl u d e d o n t h e A B C S G  D el e g ati o n of A ut h orit y F or m. 
S o ur c e d o c u m e nt s ar e ori gi n al d o c u m e nt s, d at a, a n d r e c or d s fr o m w hi c h t h e s u bj e ct’ s 
c a s e r e p ort f or m d at a ar e o bt ai n e d.  T h e s e i n cl u d e b ut ar e n ot li mit e d t o h o s pit al 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
r e c or d s, cli ni c al a n d offi c e c h art s, l a b or at or y a n d p h ar m a c y r e c or d s, di ari e s, mi cr ofi c h e s, 
r a di o gr a p h s, a n d c orr e s p o n d e n c e.   
T h e i n v e sti g at or a n d st u d y st aff ar e r e s p o n si bl e f or m ai nt ai ni n g a c o m pr e h e n si v e a n d 
c e ntr ali z e d fili n g s y st e m of all st u d y-r el at e d ( e s s e nti al) d o c u m e nt ati o n, s uit a bl e f or 
i n s p e cti o n at a n y ti m e b y r e pr e s e nt ati v e s fr o m A m g e n a n d/ or a p pli c a bl e r e g ul at or y 
a ut h oriti e s.  El e m e nt s s h o ul d i n cl u d e: 
 
S u bj e ct fil e s c o nt ai ni n g c o m pl et e d i nf or m e d c o n s e nt f or m s a n d s u bj e ct i d e ntifi c ati o n 
li st.  D o c u m e nt ati o n of C R F s i s vi si bl e vi a w e b-b a s e d el e ctr o ni c d at a c a pt ur e 
(E D C ) s y st e m at a n y ti m e d uri n g t h e st u d y.  At d at a b a s e cl o s ur e d at a will b e 
pr o vi d e d o n c o m p a ct di s c s f or fili n g p ur p o s e s.  
 
St u d y fil e s c o nt ai ni n g t h e pr ot o c ol wit h all a m e n d m e nt s, i n v e sti g at or’ s br o c h ur e, 
c o pi e s of pr e st u d y d o c u m e nt ati o n ( s e e S e cti o n 1 2. 3 ), a n d all c orr e s p o n d e n c e t o a n d 
fr o m t h e I E C a n d A m g e n 
 
If ke pt, pr o of of r e c ei pt, I n v e sti g ati o n al Pr o d u ct A c c o u nt a bilit y R e c or d, R et ur n of 
I n v e sti g ati o n al Pr o d u ct f or D e str u cti o n, Fi n al I n v e sti g ati o n al Pr o d u ct R e c o n cili ati o n 
St at e m e nt, a n d all dr u g-r el at e d c orr e s p o n d e n c e 
I n a d diti o n, all ori gi n al s o ur c e d o c u m e nt s s u p p orti n g e ntri e s i n t h e c a s e r e p ort f or m s 
m u st b e m ai nt ai n e d a n d b e r e a dil y a v ail a bl e. 
N o st u d y d o c u m e nt s h o ul d b e d e str o y e d wit h o ut pri or writt e n a gr e e m e nt b et w e e n 
A m g e n a n d t h e i n v e sti g at or.  S h o ul d t h e i n v e sti g at or wi s h t o a s si g n t h e st u d y r e c or d s t o 
a n ot h er p art y or m o v e t h e m t o a n ot h er l o c ati o n, h e/ s h e m u st n otif y A m g e n i n writi n g of 
t h e n e w r e s p o n si bl e p er s o n a n d/ or t h e n e w l o c ati o n. 
1 3. 3   
St u d y M o nit ori n g a n d D at a C oll e cti o n 
T h e A m g e n r e pr e s e nt ati v e a n d r e g ul at or y a ut h orit y i n s p e ct or s ar e r e s p o n si bl e f or 
c o nt a cti n g a n d vi siti n g t h e i n v e sti g at or f or t h e p ur p o s e of i n s p e cti n g t h e f a ciliti e s a n d, 
u p o n r e q u e st, i n s p e cti n g t h e v ari o u s r e c or d s of t h e cli ni c al st u d y ( e g,  c a s e r e p ort f or m s 
a n d ot h er p erti n e nt d at a) pr o vi d e d t h at s u bj e ct c o nfi d e nti alit y i s r e s p e ct e d. 
T h e A B C S G m o nit or i s r e s p o n si bl e f or v erif yi n g t h e c a s e r e p ort f or m s at r e g ul ar i nt er v al s 
t hr o u g h o ut t h e st u d y t o v erif y a d h er e n c e t o t h e pr ot o c ol; c o m pl et e n e s s, a c c ur a c y, a n d 
c o n si st e n c y of t h e d at a; a n d a d h er e n c e t o l o c al r e g ul ati o n s o n t h e c o n d u ct of cli ni c al 
r e s e ar c h.  T h e m o nit or s h o ul d h a v e a c c e s s t o s u bj e ct m e di c al r e c or d s a n d ot h er 
st u d y-r el at e d r e c or d s n e e d e d t o v erif y t h e e ntri e s o n t h e c a s e r e p ort f or m s. 
T h e i n v e sti g at or a gr e e s t o c o o p er at e wit h t h e m o nit or t o e n s ur e t h at a n y pr o bl e m s 
d et e ct e d i n t h e c o ur s e of t h e s e m o nit ori n g vi sit s, i n cl u di n g d el a y s i n c o m pl eti n g c a s e 
r e p ort f or m s, ar e r e s ol v e d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
I n a c c or d a n c e wit h I C H G C P a n d t h e s p o n s or’ s a u dit pl a n s, t hi s st u d y m a y b e s el e ct e d 
f or a u dit b y r e pr e s e nt ati v e s fr o m A m g e n’ s Cli ni c al Q u alit y A s s ur a n c e D e p art m e nt ( or 
d e si g n e e s).  I n s p e cti o n of sit e f a ciliti e s ( e g,  p h ar m a c y, dr u g st or a g e ar e a s, l a b or at ori e s) 
a n d r e vi e w of st u d y-r el at e d r e c or d s will o c c ur t o e v al u at e t h e st u d y c o n d u ct a n d 
c o m pli a n c e wit h t h e pr ot o c ol, I C H G C P, a n d a p pli c a bl e r e g ul at or y r e q uir e m e nt s. 
D u e t o a n u n e x p e ct e d c h a n g e of t h e d at a m a n a g e m e nt s y st e m, t h e I nt erf a c e 
D A T A P O R T/ T RI A L D A T A P O R T  (E D C s y st e m  M A C R O, pr o vi d e d b y I nf er M E D), h a s 
r e pl a c e d "I nt Tri al".  T h e c urr e nt E D C s y st e m , e n a bl e s t h e i n v e sti g at or t o w or k o n a 
w e b- b a s e d o nli n e d o c u m e nt ati o n ( e- C R F). 
M A C R O pr o vi d e s c o m m u ni c ati o n t o ol s w hi c h will h el p u s er s t o m a n a g e di s cr e p a n ci e s 
el e ctr o ni c all y, t o c o n d u ct s o ur c e d at a v erifi c ati o n a n d t o i m pr o v e c o m m u ni c ati o n wit hi n 
t h e st u d y t e a m.  
 
T o e n s ur e t h e q u alit y of cli ni c al d at a a cr o s s all s u bj e ct s a n d sit e s, a cli ni c al d at a 
m a n a g e m e nt r e vi e w will b e p erf or m e d o n s u bj e ct d at a r e c ei v e d at A B C S G.  D uri n g 
t hi s r e vi e w, s u bj e ct d at a will b e c h e c k e d f or c o n si st e n c y, o mi s si o n s, a n d a n y 
a p p ar e nt di s cr e p a n ci e s.  I n a d diti o n, t h e d at a will b e r e vi e w e d f or a d h er e n c e t o t h e 
pr ot o c ol a n d G C P.  T o r e s ol v e a n y q u e sti o n s ari si n g fr o m t h e cli ni c al d at a 
m a n a g e m e nt r e vi e w pr o c e s s, d at a q u eri e s a n d/ or sit e n otifi c ati o n s will b e r ai s e d vi a 
E D C f or sit e c o m pl eti o n.  
 
T h e pri n ci p al i n v e sti g at or will si g n o nl y t h e C o nfir m ati o n of D at a F or m .  T h e s e 
si g n at ur e s will i n di c at e t h at t h e pri n ci p al i n v e sti g at or i n s p e ct e d or r e vi e w e d t h e C R F, 
t h e d at a q u eri e s, a n d t h e sit e n otifi c ati o n s, a n d a gr e e s wit h t h e c o nt e nt.  P a p er 
o ut p ut of t h e C R F c a n b e pri nt e d o ut (t a b ul ar f or m at) b y t h e i n v e sti g at or 
w h e n e v er n e e d e d.   
 
A B C S G’ s cli ni c al d at a m a n a g e m e nt d e p art m e nt will e n s ur e t h at t h e d at a b a s e i s 
c orr e ct e d f or t h e f oll o wi n g C R F  i s s u e s wit h o ut n otifi c ati o n t o sit e st aff: 
 
F or m al c orr e cti o n s ( e g, 1 2. 0 1. 2 0 1 2 -> 1 2/ 0 1/ 2 0 1 2, 1 p er d a y - > 1/ d a y) 
 
mi s s p elli n g s t h at d o n ot c h a n g e t h e m e a ni n g of t h e w or d ( e x cl u di n g a d v er s e 
e v e nt s a n d m e di c ati o n s) 
 l o c ati o n of d at a r e c or d e d o n a n i n c orr e ct C R F ( e g, m o vi n g l a b d at a fr o m g e n er al 
c o m m e nt s t o t h e a p pr o pri at e l a b t a bl e) 
 
d at e err or s t h at o c c ur i nto t h e n e w y e ar  
 
st a n d ar d ti m e t o 2 4- h o ur cl o c k 
 
a d mi ni str ati v e d at a ( e g, e v e nt n a m e s f or u n s c h e d ul e d vi sit s or r et e st s) 
 if b ot h t h e e n d d at e a n d a st at u s of c o nti n ui n g i s i n di c at e d ( e g, f or a d v er s e 
e v e nt s, c o n c o mit a nt m e di c ati o n, h o s pit ali z ati o n), t h e e n d d at e will s u p er s e d e 
 If e q ui v al e nt u nit s or t er m s ar e r e c or d e d i n st e a d of t h e a c c e pt a bl e A m g e n 
st a n d ar d ( e g, c c f or m L, S Q f or S C r o ut e, N ot E x a mi n e d f or N ot D o n e), t h e 
A m g e n u nit s or t er m s will b e u s e d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
 if t h e a n s w er t o a Y E S or N O q u e sti o n i s bl a n k or o b vi o u sl y i n c orr e ct 
( e g, A n s w er s t o t h e f oll o wi n g q u e sti o n s d o n ot r efl e ct t h e d at a t h at ar e r e c or d e d 
or mi s si n g:  W er e t h er e a n y a d v er s e e v e nt s ?  C o n c o mit a nt m e di c ati o n s ?  
H o s pit ali z ati o n s ?) 
 
c orr e ct C R F  p a g e n u m b er s  
A d et ail e d d e s cri pti o n of f urt h er it e m s f or c orr e cti o n s wit h o ut n otifi c ati o n t o sit e st aff i s 
gi v e n i n t h e r e s p e cti v e  D at a M a n a g e m e nt Pl a n ( D M P). 
1 3. 4  
L a n g u a g e  
C a s e r e p ort f or m s m u st b e c o m pl et e d i n E n gli s h. T R A D E N A M E S  f or c o n c o mit a nt 
m e di c ati o n s m a y b e e nt er e d i n t h e l o c al l a n g u a g e. 
All writt e n i nf or m ati o n a n d ot h er m at eri al t o b e u s e d b y s u bj e ct s a n d i n v e sti g ati v e st aff 
m u st u s e v o c a b ul ar y a n d l a n g u a g e t h at ar e cl e arl y u n d er st o o d.  C o n s ult t h e 
c o u ntr y- s p e cifi c r e q uir e m e nt s f or l a n g u a g e r e q uir e m e nt s. 
1 3. 5   
P u bli c ati o n P oli c y 
T o c o or di n at e di s s e mi n ati o n of d at a fr o m t hi s st u d y, A m g e n e n c o ur a g e s t h e f or m ati o n of 
a p u bli c ati o n c o m mitt e e c o n si sti n g of s e v er al pri n ci p al i n v e sti g at or s a n d a p pr o pri at e 
A m g e n st aff.  T h e c o m mitt e e i s e x p e ct e d t o s oli cit i n p ut a n d a s si st a n c e fr o m ot h er 
i n v e sti g at or s a n d A m g e n st aff a s a p pr o pri at e.  M e m b er s hi p o n t h e c o m mitt e e ( b ot h f or 
i n v e sti g at or s a n d A m g e n st aff) d o e s n ot g u ar a nt e e a ut h or s hi p —t h e crit eri a d e s cri b e d 
b el o w s h o ul d b e m et f or e v er y p u bli c ati o n. 
A ut h or s hi p of a n y p u bli c ati o n s r e s ulti n g fr o m t hi s st u d y will b e d et er mi n e d o n t h e b a si s 
of t h e U nif or m R e q uir e m e nt f or M a n u s cri pt s S u b mitt e d t o Bi o m e di c al J o ur n al s 
(I nt er n ati o n al C o m mitt e e of M e di c al J o ur n al E dit or s, 2 0 0 4), w hi c h st at e s: 
 
A ut h or s hi p cr e dit s h o ul d b e b a s e d o n ( 1) s u b st a nti al c o ntri b uti o n s t o c o n c e pti o n a n d 
d e si g n, a c q ui siti o n of d at a, or a n al y si s a n d i nt er pr et ati o n of d at a; ( 2) dr afti n g t h e 
arti cl e or r e vi si n g it criti c all y f or i m p ort a nt i nt ell e ct u al c o nt e nt; ( 3) fi n al a p pr o v al of t h e 
v er si o n t o b e p u bli s h e d.  A ut h or s s h o ul d m e et c o n diti o n s 1, 2, a n d 3. 
 
W h e n a l ar g e, m ulti c e nt er gr o u p h a s c o n d u ct e d t h e w or k, t h e gr o u p s h o ul d i d e ntif y 
t h e i n di vi d u al s w h o a c c e pt dir e ct r e s p o n si bilit y f or t h e m a n u s cri pt.  T h e s e i n di vi d u al s 
s h o ul d f ull y m e et t h e crit eri a f or a ut h or s hi p d efi n e d a b o v e. 
 
A c q ui siti o n of f u n di n g, c oll e cti o n of d at a, or g e n er al s u p er vi si o n of t h e r e s e ar c h 
gr o u p, al o n e, d o e s n ot j u stif y a ut h or s hi p. 
 
All p er s o n s d e si g n at e d a s a ut h or s s h o ul d q u alif y f or a ut h or s hi p, a n d all t h o s e w h o 
q u alif y s h o ul d b e li st e d. 
 
E a c h a ut h or s h o ul d h a v e p arti ci p at e d s uffi ci e ntl y i n t h e w or k t o t a k e p u bli c 
r e s p o n si bilit y f or a p pr o pri at e p orti o n s of t h e c o nt e nt. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
All p u bli c ati o n s ( e g, m a n u s cri pt s, a b str a ct s, or al/ sli d e pr e s e nt ati o n s, b o o k c h a pt er s) 
b a s e d o n t hi s st u d y m u st b e s u b mitt e d t o A m g e n f or c or p or at e r e vi e w.  T h e Cli ni c al 
St u d y A gr e e m e nt a m o n g t h e i n stit uti o n, pri n ci p al i n v e sti g at or, a n d A m g e n will d et ail t h e 
pr o c e d ur e s f or, a n d ti mi n g of, A m g e n’ s r e vi e w of p u bli c ati o n s. 
1 3. 6   
C o m p e n s ati o n 
S u bj e ct will b e tr e at e d a n d/ or c o m p e n s at e d f or a n y st u d y-r el at e d ill n e s s/i nj ur y p ur s u a nt 
t o t h e i nf or m atio n pr o vi d e d i n t h e C o m p e n s ati o n f or I nj ur y s e cti o n of t h e I nf or m e d 
C o n s e nt.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 4.   
R E F E R E N C E S 
A M G 1 6 2 I n v e sti g at or’ s Br o c h ur e, T h o u s a n d O a k s, C A: A m g e n I n c 
A T A C tri ali st s gr o u p .  Re s ult s of t h e A T A C ( Ari mi d e x, T a m o xif e n, Al o n e or i n 
C o m bi n ati o n) tri al aft er c o m pl eti o n of 5 y e ar s’ a dj u v a nt tr e at m e nt f or br e a st c a n c er .  
L a n c et.   2 0 0 5;3 6 5: 6 0 -6 2.  
Br e a st I nt er n ati o n al Gr o u p ( BI G) 1- 9 8 C oll a b or ati v e Gr o u p.  A c o m p ari s o n of l etr o z ol e 
a n d t a m o xif e n i n p o st m e n o p a u s al w o m e n wit h e arl y br e a st c a n c er .  N e w E n gl J M e d.   
2 0 0 5; 3 5 3( 2 6): 2 7 4 7- 2 7 5 7.  
Br uf s k y A, H ar k er W G, B e c k J T et al.  Z ol e dr o ni c a ci d f or pr e v e nti o n of c a n c er tr e at m e nt 
i n d u c e d b o n e l o s s i n p o st m e n o p a u s al w o m e n wit h br e a st c a n c er r e c ei vi n g a dj u v a nt 
l etr o z ol e: pr eli mi n ar y r e s ult s of t h e Z-F A S T tri al .  S A B C S.   2 0 0 4; A b s 1 1 1 4.  
C o x, D. R.  R e gr e s si o n m o d el s a n d lif e t a bl e s ( wit h di s c u s si o n).  J R o y al St ati sti c al 
S o ci et y, S eri e s B .  1 9 7 2  3 4: 1 8 7 -2 2 0.  
C u m mi n g s S R, S a n M arti n J, M c Cl u n g M R, et al.  D e n o s u m a b f or pr e v e nti o n of 
fr a ct ur e s i n p o st m e n o p a u s al w o m e n wit h o st e o p or o si s.  N E n gl J M e d  
2 0 0 9; 3 6 1( 8): 7 5 6 -7 6 5.  
D o m b er n o w s k y P, S mit h I, F al k s o n G, et al .  L etr o z ol e, a n e w or al ar o m at a s e i n hi bit or 
f or a d v a n c e d br e a st c a n c er: d o u bl e-bli n d r a n d o mi z e d tri al s h o wi n g a d o s e eff e ct a n d 
i m pr o v e d effi c a c y a n d t ol er a bilit y c o m p ar e d wit h m e g e str ol a c et at e.  J  Cli n O n c ol .  
1 9 9 8; 1 6( 2): 4 5 3 -4 6 1.  
G n a nt M, Pf eil er G, D u b s k y P C, et al. A dj u v a nt d e n o s u m a b i n br e a st c a n c er 
( A B C S G- 1 8): a m ulti c e ntr e, r a n d o mi s e d, d o u bl e-bli n d, pl a c e b o - c o ntr oll e d tri al. L a n c et . 
2 0 1 5 ;3 8 6( 9 9 9 2): 4 3 3- 4 3 . E p u b 2 0 1 5 M a y 3 1. 
E a st ell R, H a n n o n R A, C u zi c k J et al.  Eff e ct of a n ar o m at a s e i n hi bit or o n B M D a n d b o n e 
t ur n o v er m ar k er s:  2-y e ar r e s ult s of t h e a n a str a z ol e, t a m o xif e n, al o n e or i n c o m bi n ati o n 
( A T A C) tri al.  J B o n e Mi n R e s  2 0 0 6; 2 1( 8): 1 2 1 5 -2 3.  
E a st ell R, A d a m s J E .  Eff e ct of a n a str o z ol e o n b o n e d e n sit y a n d b o n e t ur n o v er: R e s ult s 
of t h e “ ari mi d e x” ( a n a str o z ol e), t a m o xif e n, al o n e or i n c o m bi n ati o n ( A T A C) tri al 
p erf or m e d b y t h e A T A C Tri ali st s’ Gr o u p .  A n n O n c ol.  2 0 0 2; 1 3: 3 2 ( s u p pl 5).  
Elli ott R, K o st e n ui k P, C h e n C, et al.  D e n o s u m a b i s a s el e cti v e i n hi bit or of h u m a n 
r e c e pt or a cti v at or of N F- li g a n d t h at bl o c k s o st e o cl a st f or m ati o n i n vitr o a n d i n vi v o.  
E ur J C a S u p pl .  2 0 0 6; 4: 6 2. 
G o s s P E, I n gl e J N, M arti n o S, et al .  A r a n d o mi z e d tri al of l etr o z ol e i n p o st m e n o p a u s al 
w o m e n aft er fi v e y e ar s of t a m o xif e n t h er a p y f or e arl y- st a g e br e a st c a n c er.  N  E n gl J 
M e d.   2 0 0 3; 3 4 9( 1 9): 1 7 9 3 -1 8 0 2.  
G e n a nt H K, W u C Y, V a n K uij k C, et al .  V ert e br al fr a ct ur e a s s e s s m e nt u si n g a 
s e mi q u a ntit ati v e t e c h ni q u e.  J  B o n e & Mi n er al R e s .  1 9 9 3; 8( 9): 1 1 3 7 -1 1 4 8.  
J a k e s z R, J o n at W, G n a nt M, et al .  S wit c hi n g of p o st m e n o p a u s al w o m e n wit h 
e n d o cri n e -r e s p o n si v e e arl y br e a st c a n c er t o a n a str o z ol e aft er 2 y e ar s' a dj u v a nt 
t a m o xif e n: c o m bi n e d r e s ult s of A B C S G tri al 8 a n d A R N O 9 5 tri al .  L a n c et.  
2 0 0 5; 3 6 6 -4 5 5.  
J e m al A, M urr a T, S a m u el s A , et al .  C a n c er St ati sti c s, 2 0 0 3.  C a n J Cli ni ci a n s.   
2 0 0 3; 5 3: 5 -2 6.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
K a pl a n, E L, a n d M ei er, P.  N o n p ar a m etri c e sti m ati o n fr o m i n c o m pl et e o b s er v ati o n.  
J A m St ati st A s s o c.   1 9 5 8;5 3: 4 5 7 -4 8 1.  
L a k e D E, H u di s C .  Ar o m at a s e i n hi bit or s i n br e a st c a n c er: a n u p d at e.  C a n c er C o ntr ol.  
2 0 0 2; 9( 6): 4 9 0- 4 9 8.  
L o n gf or d N T.  R a n d o m C o effi ci e nt M o d el s.  N e w Y or k:  O xf or d U ni v er sit y Pr e s s, I n c. 
1 9 9 3.  
M o uri d s e n H, S u n Y, G er s h a n o vi c h M, et al.  F i n al s ur vi v al a n al y si s of t h e d o u bl e-bli n d, 
r a n d o mi z e d, m ulti n ati o n al p h a s e III tri al of l etr o z ol e ( F e m ar a) c o m p ar e d  t o t a m o xif e n a s 
fir st-li n e h or m o n al t h er a p y f or a d v a n c e d br e a st c a n c er.  B r e a st C a n c er R e s Tr e at.  
2 0 0 1; 6 9: 2 1 1.  
N a b h olt z J M, B u z d ar A, P oll a k M, et al .  An a str o z ol e i s s u p eri or t o t a m o xif e n a s fir st-li n e 
t h er a p y f or a d v a n c e d br e a st c a n c er i n p o st m e n o p a u s al w o m e n: r e s ult s of a N ort h 
A m eri c a n m ulti c e nt er r a n d o mi z e d tri al .  Ari mi d e x St u d y Gr o u p.  J Cli n O n c ol.   
2 0 0 0; 1 8( 2 2): 3 7 5 8 -3 7 6 7.  
T hij s s e n J H, Bl a n k e n st ei n M A .  En d o g e n o u s o e str o g e n s a n d a n dr o g e n s i n n or m al a n d 
m ali g n a nt e n d o m etri al a n d m a m m ar y ti s s u e s .  E ur J C a n c er Cli n O n c ol.   
1 9 8 9; 2 5: 1 9 5 3 -5 9.  
T eit el b a u m S L, R o s s F P.  G e n eti c r e g ul ati o n of o st e o cl a st d e v el o p m e nt a n d f u n cti o n. 
N at R e v G e n et.   2 0 0 3; 4: 6 3 8- 6 4 9.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
1 5.   
A P P E N DI C E S 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 6  of 10 4  
C O N FI D E N TI A L 
 
 
A p p e n di x A .  S c h e d ul e of A s s e s s m e nt s f or Bli n d e d a n d O p e n- l a b el Tr e at m e nt P h a s e s 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
S c h e d ul e of A s s e s s m e nt s f or O p e n-l a b el P h a s e 
 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x B .  A d v er s e E v e nt A s s e s s m e nt s 
A d v er s e E v e nt R el at e d n e s s 
I s t h er e a r e a s o n a bl e p o s si bilit y t h at t h e e v e nt m a y h a v e b e e n c a u s e d b y i n v e sti g ati o n al 
pr o d u ct ?  N o _ _ _ Y e s _ _ _ 
T h e d e s cri pti o n s pr o vi d e d b el o w will h el p g ui d e t h e pri n ci p al i n v e sti g at or i n m a ki n g t h e 
d e ci si o n t o c h o o s e eit h er “ y e s” or “ n o”: 
N o = T h er e i s n ot a r e a s o n a bl e p o s si bilit y t h at t h e e v e nt m a y h a v e b e e n c a u s e d b y 
i n v e sti g ati o n al pr o d u ct. 
T h e a d v er s e e v e nt: 
 
m a y b e j u d g e d t o b e d u e t o e xtr a n e o u s c a u s e s s u c h a s di s e a s e or e n vir o n m e nt or 
t o xi c f a ct or s 
 
m a y b e j u d g e d t o b e d u e t o t h e s u bj e ct’ s cli ni c al st at e or ot h er t h er a p y b ei n g 
a d mi ni st er e d 
 
i s n ot bi ol o gi c all y pl a u si bl e 
 
d o e s n ot r e a p p e ar or w or s e n w h e n i n v e sti g ati o n al pr o d u ct i s r e- a d mi ni st er e d 
 
d o e s n ot f oll o w a t e m p or al s e q u e n c e fr o m a d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct 
Y e s = T h er e i s a r e a s o n a bl e p o s si bilit y t h at t h e e v e nt m a y h a v e b e e n c a u s e d b y 
i n v e sti g ati o n al pr o d u ct. 
T h e a d v er s e e v e nt: 
 
f oll o w s a t e m p or al s e q u e n c e fr o m a d mi ni str ati o n of i n v e sti g ati o n al pr o d u ct 
 
i s a k n o w n r e s p o n s e t o t h e i n v e sti g ati o n al pr o d u ct b a s e d o n cli ni c al or pr e cli ni c al 
d at a  
 
c o ul d n ot b e e x pl ai n e d b y t h e k n o w n c h ar a ct eri sti c s of t h e s u bj e ct’ s cli ni c al st at e, 
e n vir o n m e nt al or t o xi c f a ct or s, or ot h er t h er a p y a d mi ni st er e d t o t h e s u bj e ct 
 
di s a p p e ar s or d e cr e a s e s u p o n c e s s ati o n or r e d u cti o n of d o s e of i n v e sti g ati o n al 
pr o d u ct 
 
r e a p p e ar s or w or s e n s w h e n i n v e sti g ati o n al pr o d u ct i s r e a d mi ni st er e d 
A d v er s e E v e nt S e v erit y S c ori n g S y st e m 
T h e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s ( C T C A E) ar e a v ail a bl e at t h e 
f oll o wi n g li n k: 
htt p:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c _ a p pli c ati o n s/ d o c s/ ct c a e v 3. p df  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x C .  P h ar m a c y G ui d e 
O p e n- L a b el E xt e n s i o n 
D e n o s u m a b will b e m a n uf a ct ur e d a n d p a c k a g e d b y A m g e n I n c. a n d di stri b ut e d u si n g 
A m g e n cli ni c al tri al dr u g di stri b uti o n pr o c e d ur e s. 
D e n o s u m a b will b e pr o vi d e d a s a st eril e, c ol orl e s s t o sli g htl y y ell o w, pr e s er v ati v e-fr e e 
s ol uti o n i n a 1 m L pr e-fill e d s yri n g e ( P F S). T h e f or m ul ati o n i s 6 0 m g/ m L d e n o s u m a b, 
 m M s o di u m a c et at e (  m g/ m L),  
% ( 
 m g/ m L) s or bit ol,  
% p ol y s or b at e 2 0, 
p H   
.  E a c h P F S i s i nt e n d e d f or si n gl e u s e o nl y.  O n e P F S will b e p a c k a g e d p er b o x. 
D e n o s u m a b s h o ul d b e t a k e n fr o m t h e A m g e n s u p pli e d st o c k h el d at t h e sit e. Pl e a s e 
e n s ur e t h e c orr e ct q u a ntit y i s s el e ct e d. 
L a b eli n g  
E a c h si n gl e- u s e pr e-fill e d s yri n g e of d e n o s u m a b will b e l a b el e d i n a c c or d a n c e wit h 
A n n e x 1 3.  I nf or m ati o n pr e s e nt e d o n t h e l a b el f or st u d y m e di c ati o n will c o m pl y wit h t h e 
l o c al r e g ul at or y r e q uir e m e nt s. 
St or a g e 
T h e b o x e s c o nt ai ni n g d e n o s u m a b will b e st or e d at t h e i n v e sti g ati o n al sit e at 2 C t o 8° C.  
Pr efill e d s yri n g e s ar e t o b e k e pt i n t h e b o x u ntil t h e ti m e of u s e.  E x p o s ur e of t h e m at eri al 
t o t e m p er at ur e s o ut si d e t h e s e li mit s m a y r e s ult i n a l o s s of a cti vit y.  A m g e n I n c. or it s 
d e si g n e e m u st b e n otifi e d if a n y t e st m at eri al i s e x p o s e d t o e x c e s si v e or u n c o ntr oll e d 
t e m p er at ur e s, i n w hi c h c a s e p o s si bl e r e pl a c e m e nt of t h e m at eri al will b e c o n si d er e d. 
A ct u al st or a g e c o n diti o n s r e c or d s d uri n g t h e p eri o d of t h e st u d y m u st b e m ai nt ai n e d a n d 
i n cl u d e t h e d at e, ti m e a n d i niti al s of t h e p er s o n c h e c ki n g o n t h e “ w or ki n g d a y” 
t e m p er at ur e s of t h e r efri g er at or u s e d f or t h e st or a g e of tri al s u p pli e s.  C o nti n u o u s 
t e m p er at ur e r e c or di n g s, or r e g ul arl y m ai nt ai n e d t e m p er at ur e al ar m s y st e m s u s e d i n 
c o nj u n cti o n wit h t e m p er at ur e r e c or di n g s h all al s o b e m ai nt ai n e d. 
Pr e p ari n g t h e S u b c ut a n e o u s I nj e cti o n s 
O n e d e n o s u m a b pr e-fill e d s yri n g e s h o ul d b e r e m o v e d fr o m t h e r efri g er at or a n d br o u g ht 
t o r oo m t e m p er at ur e.  O n c e r e m o v e d fr o m t h e r efri g er at or, t h e pr e -fill e d s yri n g e m u st b e 
u s e d wit hi n 2 4 h o ur s.   T h er e ar e n o ot h er s p e ci al pr e p ar ati o n s r e q uir e d pri or t o 
i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
S u p pl y a n d R et ur n of Dr u g 
At t h e st art of t h e O L P a n d a s n e e d e d t h er e aft er, d e n o s u m a b will b e s hi p p e d t o t h e 
r e s p o n si bl e p er s o n ( e g, a p h ar m a ci st) at t h e i n v e sti g at or’ s i n stit uti o n, w h o will c h e c k t h e 
a m o u nt a n d c o n diti o n of t h e dr u g a n d e nt er t h e s e d at a i nt o t h e Pr o of of R e c ei pt F or m.  
T h e Pr o of of R e c ei pt F or m s h o ul d t h e n b e r et ur n e d t o A m g e n, a n d t h e ori gi n al r et ai n e d 
at t h e sit e.   
A m g e n r e c o m m e n d s t h at sit e s d e str o y u s e d a n d u n u s e d pr o d u ct if l o c al c a p a biliti e s a n d 
r e g ul ati o n s p er mit.  If t hi s i s n ot p er mi s si bl e, at t h e e n d of t h e st u d y, or a s dir e ct e d, 
u n u s e d c o nt ai n er s, will b e r et ur n e d t o A m g e n or d e si g n e e.  T h e R et ur n of I n v e sti g ati o n al 
Pr o d u ct f or D e str u cti o n F or m m u st b e c o m pl et e d a n d i n cl u d e d i n a n y s hi p m e nt of 
u n u s e d i n v e sti g ati o n al pr o d u ct t o A m g e n or d e si g n e e.  U s e d pr e-fill e d s yri n g e s will b e 
di s p o s e d at t h e cli ni c al sit e s u si n g sit e st a n d ar d s. 
I n v e sti g ati o n al Pr o d u ct A c c o u nt a bilit y 
A n I n v e sti g ati o n al Pr o d u ct A c c o u nt a bilit y R e c or d f or t h e i n v e sti g ati o n al pr o d u ct s i s 
m a n d at e d b y t h e pr ot o c ol, m u st b e k e pt c urr e nt a n d s h o ul d c o nt ai n: 
 
t h e d at e s an d q u a ntiti e s of d e n o s u m a b r e c ei v e d fr o m A m g e n 
 
p a c k a gi n g l ot n u m b er f or pr o d u ct r e c ei v e d 
 
s u bj e ct’ s i d e ntifi c ati o n ( s u bj e ct n u m b er) 
 
d at e d e n o s u m a b di s p e n s e d  
 
t h e i niti al s of t h e di s p e n s er 
T h e s e i n v e nt ori e s m u st b e m a d e a v ail a bl e f or i n s p e cti o n b y a n a ut h ori z e d A m g e n 
r e pr e s e nt ati v e or d e si g n e e a n d r e g ul at or y a g e n c y i n s p e ct or s.  T h e i n v e sti g at or i s 
r e s p o n si bl e f or t h e a c c o u nt a bilit y of all u s e d a n d u n u s e d tri al s u p pli e s.  
D o u bl e- bli n d Tr e at m e nt P h a s e  P a c k a gi n g a n d F or m ul ati o n 
D e n o s u m a b will b e m a n uf a ct ur e d a n d p a c k a g e d b y A m g e n I n c a n d di stri b ut e d u si n g 
A m g e n cli ni c al tri al dr u g di stri b uti o n pr o c e d ur e s. 
D e n o s u m a b m a y b e pr o vi d e d a s eit h er of t h e 2 f oll o wi n g f or m ul ati o n s:  1) a s a st eril e, 
cl e ar, c ol orl e s s  t o sli g htl y y ell o w, pr e s er v ati v e fr e e li q ui d i n bli n d e d-l a b el gl a s s vi al s;   
2) a s a pr efill e d s yri n g e ( P F S) a s a st eril e, si n gl e u s e, pr e s er v ati v e fr e e s ol uti o n f or 
s u b c ut a n e o u s i nj e cti o n.  T h e vi al f or m ul ati o n i s 6 0 m g d e n o s u m a b p er m L of  
 m M 
S o di u m A c et at e, 
% s or bit ol, wit h a p H of  
.  T h e P F S f or m ul ati o n c o nt ai n s 6 0 m g/ m L 
d e n o s u m a b,  
 m M a c et at e (  m g/ m L),  
% ( 
 m g/ m L) s or bit ol a n d  
% 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
( 
 m g/ m L) p ol y s or b at e 2 0 at a p H of 
.  T h e P F S i s fill e d t o a t ar g et d eli v er a bl e 
v ol u m e of 1. 0 m L.  Pl a c e b o will b e s u p pli e d i n m at c h e d c o nt ai n er s a n d t h e f or m ul ati o n 
will b e i d e nti c al t o d e n o s u m a b wit h t h e e x c e pti o n of t h e pr ot ei n c o nt e nt. 
I n v e sti g ati o n al pr o d u ct will b e p a c k a g e d i n b o x e s a s i n di vi d u al p ati e nt kit s c o nt ai ni n g 
si n gl e- u s e vi al s or pr e-fill e d s yri n g e s of d e n o s u m a b or m at c hi n g pl a c e b o .  E a c h kit of 
i n v e sti g ati o n al pr o d u ct will b e c o d e d al p h a n u m eri c all y f or tr e at m e nt a s si g n m e nt.  
U ni q u e b o x e s will b e a s si g n e d f or e a c h d o s e t h e s u bj e ct will r e c ei v e w hil e o n st u d y .  To 
o bt ai n b o x n u m b er a s si g n m e nt f or a s c h e d ul e d d o s e, sit e p er s o n n el s h o ul d c all t h e 
I V R S v e n d or.  Th e b o x n u m b er of i n v e sti g ati o n al pr o d u ct i s t o b e r e c or d e d o n e a c h 
s u bj e ct’ s I n v e sti g ati o n al Pr o d u ct A d mi ni str ati o n c a s e r e p ort f or m.  I n a d diti o n, t h e 
s u bj e ct’ s i d e ntifi c ati o n n u m b er, r a n d o mi z ati o n i d e ntifi c ati o n n u m b er a n d b o x n u m b er 
m u st b e writt e n o n all a p pr o pri at e dr u g a c c o u nt a bilit y a n d di s p e n si n g r e c or d s. 
T h e i d e ntit y of i n v e sti g ati o n al pr o d u ct a s si g n e d t o s u bj e ct n u m b er s or t o i n di vi d u al b o x e s 
of i n v e sti g ati o n al pr o d u ct will b e c o nt ai n e d i n t h e I V R S.  A ut h ori z e d sit e st aff will b e 
pr o vi d e d wit h a u ni q u e P er s o n al I d e ntifi c ati o n N u m b er ( PI N) t o a c c e s s t h e I V R S t o 
o bt ai n u n bli n di n g i nf or m ati o n .  Thi s PI N i s u ni q u e t o t h e i n di vi d u al a n d m u st n ot b e 
s h ar e d.  A s u bj e ct’ s tr e at m e nt a s si g n m e nt s h o ul d o nl y b e u n bli n d e d w h e n k n o wl e d g e of 
t h e tr e atm e nt i s e s s e nti al f or t h e f urt h er m a n a g e m e nt of t h e s u bj e ct .  Un bli n di n g at t h e 
st u d y sit e f or a n y ot h er r e a s o n will b e c o n si d er e d a pr ot o c ol d e vi ati o n. 
T h e pri n ci p al i n v e sti g at or i s str o n gl y e n c o ur a g e d t o c o nt a ct t h e A m g e n St u d y M a n a g er 
b ef or e u n bli n di n g a n y s u bj e ct’ s tr e at m e nt a s si g n m e nt, b ut m u st d o s o wit hi n 1 w or ki n g 
d a y aft er t h e e v e nt a n d m u st d o c u m e nt t h e u n bli n di n g i n t h e s u bj e ct’ s c a s e r e p ort f or m. 
I n v e sti g ati o n al Pr o d u ct Si n gl e U s e Vi al 
L a b eli n g  
E a c h si n gl e- u s e vi al of d e n o s u m a b or pl a c e b o will b e l a b el e d i n a c c or d a n c e wit h 
A n n e x 1 3 .  Inf or m ati o n pr e s e nt e d o n t h e l a b el f or st u d y m e di c ati o n will c o m pl y wit h t h e 
l o c al r e g ul at or y r e q uir e m e nt s. 
St or a g e 
T h e b o x e s c o nt ai ni n g d e n o s u m a b or pl a c e b o will b e st or e d at t h e i n v e sti g ati o n al sit e at 
2 C t o 8° C.   Vi al s ar e t o b e k e pt i n t h e b o x u ntil t h e ti m e of u s e.  E x p o s ur e of t h e m at eri al 
t o t e m p er at ur e s o ut si d e t h e s e li mit s m a y r e s ult i n a l o s s of a cti vit y.  A m g e n, I n c. or it s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
d e si g n e e m u st b e n otifi e d if a n y t e st m at eri al i s e x p o s e d t o e x c e s si v e or u n c o ntr oll e d 
t e m p er at ur e s, i n w hi c h c a s e p o s si bl e r e pl a c e m e nt of t h e m at eri al will b e c o n si d er e d. 
A ct u al st or a g e c o n diti o n s r e c or d s d uri n g t h e p eri o d of t h e st u d y m u st b e m ai nt ai n e d a n d 
i n cl u d e t h e d at e, ti m e a n d i niti al s of t h e p er s o n c h e c ki n g o n t h e “ w or ki n g d a y” 
t e m p er at ur e s of t h e r efri g er at or u s e d f or t h e st or a g e of tri al s u p pli e s.  Co nti n u o u s 
t e m p er at ur e r e c or di n g s, or r e g ul arl y m ai nt ai n e d t e m p er at ur e al ar m s y st e m s u s e d i n 
c o nj u n cti o n wit h t e m p er at ur e r e c or di n g s h all al s o b e m ai nt ai n e d. 
Pr e p ari n g t h e S u b c ut a n e o u s I nj e cti o n s  
O n e i n v e sti g ati o n al pr o d u ct vi al s s h o ul d b e r e m o v e d fr o m t h e r efri g er at or a n d br o u g ht t o 
r o o m t e m p er at ur e.  On e 1. 0 m L s yri n g e s h o ul d b e u s e d t o pr e p ar e t h e d o s e.  T h er e ar e 
n o ot h er s p e ci al pr e p ar ati o n s r e q uir e d pri or t o i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n.  
I n v e sti g ati o n al Pr o d u ct Si n gl e U s e Pr e-fill e d S yri n g e 
L a b eli n g  
E a c h si n gl e- u s e pr e-fill e d s yri n g e of d e n o s u m a b or pl a c e b o will b e l a b el e d i n 
a c c or d a n c e wit h A n n e x 1 3.  I nf or m ati o n pr e s e nt e d o n t h e l a b el f or st u d y m e di c ati o n will 
c o m pl y wit h t h e l o c al r e g ul at or y r e q uir e m e nt s. 
St or a g e 
T h e b o x e s c o nt ai ni n g d e n o s u m a b or pl a c e b o will b e st or e d at t h e i n v e sti g ati o n al sit e at 
2 C t o 8° C.  Pr e-fill e d s yri n g e s ar e t o b e k e pt i n t h e b o x u ntil t h e ti m e of u s e.  E x p o s ur e 
of t h e m at eri al t o t e m p er at ur e s o ut si d e t h e s e li mit s m a y r e s ult i n a l o s s of a cti vit y.  
A m g e n, I n c. or it s d e si g n e e m u st b e n otifi e d if a n y t e st m at eri al i s e x p o s e d t o e x c e s si v e 
or u n c o ntr oll e d t e m p er at ur e s, i n w hi c h c a s e p o s si bl e r e pl a c e m e nt of t h e m at eri al will b e 
c o n si d er e d. 
A c t u al st or a g e c o n diti o n s r e c or d s d uri n g t h e p eri o d of t h e st u d y m u st b e m ai nt ai n e d a n d 
i n cl u d e t h e d at e, ti m e a n d i niti al s of t h e p er s o n c h e c ki n g o n t h e “ w or ki n g d a y” 
t e m p er at ur e s of t h e r efri g er at or u s e d f or t h e st or a g e of tri al s u p pli e s.  C o nti n u o u s 
t e m p er at ur e r e c or di n g s, or r e g ul arl y m ai nt ai n e d t e m p er at ur e al ar m s y st e m s u s e d i n 
c o nj u n cti o n wit h t e m p er at ur e r e c or di n g s h all al s o b e m ai nt ai n e d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
Pr e p ari n g t h e S u b c ut a n e o u s I nj e cti o n s 
O n e i n v e sti g ati o n al pr o d u ct pr e-fill e d s yri n g e s h o ul d b e r e m o v e d fr o m t h e r efri g er at or 
a n d br o u g ht t o r o o m t e m p er at ur e.  T h er e ar e n o ot h er s p e ci al pr e p ar ati o n s r e q uir e d pri or 
t o i n v e sti g ati o n al pr o d u ct a d mi ni str ati o n.  
S u p pl y a n d R et ur n of Dr u g 
At st u d y i niti ati o n a n d a s n e e d e d t h er e aft er, i n v e sti g ati o n al pr o d u ct will b e s hi p p e d t o t h e 
r e s p o n si bl e p er s o n ( eg,  a p h ar m a ci st) at t h e i n v e sti g at or’ s i n stit uti o n, w h o will c h e c k t h e 
a m o u nt a n d c o n diti o n of t h e dr u g a n d e nt er t h e s e d at a i nt o t h e Pr o of of R e c ei pt F or m.  
T h e Pr o of of R e c ei pt F or m s h o ul d t h e n b e r et ur n e d t o A m g e n, a n d t h e ori gi n al r et ai n e d 
at t h e sit e.  
T h e p er s o n r e s p o n si bl e f or r e c ei vi n g t h e dr u g s hi p m e nt will al s o n e e d t o c o nt a ct t h e 
I V R S v e n d or t o c o nfir m r e c ei pt of i n v e sti g ati o n al pr o d u ct.  
At t h e e n d of t h e st u d y, or a s dir e ct e d, all i n v e sti g ati o n al pr o d u ct s u p pli e s, i n cl u di n g 
u n u s e d, p arti all y u s e d, or e m pt y c o nt ai n er s, will b e r et ur n e d t o t h e A m g e n or d e si g n e e , 
e x c e pt u s e d pr e-fill e d s yri n g e s.  U s e d pr e-fill e d s yri n g e s will b e di s p o s e d at t h e cli ni c al 
sit e s u si n g sit e st a n d ar d s. 
I n v e sti g ati o n al Pr o d u ct A c c o u nt a bilit y 
A n I n v e sti g ati o n al Pr o d u ct A c c o u nt a bilit y R e c or d f or t h e i n v e sti g ati o n al pr o d u ct s 
m a n d at e d b y t h e pr ot o c ol m u st b e k e pt c urr e nt a n d s h o ul d c o nt ai n: 
 
t h e d at e s a n d q u a ntiti e s of i n v e sti g ati o n al pr o d u ct r e c ei v e d fr o m A m g e n 
 
p a c k a gi n g l ot n u m b er A N D b o x n u m b er s f or pr o d u ct r e c ei v e d 
 
s u bj e ct’ s i d e ntifi c ati o n ( s u bj e ct n u m b er a n d i niti al s) 
 
d at e a n d b o x n u m b er of i n v e sti g ati o n al pr o d u ct di s p e n s e d  
 
t h e i niti al s of t h e di s p e n s er 
T h e R et ur n of I n v e sti g ati o n al Pr o d u ct f or D e str u cti o n F or m m u st b e c o m pl et e d a n d 
i n clu d e d i n t h e s hi p m e nt of u s e d a n d u n u s e d i n v e sti g ati o n al pr o d u ct t o A m g e n or 
d e si g n e e .   
T h e s e i n v e nt ori e s m u st b e m a d e a v ail a bl e f or i n s p e cti o n b y a n a ut h ori z e d A m g e n 
r e pr e s e nt ati v e or d e si g n e e a n d r e g ul at or y a g e n c y i n s p e ct or s.  Th e i n v e sti g at or i s 
r e s p o n si bl e f or t h e a c c o u nt a bilit y of all u s e d a n d u n u s e d tri al s u p pli e s.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
C al ci u m a n d Vit a mi n D S u p pl e m e nt s 
C al ci u m a n d vit a mi n D s u p pl e m e nt s will n ot b e pr o vi d e d b y A m g e n.  T h e y s h o ul d b e 
o bt ai n e d fr o m s u p pli er s a p pr o v e d b y t h e p h ar m a c y of t h e i n di vi d u al i n stit uti o n.  T h e s e 
dr u g s will b e f or m ul at e d, p a c k a g e d, l a b el e d, a n d st or e d a c c or di n g t o l o c al m a n uf a ct ur er, 
s u p pli er, a n d i n stit uti o n al pr o c e d ur e s.  T h e i n v e sti g at or will b e r e s p o n si bl e f or o bt ai ni n g 
s u p pli e s of t h e s e dr u g s. 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x D .  Pr e g n a n c y N otifi c ati o n W or k s h e et 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x E .  Cl a s sifi c ati o n E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) 
P erf or m a n c e S c al e 
E C O G S c al e 
P erf or m a n c e St at u s 
 
0   
-  
F ull y a cti v e, a bl e t o c arr y o ut all pr e- di s e a s e p erf or m a n c e wit h o ut 
r e stri cti o n. 
1   
-  
R e stri ct e d i n p h y si c all y str e n u o u s a cti vit y, b ut a m b ul at or y a n d a bl e t o 
c arr y o ut w or k of a li g ht or s e d e nt ar y n at ur e, ( e g,  li g ht h o u s e w or k, offi c e 
w or k). 
2   
-  
A m b ul at or y a n d c a p a bl e of all s elf c ar e, b ut u n a bl e t o c arr y o ut a n y w or k 
a cti viti e s.  U p a n d a b o ut m or e t h a n 5 0 % of w a ki n g h o ur s. 
3   
-  
C a p a bl e of o nl y li mit e d s elf- c ar e, c o nfi n e d t o b e d or c h air m or e t h a n 5 0 % 
of w a ki n g h o ur s. 
4   
-  
C o m pl et el y di s a bl e d.  C a n n ot c arr y o ut a n y s elf- c ar e.  T ot all y c o nfi n e d t o 
b e d or c h ai r. 
5   
-  
D e a d. 
 
 
K ar n of s k y P erf or m a n c e St at u s 
 
1 0 0 %  - 
N or m al; n o c o m pl ai nt s; n o e vi d e n c e of di s e a s e. 
9 0 %  
- 
A bl e t o c arr y o n n or m al a cti vit y; mi n or si g n s or s y m pt o m s of di s e a s e. 
8 0 %  
- 
N or m al a cti vit y wit h eff ort; s o m e si g n s or s y m pt o m s of di s e a s e. 
7 0 %  
- 
C ar e s f or s elf, u n a bl e t o c arr y o n n or m al a cti vit y or d o a cti v e w or k. 
6 0 %  
- 
R e q uir e s o c c a si o n al a s si st a n c e, b ut i s a bl e t o c ar e f or m o st 
p er s o n al n e e d s. 
5 0 %  
- 
R e q uir e s c o n si d er a bl e a s si st a n c e a n d fr e q u e nt m e di c al c ar e. 
4 0 %  
- 
S e v er el y di s a bl e d; h o s pit ali z ati o n i n di c at e d, alt h o u g h d e at h n ot i m mi n e nt. 
3 0 %  
- 
S e v er el y di s a bl e d; h o s pit ali z ati o n n e c e s s ar y; a cti v e s u p p ort tr e at m e nt i s 
n e c e s s ar y. 
2 0 %  
- 
V er y si c k; h o s pit ali z ati o n n e c e s s ar y; a cti v e s u p p ort tr e at m e nt i s 
n e c e s s ar y. 
1 0 %  
- 
M ori b u n d; f at al pr o c e s s e s pr o gr e s si n g r a pi dl y. 
0 %   
- 
D e a d. 
 
 
K ar n of s k y S c or e of 1 0 0 % - 9 0 % c orr e s p o n d s t o E C O G 0 
K ar n of s k y S c or e of   8 0 % - 7 0 % c orr e s p o n d s t o E C O G 1 
K ar n of s k y S c or e of   6 0 % - 5 0 % c orr e s p o n d s t o E C O G 2 
K ar n of s k y S c or e of   4 0 % - 3 0 % c orr e s p o n d s t o E C O G 3 
K ar n of s k y S c or e of   2 0 % - 1 0 % c orr e s p o n d s t o E C O G 4 
K ar n of s k y S c or e of                 0 % c orr e s p o n d s t o E C O G 5 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x F .  S eri o u s A d v er s e E v e nt F or m 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 0  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p p e n di x G .  Z ol e dr o ni c A ci d S u b st u d y 
1.  
E X P L O R A T O R Y O B J E C TI V E 
2.  
R A TI O N A L E 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h d e cli n e s i n b o n e m a s s t h at a p pr o a c h 
pr e-tr e at m e nt l e v el s a n d a v ail a bl e d at a d o s u g g e st a n i n cr e a s e i n m ulti pl e 
v ert e br al fr a ct ur e s aft er di s c o nti n u ati o n.  Bi s p h o s p h o n at e tr e at m e nt aft er 
d e n o s u m a b m a y b e w arr a nt e d t o p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y 
i n p ati e nt s n ot pr e vi o u sl y e x p o s e d t o bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h 
fr a ct ur e ri s k (i e, o st e o p or o si s wit h pr e vi o u s v ert e br al fr a ct ur e s), b ut li mit e d d at a 
ar e a v ail a bl e c o nfir mi n g t h e v ali dit y of t hi s h y p ot h e si s.  T h er ef or e, t h er e i s a d at a 
g a p r e g ar di n g o pti m al str at e gi e s f or p ati e nt s w h o will di s c o nti n u e d e n o s u m a b.  
T h e Z A s u b st u d y i s d e si g n e d t o e v al u at e s u bj e ct s c o m pl eti n g o p e n- l a b el 
d e n o s u m a b tr e at m e nt , t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e m a n a g e d 
a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or r e s p e cti v e p ati e nt p o p ul ati o n .  
St a n d ar d of C ar e ( S o C) f or t hi s s u b st u d y p ati e nt p o p ul ati o n d e p e n d s o n i n di vi d u al 
f a ct or s s u c h a s b o n e d e n sit y, lif e st yl e r e c o m m e n d ati o n s b y t h e I n v e sti g at or s u c h 
a s d i et, p h y si c al a cti viti e s a n d s u n e x p o s ur e, a s w ell a s l o c al tr e at m e nt st a n d ar d s 
a n d will b e a gr e e d u p o n wit h t h e tr e ati n g I n v e sti g at or.  
T h er e ar e c urr e ntl y n o g ui d eli n e s or e vi d e n c e r e g ar di n g t h e b e st str at e g y t o b e 
c o n si d er e d w h e n di s c o nti n ui n g d e n o s u m a b  i n c a n c er tr e at m e nt-i n d u c e d b o n e 
l o s s.  T h er e h a s b e e n e x p ert o pi ni o n p u bli s h e d st ati n g t h at a tr a n siti o n t o a 
bi s p h o s p h o n at e r e pr e s e nt s a tr e at m e nt o pti o n ( H a dji et al, 2 0 1 7 ). 
3.  
E X P E RI M E N T A L P L A N 
3. 1.   
S u b st u d y D e si g n 
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 6 ( a d d e d Z A 
s u b st u d y), willi n g a n d eli gi bl e s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 1  of 1 0 4 
C O N FI D E N TI A L 
 
 
a n d c o m pl et e d O L d e n o s u m a b m a y o pt i n t hi s Z A s u b st u d y a n d eit h er r e c ei v e a 
si n gl e d o s e of Z A ( T h er a p y Ar m), or ar e m a n a g e d a c c or di n g t o t h e c urr e nt S O C 
f or t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  S u bj e ct s w h o c o m pl et e d O L P 
d e n o s u m a b ar e eli gi bl e t o p arti ci p at e i n t h e Z A s u b st u d y a s l o n g a s t h e o utli n e d 
crit eri a ar e f ulfill e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b 
a d mi ni str ati o n u ntil 9  m o nt h s aft er.  T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e 
l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n, 
b ut m u st o c c ur aft er writt e n c o n s e nt h a s b e e n o bt ai n e d.  
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 
1 si n gl e 5  m g I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 
8 d a y s pri or t o D a y 1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m 
t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s 
vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n 
will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or 
N o).   
Aft er d a y 1, s u bj e ct s will b e e v al u at e d e v er y 6 m o nt h s.  D X A s c a n c a n b e 
p erf or m e d b et w e e n 7  t o 9  m o nt h s  aft er t h e d at e of t h e l a st d e n o s u m a b 
a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A a d mi ni str ati o n.  R o uti n e 
D X A s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w c a n b e u s e d a s b a s eli n e 
D X A s c a n s.  
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A 
s u b st u d y will c o m pl et e O L P a s s e s s m e nt s o nl y.   
S u bj e ct s w h o p arti ci p at e i n t h e Z A s u b st u d y, will u n d er g o t h e f oll o wi n g 
a s s e s s m e nt s:  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 2  of 1 0 4 
C O N FI D E N TI A L 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 3  of 1 0 4 
C O N FI D E N TI A L 
 
 
3. 2.   
Sc h e m a  
Z A S u b st u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
 
I V = i ntr a v e n o u s; Z A = z ol e dr o ni c a ci d. 
 
 
E n d of o p e n -l a b el p h a s e d e n o s u m a b 
R a n d o mi z ati o n ( 1: 1) i nt o Z A S u b st u d y  
St a n d ar d of c ar e  
Si n gl e d o s e Z A I V 5 m g 8 m o nt h s (  4 
w e e k s) aft er O L P d e n o s u m a b  
6, 1 2, a n d 1 8 m o nt h f oll o w -u p  
( 2  w e e k s) aft er d a y  1  
E n d of Z A S u b s t u d y 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 4  of 1 0 4 
C O N FI D E N TI A L 
 
 
3. 3.   
N u m b er of C e nt er s 
A p pr o xi m at el y 3 0 sit e s i n A u stri a ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A s u b st u d y. 
3. 4.   
N u m b er of S u bj e ct s 
A p pr o xi m at el y 2 0 0 s u bj e ct s ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A s u b st u d y. 
3. 5.   
E sti m at e d S u b st u d y D ur ati o n  
3. 5. 1.  
E sti m at e d S u b st u d y D ur ati o n f or P arti ci p a nt s 
S u bj e ct s will b e i n t hi s s u b st u d y f or a m a xi m u m d ur ati o n of a p pr o xi m at el y 
2 7  m o nt h s. 
3. 5. 2.  
Z A S u b st u d y Tr e at m e nt 
S u bj e ct s t h at c o m pl et e d t h eir O L P d e n o s u m a b vi sit ar e eli gi bl e t o p arti ci p at e i n 
t h e Z A s u b st u d y a s l o n g a s all t h e s u b st u d y i n cl u si o n/ e x cl u si o n crit eri a ar e m et. 
Z ol e dr o ni c a ci d will b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) aft er l a st O L P 
a d mi ni str ati o n f or s u bj e ct s r a n d o mi z e d t o tr e at m e nt ar m.  S u bj e ct s r a n d o mi z e d t o 
S O C, will att e n d t h e sit e f or vi sit s at t h e s a m e vi sit s c h e d ul e a s t h e tr e at m e nt ar m 
s u bj e ct s. 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit. 
3. 5. 3.  
E n d of Z A S u b st u d y 
T h e e n d of Z A s u b st u d y will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
s u b st u d y h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n 
c a s e of e arl y wit h dr a w al fr o m t h e Z A s u b st u d y.    
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, a n d 
c o n s e nt wit h dr a w al) a n d p er pr ot o c ol E O S of Z A s u b st u d y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 5  of 1 0 4 
C O N FI D E N TI A L 
 
 
4.  
E LI GI BI LI T Y C RI T E RI A 
4. 5.  
I n cl u si o n Crit eri a f or Z A S u b st u d y 
4. 5. 1.  
O bt ai n si g n e d a n d d at e d writt e n i nf or m e d c o n s e nt pri or t o p erf or mi n g a n y 
s u b st u d y- s p e cifi c pr o c e d ur e 
4. 5. 2.  
S u bj e ct s t h at r e c ei v e d O L P d e n o s u m a b a n d c o m pl et e d O L P tr e at m e nt 
4. 5. 3.  
L a st O L P d e n o s u m a b a d mi ni str ati o n n o l o n g er t h a n 9 m o nt h s a g o 
4. 6.   
E x cl u si o n Crit eri a f or Z A S u b st u d y 
4. 6. 1.  
C urr e nt or pri or Z A a d mi ni str ati o n. 
4. 6. 2.  
S u bj e ct s w h o e n d e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct (I P) pr e m at ur el y 
i n t h e d o u bl e-bli n d p h a s e a n d O L p h a s e  
4. 6. 3.  
K n o w n s e n siti vit y or i nt ol er a n c e t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d 
d uri n g t h e s u b st u d y ( e g, Z A, c al ci u m or vit a mi n D) 
4. 6. 4.  
K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf 
r e p ort or c h art r e vi e w 
 
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a or ot h er 
a cti v e m et a b oli c b o n e di s e a s e  
 
K n o w n hi st or y of h y p o c al c e mi a  
 
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s 
pri or t o r a n d o mi z ati o n 
 
P ar at h yr oi d gl a n d s i n n e c k s ur gi c all y r e m o v e d. 
 
A n y s e cti o n s of i nt e sti n e r e m o v e d. 
 
K n o w n h u m a n i m m u n o d efi ci e n c y vir u s i nf e cti o n 
 
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s  
4. 6. 5.  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d 
i n di c at e d b y t h e f oll o wi n g crit eri a: 
 
A s p art at e a mi n otr a n sf er a s e ≥ 2. 5 x U L N  
 
Al a ni n e tr a n s a mi n a s e ≥ 2. 5 x U L N  
 
S er u m cr e ati ni n e ≥ 2 x U L N 
 
Cr e ati n e cl e ar a n c e < 3 5 ml/ mi n  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 6  of 1 0 4 
C O N FI D E N TI A L 
 
 
4. 6. 6.  
S u bj e ct s t h at ar e pr e g n a nt or br e a stf e e di n g 
 
All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a n e g ati v e 
pr e g n a n c y t e st wit hi n 7 d a y s b ef or e r a n d o mi z ati o n 
4. 6. 7.  
S u bj e ct s w h o ar e o st e o p or oti c i n b a s eli n e B M D 
5.  
S U B J E C T E N R O L L M E N T 
A s u bj e ct will b e a s si g n e d b y a n I nt er a cti v e V oi c e/ W e b R e s p o n s e S y st e m t o 1 of 
2 tr e at m e nt gr o u p s ( Z A or S O C), i n a 1: 1 r ati o.  T h e r a n d o mi z ati o n s c h e d ul e will 
u s e r a n d o ml y p er m ut e d bl o c k s a n d will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of 
O L P d e n o s u m a b c o m pl eti o n ( Y e s or N o).  A s u bj e ct w h o i s r a n d o mi z e d t o t h e Z A 
s u b st u d y will m ai nt ai n t h e s a m e s u bj e ct n u m b er w hi c h i s al s o t h e s u bj e ct n u m b er 
a s a s si g n e d i n t h e d o u bl e -bli n d  ( m ai n) st u d y.  A s u bj e ct m a y o nl y b e r a n d o mi z e d 
o n c e i nt o Z A s u b st u d y .  T h e Z A r a n d o mi z ati o n li st will b e g e n er at e d a n d 
m ai nt ai n e d b y a n A m g e n r e pr e s e nt ati v e n ot i n v ol v e d i n t h e c o n d u ct of t h e st u d y. 
6.  
T R E A T M E N T P R O C E D U R E S 
6. 1.  
I n v e sti g ati o n al Pr o d u ct ( Z ol e dr o ni c A ci d) D o s a g e, A d mi ni str ati o n, a n d 
S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5 m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er 
all ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o s u bj e ct s b y 
h e alt h c ar e pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V 
bi s p h o s p h o n at e s.  S u bj e ct s tr e at e d wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et.   
Z A will b e l o c all y pr o vi d e d b y p arti ci p ati n g sit e s a n d will b e r ei m b ur s e d b y t h e 
s p o n s or. 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n 
a c c or d a n c e wit h l o c al r e q uir e m e nt s. R ef er t o t h e s u m m ar y of pr o d u ct 
c h ar a ct eri sti c s ( S m P C) 
(htt p s:// w w w. e m a. e ur o p a. e u/ e n/ m e di ci n e s/ h u m a n/ E P A R/ z o m et a # pr o d u ct -
i nf or m ati o n- s e cti o n) for d et ail e d i nf or m ati o n o n t h e a d mi ni str ati o n of Z A. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 7  of 1 0 4 
C O N FI D E N TI A L 
 
 
6. 2.   
Pr o hi bit e d m e di c ati o n s 
T h er e ar e n o pr o hi bit e d m e di c ati o n s i n t h e Z A s u b st u d y. 
7.  
S T U D Y P R O C E D U R E S 
7. 4.   
L a b or at or y A s s e s s m e nt s  
A s d e s cri b e d i n eli gi bilit y crit eri a f or t hi s s u b st u d y, r o uti n e l a b or at or y 
a s s e s s m e nt s ( at l e a st f or A L T, A S T, s er u m cr e ati ni n e, cr e ati n e cl e ar a n c e a n d 
c al ci u m ) t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e r a n d o mi z ati o n.  
P ati e nt s wit h c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y t e st wit hi n 
7 d a y s pri or t o r a n d o mi z ati o n.  S u bj e ct s w h o h a v e u n d er g o n e a h y st er e ct o m y d o 
n ot r e q uir e a pr e g n a n c y t e st. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 8  of 1 0 4 
C O N FI D E N TI A L 
 
 
8.  
A D V E R S E E V E N T R E P O R TI N G 
D uri n g t h e s u b st u d y, all S A E s  a n d A E s of s p e ci al i nt er e st ( r e n al t o xi cit y, cli ni c all y 
r el e v a nt h y p er/ h y p o c al c e mi a, a n d or al e v e nt s) will b e d o c u m e nt e d fr o m si g ni n g 
t h e I C F f or t h e Z A s u b st u d y u ntil t h e l a st st u d y vi sit ( 1 8 m o nt h s aft er D a y 1) i n t h e 
A d v er s e E v e nt e C R F. 
F or s u bj e ct s p arti ci p ati n g i n t h e s u b st u d y, t h e i n v e sti g at or i s r e s p o n si bl e f or 
e n s uri n g all S A E s o b s er v e d b y t h e i n v e sti g at or or r e p ort e d b y t h e s u bj e ct t h at 
o c c ur aft er si g ni n g of  t h e I C F f or t h e Z A s u b st u d y u ntil t h e l a st st u d y vi sit 
( 1 8 m o nt h s aft er D a y 1), ar e r e c or d e d i n t h e s u bj e ct s m e di c al r e c or d, t h e A d v er s e 
E v e nt e C R F, a n d ar e s u b mitt e d t o A m g e n .   
N e w cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, or f e m ur di st al) 
a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s sifi e d a s a n S A E f or all s u bj e ct s ( s e e 
S e cti o n 9. 1. 2 ), a n d s h o ul d b e r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d, a p pli c a bl e 
fr a ct ur e-r e c or di n g C R F, a n d  o n a S eri o u s A d v er s e E v e nt R e p ort f or m ( s e e 
A p p e n di x F ) t h e n f a x e d t o t h e l o c al A m g e n S af et y S p e ci ali st wit hi n 2 4 h o ur s of 
di s c o v er y or n otifi c ati o n of t h e e v e nt ( s e e S e cti o n 9. 3 ). 
S A E r e p orti n g p eri o d f or s u s p e ct e d at y pi c al f e m or al fr a ct ur e will b e u ntil E O S. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 9  of 1 0 4 
C O N FI D E N TI A L 
 
 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S 
9. 1.   
E x pl or at or y E n d p oi nt s 
9. 2.   
S u b s et s 
9. 3.   
S a m pl e Si z e C o n si d er ati o n s 
F or t h e Z A s u b st u d y, it i s a nti ci p at e d t h at a p pr o xi m at el y 2 0 0 s u bj e ct s c o ul d b e 
r a n d o mi z e d. 
D at a i s li mit e d o n B M D f or s u bj e ct s w h o di s c o nti n u e d e n o s u m a b 6 0 m g Q 6 M i n 
t h e o n c ol o g y s etti n g.  T h er ef or e, d at a fr o m p o st m e n o p a u s al o st e o p or o si s w a s 
u s e d i n t h e s a m pl e si z e.  
A p h a s e 2 r a n d o mi z e d bli n d e d cli ni c al tri al i n p o st m e n o p a u s al w o m e n wit h l o w 
b o n e m a s s a s s e s s e d t h e eff e ct of d e n o s u m a b 6 0  m g Q 6 M o n B M D a n d b o n e 
t ur n o v er m ar k er s ( C T X a n d O st e o c al ci n) aft er l o n g-t er m c o nti n u e d, di s c o nti n u e d, 
a n d r e st arti n g of t h er a p y ( Mill er et  al,  2 0 0 8 ).  O n e of t h e tr e at m e nt c o h ort s 
r e c ei v e d d e n o s u m a b 2 1 0 m g Q 6 M f or 2 4 m o nt h s t h e n pl a c e b o f or t h e n e xt 
2 4  m o nt h s.  B a s e d o n t hi s st u d y, a 5 % ( S D = 4. 3 %), 5. 2 % ( S D = 2. 6 %), a n d 3. 9 % 
( S D = 3. 8 %) d e cr e a s e i n t h e l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k B M D wa s 
s e e n d uri n g t h e 2  y e ar s aft er d e n o s u m a b di s c o nti n u ati o n ( d at a o n fil e). 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0 0  of 1 0 4  
C O N FI D E N TI A L 
 
 
A p a p er r e p orti n g 2 2 c a s e st u di e s of p o st m e n o p a u s al w o m e n w h o r e c ei v e d 
5 i nj e cti o n s ( a p pr o xi m at el y 2. 5 y e ar s) of d e n o s u m a b 6 0 m g Q 6 M a n d w er e t h e n 
gi v e n a si n gl e d o s e of Z A 6 m o nt h s  aft er t h e fift h i nj e cti o n  
(L e h m a n n a n d A e b erli, 2 0 1 7 ).  A 3. 8 % ( S D = 2. 8 %), 1. 7 % ( S D = 3. 3 %), a n d  
0. 6 % ( S D = 5 %) d e cr e a s e i n t h e l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k B M D w a s 
s e e n d uri n g t h e 2. 5 y e ar s aft er d e n o s u m a b di s c o nti n u ati o n.  
A t a bl e s h o wi n g t h e l e v el of pr e ci si o n (i e, h alf wi dt h of 9 5 % CI) f or e a c h tr e at m e nt 
ar m a n d e a c h B M D t y p e f or diff er e nt s a m pl e si z e s, c al c ul at e d b a s e d o n t h e 
st a n d ar d d e vi ati o n s e sti m at e d fr o m t h e 2 st u di e s m e nti o n e d a b o v e, i s pr e s e nt e d 
b el o w. 
T a bl e 3.  S a m pl e Si z e s 
N u m b er of 
s u bj e ct s i n  
e a c h ar m  
Pr e ci si o n ( h alf wi dt h of 9 5 % c o nfi d e n c e i nt er v al)  
St a n d ar d of c ar e  
I V z ol e dr o ni c a ci d 
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
7 5  
 1. 0 %  
 0. 6 %  
 0. 9 %  
 0. 6 %  
 0. 8 %  
 1. 1 %  
1 0 0  
 0. 9 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 7 %  
 1. 0 %  
1 2 5  
 0. 8 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 6 %  
 0. 9 %  
I V = i ntr a v e n o u s 
9. 4.   
A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s 
S u bj e ct s i n Z A s u b st u d y will b e r a n d o mi z e d 1: 1 t o r e c ei v e si n gl e d o s e Z A 5 m g I V 
(i n v e sti g ati o n al pr o d u ct) or S O C. 
9. 5.  
Ti m e p oi nt of A n al y si s  
9. 6.   
Pl a n n e d M et h o d s of A n al y si s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0 1  of 1 0 4  
C O N FI D E N TI A L 
 
 
1 0.  R E F E R E N C E S 
H a dji P, A a pr o M S, B o d y J J, G n a nt M, et al.  M a n a g e m e nt of Ar o m at a s e 
I n hi bit or- A s s o ci at e d B o n e L o s s ( AI B L) i n p o st m e n o p a u s al w o m e n wit h h or m o n e 
s e n siti v e br e a st c a n c er: J oi nt p o siti o n st at e m e nt of t h e I O F, C A B S, E C T S, I E G, 
E S C E O I M S, a n d SI O G.   J B o n e O n c ol .  2 0 1 7 ; 2 3; 7: 1-1 2.   
L e h m a n n T, A e b erli D.  P o s si bl e pr ot e cti v e eff e ct of s wit c hi n g fr o m d e n o s u m a b t o 
z ol e dr o ni c a ci d o n v ert e br al fr a ct ur e s.  O st e o p or o s I nt.   2 0 1 7; 2 8( 1 0): 3 0 6 7- 3 0 6 8.  
Mill er P D, B ol o g n e s e M S, L e wi e c ki E M, et al.  Eff e ct of d e n o s u m a b o n b o n e 
d e n sit y a n d t ur n o v er i n p o st m e n o p a u s al w o m e n wit h l o w b o n e m a s s aft er 
l o n g-t er m c o nti n u e d, di s c o nti n u e d, a n d r e st arti n g of t h er a p y:  a r a n d o mi z e d 
bli n di n g p h a s e 2 cli ni c al tri al.  B o n e.   2 0 0 8; 4 3( 2): 2 2 2- 2 2 9.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0 2  of 1 0 4  
C O N FI D E N TI A L 
 
 
1 1.  S C H E D U L E O F A S S E S S M E N T S 
T a bl e 4.  S c h e d ul e of A s s e s s m e nt s f or Z A S u b st u d y 
St u d y a s s e s s m e nt  
S cr e e ni n g/ b a s eli n e  
R a n d o mi z ati o n  
Q 6 M Vi sit  
Q 1 2 M Vi sit  
Q 1 8 M Vi sit = 
E O S a  
R e -c o n s e nt  
X  
 
 
 
 
R a n d o mi z ati o n  
 
X  
 
 
 
I V Z ol e dr o ni c a ci d ( 5 m g x 1) b  
 
X  
 
 
 
L a b or at or y A s s e s s m e nt e  
X  
 
 
 
 
 E O S = e n d of st u d y; I V = i ntr a v e n o u s; M = m o nt h; 
O L  = o p e n-l a b el; O L P = o p e n-l a b el p h a s e; Q X M = e v er y X m o nt h s; 
 S O C = st a n d ar d of c ar e; Z A = z ol e dr o ni c 
a ci d. 
T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n b ut m u st o c c ur aft er writt e n 
c o n s e nt h a s b e e n o bt ai n e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n u ntil 9 m o nt h s aft er. 
R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o D a y 1. 
Vi sit s t o sit e:  D a y  1 aft er r e -c o n s e nt a n d r a n d o mi z a ti o n, 6, 1 2, a n d 1 8  m o nt h s (  2  w e e k s) aft er d a y  1.  
a E O S:  E n d of Z A s u b st u d y will b e 1 8 m o nt h s aft er d a y  1; or t h e l a st s c h e d ul e d vi sit i n c a s e p ati e nt e n d s st u d y pr e m at ur el y. 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0 3  of 1 0 4  
C O N FI D E N TI A L 
 
 
b  Z A a d mi ni str ati o n m u st t a k e pl a c e wit hi n 8 d a y s aft er r a n d o mi z ati o n.  H alf of t h e p ati e nt s will b e r a n d o mi z e d t o S O C ( N o Z A).  D a y  1 f or b ot h ar m s s h o ul d 
b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  Vi sit s will t a k e pl a c e 6, 1 2, 
1 8  m o nt h s aft er d a y 1. S 
e R o uti n e l a b or at or y at l e a st f or A L T, A S T, s er u m cr e ati ni n e, cr e ati n e cl e ar a n c e a n d c al ci u m a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e 
r a n d o mi z ati o n.  A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n h a s t o b e a v ail a bl e f or w o m e n of c hil d b e ari n g p ot e nti al.  S u bj e ct s w h o 
h a v e u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st. 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0 4  of 1 0 4  
C O N FI D E N TI A L 
 
 
1 2.  P H A R M A C Y G UI D E F O R Z A S U B S T U D Y 
Z A S u b st u d y I n v e sti g ati o n al Pr o d u ct ( Z ol e dr o ni c A ci d) D o s a g e, A d mi ni str ati o n, 
a n d S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5 m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er 
all ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o s u bj e ct s b y 
h e alt h c ar e pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V 
bi s p h o s p h o n at e s.  S u bj e ct s tr e at e d wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et.  
Z A will b e l o c all y pr o vi d e d b y p arti ci p ati n g sit e s a n d will b e r ei m b ur s e d b y t h e 
s p o n s or. 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n 
a c c or d a n c e wit h l o c al r e q uir e m e nt s.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 of 7 1  
C O N FI D E N TI A L 
 
 
A m e n d m e nt 6 ( a d d e d Z A s u b st u d y) 
Pr ot o c ol Titl e:  A R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, M ulti- C e nt er 
P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s W it h 
N o n- M et a st ati c Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y 
 
A m g e n Pr ot o c ol N u m b er 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol N u m b er A B C S G 1 8 
E u dr a C T N u m b er 2 0 0 5- 0 0 5 2 7 5 -1 5  
N C T 0 0 5 5 6 3 7 4 
 
A m e n d m e nt 5 D at e:  
0 1 A pril  2 0 1 9  
A m e n d m e nt 6 D at e:  
1 5 J ul y 2 0 1 9  
R ati o n al e f or A m e n d m e nt 5 a n d 6: 
Pr ot o c ol a m e n d m e nt 5 d at e d 0 1 A pril 2 0 1 9 w a s d o n e t o a d d a n o pti o n al i n v e sti g ati o n of 
a d diti o n al z ol e dr o ni c a ci d ( Z A) aft er c o m pl eti n g o p e n -l a b el d e n o s u m a b t o t h e m ai n b o d y 
of t h e pr ot o c ol.  Aft er t h eir r e vi e w, t h e l e a d et hi c s c o m mitt e e a d vi s e d t h at t hi s r e s e ar c h 
q u e sti o n of a d diti o n al Z A a d mi ni str ati o n s h o ul d r at h er b e str u ct ur e d a n d s u b mitt e d a s a 
s u b st u d y.  A s sit e s h a v e n ot s e e n pr ot o c ol a m e n d m e nt 5, b ot h c h a n g e s f or pr ot o c ol 
a m e n d m e nt 5 a n d pr ot o c ol a m e n d m e nt 6 ar e pr e s e nt e d b el o w.    
R ati o n al e f or A m e n d m e nt 5: 
T hi s pr ot o c ol i s b ei n g a m e n d e d t o:  
 
A d d a r a n d o mi z ati o n o n p ati e nt s still o n o p e n l a b el d e n o s u m a b t o b e tr e at e d wit h 
eit h er a bi s p h o s p h o n at e or st a n d ar d of c ar e u p o n d e n o s u m a b di s c o nti n u ati o n 
 
A d d e x pl or at or y o bj e cti v e t o 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 of 7 1  
C O N FI D E N TI A L 
 
 
 
U p d at e t h e ti mi n g of Z A d o s e t o 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of 
o p e n -l a b el d e n o s u m a b b e c a u s e t hi s i s t h e m o m e nt w h er e t h er e i s i n cr e a s e i n t h e 
b o n e t ur n o v er m ar k er, C T X, m a ki n g it t h e n t h e o pti m al m o m e nt f or Z A t o a ct 
 
Cl arif y t h at C-t er mi n al t el o p e pti d e d at a will b e c oll e ct e d d uri n g p o st o p e n- l a b el 
d e n o s u m a b e xt e n si o n at s p e cifi e d ti m e s 
 
Cl arif y ti m e p eri o d s f or a s s e s s m e nt d uri n g t h e e xt e n si o n t o t h e o p e n -l a b el p h a s e. 
 
Cl arif y a n al y si s of t h e e n d p oi nt s f oll o wi n g t h e p o st o p e n-l a b el d e n o s u m a b e xt e n si o n  
 
A d d s c h e m a d e s cri bi n g p o st o p e n-l a b el d e n o s u m a b di s c o nti n u ati o n e xt e n si o n  
 
S p e cif y t h e a p pr o xi m at e n u m b er of st u d y sit e s i n A u stri a p arti ci p ati n g i n t h e p o st 
o p e n -l a b el d e n o s u m a b e xt e n si o n 
 
S p e cif y t h e a p pr o xi m at e n u m b er of s u bj e ct s p arti ci p ati n g i n t h e p o st o p e n- l a b el 
d e n o s u m a b e xt e n si o n 
 
A d d a m a xi m u m of a p pr o xi m at el y 1 8 m o nt h s t o t h e st u d y d ur ati o n 
 
A d d i n cl u si o n a n d e x cl u si o n crit eri a f or p o st o p e n- l a b el d e n o s u m a b z ol e dr o ni c a ci d 
e xt e n si o n 
 
A d d e x cl u si o n crit eri a f or d o u bl e- bli n d p h a s e of t h e st u d y 
 
E xt e n d t h e e x p e ct e d ti m e o n st u d y 
 
Cl arif y t h e E n d of St u d y d efi niti o n 
 
Cl arif y t h at d uri n g t h e p o st o p e n-l a b el d e n o s u m a b e xt e n si o n, n o i n v e sti g ati o n al 
pr o d u ct will b e pr o vi d e d 
 
M a k e e dit ori al a n d a d mi ni str ati v e c h a n g e s f or gr a m m ati c al r e a s o n s a s w ell a s f or 
i nt er n al c o n si st e n c y wit hi n t h e pr ot o c ol. 
R ati o n al e f or A m e n d m e nt 6: 
 
D e s cri pti o n of Z A s u b st u d y w a s r e m o v e d fr o m t h e b o d y of t h e pr ot o c ol a n d a d d e d t o 
A p p e n di x G.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 of 7 1  
C O N FI D E N TI A L 
 
 
D e s cri pti o n of C h a n g e s f or Pr ot o c ol A m e n d m e nt 5: 
S e cti o n:   Gl o b al  
C h a n g e:   T h e A m g e n gl o b al v er si o n d at e w a s c h a n g e d fr o m 2 2 F e br u ar y 2 0 1 6 t o 
0 1  A pril 2 0 1 9. 
S e cti o n:   Gl o b al  
C h a n g e:   E dit ori al, t y p o gr a p hi c al, a n d f or m atti n g c h a n g e s w er e m a d e t hr o u g h o u t t h e 
d o c u m e nt.  
S e cti o n:   Titl e P a g e  
A d d:   
A m g e n Pr ot o c ol N u m b er 2 0 0 5 0 2 0 9 
A B C S G Pr ot o c ol N u m b er A B C S G 1 8 
E u dr a C T #: 2 0 0 5- 0 0 5 2 7 5 -1 5  
N C T 0 0 5 5 6 3 7 4 
S e cti o n:   Titl e P a g e  
R e pl a c e: 
K e y S p o n s or C o nt a ct:  
 
Cli ni c al R e s e ar c h St u d y M a n a g er  
A m g e n Li mit e d  
U nit e d Ki n g d o m  
P h o n e:
e m ail: 
Wit h: 
K e y S p o n s or C o nt a ct:  
Gl o b al Cli ni c al Tri al M a n a g er  
A m g e n Li mit e d  
U nit e d Ki n g d o m  
P h o n e:
E m ail:  
S e cti o n:   Titl e P a g e  
A d d:  
D at e:  
0 1 A pril  2 0 1 9 A m e n d m e nt 5  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 4 of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n :  Pr ot o c ol S y n o p si s ( E x pl or at or y O bj e cti v e s) , B ull et p oi nt 3  
A d d:   
S e cti o n:   Pr ot o c ol S y n o p si s ( St u d y D e si g n), P ar a gr a p h s 1 4 a n d 1 7 t hr o u g h 2 5 
A d d:   
I n a d diti o n, f or all s u bj e ct s, B M D d at a will b e c oll e ct e d at a n y ti m e a D X A s c a n i s 
p erf or m e d f or B M D a n al y si s a s st a n d ar d of c ar e ( S O C) fr o m P A D C D t o e n d of st u d y 
( E O S); t h e s e d at a will b e c oll e ct e d i n t h e C R F. 
At t h e e n d of t h e m ai n  st u d y (L T F U  a n d O L P), a fi n al a n al y si s will o c c ur l o o ki n g at t h e 
s e c o n d ar y di s e a s e o ut c o m e-r el at e d e n d p oi nt s ( O S a n d B M F S) a s w ell a s a n e x pl or at or y 
a n al y si s of 
.  D at a c oll e ct e d d uri n g t h e p o st O L 
d e n o s u m a b e xt e n si o n will b e c e n s or e d at t h e E n d of O p e n -l a b el Tr e at m e nt Vi sit or 
t h e E O S Vi sit (L T F U  a n d O L P), w hi c h e v er o c c ur s l at er, f or t h e fi n al a n al y si s.  
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A e xt e n si o n): 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h a d e cli n e i n b o n e m a s s t h at a p pr o a c h 
pr e-tr e at m e nt l e v el s a n d a v ail a bl e d at a s u g g e st a n i n cr e a s e i n m ulti pl e v ert e br al 
fr a ct ur e s aft er di s c onti n u ati o n.  Bi s p h o s p h o n at e  tr e at m e nt aft er d e n o s u m a b m a y 
b e w arr a nt e d t o p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y i n p ati e nt s n ot 
pr e vi o u sl y e x p o s e d t o bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h fr a ct ur e ri s k  
(i e, o st e o p or o si s wit h pr e vi o u s v ert e br al fr a ct ur e s), b ut li mit e d d at a i s a v ail a bl e 
c o nfir mi n g t h e v ali dit y of t hi s h y p ot h e si s.  T h er ef or e, t h er e i s a d at a g a p r e g ar di n g 
o pti m al str at e gi e s f or p ati e nt s w h o will di s c o nti n u e d e n o s u m a b a n d t hi s pr ot o c o l 
a m e n d m e nt i s d e si g n e d t o h el p a d dr e s s t h at q u e sti o n.  
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 5, willi n g a n d 
eli gi bl e s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y a n d c o m pl et e d O L 
d e n o s u m a b m a y o pt i n t hi s Z A e xt e n si o n a n d eit h er r e c ei v e a si n gl e d o s e of Z A 
( T h er a p y Ar m), or ar e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or t hi s p ati e nt 
p o p ul ati o n ( C o ntr ol Ar m).   P ati e nt s w h o c o m pl et e d O L P d e n o s u m a b a n d e n d e d 
st u d y a s d efi n e d p er pr ot o c ol ar e eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n tri al a s 
l o n g a s t h e o utli n e d crit eri a ar e f ulfill e d.  Writt e n c o n s e nt m a y b e o bt ai n e d fr o m 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 of 7 1  
C O N FI D E N TI A L 
 
 
d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n u ntil 9  m o nt h s aft er.  T h e 
s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e 
e arli e st a n d l a st s u ntil r a n d o mi z ati o n, b ut m u st o c c ur aft er writt e n c o n s e nt h a s 
b e e n o bt ai n e d.  
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 
1 si n gl e 5  m g I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 
8 d a y s pri or t o D a y  1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s ( 4 w e e k s) fr o m 
t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s 
vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n 
will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or 
N o). 
D X A s c a n c a n b e p erf or m e d b et w e e n 7 t o 9 m o nt h s aft er t h e d at e of t h e l a st 
d e n o s u m a b a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A 
a d mi ni str ati o n.  R o uti n e D X A s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w 
c a n b e u s e d a s b a s eli n e D X A s c a n s.  
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A 
e xt e n si o n will c o m pl et e O L P a s s e s s m e nt s o nl y. 
S u bj e ct s w h o p arti ci p at e i n t h e Z A e xt e n si o n, will u n d er g o t h e f oll o wi n g 
a s s e s s m e nt s:  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   Pr ot o c ol S y n o p si s ( E x pl or at or y E n d p oi nt s ) 
A d d:   
E x pl or at or y E n d p oi nt s:  
S u bj e ct s w h o p arti ci p at e i n t h e Z A e xt e n si o n:  
S e cti o n:   Pr ot o c ol S y n o p si s ( S u m m ar y of S u bj e ct Eli gi bilit y Crit eri a)  
A d d: 
S u m m ar y of S u bj e ct Eli gi bilit y Crit eri a  ( Do u bl e -bli n d P h a s e)  
S e cti o n:   Pr ot o c ol S y n o p si s ( E x cl u si o n Crit eri a) 
A d d:   
S u bj e ct s c o m pl eti n g O L  d e n o s u m a b m a y b e eli gi bl e f or t h e Z A e xt e n si o n. 
S e cti o n:   Pr ot o c ol S y n o p si s (I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n 
d o u bl e - bli n d p h a s e a n d i n t h e O L P) 
A d d: 
I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n Do u bl e - bli n d P h a s e a n d i n 
t h e O L P: 
S e cti o n:   Pr ot o c ol S y n o p si s (I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n Z A 
E xt e n si o n)  
A d d: 
I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n Z A E xt e n si o n: 
T h er a p y Ar m:  Z A 5 m g I V si n gl e d o s e  
C o ntr ol Ar m:  S O C 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   Pr ot o c ol S y n o p si s ( L o n g-t er m F oll o w- u p) , P ar a gra p h 6 
A d d:   
P o st O p e n- l a b el D e n o s u m a b E xt e n si o n ( Z A e xt e n si o n): 
S e cti o n:   Pr ot o c ol S y n o p si s ( St ati sti c al C o n si d er ati o n s), P ar a gr a p h 4 a n d 7  
A d d:   
At t h e e n d of t h e m ai n st u d y (L T F U  a n d O L P), a fi n al a n al y si s will o c c ur l o o ki n g at t h e 
s e c o n d ar y di s e a s e o ut c o m e-r el at e d e n d p oi nt s ( O S a n d B M F S) a s w ell a s a n e x pl or at or y 
a n al y si s of 
 f or t h e m ai n st u d y.  
 
 
.  O nl y d at a c oll e ct e d u p t o t h e E O S 
vi sit ( e n d of O L tr e at m e nt vi sit or t h eir l a st s c h e d ul e d L T F U vi sit) will b e i n cl u d e d 
i n t h e fi n al a n al y si s.  A n y dat a c oll e ct e d f or t h e p o st O L  d e n o s u m a b e xt e n si o n will 
b e e x cl u d e d.  
A n al y si s of t h e e n d p oi nt s fr o m t h e Z A E xt e n si o n will b e d e s cri pti v e o nl y a n d will 
t a k e pl a c e w h e n all s u bj e ct s r a n d o mi z e d t o t h e e xte n si o n h a v e att e n d e d t h eir 
l a st st u d y vi sit.  T h e a n al y s e s will b e p erf or m e d aft er t h e fi n al a n al y si s of 
fr a ct ur e-r el at e d a n d di s e a s e-r el at e d o ut c o m e s f or t h e m ai n st u d y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 8 of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   St u d y s c h e m a, P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n St u d y D e si g n a n d 
Tr e at m e nt S c h e m a  
A d d: 
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n St u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
I V = i ntr a v e n o u s; Z A = z ol e dr o ni c a ci d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 9 of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   St u d y Gl o s s ar y 
A d d :   
A b br e vi ati o n/ A cr o n y m/ St u d y 
t er m 
D efi niti o n  
C T X  
C -t er mi n al t el o p e pti d e 
D a y 1 i n d o u bl e-bli n d p h a s e 
a n d O L P  
fir st d a y i n v e sti g ati o n al pr o d u ct i s a d mi ni st er e d 
D a y 1 i n Z A e xt e n si o n  
D efi n e d a s 8  m o nt h s (  4  w e e k s) aft er t h e l a st O L P 
d e n o s u m a b d o s e  
F or tr e at m e nt ar m:  fir st d a y Z A i s a d mi ni st er e d  
F or c o ntr ol ar m ( S O C tr e at m e nt):  S O C d a y  1 vi sit  
E n d of O p e n -L a b el Tr e at m e nt 
Vi sit  
t h e l a st a s s e s s m e nt of t h e pr ot o c ol s p e cifi e d o p e n-l a b el 
tr e at m e nt f or a s u bj e ct.  If n ot eli gi bl e f or p o st O L  
d e n o s u m a b Z A e xt e n si o n or willi n g t o t a k e p art i n t hi s 
st u d y, s u bj e ct s wi ll c o m pl et e a n e n d of O L tr e at m e nt vi sit 
3 0 t o 4 5 d a y s a ft er t h e l a st d o s e of O L d e n o s u m a b eit h er 
b y cli ni c vi sit  or t el e p h o n e c o nt a ct.  
E n d of St u d y ( E O S) of Z A 
E xt e n si o n  
T h e d at e w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
E xt e n si o n c o m pl et e s t h e l a st f or m al vi sit or a n 
u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m 
t h e Z A e xt e n si o n 
E n d of Tr e at m e nt i n 
d o u bl e -bli n d p h a s e  
l a st a d mi ni str ati o n of d o u bl e-bli n d i n v e sti g ati o n al pr o d u ct f or 
e a c h s u bj e ct  
E n d of Tr e at m e nt vi sit  i n 
d o u bl e -bli n d p h a s e  
t h e vi sit at w hi c h t h e s u bj e ct r e c ei v e s t h e l a st d o s e of I P; f or 
all s u bj e ct s, w h o s e l a st r e g ul ar st u d y vi sit wi t hi n 6 m o nt h s  
( + 4 5 d a y s ti m e wi n d o w) pri or t o t h e P A D C D w a s a y e arl y vi sit 
( e g, m o nt h s 1 2, 2 4, et c) a n d r a di ol o gi c al a s s e s s m e nt s w er e 
p erf or m e d, t hi s vi sit will b e c o n si d er e d a n E O T vi sit.  T h o s e 
s u bj e ct s, f or w h o m t h e r a di ol o gi c al a s s e s s m e nt s w er e n ot 
p erf or m e d, will n e e d t o att e n d t h e n e xt s c h e d ul e d 6 m o nt h s 
vi sit, w h e n r a di ol o gi c al a s s e s s m e nt s ( v ert e br al x -r a y s, D X A) 
will t a k e pl a c e a n d a n a nti b o d y s a m pl e will b e t a k e n.  F or 
t h e s e s u bj e ct s t hi s vi sit will b e c o n si d er e d a s E O T vi sit.  F or 
t h o s e w h o s e l ast r e g ul ar st u d y vi sit wit hi n 6 m o nt h s 
( + 4 5  d a y s ti m e wi n d o w) pri or t o t h e P A D C D w a s a 6  m o nt h s 
vi sit ( e g, m o nt h 6, 1 8, et c), t h e n e xt r e g ul arl y s c h e d ul e d 
y e arl y st u d y vi sit ( e g, Q 1 2 M) wit hi n 6 m o nt h s aft er P A D C D 
will b e c o n si d er e d a n E O T vi sit  
Fi n al a n a l y si s 
a n al y si s p erf or m e d aft er l o n g -t er m f oll o w u p, a n d O L P , 
a p pr o xi m at el y 6 6  m o nt h s aft er P A D C D, d e p e n di n g o n t h e 
i nt eri m a n al y si s 
M  
m o nt h ( s) 
O L  
o p e n -l a b el 
S m P C  
s u m m ar y of pr o d u ct c h ar a ct eri sti c s  
S O C  
st a n d ar d of c ar e  
Z A  
z ol e dr o ni c a ci d  
Z A E xt e n si o n Tr e at m e nt  
S u bj e ct r a n d o mi z e d t o tr e at m e nt ar m will r e c ei v e a 
si n gl e  d o s e Z A.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 0  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1. 3 E x pl or at or y, B ull et p oi nt 3 
A d d:   
S e cti o n:   2. 3 R ati o n al e, P ar a gr a p h 1 1 
A d d: 
B M D C h a n g e s Aft er O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A 
E xt e n si o n): 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h d e cli n e s i n b o n e m a s s t h at a p pr o a c h 
pr e-tr e at m e nt l e v el s a n d a v ail a bl e d at a d o s u g g e st a n i n cr e a s e i n m ulti pl e 
v ert e br al fr a ct ur e s aft er di s c o nti n u ati o n.  Bi s p h o s p h o n at e tr e at m e nt aft er 
d e n o s u m a b m a y b e w arr a nt e d t o p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y 
i n p ati ent s n ot pr e vi o u sl y e x p o s e d t o bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h 
fr a ct ur e ri s k (i e, o st e o p or o si s wit h pr e vi o u s v ert e br al fr a ct ur e s), b ut li mit e d d at a 
ar e a v ail a bl e c o nfir mi n g t h e v ali dit y of t hi s h y p ot h e si s.  T h er ef or e, t h er e i s a d at a 
g a p r e g ar di n g o pti m al str at e gi e s f or p ati e nt s w h o will di s c o nti n u e d e n o s u m a b.  
T h e A B C S G 1 8 P o st O p e n-l a b el D e n o s u m a b E xt e n si o n ( Z A E xt e n si o n) i s d e si g n e d 
t o e v al u at e o n p ati e nt s di s c o nti n ui n g d e n o s u m a b, t o eit h er r e c eiv e a si n gl e d o s e 
of Z A, or t o b e m a n a g e d a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or 
r e s p e cti v e p ati e nt p o p ul ati o n aft er d e n o s u m a b di s c o nti n u ati o n. 
S e cti o n:   3. 1 St u d y D e si g n ( O p e n-l a b el P h a s e), P ar a gr a p h 4, B ull et 2 
A d d :   
 
C oll e cti o n of s eri o u s a n d n o n- s eri o u s a d v er s e e v e nt s  [( S) A E s] of s p e ci al i nt er e st 
( or al e v e nt s) a n d S A E s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 1  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   3. 1 St u d y D e si g n ( P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n [ Z A 
E xt e n si o n]) 
A d d: 
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n): 
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 5, willi n g a n d 
eli gi bl e s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y a n d c o m pl et e d O L  
d e n o s u m a b m a y o pt i n t hi s Z A e xt e n si o n a n d eit h er r e c ei v e a si n gl e d o s e of Z A 
( T h er a p y Ar m), or ar e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or t hi s p ati e nt 
p o p ul ati o n ( C o ntr ol Ar m).  P ati e nt s w h o c o m pl et e d O L P d e n o s u m a b a n d e n d e d 
st u d y a s d efi n e d p er pr ot o c ol ar e eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n tri al a s 
l o n g a s t h e o utli n e d crit eri a ar e f ulfill e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b 
a d mi ni str ati o n u ntil 9  m o nt h s aft er.  T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e 
l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n, 
b ut m u st o c c ur aft er writt e n c o n s e nt h a s b e e n o bt ai n e d . 
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 
1 si n gl e 5  m g I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 
8 d a y s pri or t o D a y 1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m 
t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A  ar m, Z A will b e a d mi ni st er e d o n t hi s 
vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n 
will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or 
N o). 
D X A s c a n c a n b e p erf or m e d b et w e e n 7 t o 9 m o nt h s aft er t h e d at e of t h e l a st 
d e n o s u m a b a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A 
a d mi ni str ati o n.  R o uti n e D X A s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w 
c a n b e u s e d a s b a s eli n e D X A s c a n s . 
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A 
e xt e n si o n will c o m pl et e O L P a s s e s s m e nt s o nl y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 2  of 7 1  
C O N FI D E N TI A L 
 
 
S u bj e ct s w h o p arti ci p at e i n t h e Z A e xt e n si o n, will u n d er g o t h e f oll o wi n g 
a s s e s s m e nt s:  
S e cti o n:   3. 1 St u d y D e si g n, D u bl e- bli n d P h a s e, P ar a gr a p h 2 
D el et e: 
F or a s u bj e ct wit h > 1 0 % l o s s of B M D at t h e t ot al hi p or l u m b ar s pi n e o v er a n y 1- y e ar 
p eri o d, a n i nf or m e d di s c u s si o n will t a k e pl a c e b et w e e n t h e i n v e sti g at or a n d t h e s u bj e ct 
r e g ar di n g alt er n ati v e t h er a pi e s a n d a p pr o pri at e tr e at m e nt.  If t h e s el e ct e d tr e at m e nt 
o pti o n d o e s n ot i n cl u d e c o m m er ci all y a v ail a bl e d e n o s u m a b (i e, X G E V A  or Pr oli a), 
i ntr a v e n o u s (I V) bi s p h o s p h o n at e s or or all y a d mi ni st er e d bi s p h o s p h o n at e t h er a p y l a sti n g 
l o n g er t h a n 3 0 d a y s, w hi c h i s e x cl u si o n ar y (l e a di n g t o e arl y E O T), t h e s u bj e ct will r e m ai n 
i n t h e st u d y. 
S e cti o n:   3. 2  N u m b er of C e nt er s, P ar a gr a p h 2 
A d d: 
A p pr o xi m at el y 3 0 sit e s i n A u stri a ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A  
e xt e n si o n. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 3  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   3. 3 N u m b er of S u bj e ct s, P ar a gr a p h 3 
A d d: 
A p pr o xi m at el y 2 0 0 s u bj e ct s ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A e xt e n si o n. 
S e cti o n:   3. 4 E sti m at e d St u d y D ur ati o n  
A d d: 
T h e a ct u al ti mi n g of a n al y s e s will b e d et er mi n e d b y t h e P A D C D.  St u d y d ur ati o n i s 
e sti m at e d t o b e 1 6 9 m o nt h s, w hi c h i n cl u d e s a n e nr oll m e nt p eri o d of a p pr o xi m at el y 
8 2  m o nt h s, a n e n d of t h e tr e at m e nt p h a s e (i e, t h e P A D C D) of a p pr o xi m at el y 2 1 m o nt h s 
a n d a p pr o xi m at el y 6 6 m o nt h s f oll o wi n g t h e P A D C D f or a 5 y e ar l o n g -t er m f oll o w-u p 
i n cl u di n g a n O L P ( 1 2 m o nt h s u n bli n di n g o pti o n an d a m a xi m u m of 3 6 m o nt h s of 
tr e at m e nt) (. s e e S e cti o n s 7.1 5 a n d 1 0. 5).  A m e n d m e nt 5 ( Z A e xt e n si o n) will a d d a 
m a xi m u m of a p pr o xi m at el y 2 7 m o nt h s ( c o n si d eri n g t h at t h e p ati e nt m a y e nt er t h e 
e xt e n si o n st u d y 9 m o nt h s aft er O L P d e n o s u m a b c o m pl eti o n) t o t h e st u d y 
d ur ati o n. 
S e cti o n:   3. 4. 1 St u d y D ur ati o n f or P arti ci p a nt s, P ar a gr a p h s 2 a n d 3 
R e pl a c e: 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d- u p u ntil c o m pl eti o n of 
3 6  m o nt h s of tr e at m e nt or a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D, w hi c h e v er i s l o n g er.  
T h e e x p e ct e d ti m e o n st u d y i s u p t o a p pr o xi m at el y 1 6 9 m o nt h s. 
Wit h: 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d- u p u ntil c o m pl eti o n of 
3 6  m o nt h s of tr e at m e nt or a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D, w hi c h e v er i s l o n g er.  
S u bj e ct s i n t h e O L P  m a y c o n s e nt t o a n e xt e n si o n t o a s s e s s di s c o nti n u ati o n fr o m 
d e n o s u m a b a n d r e c ei v e eit h er si n gl e d o s e Z A 5 m g I V or S O C tr e at m e nt, w hi c h 
will b e f or a m a xi m u m d ur ati o n of a p pr o xi m at el y 2 7 f urt h er m o nt h s.  
T h e e x p e ct e d ti m e o n st u d y i s u p t o a p pr o xi m at el y 1 9 6  m o nt h s. 
S e cti o n:   3. 4. 3 L o n g -t er m F oll o w- u p, P ar a gr a p h 1 
R e pl a c e: 
S u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S Q 1 2 M b y cli ni c vi sit s or t el e p h o n e 
c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O S vi sit) f or a p pr o xi m at el y 
6 6  m o nt h s aft er t h e P A D C D ( s e e S e cti o n s 7. 1 5 a n d 1 0. 5).  F oll o wi n g r e g ul at or y a n d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 4  of 7 1  
C O N FI D E N TI A L 
 
 
I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d  
( s e e S e cti o n 3. 1). 
Wit h: 
S u bj e ct s will b e f oll o w e d f or D F S, B M F S, a n d O S Q 1 2 M b y cli ni c vi sit s or t el e p h o n e 
c o nt a ct s st arti n g fr o m t h eir l a st st u d y vi sit ( c o n si d er e d a s E O T  vi sit) f or a p pr o xi m at el y 
6 6  m o nt h s aft er t h e P A D C D ( s e e S e cti o n s 7. 1 5 a n d 1 0. 5).  F oll o wi n g r e g ul at or y a n d 
I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 4, f urt h er d at a will b e a s s e s s e d ( s e e  
S e cti o n 3. 1 ). 
S e cti o n:   3. 4. 5 P o st O p e n- l a b el D e n o s u m a b Z A  E xt e n si o n Tr e at m e nt ( N e w S e cti o n) 
A d d:   
3. 4. 5  
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n Tr e at m e nt 
P ati e nt s t h at c o m pl et e d t h eir O L P d e n o s u m a b  vi sit a n d e n d e d t h e st u d y a s 
d efi n e d p er pr ot o c ol ar e eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n a s l o n g a s all 
i n cl u si o n/ e x cl u si o n crit eri a ar e m et. 
Z ol e dr o ni c a ci d will b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) aft er l a st O L P 
a d mi ni str ati o n f or s u bj e ct s r a n d o mi z e d t o tr e at m e nt ar m.  S u bj e ct s r a n d o mi z e d t o 
S O C, will att e n d t h e sit e f or vi sit s at t h e s a m e vi sit s c h e d ul e a s t h e tr e at m e nt ar m 
s u bj e ct s. 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 5  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   3. 4. 6 E n d of St u d y ( D o u bl e- bli n d P h a s e a n d O L P) , P ar a gr a p h 1 
R e pl a c e: 
3. 4. 6  
E n d of St u d y 
T h e e n d of t h e st u d y will o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit 
or l a st f or m al c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e 
st u d y.  T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h eir e n d of o p e n-l a b el 
tr e at m e nt vi sit or t h eir l a st s c h e d ul e d L T F U vi sit. 
Wit h: 
3. 4. 6  
E n d of St u d y ( Do u bl e - bli n d Ph a s e a n d O L P)  
T h e e n d of t h e st u d y will o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi si t 
or l a st f or m al c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e 
st u d y.  T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h e e xt e n si o n t o t h e 
O L  tr e at m e nt p eri o d or t h eir l a st s c h e d ul e d L T F U vi sit. 
S e cti o n:   3. 4. 7 E n d of St u d y of Z A E xt e n si o n ( N e w S e cti o n) 
A d d: 
3. 4. 7  
E n d of St u d y of Z A E xt e n si o n 
T h e e n d of Z A E xt e n si o n will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
E xt e n si o n h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n 
c a s e of e arl y wit h dr a w al fr o m t h e Z A e xt e n si o n. 
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, a n d 
c o n s e nt wit h dr a w al) a n d p er pr ot o c ol E O S of Z A E xt e n si o n. 
S e cti o n:   4. 2 E x cl u si o n Crit eri a f or D o u bl e- bli n d P h a s e, E x cl u si o n crit eri a 4. 2. 7 , b ull et 1 
R e pl a c e: 
4. 2. 7  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d i n di c at e d b y 
t h e f oll o wi n g crit eri a: 
 
A s p ar at e a mi n otr a n sf er a s e ≥ 2. 5 x u p p er li mit of n or m al ( U L N) 
Wit h: 
4. 2. 7  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d i n di c at e d b y 
t h e f oll o wi n g crit eri a: 
 
A s p art at e  a mi n otr a n sf er a s e ≥ 2. 5 x u p p er li mit of n or m al ( U L N) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 6  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   4. 5 I n cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n ( Z A E xt e n si o n) ( N e w S e cti o n) 
A d d: 
4. 5  
I n cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n ( Z A E xt e n si o n) 
4. 5. 1  
O bt ai n si g n e d a n d d at e d writt e n i nf or m e d c o n s e nt pri or t o p erf or mi n g a n y 
st u d y- s p e cifi c pr o c e d ur e 
4. 5. 2  
S u bj e ct s t h at r e c ei v e d O L P d e n o s u m a b a n d c o m pl et e d O L P tr e at m e nt 
4. 5. 3  L a st O L P d e n o s u m a b a d mi ni str ati o n n o l o n g er t h a n 9 m o nt h s a g o 
S e cti o n:   4. 6 E x cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n ( N e w S e cti o n) 
A d d: 
4. 6   
E x cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n 
4. 6. 1  
C urr e nt or pri or Z A a d mi ni str ati o n. 
4. 6. 2  
S u bj e ct s w h o e n d e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct (I P) pr e m at ur el y 
i n t h e d o u bl e-bli n d p h a s e a n d O L p h a s e  
4. 6. 3  
K n o w n s e n siti vit y or i nt ol er a n c e t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d 
d uri n g t h e st u d y ( e g, Z A , c al ci u m or vit a mi n D) 
4. 6. 4  
K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf 
r e p ort or c h art r e vi e w 
 
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a or ot h er 
a cti v e m et a b oli c b o n e di s e a s e 
 
K n o w n hi st or y of h y p o c al c e mi a 
 
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s pri or 
t o r a n d o mi z ati o n 
 
P ar at h yr oi d gl a n d s i n n e c k s ur gi c all y r e m o v e d  
 
A n y s e cti o n s of i nt e sti n e r e m o v e d  
 
K n o w n h u m a n i m m u n o d efi ci e n c y vir u s i nf e cti o n 
 
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 7  of 7 1  
C O N FI D E N TI A L 
 
 
4. 6. 5  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d 
i n di c at e d b y t h e f oll o wi n g crit eri a: 
 
A s p art at e a mi n otr a n sf e r a s e ≥ 2. 5 x U L N  
 
Al a ni n e tr a n s a mi n a s e ≥ 2. 5 x U L N  
 
S er u m cr e ati ni n e ≥ 2 x U L N 
 
Cr e ati n e cl e ar a n c e < 3 5 ml/ mi n  
4. 6. 6  
S u bj e ct s t h at ar e pr e g n a nt or br e a stf e e di n g 
 
All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y 
t e st wit hi n 7 d a y s b ef or e r a n d o mi z ati o n 
4. 6. 7  
S u bj e ct s w h o ar e o st e o p or oti c i n b a s eli n e B M D 
S e cti o n:   5. 6 P o st O p e n- l a b el D e n o s u m a b Z A  E xt e n si o n ( N e w s e cti o n) 
A d d: 
5. 6   
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n 
A s u bj e ct will b e a s si g n e d b y a n I nt er a cti v e V oi c e/ W e b R e s p o n s e S y st e m t o 1 of 
2 tr e at m e nt gr o u p s ( Z A or S O C), i n a 1: 1 r ati o.  T h e r a n d o mi z ati o n s c h e d ul e will 
u s e r a n d o ml y p er m ut e d bl o c k s a n d will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of 
O L P d e n o s u m a b c o m pl eti o n ( Y e s or N o).  A s u bj e ct w h o i s r a n d o mi z e d t o t h e Z A 
E xt e n si o n will m ai nt ai n t h e s a m e s u bj e ct n u m b er w hi c h i s al s o t h e s u bj e ct 
n u m b er a s a s si g n e d i n t h e d o u bl e- bli n d st u d y.  A s u bj e ct m a y o nl y b e r a n d o mi z e d 
o n c e i nt o Z A E xt e n si o n.  T h e Z A r a n d o mi z ati o n li st will b e g e n er at e d a n d 
m ai nt ai n e d b y a n A m g e n r e pr e s e nt ati v e n ot i n v ol v e d i n t h e c o n d u ct of t h e st u d y. 
S e cti o n:   6. 3 Pr o hi bit e d M e di c ati o n i n P o st O p e n- l a b el D e n o s u m a b Z A  E xt e n si o n ( N e w 
s e cti o n) 
A d d: 
6. 3   
Pr o hi bit e d M e di c ati o n i n P o st O p e n-l a b el D e n o s u m a b Z A  E xt e n si o n 
S u bj e ct s p arti ci p ati n g i n t h e Z A E xt e n si o n will f oll o w t h e s a m e vi sit s c h e d ul e a s 
o utli n e d i n t h e Z A E xt e n si o n ( A p p e n di x A, S c h e d ul e of A s s e s s m e nt s).  T h er e ar e 
n o pr o hi bit e d m e di c ati o n s i n t hi s e xt e n si o n. 
6. 3. 1  I n v e sti g ati o n al Pr o d u ct ( D e n o s u m a b) 
N o d e n o s u m a b i s r e q uir e d or pr o vi d e d f or p ati e nt s i n t h e p o st  O L  d e n o s u m a b 
e xt e n si o n. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 8  of 7 1  
C O N FI D E N TI A L 
 
 
6. 3. 2  
N o n I n v e sti g ati o n al Pr o d u ct D o s a g e, A d mi ni str ati o n, a n d S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5  m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er 
all ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o p ati e nt s b y 
h e alt h c a r e pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V 
bi s p h o s p h o n at e s.  P ati e nt s tr e at e d wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et . 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n 
a c c or d a n c e wit h l o c al r e q uir e m e nt s. 
R ef er t o t h e s u m m ar y of pr o d u ct c h ar a ct eri sti c s ( S m P C) 
( htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ pr o d u ct/ 4 4/ s m p c) f or d et ail e d i nf or m ati o n o n 
t h e a d mi ni str ati o n of Z A . 
6. 3. 3  
Pr o hi bit e d m e di c ati o n s 
T h er e ar e n o pr o hi bit e d m e di c ati o n s i n t h e p o st O L d e n o s u m a b e xt e n si o n . 
S e cti o n:   7. 7. 1 A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n-l a b el P h a s e , S u btitl e 
A d d: 
7. 7. 1  
A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n-l a b el P h a s e a n d Z A  E xt e n si o n 
 
A d d: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 1 9  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   
 
 
A d d: 
S e cti o n:   7. 1 3 L a b or at or y A s s e s s m e nt s i n Z A St u d y ( N e w S e cti o n)  
A d d: 
7. 1 3  
L a b or at or y A s s e s s m e nt s i n Z A St u d y 
R o uti n e l a b or at or y a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e 
r a n d o mi z ati o n.  P ati e nt s wit h c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e 
pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n.  S u bj e ct s w h o h a v e 
u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st. 
S e cti o n:   7. 1 4. 1 Bl o o d a n d S er u m A s s e s s m e nt s i n Z A E xt e n si o n ( N e w S e cti o n) 
A d d: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 0  of 7 1  
C O N FI D E N TI A L 
 
 
T a bl e  1.  S er u m a n d Bl o o d S a m pl e A n al yt e Li sti n g 
S er u m C h e mi str y  
H e m at ol o g y  
Ot h er  
S o di u m  
R e d bl o o d c ell s  
D e n o s u m a b a nti b o d y a s s a y  ( o nl y 
d o u bl e -bli n d st u d y)  
P ot a s si u m  
H e m o gl o bi n  
 
 
C al ci u m  
H e m at o crit  
 
Bl o o d Ur e a Nitr o g e n/ Ur e a  
Pl at el et s  
 
Cr e ati ni n e  
W hit e bl o o d c ell s  
 
T ot al bilir u bi n  
 
 
Al k ali n e p h o s p h at a s e  
 
 
Al a ni n e tr a n s a mi n a s e   
 
 
A s p ar at e a mi n otr a n sf er a s e  
 
 
L D H  
 
 
G a m m a G T  
 
 
Al b u mi n  
 
 
 
S e cti o n:   7. 1 5 A d v er s e E v e nt s, O p e n-l a b el P h a s e/ L o n g-t er m F oll o w- u p, P ar a gr a p h s 3 
a n d 4  
A d d: 
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n): 
D uri n g t h e p o st O L d e n o s u m a b e xt e n si o n , ( S) A E s of s p e ci al i nt er e st ( c a u s al 
r el ati o n s hi p t o Z A  a n d or al e v e nt s) will b e d o c u m e nt e d f or s u bj e ct s r e c ei vi n g Z A. 
N e w cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, or f e m ur di st al) 
a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s sifi e d a s a n S A E f or all s u bj e ct s ( s e e 
S e cti o n 9. 1. 2), a n d s h o ul d b e r e c or d e d o n a S eri o u s A d v er s e E v e nt R e p ort f or m 
( s e e Ap p e n di x  F) a n d f a x e d t o t h e l o c al A m g e n S af et y S p e ci ali st wit hi n 2 4  h o ur s 
of di s c o v er y or n otifi c ati o n of t h e e v e nt ( s e e S e cti o n  9. 3). 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 1  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   7. 2 0  P o st O p e n-l a b el D e n o s u m a b E xt e n si o n ( N e w S e cti o n) 
A d d: 
7. 2 0  
P o st O L D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n) 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit. 
F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1 . 
S e cti o n:   7. 2 1  E n d of St u d y, P ar a gr a p h 1 
A d d: 
T h e p ati e nt i n di vi d u al  E O S i s d efi n e d a s t h e l a st f or m al vi sit or c o nt a ct f or a s u bj e ct or 
a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m st u d y.  T h e o v er all E O S  will 
o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit or l a st f or m al 
c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e st u d y.   
T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h eir e n d of o p e n- l a b el 
tr e at m e nt vi sit or t h eir l a st s c h e d ul e d L T F U vi sit. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 2  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   7. 2 2 E n d of St u d y of Z A E xt e n si o n ( N e w S e cti o n) 
A d d: 
7. 2 2  
E n d of St u d y of Z A E xt e n si o n 
T h e e n d of Z A e xt e n si o n will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
e xt e n si o n h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n 
c a s e of e arl y wit h dr a w al fr o m t h e Z A e xt e n si o n. 
E n d of Z A e xt e n si o n st u d y will b e 1 8 m o nt h s aft er d a y 1 .  
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, 
c o n s e nt wit h dr a w al) a n d p er pr ot o c ol E O S of Z A e xt e n si o n. 
S e cti o n:   9. 3. 1 , A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s A d v er s e E v e nt 
R e p orti n g D uri n g t h e O p e n-l a b el P h a s e ( S e cti o n Titl e) 
A d d: 
9. 3. 1  
A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s A d v er s e E v e nt R e p orti n g D uri n g 
t h e Op e n -l a b el P h a s e a n d P o st O p e n-l a b el D e n o s u m a b E xt e n si o n  
S e cti o n:   9. 3. 1. 2, S eri o u s A d v er s e E v e nt R e p orti n g, P ar a gr a p h s 3 a n d 4  
A d d: 
F or s u bj e ct s p art i ci p ati n g i n t h e p o st O L d e n o s u m a b e xt e n si o n a n d r e c ei vi n g Z A , 
t h e i n v e sti g at or i s r e s p o n si bl e f or e n s uri n g all S A E s o b s er v e d b y t h e i n v e sti g at or 
or r e p ort e d b y t h e s u bj e ct t h at o c c ur aft er si g ni n g t h e I C F f or t h e e xt e n si o n u ntil 
t h e l a st st u d y vi sit ( 1 8 m o nt h s aft er D a y 1), ar e r e c or d e d i n t h e s u bj e ct s m e di c al 
r e c ord a n d ar e s u b mitt e d t o A m g e n.  N e w c li ni c al fr a ct ur e s will b e c oll e ct e d a n d 
a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur 
s u btr o c h a nt eri c, or f e m ur di st al) a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s sifi e d 
a s a n S A E f or all s u bj e ct s ( s e e S e cti o n 9. 1. 2), a n d s h o ul d b e r e c or d e d o n a 
S eri o u s A d v er s e E v e nt R e p ort f or m ( s e e A p p e n di x F) a n d f a x e d t o t h e l o c al 
A m g e n S af et y S p e ci ali st wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of t h e e v e nt 
( s e e S e cti o n 9. 3). 
I n a d diti o n, a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e (f e m ur mi d s h aft fr a ctur e, 
f e m ur s u btr o c h a nt eri c, or f e m ur di st al) a s s o ci at e d wit h mi ni m al tr a u m a will b e 
cl a s si fi e d a s a n S A E f or all s u bj e ct s, a n d s h o ul d b e r e c or d e d i n t h e s u bj e ct’ s 
m e di c al r e c or d a n d s u b mitt e d t o A m g e n ( s e e A p p e n di x F- Cli ni c al Tri al S eri o u s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 3  of 7 1  
C O N FI D E N TI A L 
 
 
A d v er s e E v e nt r e p ort f or m) a n d r e c or d e d i n t h e a p pli c a bl e fr a ct ur e r e c or di n g C R F.  
S A E r e p orti n g p eri o d f or s u s p e ct e d at y pi c al f e m or al fr a ct ur e will b e u ntil E O S.  
S e cti o n:   1 0. 1 St u d y D e si g n, P ar a gr a p h 2 
A d d: 
S e cti o n:   1 0. 2. 4 E x pl or at or y E n d p oi n t s, S u b h e a di n g a n d b ull et s 6 t hr o u g h 8 
A d d: 
P o st O p e n-l a b el D e n o s u m a b E xt e n si o n ( Z A e xt e n si o n):  
S e cti o n:   1 0. 2. 5 S u b s et s, P ar a gr a p h s 2 a n d 3  
A d d: 
T h e p o st d e n o s u m a b O L s af et y a n al y si s s et wi ll c o n si st of all r a n d o mi z e d 
s u bj e ct s s u m m ari z e d u n d er t h e a ct u al tr e at m e nt t h e y r e c ei v e d .  S u bj e ct s w h o 
r e c ei v e Z A will b e s u m m ari z e d i n t h e Z A ar m w hil e all ot h er s u bj e ct s will b e 
s u m m ari z e d i n t h e S O C ar m.  S eri o u s a d v er s e e v e nt s a s s o ci at e d wit h Z A 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 4  of 7 1  
C O N FI D E N TI A L 
 
 
a d mi ni str ati o n, 
 
 
S e cti o n:   1 0. 3 S a m pl e Si z e C o n si d er ati o n s, P ar a gr a p h s 6 t o 1 0 
A d d: 
F or t h e Z A e xt e n si o n, it i s e x p e ct e d t h at a p pr o xi m at el y 2 0 0 s u bj e ct s c o ul d b e 
r a n d o mi z e d. 
D at a i s li mit e d o n B M D f or s u bj e ct s w h o di s c o nti n u e d e n o s u m a b 6 0 m g Q 6 M i n 
t h e o n c ol o g y s etti n g.  T h er ef or e d at a fr o m p o st m e n o p a u s al o st e o p or o si s w a s 
u s e d i n t h e s a m pl e si z e . 
A p h a s e 2 r a n d o mi z e d bli n d e d cli ni c al tri al i n p o st m e n o p a u s al w o m e n wit h l o w 
b o n e m a s s a s s e s s e d t h e eff e ct of d e n o s u m a b 6 0  m g Q 6 M o n B M D a n d b o n e 
t ur n o v er m ar k er s ( C T X a n d O st e o c al ci n) aft er l o n g-t er m c o nti n u e d, di s c o nti n u e d, 
a n d r e st arti n g of t h er a p y ( Mill er et  al,  2 0 0 8).  O n e of t h e tr e at m e nt c o h ort s 
r e c ei v e d d e n o s u m a b 2 1 0 m g Q 6 M f or 2 4 m o nt h s t h e n pl a c e b o f or t h e n e xt 
2 4  m o nt h s.  B a s e d o n t hi s st u d y, a 5 % ( S D = 4. 3 %), 5. 2 % ( S D = 2. 6 %), a n d 3. 9 % 
( S D = 3. 8 %) d e cr e a s e i n t h e l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k B M D w a s 
s e e n d uri n g t h e 2  y e ar s aft er d e n o s u m a b di s c o nti n u ati o n ( d at a o n fil e). 
A p a p er r e p orti n g 2 2 c a s e st u di e s of p o st m e n o p a u s al w o m e n w h o r e c ei v e d 
5 i nj e cti o n s ( a p pr o xi m at el y 2. 5 y e ar s) of d e n o s u m a b 6 0 m g Q 6 M a n d w er e t h e n 
gi v e n a si n gl e d o s e of Z A 6 m o nt h s aft er t h e fift h i nj e cti o n ( L e h m a n n a n d A e b erli, 
2 0 1 7).  A 3. 8 % ( S D = 2. 8 %), 1. 7 % ( S D = 3. 3 %), a n d 0. 6 % ( S D = 5 %) d e cr e a s e i n t h e 
l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k B M D w a s s e e n d uri n g t h e 2. 5 y e ar s aft er 
d e n o s u m a b di s c o nti n u ati o n . 
A t a bl e s h o wi n g t h e l e v el of pr e ci si o n (i e, h alf wi dt h of 9 5 % CI) f or e a c h tr e at m e nt 
ar m a n d e a c h B M D t y p e f or diff er e nt s a m pl e si z e s, c al c ul at e d b a s e d o n t h e 
st a n d ar d d e vi ati o n s e sti m at e d fr o m t h e 2 st u di e s m e nti o n e d a b o v e, i s pr e s e nt e d 
b el o w. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 5  of 7 1  
C O N FI D E N TI A L 
 
 
T a bl e  2.  S a m pl e Si z e s 
N u m b er of 
s u bj e ct s i n  
e a c h ar m  
P r e ci si o n ( h alf wi dt h of 9 5 % c o nfi d e n c e i nt er v al) 
St a n d ar d of c ar e  
I V z ol e dr o ni c a ci d 
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
7 5  
 1. 0 %  
 0. 6 %  
 0. 9 %  
 0. 6 %  
 0. 8 %  
 1. 1 %  
1 0 0  
 0. 9 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 7 %  
 1. 0 %  
1 2 5  
 0. 8 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 6 %  
 0. 9 %  
I V = i ntr a v e n o u s 
S e cti o n:   1 0. 4  A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s, P ar a gr a p h 5 
A d d: 
Eli gi bl e s u bj e ct s w h o c o n s e nt t o t h e Z A e xt e n si o n d o n ot r e c ei v e a n y 
i n v e sti g ati o n al pr o d u ct ( d e n o s u m a b), b ut will b e r a n d o mi z e d 1: 1 t o r e c ei v e 
si n gl e  d o s e Z A  5 m g I V or S O C. 
S e cti o n:   1 0. 5 I nt eri m A n al y si s, E arl y St o p pi n g G ui d eli n e s, a n d Ti m e - p oi nt s of 
A n al y s e s, P ar a gr a p h s 5, 6, a n d  7 
A d d: 
A fi n al e x pl or at or y  
 a n al y si s a s w ell a s t h e m ai n a n al y s e s f or effi c a c y of t h e 
s e c o n d ar y e n d p oi nt s B M F S a n d O S will b e p erf or m e d at t h e e n d of t h e m ai n st u d y.  
A d diti o n all y, 
 
 will b e e v al u at e d i n a fi n al 
e x pl or at or y a n al y si s at t hi s ti m e p oi nt.   O nl y d at a c oll e ct e d u p t o t h e E O S vi sit ( e n d of 
O L  tr e at m e nt vi sit or t h eir l a st s c h e d ul e d L T F U vi sit) will b e i n cl u d e d i n t h e fi n al 
a n al y si s.  A n y d at a c oll e ct e d f or t h e p o st O L d e n o s u m a b e xt e n si o n will b e 
e x cl u d e d.  
  D at a c oll e ct e d d uri n g t h e Z A e xt e n si o n will b e c e n s or e d f or t hi s fi n al 
a n al y si s at t h e E n d of O p e n -L a b el Tr e at m e nt Vi sit or t h e E O S  Vi sit ( L T F U a n d 
O L P), w hi c h e v er o c c ur s l at er.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 6  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 0. 6. 2 . 2 S af et y A n al y s e s, P ar a gr a p h 2 
R e pl a c e: 
T h e s u bj e ct i n ci d e n c e r at e s of 
 
 r e p ort e d d uri n g t h e O L P will b e t a b ul at e d s e p ar at el y b y s y st e m or g a n cl a s s 
a n d pr ef err e d t er m. 
Wit h: 
T h e s u bj e ct i n ci d e n c e r at e s of 
 
 r e p ort e d d uri n g t h e O L P will b e t a b ul at e d s e p ar at el y b y 
s y st e m or g a n cl a s s a n d pr ef err e d t er m. 
S e cti o n:   1 0. 6. 2 . 4 E x pl or at or y A n al y s e s, P ar a gr a p h 4 
A d d: 
 
. 
S e cti o n:   1 0. 6. 2. 4 E x pl or at or y A n al y s e s, P ar gr a p h s 7 t hr o u g h 1 0  
A d d: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 7  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 1. 1 D e n o s u m a b ( P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n) ( N e w 
s u b s e cti o n) 
A d d: 
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n:  
N o Z A will b e pr o vi d e d f or t hi s e xt e n si o n. 
P ati e nt s i n cl u d e d i n t h e tr e at m e nt ar m of t h e Z A e xt e n si o n will o bt ai n Z A (I V 5 m g) 
vi a a pr e s cri pti o n fr o m t h eir p h y si ci a n.  
T h er e ar e c urr e ntl y n o g ui d eli n e s or e vi d e n c e r e g ar di n g t h e b e st str at e g y t o b e 
c o n si d er e d w h e n di s c o nti n ui n g d e n o s u m a b i n c a n c er tr e at m e nt -i n d u c e d b o n e 
l o s s.  T h er e h a s b e e n e x p ert o pi ni o n p u bli s h e d st ati n g t h at a tr a n siti o n t o a 
bi s p h o s p h o n at e r e pr e s e nt s a tr e at m e nt o pti o n ( H a dji et al, 2 0 1 7) . 
S e cti o n:   1 1. 2. 3 P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n ( N e w s e cti o n) 
A d d: 
1 1. 2. 3  P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n 
Aft er t h e I C F i s si g n e d, r a n d o mi z ati o n of s u bj e ct s d e e m e d eli gi bl e f or t h e Z A 
E xt e n si o n c a n o c c ur, a n d Z A s h all b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) fr o m t h e 
l a st d o se of O L d e n o s u m a b . 
P ati e nt s i n cl u d e d i n t h e Z A  ar m of t h e p o st d e n os u m a b di s c o nti n u ati o n O L  
a d mi ni str ati o n will o bt ai n Z A (I V 5 m g) vi a a pr e s cri pti o n fr o m t h eir p h y si ci a n . 
R ef er t o t h e S m P C ( htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ pr o d u ct/ 4 4/ s m p c) f or 
d et ail e d i nf or m ati o n o n t h e a d mi ni str ati o n of Z A . 
S e cti o n:   1 2. 4 S u bj e ct C o nfi d e nti alit y  
R e pl a c e: 
T h e i n v e sti g at or m u st e n s ur e t h at t h e s u bj e ct’ s c o nfi d e nti alit y i s m ai nt ai n e d.  O n t h e 
c a s e r e p ort f or m s or ot h er d o c u m e nt s s u b mitt e d t o A m g e n/ A B C S G, s u bj e ct s s h o ul d b e 
i d e ntifi e d b y t h e s u bj e ct st u d y n u m b er o nl y.  D o c u m e nt s t h at ar e n ot f or s u b mi s si o n t o 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 8  of 7 1  
C O N FI D E N TI A L 
 
 
A m g e n/ A B S C G ( e g, si g n e d i nf or m e d c o n s e nt f or m s) s h o ul d b e k e pt i n stri ct c o nfi d e n c e 
b y t h e i n v e sti g at or. 
Wit h: 
T h e i n v e sti g at or m u st e n s ur e t h at t h e s u bj e ct’ s c o nfi d e nti alit y i s m ai nt ai n e d.  O n t h e 
c a s e r e p ort f or m s or ot h er d o c u m e nt s s u b mitt e d t o A m g e n/ A B C S G, s u bj e ct s s h o ul d b e 
i d e ntifi e d b y t h e s u bj e ct st u d y n u m b er o nl y.  D o c u m e nt s t h at ar e n ot f or s u b mi s si o n t o 
A m g e n/ A B C S G ( e g, si g n e d i nf or m e d c o n s e nt f or m s) s h o ul d b e k e pt i n stri ct c o nfi d e n c e 
b y t h e i n v e sti g at or.  
S e cti o n:   1 3. 1 Pr ot o c ol A m e n d m e nt s a n d St u d y T er mi n ati o n, P ar a gr a p h 1  
D el et e: 
Pr ot o c ol a m e n d m e nt s, e x c e pt w h er e n e c e s s ar y t o eli mi n at e a n i m m e di at e h a z ar d t o 
s u bj e ct s, m u st b e m a d e o nl y wit h t h e pri or a p pr o v al of A m g e n.  A gr e e m e nt fr o m t h e 
i n v e sti g at or m u st b e o bt ai n e d f or all pr ot o c ol a m e n d m e nt s a n d a m e n d m e nt s t o t h e 
i nf or m e d c o n s e nt d o c u m e nt.  T h e I E C m u st b e i nf or m e d of all a m e n d m e nt s a n d gi v e 
a p pr o v al.  A B C S G m u st s e n d a c o p y of t h e a p pr o v al l ett er fr o m t h e I E C t o A m g e n. 
S e cti o n:   1 3. 2 St u d y D o c u m e nt ati o n a n d Ar c hi v e, P ar a gr a p h 1  
R e pl a c e: 
T h e i n v e sti g at or s h o ul d m ai nt ai n a li st of a p pr o pri at el y q u alifi e d p er s o n s t o w h o m h e/ s h e 
h a s d el e g at e d st u d y d uti e s.  All p er s o n s a ut h ori z e d t o m a k e e ntri e s a n d/ or c orr e cti o n s 
o n  c a s e r e p ort f or m s will b e i n cl u d e d o n t h e A m g e n D el e g ati o n of A ut h orit y F or m. 
Wit h: 
T h e i n v e sti g at or s h o ul d m ai nt ai n a li st of a p pr o pri at el y q u alifi e d p er s o n s t o w h o m h e/ s h e 
h a s d el e g at e d st u d y d uti e s.  All p er s o n s a ut h ori z e d t o m a k e e ntri e s a n d/ or c orr e cti o n s 
o n c a s e r e p ort f or m s will b e i n cl u d e d o n t h e A B C S G  D el e g ati o n of A ut h orit y F or m. 
S e cti o n:   1 3. 2 St u d y D o c u m e nt ati o n a n d Ar c hi v e, P ar a gr a p h 3, B ull et 1  
R e pl a c e: 
 
S u bj e ct fil e s c o nt ai ni n g c o m pl et e d c a s e r e p ort f or m s, i nf or m e d c o n s e nt f or m s, a n d 
s u bj e ct i d e ntifi c ati o n li st. 
Wit h: 
 
S u bj e ct fil e s c o nt ai ni n g c o m pl et e d i nf or m e d c o n s e nt f or m s a n d s u bj e ct i d e ntifi c ati o n 
li st.  D o c u m e nt ati o n of C R F s i s vi si bl e vi a w e b-b a s e d el e ctr o ni c d at a c a pt ur e 
( E D C) s y st e m at a n y ti m e d uri n g t h e st u d y.  At d at a b a s e cl o s ur e d at a will b e 
pr o vi d e d o n c o m p a ct di s c s f or fili n g p ur p o s e s.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 2 9  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 3. 3 St u d y M o nit ori n g a n d D at a C oll e cti o n, P ar a gr a p h 5, 6, a n d 7  
R e pl a c e: 
D u e t o a n u n e x p e ct e d c h a n g e of t h e d at a m a n a g e m e nt s y st e m, D A T A P O R T ( s oft w ar e 
M A C R O, pr o vi d e d b y I nf er M E D), h a s r e pl a c e d "I nt Tri al
".  T h e c urr e nt s y st e m, 
D A T A P O R T, e n a bl e s t h e i n v e sti g at or t o w or k o n a w e b- b a s e d o nli n e d o c u m e nt ati o n 
( e- C R F). 
M A C R O pr o vi d e s c o m m u ni c ati o n t o ol s w hi c h will h el p u s er s t o m a n a g e di s cr e p a n ci e s 
el e ctr o ni c all y, t o c o n d u ct s o ur c e d at a v erifi c ati o n a n d t o i m pr o v e c o m m u ni c ati o n wit hi n 
t h e st u d y t e a m.  
 
T o e n s ur e t h e q u alit y of cli ni c al d at a a cr o s s all s u bj e ct s a n d sit e s, a cli ni c al d at a 
m a n a g e m e nt r e vi e w will b e p erf or m e d o n s u bj e ct d at a r e c ei v e d at A B C S G.  D uri n g 
t hi s r e vi e w, s u bj e ct d at a will b e c h e c k e d f or c o n si st e n c y, o mi s si o n s, a n d a n y 
a p p ar e nt di s cr e p a n ci e s.  I n a d diti o n, t h e d at a will b e r e vi e w e d f or a d h er e n c e t o t h e 
pr ot o c ol a n d G C P.  T o r e s ol v e a n y q u e sti o n s ari si n g fr o m t h e cli ni c al d at a 
m a n a g e m e nt r e vi e w pr o c e s s, d at a q u eri e s a n d/ or sit e n otifi c ati o n s will b e r ai s e d vi a 
E D C f or sit e c o m pl eti o n.  
 
T h e pri n ci p al i n v e sti g at or will si g n o nl y t h e I n v e sti g at or V erifi c ati o n F or m a n d si g n 
a n d d at e t h e i n di c at e d pl a c e s o n t h e C R F.  T h e s e si g n at ur e s will i n di c at e t h at t h e 
pri n ci p al i n v e sti g at or i n s p e ct e d or r e vi e w e d t h e C R F, t h e d at a q u eri e s, a n d t h e sit e 
n otifi c ati o n s, a n d a gr e e s wit h t h e c o nt e nt.  P a p er o ut p ut of t h e C R F i s a v ail a bl e i n 
c a s e t h at t h e i n v e sti g at or or t h e I R B r e q uir e h ar d c o p y o ut p ut f or r e vi e w, si g n at ur e, 
a n d st or a g e at t h e e n d of t h e st u d y.  
 
A B C S G’ s cli ni c al d at a m a n a g e m e nt d e p art m e nt will e n s ur e t h at t h e d at a b a s e i s 
c orr e ct e d f or t h e f oll o wi n g C R F i s s u e s wit h o ut n otifi c ati o n t o sit e st aff: 
 
F or m al c orr e cti o n s ( e g, 1 2. 0 1. 2 0 1 2 -> 1 2/ 0 1/ 2 0 1 2, 1 p er d a y - > 1/ d a y) 
 
mi s s p elli n g s t h at d o n ot c h a n g e t h e m e a ni n g of t h e w or d ( e x cl u di n g a d v er s e 
e v e nt s a n d m e di c ati o n s) 
 l o c ati o n of d at a r e c or d e d o n a n i n c orr e ct C R F ( e g, m o vi n g l a b d at a fr o m g e n er al 
c o m m e nt s t o t h e a p pr o pri at e l a b t a bl e) 
 
d at e err or s t h at o c c ur i nt o t h e n e w y e ar 
 
st a n d ar d ti m e t o 2 4- h o ur cl o c k 
 
a d mi ni str ati v e d at a ( e g, e v e nt n a m e s f or u n s c h e d ul e d vi sit s or r et e st s) 
 if b ot h t h e e n d d at e a n d a st at u s of c o nti n ui n g i s i n di c at e d ( e g, f or a d v er s e 
e v e nt s, c o n c o mit a nt m e di c ati o n, h o s pit ali z ati o n), t h e e n d d at e will s u p er s e d e 
 If e q ui v al e nt u nit s or t er m s ar e r e c or d e d i n st e a d of t h e a c c e pt a bl e A m g e n 
st a n d ar d ( e g, c c f or m L, S Q f or S C r o ut e, N ot E x a mi n e d f or N ot D o n e), t h e 
A m g e n u nit s or t er m s will b e u s e d 
 if t h e a n s w er t o a Y E S or N O q u e sti o n i s bl a n k or o b vi o u sl y i n c orr e ct 
( e g, A n s w er s t o t h e f oll o wi n g q u e sti o n s d o n ot r efl e ct t h e d at a t h at ar e r e c or d e d 
or mi s si n g:  W er e t h er e a n y a d v er s e e v e nt s ?  C o n c o mit a nt m e di c ati o n s ?  
H o s pit ali z ati o n s ?) 
 
c orr e ct C R F p a g e n u m b er s 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 0  of 7 1  
C O N FI D E N TI A L 
 
 
A d et ail e d d e s cri pti o n of f urt h er it e m s f or c orr e cti o n s wit h o ut n otifi c ati o n t o sit e st aff will 
b e gi v e n i n t h e D at a M a n a g e m e nt Pl a n ( D M P). 
Wit h: 
D u e t o a n u n e x p e ct e d c h a n g e of t h e d at a m a n a g e m e nt s y st e m, t h e I nt erf a c e 
D A T A P O R T / T RI A L D A T A P O R T (E D C s y st e m  M A C R O, pr o vi d e d b y I nf er M E D), h a s 
r e pl a c e d "I nt Tri al".  T h e c urr e nt E D C s y st e m , e n a bl e s t h e i n v e sti g at or t o w or k o n a 
w e b- b a s e d o nli n e d o c u m e nt ati o n ( e- C R F). 
M A C R O pr o vi d e s c o m m u ni c ati o n t o ol s w hi c h will h el p u s er s t o m a n a g e di s cr e p a n ci e s 
el e ctr o ni c all y, t o c o n d u ct s o ur c e d at a v erifi c ati o n a n d t o i m pr o v e c o m m u ni c ati o n wit hi n 
t h e st u d y t e a m.  
 
T o e n s ur e t h e q u alit y of cli ni c al d at a a cr o s s all s u bj e ct s a n d sit e s, a cli ni c al d at a 
m a n a g e m e nt r e vi e w will b e p erf or m e d o n s u bj e ct d at a r e c ei v e d at A B C S G.  D uri n g 
t hi s r e vi e w, s u bj e ct d at a will b e c h e c k e d f or c o n si st e n c y, o mi s si o n s, a n d a n y 
a p p ar e nt di s cr e p a n ci e s.  I n a d diti o n, t h e d at a will b e r e vi e w e d f or a d h er e n c e t o t h e 
pr ot o c ol a n d G C P.  T o r e s ol v e a n y q u e sti o n s ari si n g fr o m t h e cli ni c al d at a 
m a n a g e m e nt r e vi e w pr o c e s s, d at a q u eri e s a n d/ or sit e n otifi c ati o n s will b e r ai s e d vi a 
E D C f or sit e c o m pl eti o n.  
 
T h e pri n ci p al i n v e sti g at or will si g n o nl y t h e C o nfir m ati o n of D at a F or m .  T h e s e 
si g n at ur e s will i n di c at e t h at t h e pri n ci p al i n v e sti g at or i n s p e ct e d or r e vi e w e d t h e C R F, 
t h e d at a q u eri e s, a n d t h e sit e n otifi c ati o n s, a n d a gr e e s wit h t h e c o nt e nt.  P ap er 
o ut p ut of t h e C R F c a n b e pri nt e d o ut (t a b ul ar f or m at) b y t h e i n v e sti g at or 
w h e n e v er n e e d e d .  
 
A B C S G’ s cli ni c al d at a m a n a g e m e nt d e p art m e nt will e n s ur e t h at t h e d at a b a s e i s 
c orr e ct e d f or t h e f oll o wi n g C R F i s s u e s wit h o ut n otifi c ati o n t o sit e st aff: 
 
F or m al c orr e cti o n s ( e g, 1 2. 0 1. 2 0 1 2 -> 1 2/ 0 1/ 2 0 1 2, 1 p er d a y - > 1/ d a y) 
 
mi s s p elli n g s t h at d o n ot c h a n g e t h e m e a ni n g of t h e w or d ( e x cl u di n g a d v er s e 
e v e nt s a n d m e di c ati o n s) 
 l o c ati o n of d at a r e c or d e d o n a n i n c orr e ct C R F ( e g, m o vi n g l a b d at a fr o m g e n er al 
c o m m e nt s t o t h e a p pr o pri at e l a b t a bl e) 
 
d at e err or s t h at o c c ur i nt o t h e n e w y e ar 
 
st a n d ar d ti m e t o 2 4- h o ur cl o c k 
 
a d mi ni str ati v e d at a ( e g, e v e nt n a m e s f or u n s c h e d ul e d vi sit s or r et e st s) 
 if b ot h t h e e n d d at e a n d a st at u s of c o nti n ui n g i s i n di c at e d ( e g, f or a d v er s e 
e v e nt s, c o n c o mit a nt m e di c ati o n, h o s pit ali z ati o n), t h e e n d d at e will s u p er s e d e 
 If e q ui v al e nt u nit s or t er m s ar e r e c or d e d i n st e a d of t h e a c c e pt a bl e A m g e n 
st a n d ar d ( e g, c c f or m L, S Q f or S C r o ut e, N ot E x a mi n e d f or N ot D o n e), t h e 
A m g e n u nit s or t er m s will b e u s e d 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 3 1  of 7 1  
C O N FI D E N TI A L 
 
 
 if t h e a n s w er t o a Y E S or N O q u e sti o n i s bl a n k or o b vi o u sl y i n c orr e ct 
( e g, A n s w er s t o t h e f oll o wi n g q u e sti o n s d o n ot r efl e ct t h e d at a t h at ar e r e c or d e d 
or mi s si n g:  W er e t h er e a n y a d v er s e e v e nt s ?  C o n c o mit a nt m e di c ati o n s ?  
H o s pit ali z ati o n s ?) 
 
c orr e ct C R F p a g e n u m b er s 
A d et ail e d d e s cri pti o n of f urt h er it e m s f or c orr e cti o n s wit h o ut n otifi c ati o n t o sit e st aff i s 
gi v e n i n t h e r e s p e cti v e D at a M a n a g e m e nt Pl a n ( D M P). 
S e cti o n:   1 4 R ef er e n c e s 
A d d: 
H a dji P, A a pr o M S, B o d y J J, G n a nt M, et al.  M a n a g e m e nt of Ar o m at a s e 
I n hi bitor - A s s o ci at e d B o n e L o s s ( AI B L) i n p o st m e n o p a u s al w o m e n wit h h or m o n e 
s e n siti v e br e a st c a n c er: J oi nt p o siti o n st at e m e nt of t h e I O F, C A B S, E C T S, I E G, 
E S C E O I M S, a n d SI O G.   J B o n e O n c ol .  2 0 1 7 ; 2 3; 7: 1-1 2.  
L e h m a n n T, A e b erli D.  P o s si bl e pr ot e cti v e eff e ct of s w it c hi n g fr o m d e n o s u m a b t o 
z ol e dr o ni c a ci d o n v ert e br al fr a ct ur e s.  O st e o p or o s I nt.   2 0 1 7; 2 8( 1 0): 3 0 6 7- 3 0 6 8.  
Mill er P D, B ol o g n e s e M S, L e wi e c ki E M, et al.  Eff e ct of d e n o s u m a b o n b o n e 
d e n sit y a n d t ur n o v er i n p o st m e n o p a u s al w o m e n wit h l o w b o n e m a s s aft er 
l o n g-t er m c o nti n u e d, di s c o nti n u e d, a n d r e st arti n g of t h er a p y:  a r a n d o mi z e d 
bli n di n g p h a s e 2 cli ni c al tri al.  B o n e.   2 0 0 8; 4 3( 2): 2 2 2- 2 2 9.  
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 2  of 7 1  
C O N FI D E N TI A L  
 
 
S e cti o n:   1 5  A p p e n di x A, S c h e d ul e of A s s e s s m e nt s f or D e n o s u m a b Di s c o nti n u ati o n E xt e n si o n ( N e w T a bl e) 
A d d: 
S c h e d ul e of A s s e s s m e nt s f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n) 
St u d y a s s e s s m e nt  
S cr e e ni n g/ b a s eli n e  
R a n d o mi z ati o n  
Q 6 M Vi sit  
Q 1 2 M Vi sit  
Q 1 8 M Vi sit = 
E O S a  
R e -c o n s e nt  
X  
 
 
 
 
R a n d o mi z ati o n  
 
X  
 
 
 
I V Z ol e dr o ni c a ci d ( 5 m g x 1)b  
 
X  
 
 
 
L a b or at or y A s s e s s m e nt e  
X  
 
 
 
 
 E O S = e n d of st u d y; I V = i ntr a v e n o u s; 
M = m o nt h; O L  = o p e n-l a b el;  O L P  = o p e n-l a b el p h a s e; Q X M = e v er y X m o nt h s; 
 S O C = st a n d ar d of c ar e; 
Z A  = z ol e dr o ni c a ci d.. 
T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n b ut m u st o c c ur aft er writt e n 
c o n s e nt h a s b e e n o bt ai n e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n u ntil 9 m o nt h s aft er. 
R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o D a y 1. 
Vi sit s t o sit e:  D a y  1 aft er r e -c o n s e nt a n d r a n d o mi z ati o n , 6, 1 2, a n d 1 8  m o nt h s (  2  w e e k s) aft e r d a y 1 . 
a E O S:  E n d of Z A e xt e n si o n st u d y will b e 1 8 m o nt h s aft er d a y 1; or t h e l a st s c h e d ul e d vi sit i n c a s e p ati e nt e n d s st u d y pr e m at ur el y. 
b  Z A a d mi ni str ati o n m u st t a k e pl a c e wit hi n 8 d a y s aft er r a n d o mi z ati o n.  H alf of t h e p ati e nt s will b e r a n d o mi z e d t o S O C ( N o Z A).  D a y 1 f or b ot h ar m s s h o ul d 
b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L  d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  Vi sit s will t a k e pl a c e  
6, 1 2, 1 8 m o nt h s aft er d a y 1. 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 3  of 7 1  
C O N FI D E N TI A L  
 
 
e R o uti n e l a b or at or y a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e r a n d o mi z ati o n.  A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o 
r a n d o mi z ati o n.  S u bj e ct s w h o h a v e u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st. 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 4  of 7 1  
C O N FI D E N TI A L 
 
 
D e s cri pti o n of C h a n g e s f or Pr ot o c ol A m e n d m e nt 6 ( a d d e d Z A s u b st u d y): 
S e cti o n:   Gl o b al  
C h a n g e:   T h e A m g e n gl o b al v er si o n d at e w a s c h a n g e d fr o m 0 1 A pril 2 0 1 9 t o 
1 5  J ul y 2 0 1 9 . 
S e cti o n:   Gl o b al  
R e pl a c e:   
P o st O L d e n o s u m a b e xt e n si o n 
Wit h:  
Z A s u b st u d y 
S e cti o n:   Gl o b al  
R e pl a c e:   
Z A e xt e n si o n 
Wit h:  
Z A s u b st u d y 
S e cti o n:   Gl o b al 
C h a n g e:   E dit ori al, t y p o gr a p hi c al, a n d f or m atti n g c h a n g e s w er e m a d e t hr o u g h o ut t h e 
d o c u m e nt. 
S e cti o n:   Titl e P a g e  
A d d: 
D at e:  
1 5 J ul y 2 0 1 9 A m e n d m e nt 6 ( a d d e d z ol e dr o ni c a ci d 
s u b st u d y)  
S e cti o n:   Pr ot o c ol S y n o p si s ( E x pl or at or y O bj e cti v e s) , B ull et p oi nt 3 
R e m o v e: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 5  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   Pr ot o c ol S y n o p si s ( St u d y D e si g n)  
R e pl a c e :   
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A e xt e n si o n): 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h a d e cli n e i n b o n e m a s s t h at a p pr o a c h 
pr e-tr e at m e nt l e v el s a n d a v ail a bl e d at a s u g g e st a n i n cr e a s e i n m ulti pl e v ert e br al 
fr a ct ur e s aft er di s c o nti n u ati o n.  Bi s p h o s p h o n at e tr e at m e nt aft er d e n o s u m a b m a y b e 
w arr a nt e d t o p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y i n p ati e nt s n ot pr e vi o u sl y 
e x p o s e d t o bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h fr a ct ur e ri s k (i e, o st e o p or o si s wit h 
pr e vi o u s v ert e br al fr a ct ur e s), b ut li mit e d d at a i s a v ail a bl e c o nfir mi n g t h e v ali dit y of t hi s 
h y p ot h e si s.  T h er ef or e, t h er e i s a d at a g a p r e g ar di n g o pti m al str at e gi e s f or p ati e nt s w h o 
will di s c o nti n u e d e n o s u m a b a n d t hi s pr ot o c ol a m e n d m e nt i s d e si g n e d t o h el p a d dr e s s 
t h at q u e sti o n. 
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 5, willi n g a n d eli gi bl e 
s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y a n d c o m pl et e d O L d e n o s u m a b m a y 
o pt i n t hi s Z A e xt e n si o n a n d eit h er r e c ei v e a si n gl e d o s e of Z A ( T h er a p y Ar m), or ar e 
m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  
P ati e nt s w h o c o m pl et e d O L P d e n o s u m a b a n d e n d e d st u d y a s d efi n e d p er pr ot o c ol ar e 
eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n tri al a s l o n g a s t h e o utli n e d crit eri a ar e f ulfill e d.  
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n 
u ntil 9  m o nt h s aft er.  T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b 
a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n, b ut m u st o c c ur aft er writt e n 
c o n s e nt h a s b e e n o bt ai n e d. 
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 1  si n gl e 
5 m g I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o 
D a y 1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  F oll o w u p will 
c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n will b e str atifi e d b y AI u s e 
at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or N o) . 
D X A s c a n c a n b e p erf or m e d b et w e e n 7 t o 9 m o nt h s aft er t h e d at e of t h e l a st d e n o s u m a b 
a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A a d mi ni str ati o n.  R o uti n e D X A 
s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w c a n b e u s e d a s b a s eli n e D X A s c a n s. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 6  of 7 1  
C O N FI D E N TI A L 
 
 
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A e xt e n si o n 
will c o m pl et e O L P a s s e s s m e nt s o nl y. 
S u bj e ct s w h o p arti ci p at e i n t h e Z A e xt e n si o n, will u n d er g o t h e f oll o wi n g a s s e s s m e nt s: 
Wit h: 
Z ol e dr o ni c A ci d ( Z A) S u b st u d y: 
A s u b st u d y h a s b e e n a d d e d i n A p p e n di x G t o e v al u at e s u bj e ct s c o m pl eti n g 
o p e n -l a b el d e n o s u m a b tr e at m e nt, t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e 
m a n a g e d a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or t h e p ati e nt p o p ul ati o n. 
S u bj e ct s e nr oll e d i n t h e m ai n st u d y w h o r e c ei v e d d e n o s u m a b d uri n g t h e o p e n 
l a b el p h a s e a n d ar e d e e m e d eli gi bl e p er t h e i n cl u si o n a n d e x cl u si o n crit eri a, m a y 
c h o o s e t o p arti ci p at e i n t hi s s u b st u d y.  S u bj e ct s t h at ar e n ot i n cl u d e d i n t h e 
s u b st u d y will e n d st u d y a s pl a n n e d.  Pr ot o c ol- d efi n e d d e n o s u m a b a d mi ni str ati o n 
will c o m pl et e at e n d of t h e o p e n- l a b el p eri o d n o m att er if s u bj e ct s p arti ci p at e i n 
t h e s u b st u d y or n ot. 
S u bj e ct s e nr oll e d i n t h e s u b st u d y will b e r a n d o mi z e d t o eit h er r e c ei v e a si n gl e 
d o s e of Z A ( T h er a p y Ar m) or will b e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or 
t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  D a y 1 f or b ot h ar m s i s 8 m o nt h s ( ± 4 w e e k s) 
fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st ere d o n 
t hi s vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 7  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   Pr ot o c ol S y n o p si s ( E x pl or at or y E n d p oi nt s)  
R e m o v e:   
E x pl or at or y E n d p oi nt s: 
S e cti o n:   Pr ot o c ol S y n o p si s ( E x cl u si o n Crit eri a)  
R e m o v e: 
S u bj e ct s c o m pl eti n g O L d e n o s u m a b m a y b e eli gi bl e f or t h e Z A e xt e n si o n. 
S e cti o n:   Pr ot o c ol S y n o p si s (I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n Z A 
E xt e n si o n)  
R e m o v e: 
I n v e sti g ati o n al Pr o d u ct D o s a g e a n d A d mi ni str ati o n i n Z A E xt e n si o n: 
T h er a p y Ar m:  Z A 5 m g I V si n gl e d o s e 
C o ntr ol Ar m:  S O C 
S e cti o n:   Pr ot o c ol S y n o p si s ( L o n g-t er m F oll o w- u p) , P ar a gr a p h 6 
R e m o v e :   
P o st O p e n-l a b el D e n o s u m a b E xt e n si o n ( Z A e xt e n si o n): 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 8  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   Pr ot o c ol S y n o p si s ( St ati sti c al C o n si d er ati o n s)  
R e m o v e:    
A n al y si s of t h e e n d p oi nt s fr o m t h e Z A E xt e n si o n will b e d e s cri pti v e o nl y a n d will t a k e 
pl a c e w h e n all s u bj e ct s r a n d o mi z e d t o t h e e xt e n si o n h a v e att e n d e d t h eir l a st st u d y vi sit.  
T h e a n al y s e s will b e p erf or m e d aft er t h e fi n al a n al y si s of fr a ct ur e -r el at e d a n d 
di s e a s e-r el at e d o ut c o m e s f or t h e m ai n st u d y. 
S e cti o n:   St u d y s c h e m a, P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n St u d y D e si g n a n d 
Tr e at m e nt S c h e m a  
R e m o v e  
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n St u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
I V = i ntr a v e n o u s; Z A = z ol e dr o ni c a ci d. 
S e cti o n:   St u d y Gl o s s ar y  
Fi n al a n al y si s  
a n al y si s p erf or m e d aft er l o n g -t er m f oll o w u p, a n d O L P,  
a p pr o xi m at el y 6 6  m o nt h s aft er P A D C D, d e p e n di n g o n t h e 
i nt eri m a nal y si s  
S e cti o n:   1. 3 E x pl or at or y , B ull et p oi nt 3 
R e m o v e:   
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 3 9  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   2. 3 R ati o n al e  
R e m o v e: 
B M D C h a n g e s Aft er O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n): 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h d e cli n e s i n b o n e m a s s t h at a p pr o a c h pr e-
tre at m e nt l e v el s a n d a v ail a bl e d at a d o s u g g e st a n i n cr e a s e i n m ulti pl e v ert e br al fr a ct ur e s 
aft er di s c o nti n u ati o n.  Bi s p h o s p h o n at e tr e at m e nt aft er d e n o s u m a b m a y b e w arr a nt e d t o 
p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y i n p ati e nt s n ot pr e vi o u sl y e x p o s e d t o 
bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h fr a ct ur e ri s k (i e, o st e o p or o si s wit h pr e vi o u s 
v ert e br al fr a ct ur e s), b ut li mit e d d at a ar e a v ail a bl e c o nfir mi n g t h e v ali dit y of t hi s 
h y p ot h e si s.  T h er ef or e, t h er e i s a d at a g a p r e g ar di n g o pti m al str at e gi e s f or p ati e nt s w h o 
will di s c o nti n u e d e n o s u m a b.  T h e A B C S G 1 8 P o st O p e n-l a b el D e n o s u m a b E xt e n si o n 
( Z A E xt e n si o n) i s d e si g n e d t o e v al u at e o n p ati e nt s di s c o nti n ui n g d e n o s u m a b, t o eit h er 
r e c ei v e a si n gl e d o s e of Z A, or t o b e m a n a g e d a c c or di n g t o c urr e nt st a n d ar d of c ar e 
( S O C) f or r e s p e cti v e p ati e nt p o p ul ati o n aft er d e n o s u m a b di s c o nti n u ati o n. 
S e cti o n 3. 1 St u d y D e si g n  
R e pl a c e : 
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n): 
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 5, willi n g a n d eli gi bl e 
s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y a n d c o m pl et e d O L d e n o s u m a b m a y 
o pt i n t hi s Z A e xt e n si o n a n d eit h er r e c ei v e a si n gl e d o s e of Z A ( T h er a p y Ar m), or ar e 
m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  
P ati e nt s w h o c o m pl et e d O L P d e n o s u m a b a n d e n d e d st u d y a s d efi n e d p er pr ot o c ol ar e 
eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n tri al a s l o n g a s t h e o utli n e d crit eri a ar e f ulfill e d . 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n 
u ntil 9  m o nt h s aft er.  T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b 
a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n, b ut m u st o c c ur aft er writt e n 
c o n s e nt h a s b e e n o bt ai n e d. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 0  of 7 1  
C O N FI D E N TI A L 
 
 
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 1  si n gl e 
5 m g  I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o 
D a y 1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  F oll o w u p will 
c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n will b e str atifi e d b y AI u s e 
at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or N o) . 
D X A s c a n c a n b e p erf or m e d b et w e e n 7 t o 9 m o nt h s aft er t h e d at e of t h e l a st d e n o s u m a b 
a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A a d mi ni str ati o n.  R o uti n e D X A 
s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w c a n b e u s e d a s b a s eli n e D X A s c a n s. 
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A e xt e n si o n 
will c o m pl et e O L P a s s e s s m e nt s o nl y. 
S u bj e ct s w h o p arti ci p at e i n t h e Z A e xt e n si o n, will u n d er g o t h e f oll o wi n g a s s e s s m e nt s: 
I n t h e e v e nt a s eri o u s or n o n- s eri o u s a d v er s e e v e nt of s p e ci al i nt er e st ( or al e v e nt) or 
ot h er S A E i s i d e ntifi e d o ut si d e t h e s u bj e ct s’ s c h e d ul e d vi sit s, t h e st a n d ar d g ui d a n c e i n 
S e cti o n 9 s h o ul d b e f oll o w e d. 
Wit h: 
Z ol e dr o ni c A ci d ( Z A) S u b st u d y: 
A s u b st u d y h a s b e e n a d d e d i n A p p e n di x G t o e v al u at e s u bj e ct s c o m pl eti n g 
o p e n -l a b el d e n os u m a b tr e at m e nt, t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e 
m a n a g e d a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or t h e p ati e nt p o p ul ati o n.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 1  of 7 1  
C O N FI D E N TI A L 
S u bj e ct s e nr oll e d i n t h e m ai n st u d y w h o r e c ei v e d d e n o s u m a b d uri n g t h e o p e n 
l a b el p h a s e a n d ar e d e e m e d eli gi bl e p er t h e i n cl u si o n a n d e x cl u si o n crit eri a, m a y 
c h o o s e t o p arti ci p at e i n t hi s s u b st u d y.  S u bj e ct s t h at ar e n ot i n cl u d e d i n t h e 
s u b st u d y will e n d st u d y a s pl a n n e d.  Pr ot o c ol- d efi n e d d e n o s u m a b a d mi ni str ati o n 
will c o m pl et e at e n d of t h e o p e n- l a b el p eri o d n o m att er if s u bj e ct s p arti ci p at e i n 
t h e s u b st u d y or n ot. 
S u bj e ct s e nr oll e d i n t h e s u b st u d y will b e r a n d o mi z e d t o eit h er r e c ei v e a si n gl e 
d o s e of Z A ( T h er a p y Ar m) or will b e m a n a g e d a c c or di n g t o t h e c urr e nt S O C f or 
t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  D a y 1 f or b ot h ar m s i s 8 m o nt h s ( ± 4 w e e k s) 
fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n 
t hi s vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1. 
I n t h e e v e nt a n  a d v er s e e v e nt of s p e ci al i nt er e st (r e n al t o xi cit y, cli ni c all y r el e v a nt 
h y p er/ h y p o c al c e mi a a n d  or al e v e nt) or ot h er S A E i s i d e ntifi e d o ut si d e t h e s u bj e ct s’ 
s c h e d ul e d vi sit s, t h e st a n d ar d g ui d a n c e i n S e cti o n 9 s h o ul d b e f oll o w e d. 
S e cti o n:   3. 2 N u m b er of C e nt er s , P ar a gr a p h 2 
R e m o v e: 
A p pr o xi m at el y 3 0 sit e s i n A u stri a ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A e xt e n si o n. 
S e cti o n:   3. 3 N u m b er of S u bj e ct s , P ar a gr a p h 3 
R e m o v e: 
A p pr o xi m at el y 2 0 0 s u bj e ct s ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A e xt e n si o n. 
S e cti o n:   3. 4 E sti m at e d St u d y D ur ati o n 
R e m o v e: 
T h e a ct u al ti mi n g of a n al y s e s will b e d et er mi n e d b y t h e P A D C D.  St u d y d ur ati o n i s 
e sti m at e d t o b e 1 6 9 m o nt h s, w hi c h i n cl u d e s a n e nr oll m e nt p eri o d of a p pr o xi m at el y 
8 2  m o nt h s, a n e n d of t h e tr e at m e nt p h a s e (i e, t h e P A D C D) of a p pr o xi m at el y 2 1 m o nt h s 
a n d a p pr o xi m at el y 6 6 m o nt h s f oll o wi n g t h e P A D C D f or a 5 y e ar l o n g-t er m f oll o w- u p 
i n cl u di n g a n O L P ( 1 2 m o nt h s u n bli n di n g o pti o n a n d a m a xi m u m of 3 6 m o nt h s of 
tr e at m e nt) ( s e e S e cti o n s 7. 1 5 a n d 1 0. 5).  A m e n d m e nt 5 ( Z A e xt e n si o n) will a d d a 
m a xi m u m of a p pr o xi m at el y 2 7 m o nt h s ( c o n si d eri n g t h at t h e p ati e nt m a y e nt er t h e 
e xt e n si o n st u d y 9 m o nt h s aft er O L P d e n o s u m a b c o m pl eti o n) t o t h e st u d y d ur ati o n. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 2  of 7 1  
C O N FI D E N TI A L 
S e cti o n:   3. 4. 1 St u d y D ur ati o n f or P arti ci p a nt s , P ar a gr a p h s 2 a n d 3  
R e pl a c e: 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d- u p u ntil c o m pl eti o n of 
3 6  m o nt h s of tr e at m e nt or a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D, w hi c h e v er i s l o n g er. 
S u bj e ct s i n t h e O L P m a y c o n s e nt t o a n e xt e n si o n t o a s s e s s di s c o nti n u ati o n fr o m 
d e n o s u m a b a n d r e c ei v e eit h er si n gl e d o s e Z A 5 m g I V or S O C tr e at m e nt, w hi c h will b e 
f or a m a xi m u m d ur ati o n of a p pr o xi m at el y 2 7 f urt h er m o nt h s. 
T h e e x p e ct e d ti m e o n st u d y i s u p t o a p pr o xi m at el y 1 9 6 m o nt h s. 
Wit h: 
S u bj e ct s w h o r e c ei v e o p e n-l a b el d e n o s u m a b will b e f oll o w e d- u p u ntil c o m pl eti o n of 
3 6  m o nt h s of tr e at m e nt or a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D, w hi c h e v er i s l o n g er. 
S u bj e ct s i n t h e O L P m a y c o n s e nt t o a n e xt e n si o n t o a s s e s s di s c o nti n u ati o n fr o m 
d e n o s u m a b a n d r e c ei v e eit h er si n gl e d o s e Z A 5 m g I V or S O C tr e at m e nt, w hi c h will b e 
f or a m a xi m u m d ur ati o n of a p pr o xi m at el y 2 7 f urt h er m o nt h s. 
T h e e x p e ct e d ti m e o n st u d y i s u p t o a p pr o xi m at el y 1 6 9  m o nt h s. 
S e cti o n:   3. 4 E sti m at e d St u d y D ur ati o n  
R e m o v e:   
3. 4. 5  
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n Tr e at m e nt 
P ati e nt s t h at c o m pl et e d t h eir O L P d e n o s u m a b vi sit a n d e n d e d t h e st u d y a s d efi n e d p er 
pr ot o c ol ar e eli gi bl e t o p arti ci p at e i n t h e Z A e xt e n si o n a s l o n g a s all i n cl u si o n/ e x cl u si o n 
crit eri a ar e m et. 
Z ol e dr o ni c a ci d will b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) aft er l a st O L P a d mi ni str ati o n 
f or s u bj e ct s r a n d o mi z e d t o tr e at m e nt ar m.  S u bj e ct s r a n d o mi z e d t o S O C, will att e n d t h e 
sit e f or vi sit s at t h e s a m e vi sit s c h e d ul e a s t h e tr e at m e nt ar m s u bj e ct s. 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 3  of 7 1  
C O N FI D E N TI A L 
S e c ti o n:  3. 4. 5 E n d of St u d y ( D o u bl e- bli n d P h a s e a n d E n d of Z A s u b st u d y )  
R e pl a c e: 
3. 4. 5 E n d of St u d y (D o u bl e- bli n d P h a s e a n d O L P) 
T h e e n d of t h e st u d y will o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit 
or l a st f or m al c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e 
st u d y.  T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h e e xt e n si o n t o t h e 
O L tr e at m e nt p eri o d or t h eir l a st s c h e d ul e d L T F U vi sit. 
Wit h  
3. 4. 5 E n d of St u d y ( D o u bl e- bli n d P h a s e a n d  e n d of Z A S u b st u d y) 
T h e e n d of t h e st u d y will o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit 
or l a st f or m al c o nt a ct or a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e 
st u d y.  T hi s i s e x p e ct e d t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h e Z A s u b st u d y . 
S e cti o n:   3. 4. E sti m at e d St u d y D ur ati o n  
R e m o v e:  
3. 4. 7  
E n d of St u d y of Z A E xt e n si o n 
T h e e n d of Z A E xt e n si o n will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
E xt e n si o n h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n c a s e of 
e arl y wit h dr a w al fr o m t h e Z A e xt e n si o n. 
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, a n d c o n s e nt 
wit h dr a w al) a n d p er pr ot o c ol E O S of Z A E xt e n si o n. 
S e cti o n:   4 S U B J E C T E LI GI BI LI T Y 
R e m o v e:  
S e cti o n:  4. 5 I n cl u si o n Crit eri a f or P o st O p e n -l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n ( Z A E xt e n si o n) 
4. 5   
I n cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A 
E xt e n si o n) 
4. 5. 1  
O bt ai n si g n e d a n d d at e d writt e n i nf or m e d c o n s e nt pri or t o p erf or mi n g a n y st u d y-
s p e cifi c pr o c e d ur e 
4. 5. 2  
S u bj e ct s t h at r e c ei v e d O L P d e n o s u m a b a n d c o m pl et e d O L P tr e at m e nt 
4. 5. 3  
L a st O L P d e n o s u m a b a d mi ni str ati o n n o l o n g er t h a n 9 m o nt h s a g o 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 4  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:  4. 6 E x cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d 
E xt e n si o n  
A d d: 
4. 6   
E x cl u si o n Crit eri a f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n 
4. 6. 1  
C urr e nt or pri or Z A a d mi ni str ati o n. 
4. 6. 2  
S u bj e ct s w h o e n d e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct (I P) pr e m at ur el y i n t h e 
d o u bl e - bli n d p h a s e a n d O L p h a s e 
4. 6 . 3 
K n o w n s e n siti vit y or i nt ol er a n c e t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d d uri n g 
t h e st u d y ( e g, Z A, c al ci u m or vit a mi n D) 
4. 6. 4  
K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf r e p ort or 
c h art r e vi e w 
 
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a or ot h er a cti v e 
m et a b oli c b o n e di s e a s e 
 
K n o w n hi st or y of h y p o c al c e mi a 
 
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s pri or t o 
r a n d o mi z ati o n 
 
P ar at h yr oi d gl a n d s i n n e c k s ur gi c all y r e m o v e d 
 
A n y s e cti o n s of i nt e sti n e r e m o v e d  
 
K n o w n h u m a n i m m u n o d efi ci e n c y vir u s i nf e cti o n 
 
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s 
4. 6. 5  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d i n di c at e d b y 
t h e f oll o wi n g crit eri a: 
 
A s p art at e a mi n otr a n sf er a s e ≥ 2. 5 x U L N  
 
Al a ni n e tr a n s a mi n a s e ≥ 2. 5 x U L N  
 
S er u m cr e ati ni n e ≥ 2 x U L N 
 
Cr e ati n e cl e ar a n c e < 3 5 ml/ mi n 
4. 6. 6  
S u bj e ct s t h at ar e pr e g n a nt or br e a stf e e di n g 
 
All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y t e st 
wit hi n 7 d a y s b ef or e r a n d o mi z ati o n 
4. 6. 7  
S u bj e ct s w h o ar e o st e o p or oti c i n b a s eli n e B M D 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 5  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   5 S U B J E C T E N R O L L M E N T  
R e m o v e: 
5. 6   
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n 
A s u bj e ct will b e a s si g n e d b y a n I nt er a cti v e V oi c e/ W e b R e s p o n s e S y st e m t o 1 of 
2 tr e at m e nt gr o u p s ( Z A or S O C), i n a 1: 1 r ati o.  T h e r a n d o mi z ati o n s c h e d ul e will u s e 
r a n d o ml y p er m ut e d bl o c k s a n d will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of O L P 
d e n o s u m a b c o m pl eti o n ( Y e s or N o).  A s u bj e ct w h o i s r a n d o mi z e d t o t h e Z A E xt e n si o n 
will m ai nt ai n t h e s a m e s u bj e ct n u m b er w hi c h i s al s o t h e s u bj e ct n u m b er a s a s si g n e d i n 
t h e d o u bl e- bli n d st u d y.  A s u bj e ct m a y o nl y b e r a n d o mi z e d o n c e i nt o Z A E xt e n si o n.  T h e 
Z A r a n d o mi z ati o n li st will b e g e n er at e d a n d m ai nt ai n e d b y a n A m g e n r e pr e s e nt ati v e n ot 
i n v ol v e d i n t h e c o n d u ct of t h e st u d y. 
S e cti o n:   6. 3 Pr o hi bit e d M e di c ati o n i n P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n   
R e m o v e: 
6. 3   
Pr o hi bit e d M e di c ati o n i n P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n 
S u bj e ct s p arti ci p ati n g i n t h e Z A E xt e n si o n will f oll o w t h e s a m e vi sit s c h e d ul e a s o utli n e d 
i n t h e Z A E xt e n si o n ( A p p e n di x A, S c h e d ul e of A s s e s s m e nt s).  T h er e ar e n o pr o hi bit e d 
m e di c ati o n s i n t hi s e xt e n si o n. 
6. 3. 1  I n v e sti g ati o n al Pr o d u ct ( D e n o s u m a b) 
N o d e n o s u m a b i s r e q uir e d or pr o vi d e d f or p ati e nt s i n t h e p o st O L d e n o s u m a b e xt e n si o n. 
6. 3. 2  
N o n I n v e sti g ati o n al Pr o d u ct D o s a g e, A d mi ni str ati o n, a n d S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5 m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er all 
ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o p ati e nt s b y h e alt h c ar e 
pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V bi s p h o s p h o n at e s.  P ati e nt s tr e at e d 
wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et. 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n a c c or d a n c e 
wit h l o c al r e q uir e m e nt s. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 6  of 7 1  
C O N FI D E N TI A L 
 
 
R ef er t o t h e s u m m ar y of pr o d u ct c h ar a ct eri sti c s ( S m P C) 
( htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ pr o d u ct/ 4 4/ s m p c) f or d et ail e d i nf or m ati o n o n t h e 
a d mi ni str ati o n of Z A. 
6. 3. 3  
Pr o hi bit e d m e di c ati o n s 
T h er e ar e n o pr o hi bit e d m e di c ati o n s i n t h e p o st O L d e n o s u m a b e xt e n si o n.  
S e cti o n:   7. 7. 1 A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n-l a b el P h a s e , S u btitl e 
R e m o v e: 
7. 7. 1  
A s s e s s m e nt of Cli ni c al Fr a ct ur e s D uri n g O p e n-l a b el P h a s e a n d Z A E xt e n si o n 
S e cti o n:  7 S T U D Y P R O C E D U R E S  
R e m o v e: 
7. 1 3  
L a b or at or y A s s e s s m e nt s i n Z A St u d y 
R o uti n e l a b or at or y a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e 
r a n d o mi z ati o n.  P ati e nt s wit h c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y 
t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n.  S u bj e ct s w h o h a v e u n d er g o n e a h y st er e ct o m y 
d o n ot r e q uir e a pr e g n a n c y t e st.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 7  of 7 1  
C O N FI D E N TI A L 
 
 
T a bl e 1.  S er u m a n d Bl o o d S a m pl e A n al yt e Li sti n g 
S er u m C h e mi str y  
H e m at ol o g y  
Ot h er  
S o di u m  
R e d bl o o d c ell s  
D e n o s u m a b a nti b o d y a s s a y 
( o nl y d o u bl e-bli n d st u d y)  
P ot a s si u m  
H e m o gl o bi n  
 
 
C al ci u m  
H e m at o crit  
 
Bl o o d Ur e a Nitr o g e n/ Ur e a  
Pl at el et s  
 
Cr e ati ni n e  
W hit e bl o o d c ell s  
 
T ot al bilir u bi n  
 
 
Al k ali n e p h o s p h at a s e  
 
 
Al a ni n e tr a n s a mi n a s e   
 
 
A s p ar at e a mi n otr a n sf er a s e  
 
 
L D H  
 
 
G a m m a G T  
 
 
Al b u mi n  
 
 
 
S e cti o n:   7. 1 5 A d v er s e E v e nt s, O p e n-l a b el P h a s e/ L o n g-t er m F oll o w- u p  
R e m o v e: 
P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n): 
D uri n g t h e p o st O L d e n o s u m a b e xt e n si o n, ( S) A E s of s p e ci al i nt er e st ( c a u s al r el ati o n s hi p 
t o Z A a n d or al e v e nt s) will b e d o c u m e nt e d f or s u bj e ct s r e c ei vi n g Z A. 
N e w cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e 
(f e m ur mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, or f e m ur di st al) a s s o ci at e d wit h mi ni m al 
tr a u m a will b e cl a s sifi e d a s a n S A E f or all s u bj e ct s ( s e e S e cti o n 9. 1. 2), a n d s h o ul d b e 
r e c or d e d o n a S eri o u s A d v er s e E v e nt R e p ort f or m ( s e e A p p e n di x F) a n d f a x e d t o t h e 
l o c al A m g e n S af et y S p e ci ali st wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of t h e e v e nt 
( s e e S e cti o n 9. 3). 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 8  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   7 S T U D Y P R O C E D U R E S  
R e m o v e: 
7. 2 0  
P o st O L D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n) 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  
F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1 . 
S e cti o n:   7. 1 8  E n d of St u d y, P ar a gr a p h 1 
R e m o v e: 
T h e p ati e nt i n di vi d u al E O S i s d efi n e d a s t h e l a st f or m al vi sit or c o nt a ct f or a s u bj e ct or a n 
u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m st u d y.  T h e o v er all E O S will 
o c c ur w h e n t h e l a st s u bj e ct h a s c o m pl et e d t h eir l a st f or m al vi sit or l a st f or m al c o nt a ct or 
a n u n s c h e d ul e d st u d y vi sit i n c a s e of e arl y wit h dr a w al fr o m t h e st u d y.  T hi s i s e x p e ct e d 
t o o c c ur w h e n t h e l a st s u bj e ct c o m pl et e s t h eir e n d of o p e n-l a b el tr e at m e nt vi sit or t h eir 
l a st s c h e d ul e d L T F U vi sit. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 4 9  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:  7 S T U D Y P R O C E D U R E S  
R e m o v e: 
7. 2 2  
E n d of St u d y of Z A E xt e n si o n 
T h e e n d of Z A e xt e n si o n will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
e xt e n si o n h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n c a s e of 
e arl y wit h dr a w al fr o m t h e Z A e xt e n si o n. 
E n d of Z A e xt e n si o n st u d y will b e 1 8 m o nt h s aft er d a y 1 .  
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, c o n s e nt 
wit h dr a w al) a n d p er pr ot o c ol E O S of Z A e xt e n si o n. 
S e cti o n:   9. 3. 1 A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s A d v er s e E v e nt 
R e p orti n g D uri n g t h e O p e n-l a b el P h a s e  
R e m o v e: 
9. 3. 1  
A d v er s e E v e nt s of S p e ci al I nt er e st a n d S eri o u s A d v er s e E v e nt R e p orti n g D uri n g 
t h e O p e n-l a b el P h a s e a n d P o st O p e n l a b el D e n o s u m a b E xt e n si o n 
S e cti o n:   9. 3. 1. 2, S eri o u s A d v er s e E v e nt R e p orti n g, P ar a gr a p h s 3 a n d 4 
R e m o v e: 
F or s u bj e ct s p arti ci p ati n g i n t h e p o st O L d e n o s u m a b e xt e n si o n a n d r e c ei vi n g Z A, t h e 
i n v e sti g at or i s r e s p o n si bl e f or e n s uri n g all S A E s o b s er v e d b y t h e i n v e sti g at or or r e p ort e d 
b y t h e s u bj e ct t h at o c c ur aft er si g ni n g t h e I C F f or t h e e xt e n si o n u ntil t h e l a st st u d y vi sit 
( 1 8 m o nt h s aft er D a y 1), ar e r e c or d e d i n t h e s u bj e ct s m e di c al r e c or d a n d ar e s u b mitt e d 
t o A m g e n.  N e w cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, or f e m ur di st al) a s s o ci at e d wit h 
mi ni m al tr a u m a will b e cl a s sifi e d a s a n S A E f or all s u bj e ct s ( s e e S e cti o n 9. 1. 2), a n d 
s h o ul d b e r e c or d e d o n a S eri o u s A d v er s e E v e nt R e p ort f or m ( s e e A p p e n di x F) a n d 
f a x e d t o t h e l o c al A m g e n S af et y S p e ci ali st wit hi n 2 4 h o ur s of di s c o v er y or n otifi c ati o n of 
t h e e v e nt ( s e e S e ctio n  9. 3). 
I n a d diti o n, a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur 
s u btr o c h a nt eri c, or f e m ur di st al) a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s sifi e d a s a n 
S A E f or all s u bj e ct s, a n d s h o ul d b e r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d a n d 
s u b mitt e d t o A m g e n ( s e e A p p e n di x F- Cli ni c al Tri al S eri o u s A d v er s e E v e nt r e p ort f or m) 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 0  of 7 1  
C O N FI D E N TI A L 
 
 
a n d r e c or d e d i n t h e a p pli c a bl e fr a ct ur e r e c or di n g C R F.  S A E r e p orti n g p eri o d f or 
s u s p e ct e d at y pi c al f e m or al fr a ct ur e will b e u ntil E O S. 
S e cti o n:   1 0. 1 St u d y D e si g n , P ar a gr a p h 2 
R e m o v e: 
S e cti o n:   1 0. 2. 4 E x pl or at or y E n d p oi nt s  
R e m o v e: 
S e cti o n:   1 0. 2. 5 S u b s et s , P ar a gr a p h s 2 a n d 3 
R e m o v e: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 1  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 0. 3 S a m pl e Si z e C o n si d er ati o n s , P ar a gr a p h s 6 t o 1 0 
R e m o v e : 
F or t h e Z A e xt e n si o n, it i s e x p e ct e d t h at a p pr o xi m at el y 2 0 0  s u bj e ct s c o ul d b e 
r a n d o mi z e d. 
D at a i s li mit e d o n B M D f or s u bj e ct s w h o di s c o nti n u e d e n o s u m a b 6 0 m g Q 6 M i n t h e 
o n c ol o g y s etti n g.  T h er ef or e d at a fr o m p o st m e n o p a u s al o st e o p or o si s w a s u s e d i n t h e 
s a m pl e si z e. 
A p h a s e 2 r a n d o mi z e d bli n d e d cli ni c al tri al i n p o st m e n o p a u s al w o m e n wit h l o w b o n e 
m a s s a s s e s s e d t h e eff e ct of d e n o s u m a b 6 0 m g Q 6 M o n B M D a n d b o n e t ur n o v er 
m ar k er s ( C T X a n d O st e o c al ci n) aft er l o n g-t er m c o nti n u e d, di s c o nti n u e d, a n d r e st arti n g 
of t h er a p y ( Mill er et  al,  2 0 0 8).  O n e of t h e tr e at m e nt c o h ort s r e c ei v e d d e n o s u m a b 
2 1 0  m g Q 6 M f or 2 4 m o nt h s t h e n pl a c e b o f or t h e n e xt 2 4 m o nt h s.  B a s e d o n t hi s st u d y, a 
5 %  ( S D = 4. 3 %), 5. 2 % ( S D = 2. 6 %), a n d 3. 9 % ( S D = 3. 8 %) d e cr e a s e i n t h e l u m b ar 
s pi n e, t ot al hi p, a n d f e m or al n e c k B M D w a s s e e n d uri n g t h e 2 y e ar s aft er d e n o s u m a b 
di s c o nti n u ati o n ( d at a o n fil e). 
A p a p er r e p orti n g 2 2 c a s e st u di e s of p o st m e n o p a u s al w o m e n w h o r e c ei v e d 5 i nj e cti o n s 
( a p pr o xi m at el y 2. 5 y e ar s) of d e n o s u m a b 6 0 m g Q 6 M a n d w er e t h e n gi v e n a si n gl e d o s e 
of Z A 6 m o nt h s aft er t h e fift h i nj e cti o n ( L e h m a n n a n d A e b erli, 2 0 1 7).  A 3. 8 % ( S D = 
2. 8 %), 1. 7 % ( S D = 3. 3 %), a n d 0. 6 % ( S D = 5 %) d e cr e a s e i n t h e l u m b ar s pi n e, t ot al hi p, 
a n d f e m or al n e c k B M D w a s s e e n d uri n g t h e 2. 5 y e ar s aft er d e n o s u m a b di s c o nti n u ati o n. 
A t a bl e s h o wi n g t h e l e v el of pr e ci si o n (i e, h alf wi dt h of 9 5 % CI) f or e a c h tr e at m e nt ar m 
a n d e a c h B M D t y p e f or diff er e nt s a m pl e si z e s, c al c ul at e d b a s e d o n t h e st a n d ar d 
d e vi ati o n s e sti m at e d fr o m t h e 2 st u di e s m e nti o n e d a b o v e, i s pr e s e nt e d b el o w.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 2  of 7 1  
C O N FI D E N TI A L 
 
 
T a bl e 2.  S a m pl e Si z e s 
N u m b er of 
s u bj e ct s i n  
e a c h ar m  
Pr e ci si o n ( h alf wi dt h of 9 5 % c o nfi d e n c e i nt er v al)  
St a n d ar d of c ar e  
I V z ol e dr o ni c a ci d 
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
7 5  
 1. 0 %  
 0. 6 %  
 0. 9 %  
 0. 6 %  
 0. 8 %  
 1. 1 %  
1 0 0  
 0. 9 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 7 %  
 1. 0 %  
1 2 5  
 0. 8 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 6 %  
 0. 9 %  
I V = i ntr a v e n o u s 
S e cti o n:   1 0. 4 A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s , P ar a gr a p h 5 
R e m o v e: 
Eli gi bl e s u bj e ct s w h o c o n s e nt t o t h e Z A e xt e n si o n d o n ot r e c ei v e a n y i n v e sti g ati o n al 
pr o d u ct ( d e n o s u m a b), b ut will b e r a n d o mi z e d 1: 1 t o r e c ei v e si n gl e d o s e Z A 5 m g I V or 
S O C.  
S e cti o n:   1 0. 5 I nt eri m A n al y si s, E arl y St o p pi n g G ui d eli n e s, a n d Ti m e - p oi nt s of A n al y s e s 
R e m o v e : 
S e cti o n:   1 0. 6. 2. 4 E x pl or at or y A n al y s e s  
R e m o v e: 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 3  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 1. 1 D e n o s u m a b  
R e m o v e: 
P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n: 
N o Z A will b e pr o vi d e d f or t hi s e xt e n si o n.  
P ati e nt s i n cl u d e d i n t h e tr e at m e nt ar m of t h e Z A e xt e n si o n will o bt ai n Z A (I V 5 m g) vi a a 
pr e s cri pti o n fr o m t h eir p h y si ci a n. 
T h er e ar e c urr e ntl y n o g ui d eli n e s or e vi d e n c e r e g ar di n g t h e b e st str at e g y t o b e 
c o n si d er e d w h e n di s c o nti n ui n g d e n o s u m a b i n c a n c er tr e at m e nt- i n d u c e d b o n e l o s s.  
T h er e h a s b e e n e x p ert o pi ni o n p u bli s h e d st ati n g t h at a tr a n siti o n t o a bi s p h o s p h o n at e 
r e pr e s e nt s a tr e at m e nt o pti o n (H a dji et al, 2 0 1 7) . 
S e cti o n:   1 1. 2  A c c e s s t o Tr e at m e nt A s si g n m e nt s  
R e m o v e: 
1 1. 2. 3  P o st O p e n-l a b el D e n o s u m a b Z A E xt e n si o n 
Aft er t h e I C F i s si g n e d, r a n d o mi z ati o n of s u bj e ct s d e e m e d eli gi bl e f or t h e Z A E xt e n si o n 
c a n o c c ur, a n d Z A s h all b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b. 
P ati e nt s i n cl u d e d i n t h e Z A ar m of t h e p o st d e n o s u m a b di s c o nti n u ati o n O L 
a d mi ni str ati o n will o bt ai n Z A (I V 5 m g) vi a a pr e s cri pti o n fr o m t h eir p h y si ci a n. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 4  of 7 1  
C O N FI D E N TI A L 
 
 
R ef er t o t h e S m P C ( htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ pr o d u ct/ 4 4/ s m p c) f or d et ail e d 
i nf or m ati o n o n t h e a d mi ni str ati o n of Z A. 
S e cti o n:   1 4 R ef er e n c e s 
R e m o v e: 
H a dji P, A a pr o M S, B o d y J J, G n a nt M, et al.  M a n a g e m e nt of Ar o m at a s e I n hi bit or-
A s s o ci at e d B o n e L o s s ( AI B L) i n p o st m e n o p a u s al w o m e n wit h h or m o n e s e n siti v e br e a st 
c a n c er: J oi nt p o siti o n st at e m e nt of t h e I O F, C A B S, E C T S, I E G, E S C E O I M S, a n d SI O G.   
J B o n e O n c ol .  2 0 1 7 ; 2 3; 7: 1-1 2.  
L e h m a n n T, A e b erli D.  P o s si bl e pr ot e cti v e eff e ct of s wit c hi n g fr o m d e n o s u m a b t o 
z ol e dr o ni c a ci d o n v ert e br al fr a ct ur e s.  O st e o p or o s I nt.   2 0 1 7; 2 8( 1 0): 3 0 6 7- 3 0 6 8.  
Mill er P D, B ol o g n e s e M S, L e wi e c ki E M, et al.  Eff e ct of d e n o s u m a b o n b o n e d e n sit y a n d 
t ur n o v er i n p o st m e n o p a u s al w o m e n wit h l o w b o n e m a s s aft er l o n g-t er m c o nti n u e d, 
di s c o nti n u e d, a n d r e st arti n g of t h er a p y:  a r a n d o mi z e d bli n di n g p h a s e 2 cli ni c al tri al.  
B o n e.   2 0 0 8; 4 3( 2): 2 2 2 -2 2 9.  
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 5  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   1 5 A p p e n di x A  
R e m o v e: 
S c h e d ul e of A s s e s s m e nt s f or P o st O p e n-l a b el D e n o s u m a b Z ol e dr o ni c A ci d E xt e n si o n ( Z A E xt e n si o n) 
St u d y a s s e s s m e nt  
S cr e e ni n g/ b a s eli n e  
R a n d o mi z ati o n  
Q 6 M Vi sit  
Q 1 2 M Vi sit  
Q 1 8 M Vi sit = 
E O S a  
R e -c o n s e nt  
X  
 
 
 
 
R a n d o mi z ati o n  
 
X  
 
 
 
I V Z ol e dr o ni c a ci d ( 5 m g x 1)b  
 
X  
 
 
 
L a b or at or y A s s e s s m e nt e  
X  
 
 
 
 
 E O S = e n d of st u d y; I V = i ntr a v e n o u s; M = m o nt h; O L = o p e n -l a b el; 
O L P = o p e n -l a b el p h a s e; Q X M = e v er y X m o nt h s; 
 S O C = st a n d ar d of c ar e; Z A = z ol e dr o ni c a ci d.. 
T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n b ut m u st o c c ur aft er writt e n c o n s e nt h a s 
b e e n o bt ai n e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n u ntil 9 m o nt h s aft er. 
R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o D a y 1. 
Vi sit s t o sit e:  D a y  1 aft er r e -c o n s e nt a n d r a n d o mi z ati o n , 6, 1 2, a n d 1 8  m o nt h s (  2  w e e k s) aft er  d a y  1.  
a E O S:  E n d of Z A e xt e n si o n st u d y will b e 1 8 m o nt h s aft er d a y 1; or t h e l a st s c h e d ul e d vi sit i n c a s e p ati e nt e n d s st u d y pr e m at ur el y. 
b  Z A a d mi ni str ati o n m u st t a k e pl a c e wit hi n 8 d a y s aft er r a n d o mi z ati o n.  H alf of t h e p ati e nt s will b e r a n d o mi z e d t o S O C ( N o Z A).  D a y 1 f or b ot h ar m s s h o ul d b e 
8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  Vi sit s will t a k e pl a c e 6, 1 2, 1 8 m o nt h s aft er 
d a y 1. 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9  
P a g e 5 6  of 7 1  
C O N FI D E N TI A L 
 
 
e R o uti n e l a b or at or y a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e r a n d o mi z ati o n.  A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n.  
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 7  of 7 1  
C O N FI D E N TI A L 
 
 
S e cti o n:   A p p e n di x G Z ol e dr o ni c A ci d S u b st u d y  
A p p e n di x F.  S eri o u s A d v er s e E v e nt F or m 
1.  
E X P L O R A T O R Y O B J E C TI V E 
2.  
R A TI O N A L E 
D e n o s u m a b c e s s ati o n i s a s s o ci at e d wit h d e cli n e s i n b o n e m a s s t h at a p pr o a c h 
pr e-tr e at m e nt l e v el s a n d a v ail a bl e d at a d o s u g g e st a n i n cr e a s e i n m ulti pl e 
v ert e br al fr a ct ur e s aft er di s c o nti n u ati o n.  Bi s p h o s p h o n at e tr e at m e nt aft er 
d e n o s u m a b m a y b e w arr a nt e d t o p ot e nti all y pr e v e nt t h e s e fr a ct ur e s, p arti c ul arl y 
i n p ati e nt s n ot pr e vi o u sl y e x p o s e d t o bi s p h o s p h o n at e s a n d w h o r e m ai n at hi g h 
fr a ct ur e ri s k (i e, o st e o p or o si s wit h pr e vi o u s v ert e br al fr a ct ur e s), b ut li mit e d d at a 
ar e a v ail a bl e c o nfir mi n g t h e v ali dit y of t hi s h y p ot h e si s.  T h er ef or e, t h er e i s a d at a 
g a p r e g ar di n g o pti m al str at e gi e s f or p ati e nt s w h o will di s c o nti n u e d e n o s u m a b.  
T h e Z A s u b st u d y i s d e si g n e d t o e v al u at e s u bj e ct s c o m pl eti n g o p e n- l a b el 
d e n o s u m a b tr e at m e nt, t o eit h er r e c ei v e a si n gl e d o s e of Z A, or t o b e m a n a g e d 
a c c or di n g t o c urr e nt st a n d ar d of c ar e ( S O C) f or r e s p e cti v e p ati e nt p o p ul ati o n .  
St a n d ar d of C ar e ( S o C) f or t hi s s u b st u d y p ati e nt p o p ul ati o n d e p e n d s o n i n di vi d u al 
f a ct or s s u c h a s b o n e d e n sit y, lif e st yl e r e c o m m e n d ati o n s b y t h e I n v e sti g at or s u c h 
a s di et, p h y si c al a cti viti e s a n d s u n e x p o s ur e, a s w ell a s l o c al tr e at m e nt st a n d ar d s 
a n d will b e a gr e e d u p o n wit h t h e tr e ati n g I n v e sti g at or.  
T h er e ar e c urr e ntl y n o g ui d eli n e s or e vi d e n c e r e g ar di n g t h e b e st str at e g y t o b e 
c o n si d er e d w h e n di s c o nti n ui n g d e n o s u m a b i n c a n c er tr e at m e nt -i n d u c e d b o n e 
l o s s.  T h er e h a s b e e n e x p ert o pi ni o n p u bli s h e d st ati n g t h at a tr a n siti o n t o a 
bi s p h o s p h o n at e r e pr e s e nt s a tr e at m e nt o pti o n ( H a dji et al, 2 0 1 7) . 
3.  
E X P E RI M E N T A L P L A N 
3. 1.   
S u b st u d y D e si g n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 8  of 7 1  
C O N FI D E N TI A L 
 
 
Aft er r e g ul at or y a n d I R B/I E C a p pr o v al of Pr ot o c ol A m e n d m e nt 6 ( a d d e d Z A 
s u b st u d y), willi n g a n d eli gi bl e s u bj e ct s w h o p arti ci p at e d i n t h e O L P of t h e st u d y 
a n d c o m pl et e d  O L d e n o s u m a b m a y o pt i n t hi s Z A s u b st u d y a n d eit h er r e c ei v e a 
si n gl e d o s e of Z A ( T h er a p y Ar m), or ar e m a n a g e d a c c or di n g t o t h e c urr e nt S O C 
f or t hi s p ati e nt p o p ul ati o n ( C o ntr ol Ar m).  S u bj e ct s w h o c o m pl et e d O L P 
d e n o s u m a b ar e eli gi bl e t o p arti ci p at e i n t h e Z A s u b st u d y a s l o n g a s t h e o utli n e d 
crit eri a ar e f ulfill e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b 
a d mi ni str ati o n u ntil 9  m o nt h s aft er.  T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e 
l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n, 
b ut m u st o c c ur aft er writt e n c o n s e nt h a s b e e n o bt ai n e d.  
Willi n g a n d eli gi bl e s u bj e ct s w h o c o m pl et e d O L d e n o s u m a b ar e r a n d o mi z e d t o 
1 si n gl e 5  m g I V d o s e of Z A or t o S O C.  R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 
8 d a y s pri or t o D a y 1.  D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m 
t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s 
vi sit.  F oll o w u p will c o nti n u e f or a t ot al of 1 8 m o nt h s aft er d a y 1.  R a n d o mi z ati o n 
will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of O L P d e n o s u m a b c o m pl eti o n ( Y e s or 
N o).   
Aft er d a y 1, s u bj e ct s will b e e v al u at e d e v er y 6 m o nt h s.  D X A s c a n c a n b e 
p erf or m e d b et w e e n 7  t o 9  m o nt h s aft er t h e d at e of t h e l a st d e n o s u m a b 
a d mi ni str ati o n, b ut i n a n y c a s e b ef or e t h e d at e of fir st Z A a d mi ni str ati o n.  R o uti n e 
D X A s c a n s p erf or m e d wit hi n t h e o utli n e d ti m e wi n d o w c a n b e u s e d a s b a s eli n e 
D X A s c a n s.  
S u bj e ct s w h o d o n ot f ulfill t h e eli gi bilit y crit eri a f or or d o n ot c o n s e nt t o t h e Z A 
s u b st u d y will c o m pl et e O L P a s s e s s m e nt s o nl y.   
S u bj e ct s w h o p arti ci p at e i n t h e Z A s u b st u d y, will u n d er g o t h e f oll o wi n g 
a s s e s s m e nt s:  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 5 9  of 7 1  
C O N FI D E N TI A L 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 0  of 7 1  
C O N FI D E N TI A L 
 
 
3. 2.   
S c h e m a 
Z A S u b st u d y D e si g n a n d Tr e at m e nt S c h e m a 
 
 
I V = i ntr a v e n o u s; Z A = z ol e dr o ni c a ci d. 
 
E
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St a n d ar d of c ar e  
Si n gl e d o s e Z A I V 5 m g 8 m o nt h s (  4 
w e e k s) aft er O L P d e n o s u m a b  
6, 
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a n d 
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m o nt
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A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 1  of 7 1  
C O N FI D E N TI A L 
 
 
3. 3.   
N u m b er of C e nt er s 
A p pr o xi m at el y 3 0 sit e s i n A u stri a ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A s u b st u d y. 
3. 4.   
N u m b er of S u bj e ct s 
A p pr o xi m at el y 2 0 0 s u bj e ct s ar e a nti ci p at e d t o p arti ci p at e i n t h e Z A s u b st u d y. 
3. 5.  
E s ti m at e d S u b st u d y D ur ati o n  
3. 5. 1.  
E sti m at e d S u b st u d y D ur ati o n f or P arti ci p a nt s 
S u bj e ct s will b e i n t hi s s u b st u d y f or a m a xi m u m d ur ati o n of a p pr o xi m at el y 
2 7  m o nt h s. 
3. 5. 2.  
Z A S u b st u d y Tr e at m e nt 
S u bj e ct s t h at c o m pl et e d t h eir O L P d e n o s u m a b vi sit ar e eli gi bl e t o p arti ci p at e i n 
t h e Z A s u b st u d y a s l o n g a s all t h e s u b st u d y i n cl u si o n/ e x cl u si o n crit eri a ar e m et. 
Z ol e dr o ni c a ci d will b e a d mi ni st er e d 8 m o nt h s (  4 w e e k s) aft er l a st O L P 
a d mi ni str ati o n f or s u bj e ct s r a n d o mi z e d t o tr e at m e nt ar m.  S u bj e ct s r a n d o mi z e d t o 
S O C, will att e n d t h e sit e f or vi sit s at t h e s a m e vi sit s c h e d ul e a s t h e tr e at m e nt ar m 
s u bj e ct s. 
D a y 1 f or b ot h ar m s s h o ul d b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L 
d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  
3. 5. 3.  
E n d of Z A S u b st u d y 
T h e e n d of Z A s u b st u d y will o c c ur w h e n t h e l a st s u bj e ct p arti ci p ati n g i n t h e Z A 
s u b st u d y h a s c o m pl et e d t h eir l a st f or m al vi sit or a n u n s c h e d ul e d st u d y vi sit i n 
c a s e of e arl y wit h dr a w al fr o m t h e Z A s u b st u d y.   
E n d of st u d y r e a s o n s i n cl u d e 3 e arl y E O S r e a s o n s ( d e at h, l o st t o f oll o w- u p, a n d 
c o n s e nt wit h dr a w al) a n d p er pr ot o c ol E O S of Z A s u b st u d y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 2  of 7 1  
C O N FI D E N TI A L 
 
 
4.  
E LI GI BI LI T Y C RI T E RI A 
4. 5.  
I n cl u si o n Crit eri a f or Z A S u b st u d y 
4. 5. 1.  
O bt ai n si g n e d a n d d at e d writt e n i nf or m e d c o n s e nt pri or t o p erf or mi n g a n y 
s u b st u d y- s p e cifi c pr o c e d ur e 
4. 5. 2.  
S u bj e ct s t h at r e c ei v e d O L P d e n o su m a b a n d c o m pl et e d O L P tr e at m e nt  
4. 5. 3.  
L a st O L P d e n o s u m a b a d mi ni str ati o n n o l o n g er t h a n 9 m o nt h s a g o 
4. 6.   
E x cl u si o n Crit eri a f or Z A S u b st u d y 
4. 6. 1.  
C urr e nt or pri or Z A a d mi ni str ati o n. 
4. 6. 2.  
S u bj e ct s w h o e n d e d tr e at m e nt wit h i n v e sti g ati o n al pr o d u ct (I P) pr e m at ur el y 
i n t h e d o u bl e- bli n d p h a s e a n d O L p h a s e 
4. 6. 3.  
K n o w n s e n siti vit y or i nt ol er a n c e t o a n y of t h e pr o d u ct s t o b e a d mi ni st er e d 
d uri n g t h e s u b st u d y ( e g, Z A, c al ci u m or vit a mi n D) 
4. 6. 4.  
K n o w n hi st or y of a n y of t h e f oll o wi n g c o n diti o n s eit h er b y s u bj e ct s elf 
r e p ort or c h art r e vi e w 
 
P a g et’ s di s e a s e ( b o n e), C u s hi n g’ s di s e a s e, h y p er pr ol a cti n e mi a or ot h er 
a cti v e m et a b oli c b o n e di s e a s e  
 
K n o w n hi st or y of h y p o c al c e mi a  
 
M aj or s ur g er y, or si g nifi c a nt tr a u m ati c i nj ur y o c c urri n g wit hi n 4 w e e k s 
pri or t o r a n d o mi z ati o n 
 
P ar at h yr oi d gl a n d s i n n e c k s ur gi c all y r e m o v e d. 
 
A n y s e cti o n s of i nt e sti n e r e m o v e d. 
 
K n o w n h u m a n i m m u n o d efi ci e n c y vir u s i nf e cti o n 
 
A cti v e i nf e cti o n wit h h e p atiti s B or h e p atiti s C vir u s  
4. 6. 5.  
K n o w n li v er or r e n al di s e a s e a s d et er mi n e d b y t h e i n v e sti g at or a n d 
i n di c at e d b y t h e f oll o wi n g crit eri a: 
 
A s p art at e a mi n otr a n sf er a s e ≥ 2. 5 x U L N  
 
Al a ni n e tr a n s a mi n a s e ≥ 2. 5 x U L N  
 
S er u m cr e ati ni n e ≥ 2 x U L N 
 
Cr e ati n e cl e ar a n c e < 3 5 ml/ mi n  
4. 6. 6.  
S u bj e ct s t h at ar e pr e g n a nt or br e a stf e e di n g 
 
All s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st h a v e a n e g ati v e 
pr e g n a n c y t e st wit hi n 7 d a y s b ef or e r a n d o mi z ati o n 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 3  of 7 1  
C O N FI D E N TI A L 
 
 
4. 6. 7.  
S u bj e ct s w h o ar e o st e o p or oti c i n b a s eli n e B M D 
5.  
S U B J E C T E N R O L L M E N T 
A s u bj e ct will b e a s si g n e d b y a n I nt er a cti v e V oi c e/ W e b R e s p o n s e S y st e m t o 1 of 
2 tr e at m e nt gr o u p s ( Z A or S O C), i n a 1: 1 r ati o.  T h e r a n d o mi z ati o n s c h e d ul e will 
u s e r a n d o ml y p er m ut e d bl o c k s a n d will b e str atifi e d b y AI u s e at t h e ti m e p oi nt of 
O L P d e n o s u m a b c o m pl eti o n ( Y e s or N o).  A s u bj e ct w h o i s r a n d o mi z e d t o t h e Z A 
s u b st u d y will m ai nt ai n t h e s a m e s u bj e ct n u m b er w hi c h i s al s o t h e s u bj e ct n u m b er 
a s a s si g n e d i n t h e d o u bl e - bli n d ( m ai n) st u d y.  A s u bj e ct m a y o nl y b e r a n d o mi z e d 
o n c e i nt o Z A s u b st u d y.  T h e Z A r a n d o mi z ati o n li st will b e g e n er at e d a n d 
m ai nt ai n e d b y a n A m g e n r e pr e s e nt ati v e n ot i n v ol v e d i n t h e c o n d u ct of t h e st u d y. 
6.  
T R E A T M E N T P R O C E D U R E S 
6. 1.  
I n v e sti g ati o n al Pr o d u ct (Z ol e dr o ni c A ci d) D o s a g e, A d mi ni str ati o n, a n d 
S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5 m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er 
all ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o s u bj e ct s b y 
h e alt h c ar e pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V 
bi s p h o s p h o n at e s.  S u bj e ct s tr e at e d wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et.  
Z A will b e l o c all y pr o vi d e d b y p arti ci p ati n g sit e s a n d will b e r ei m b ur s e d b y t h e 
s p o n s or. 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n 
a c c or d a n c e wit h l o c al r e q uir e m e nt s. R ef er t o t h e s u m m ar y of pr o d u ct 
c h ar a ct eri sti c s ( S m P C) 
(htt p s:// w w w. e m a. e ur o p a. e u/ e n/ m e di ci n e s/ h u m a n/ E P A R/ z o m et a # pr o d u ct -
i nf or m ati o n- s e cti o n) f or d et ail e d i nf or m ati o n o n t h e a d mi ni str ati o n of Z A. 
6. 2.   
Pr o hi bit e d m e di c ati o n s 
T h er e ar e n o pr o hi bit e d m e di c ati o n s i n t h e Z A s u b st u d y. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 4  of 7 1  
C O N FI D E N TI A L 
 
 
7.  
S T U D Y P R O C E D U R E S 
7. 4.   
L a b or at or y A s s e s s m e nt s  
A s d e s cri b e d i n eli gi bilit y crit eri a f or t hi s s u b st u d y, r o uti n e l a b or at or y 
a s s e s s m e nt s ( at l e a st f or A L T, A S T, s er u m cr e at i ni n e, cr e ati n e cl e ar a n c e a n d 
c al ci u m ) t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e r a n d o mi z ati o n.  
P ati e nt s wit h c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e pr e g n a n c y t e st wit hi n 
7 d a y s pri or t o r a n d o mi z ati o n.  S u bj e ct s w h o h a v e u n d er g o n e a h y st er e ct o m y d o 
n ot r e q uir e a pr e g n a n c y t e st. 
A d diti o n all y, s u bj e ct s will h a v e l a b a s s e s s m e nt s t o d et er mi n e eli gi bilit y a s 
o utli n e d i n T a bl e  2. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 5  of 7 1  
C O N FI D E N TI A L 
 
 
T a bl e  2.  S er u m a n d Bl o o d S a m pl e A n al yt e Li sti n g f or Z A S u b st u d y 
S er u m C h e mi str y  
H e m at ol o g y  
Ot h er  
S o di u m  
R e d bl o o d c ell s  
P ot a s si u m  
H e m o gl o bi n  
 
C al ci u m a  
H e m at o crit  
 
Bl o o d Ur e a Nitr o g e n/ Ur e a  
Pl at el et s  
 
Cr e ati ni n e a  
W hit e bl o o d c ell s  
 
T ot al bilir u bi n  
 
 
Al k ali n e p h o s p h at a s e  
 
 
Al a ni n e tr a n s a mi n a s e a   
 
 
A s p ar at e a mi n otr a n sf er a s e a  
 
 
L D H  
 
 
G a m m a G T  
 
 
Al b u mi n  
 
 
8.  
A D V E R S E E V E N T R E P O R TI N G 
D uri n g t h e s u b st u d y, all S A E s a n d A E s of s p e ci al i nt er e st (r e n al t o xi cit y, cli ni c all y 
r el e v a nt h y p er/ h y p o c al c e mi a, a n d or al e v e nt s) will b e d o c u m e nt e d fr o m si g ni n g 
t h e I C F f or t h e Z A s u b st u d y u ntil t h e l a st st u d y vi sit ( 1 8 m o nt h s aft er D a y 1) i n t h e 
A d v er s e E v e nt e C R F. 
F or s u bj e ct s p arti ci p ati n g i n t h e s u b st u d y, t h e i n v e sti g at or i s r e s p o n si bl e f or 
e n s uri n g all S A E s o b s er v e d b y t h e i n v e sti g at or or r e p ort e d b y t h e s u bj e ct t h at 
o c c ur aft er si g ni n g of t h e I C F f or t h e Z A s u b st u d y u ntil t h e l a st st u d y vi sit 
( 1 8 m o nt h s aft er D a y 1), ar e r e c or d e d i n t h e s u bj e ct s m e di c al r e c or d, t h e A d v er s e 
E v e nt e C R F, a n d ar e s u b mitt e d t o A m g e n.   
N e w cli ni c al fr a ct ur e s will b e c oll e ct e d a n d a n y s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e (f e m ur mi d s h aft fr a ct ur e, f e m ur s u btr o c h a nt eri c, or f e m ur di st al) 
a s s o ci at e d wit h mi ni m al tr a u m a will b e cl a s si fi e d a s a n S A E f or all s u bj e ct s  
( s e e S e cti o n 9. 1. 2 ), a n d s h o ul d b e r e c or d e d i n t h e s u bj e ct’ s m e di c al r e c or d, 
a p pli c a bl e fr a ct ur e -r e c or di n g C R F, a n d o n a S eri o u s A d v er s e E v e nt R e p ort f or m 
( s e e A p p e n di x F ) t h e n f a x e d t o t h e l o c al A m g e n S af et y S p e ci ali st withi n 2 4 h o ur s 
of di s c o v er y or n otifi c ati o n of t h e e v e nt ( s e e S e cti o n  9. 3 ). 
S A E r e p orti n g p eri o d f or s u s p e ct e d at y pi c al f e m or al fr a ct ur e will b e u ntil E O S. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 6  of 7 1  
C O N FI D E N TI A L 
 
 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S 
9. 1.   
E x pl or at or y E n d p oi nt s 
9. 2.   
S u b s et s 
9. 3.   
S a m pl e Si z e C o n si d er ati o n s 
F or t h e Z A s u b st u d y, it i s a nti ci p at e d t h at a p pr o xi m at el y 2 0 0 s u bj e ct s c o ul d b e 
r a n d o mi z e d. 
D at a i s li mit e d o n B M D f or s u bj e ct s w h o di s c o nti n u e d e n o s u m a b 6 0 m g Q 6 M i n 
t h e o n c ol o g y s etti n g.  T h er ef or e, d at a fr o m p o st m e n o p a u s al o st e o p or o si s w a s 
u s e d i n t h e s a m pl e si z e. 
A p h a s e 2 r a n d o mi z e d bli n d e d cli ni c al tri al i n p o st m e n o p a u s al w o m e n wit h l o w 
b o n e m a s s a s s e s s e d t h e eff e ct of d e n o s u m a b 6 0  m g Q 6 M o n B M D a n d b o n e 
t ur n o v er m ar k er s ( C T X a n d O st e o c al ci n) aft er l o n g-t er m c o nti n u e d, di s c o nti n u e d, 
a n d r e st arti n g of t h er a p y ( Mill er  et  al,  2 0 0 8).  O n e of t h e tr e at m e nt c o h ort s 
r e c ei v e d d e n o s u m a b 2 1 0 m g Q 6 M f or 2 4 m o nt h s t h e n pl a c e b o f or t h e n e xt 
2 4  m o nt h s.  B a s e d o n t hi s st u d y, a 5 % ( S D = 4. 3 %), 5. 2 % ( S D = 2. 6 %), a n d 3. 9 % 
( S D = 3. 8 %) d e cr e a s e i n t h e l u m b ar s pi n e, tot al hi p, a n d f e m or al n e c k B M D w a s 
s e e n d uri n g t h e 2  y e ar s aft er d e n o s u m a b di s c o nti n u ati o n ( d at a o n fil e). 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 7  of 7 1  
C O N FI D E N TI A L 
 
 
A p a p er r e p orti n g 2 2 c a s e st u di e s of p o st m e n o p a u s al w o m e n w h o r e c ei v e d 
5 i nj e cti o n s ( a p pr o xi m at el y 2. 5 y e ar s) of d e n o s u m a b 6 0 m g Q 6 M a n d w er e t h e n 
gi v e n a si n gl e d o s e of Z A 6 m o nt h s aft er t h e fift h i nj e cti o n  
( L e h m a n n a n d A e b erli, 2 0 1 7).  A 3. 8 % ( S D = 2. 8 %), 1. 7 % ( S D = 3. 3 %), a n d  
0. 6 % ( S D = 5 %) d e cr e a s e i n t h e l u m b ar s pi n e, t ot al hi p, a n d f e m or al n e c k B M D w a s 
s e e n d uri n g t h e 2. 5 y e ar s aft er d e n o s u m a b di s c o nti n u ati o n.  
A t a bl e s h o wi n g t h e l e v el of pr e ci si o n (i e, h alf wi dt h of 9 5 % CI) f or e a c h tr e at m e nt 
ar m a n d e a c h B M D t y p e f or diff er e nt s a m pl e si z e s, c al c ul at e d b a s e d o n t h e 
st a n d ar d d e vi ati o n s e sti m at e d fr o m t h e 2 st u di e s m e nti o n e d a b o v e, i s pr e s e nt e d 
b el o w. 
T a bl e 3.  S a m pl e Si z e s 
N u m b er of 
s u bj e ct s i n  
e a c h ar m  
Pr e ci si o n ( h alf wi dt h of 9 5 % c o nfi d e n c e i nt er v al)  
St a n d ar d of c ar e  
I V z ol e dr o ni c a ci d 
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
L u m b ar 
S pi n e  
T ot al Hi p  
F e m or al 
N e c k  
7 5  
 1. 0 %  
 0. 6 %  
 0. 9 %  
 0. 6 %  
 0. 8 %  
 1. 1 %  
1 0 0  
 0. 9 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 7 %  
 1. 0 %  
1 2 5  
 0. 8 %  
 0. 5 %  
 0. 7 %  
 0. 5 %  
 0. 6 %  
 0. 9 %  
I V = i ntr a v e n o u s 
9. 4.   
A c c e s s t o I n di vi d u al S u bj e ct Tr e at m e nt A s si g n m e nt s 
S u bj e ct s i n Z A s u b st u d y will b e r a n d o mi z e d 1: 1 t o r e c ei v e si n gl e d o s e Z A 5 m g I V 
(i n v e sti g ati o n al pr o d u ct) or S O C. 
9. 5.  
Ti m e p oi nt of A n al y si s  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 8  of 7 1  
C O N FI D E N TI A L 
 
 
9. 6.   
Pl a n n e d M et h o d s of A n al y si s 
  A n al y s e s will b e c o n d u ct e d o n t h e Z A a n al y si s s et.   
 will b e s u m m ari z e d b y tr e at m e nt gr o u p o n t h e 
Z A s af et y a n al y si s s et.   
1 0.  R E F E R E N C E S 
H a dji P, A a pr o M S, B o d y J J, G n a nt M, et al.  M a n a g e m e nt of Ar o m at a s e I n hi bit or-
A s s o ci at e d B o n e L o s s ( AI B L) i n p o st m e n o p a u s al w o m e n wit h h or m o n e s e n siti v e 
br e a st c a n c er: J oi nt p o siti o n st at e m e nt of t h e I O F, C A B S, E C T S, I E G, E S C E O I M S, 
a n d SI O G.   J B o n e O n c ol .  2 0 1 7 ; 2 3; 7: 1-1 2.   
L e h m a n n T, A e b erli D.  P o s si bl e pr ot e cti v e eff e ct of s wit c hi n g fr o m d e n o s u m a b t o 
z ol e dr o ni c a ci d o n v ert e br al fr a ct ur e s.  O st e o p or o s I nt.   2 0 1 7; 2 8( 1 0): 3 0 6 7- 3 0 6 8.  
Mill er P D, B ol o g n e s e M S, L e wi e c ki E M, et al.  Eff e ct of d e n o s u m a b o n b o n e 
d e n sit y a n d t ur n o v er i n p o st m e n o p a u s al w o m e n wit h l o w b o n e m a s s aft er l o n g-
t er m c o nti n u e d, di s c o nti n u e d, a n d r e st arti n g of t h er a p y:  a r a n d o mi z e d bli n di n g 
p h a s e 2 cli ni c al tri al.  B o n e.   2 0 0 8; 4 3( 2): 2 2 2- 2 2 9.  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 6 9  of 7 1  
C O N FI D E N TI A L 
 
 
1 1.  S C H E D U L E O F A S S E S S M E N T S 
T a bl e 4.  S c h e d ul e of A s s e s s m e nt s f or Z A S u b st u d y 
St u d y a s s e s s m e nt  
S cr e e ni n g/ b a s eli n e  
R a n d o mi z ati o n  
Q 6 M Vi sit  
Q 1 2 M Vi sit  
Q 1 8 M Vi sit = 
E O S a  
R e -c o n s e nt  
X  
 
 
 
 
R a n d o mi z ati o n  
 
X  
 
 
 
I V Z ol e dr o ni c a ci d ( 5 m g x 1)b  
X  
L a b or at or y A s s e s s m e nt e  
X  
 
 
 
 
 E O S = e n d of st u d y; I V = i ntr a v e n o u s; M = m o nt h; 
O L  = o p e n-l a b el; O L P = o p e n-l a b el p h a s e; Q X M = e v er y X m o nt h s; 
 S O C = st a n d ar d of c ar e; 
Z A  =  z ol e dr o ni c a ci d. 
T h e s cr e e ni n g p h a s e st art s fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n at t h e e arli e st a n d l a st s u ntil r a n d o mi z ati o n b ut m u st o c c ur aft er writt e n 
c o n s e nt h a s b e e n o bt ai n e d. 
Writt e n c o n s e nt m a y b e o bt ai n e d fr o m d at e of t h e l a st O L P d e n o s u m a b a d mi ni str ati o n u ntil 9 m o nt h s aft er. 
R a n d o mi z ati o n c a n b e p erf or m e d wit hi n 8 d a y s pri or t o D a y 1. 
Vi sit s t o sit e:  D a y  1 aft er r e -c o n s e nt a n d r a n d o mi z ati o n , 6, 1 2, a n d 1 8  m o nt h s (  2  w e e k s) aft er d a y  1.  
a E O S:  E n d of Z A s u b st u d y will b e 1 8 m o nt h s aft er d a y  1; or t h e l a st s c h e d ul e d vi sit i n c a s e p ati e nt e n d s st u d y pr e m at ur el y. 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 0  of 7 1  
C O N FI D E N TI A L 
 
 
b  Z A a d mi ni str ati o n m u st t a k e pl a c e wit hi n 8 d a y s aft er r a n d o mi z ati o n.  H alf of t h e p ati e nt s will b e r a n d o mi z e d t o S O C ( N o Z A).  D a y  1 f or b ot h ar m s s h o ul d 
b e 8 m o nt h s (  4 w e e k s) fr o m t h e l a st d o s e of O L d e n o s u m a b.  F or t h e Z A ar m, Z A will b e a d mi ni st er e d o n t hi s vi sit.  Vi sit s will t a k e pl a c e 6, 1 2, 
e R o uti n e l a b or at or y at l e a st f or A L T, A S T, s er u m cr e ati ni n e, cr e ati n e cl e ar a n c e a n d c al ci u m a s s e s s m e nt s t o d et er mi n e eli gi bilit y m u st b e p erf or m e d b ef or e 
r a n d o mi z ati o n.  A n e g ati v e pr e g n a n c y t e st wit hi n 7 d a y s pri or t o r a n d o mi z ati o n h a s t o b e a v ail a bl e f or w o m e n of c hil d b e ari n g p ot e nti al.  S u bj e ct s w h o 
h a v e u n d er g o n e a h y st er e ct o m y d o n ot r e q uir e a pr e g n a n c y t e st. 
 
 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
D at e:  1 5 J ul y 2 0 1 9 
P a g e 7 1  of 7 1  
C O N FI D E N TI A L 
 
 
1 2.  P H A R M A C Y G UI D E F O R Z A S U B S T U D Y 
Z A S u b st u d y I n v e sti g ati o n al Pr o d u ct ( Z ol e dr o ni c A ci d) D o s a g e, A d mi ni str ati o n, 
a n d S c h e d ul e 
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e a si n gl e 5 m g I V of Z A or S O C 8 m o nt h s 
( 4 w e e k s) aft er c o m pl eti n g O L P. 
F or t h o s e s u bj e ct s r a n d o mi z e d t o r e c ei v e Z A, t hi s will b e a d mi ni st er e d sl o wl y a s a 
c o n st a nt i nf u si o n r at e.  T h e i nf u si o n ti m e m u st n ot b e l e s s t h a n 1 5 mi n ut e s, aft er 
all ot h er st u d y vi sit pr o c e d ur e s h a v e b e e n c o m pl et e d. 
Z ol e dr o ni c A ci d m u st o nl y b e pr e s cri b e d a n d a d mi ni st er e d t o s u bj e ct s b y 
h e alt h c ar e pr of e s si o n al s e x p eri e n c e d i n t h e a d mi ni str ati o n of I V 
bi s p h o s p h o n at e s.  S u bj e ct s tr e at e d wit h Z A s h o ul d b e gi v e n t h e p a c k a g e l e afl et.  
Z A will b e l o c all y pr o vi d e d b y p arti ci p ati n g sit e s a n d will b e r ei m b ur s e d b y t h e 
s p o n s or. 
A n y u n u s e d m e di ci n al pr o d u ct or w a st e m at eri al s h o ul d b e di s p o s e d of i n 
a c c or d a n c e wit h l o c al r e q uir e m e nt s. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  0 1 A pril  2 0 1 9  
P a g e 1 of 3 3  
C O N FI D E N TI A L  
 
 
A m e n d m e nt 5 
Pr ot o c ol Titl e:  A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, M ulti -C e nt er 
P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s W it h 
N o n -M et a st ati c Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
 
A m g e n Pr ot o c ol N u m b e r 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol N u m b er A B C S G 1 8  
E u dr a C T N u m b er 2 0 0 5 -0 0 5 2 7 5 -1 5  
N C T 0 0 5 5 6 3 7 4  
 
A m e n d m e nt D at e:  
0 1 A pril  2 0 1 9  
 
R ati o n al e:  
T hi s pr ot o c ol i s b ei n g a m e n d e d t o:  
•  
A d d a r a n d o mi z ati o n o n p ati e nt s still o n o p e n l a b el d e n o s u m a b t o b e tr e at e d wit h 
eit h er a bi s p h o s p h o n at e or st a n d ar d of c ar e u p o n d e n o s u m a b di s c o nti n u ati o n  
•  
A d d e x pl or at or y o bj e cti v e t o 
 
•  
U p d at e t h e ti mi n g of Z A d o s e t o 8 m o nt h s ( ±  4 w e e k s) fr o m t h e l a st d o s e of 
o p e n -l a b el d e n o s u m a b b e c a u s e t hi s i s t h e m o m e nt w h er e t h er e i s i n cr e a s e i n t h e 
b o n e t ur n o v er m ar k er, C T X, m a ki n g it t h e n t h e o pti m al m o m e nt f or Z A t o a ct  
•  
Cl arif y t h at  C-t er mi n al t el o p e pti d e d at a will b e c oll e ct e d d uri n g p o st o p e n-l a b el 
d e n o s u m a b e xt e n si o n  at s p e cifi e d ti m e s  
•  
Cl arif y ti m e p eri o d s f or a s s e s s m e nt d uri n g t h e e xt e n si o n t o t h e o p e n -l a b el p h a s e. 
•  
Cl arif y a n al y si s of t h e e n d p oi nt s f oll o wi n g t h e p o st o p e n -l a b el de n o s u m a b e xt e n si o n  
•  
A d d s c h e m a d e s cri bi n g p o st o p e n -l a b el d e n o s u m a b di s c o nti n u ati o n e xt e n si o n  
•  
S p e cif y t h e a p pr o xi m at e n u m b er of st u d y sit e s i n A u stri a p arti ci p ati n g i n t h e p o st 
o p e n -l a b el d e n o s u m a b e xt e n si o n 
•  
S p e cif y t h e a p pr o xi m at e n u m b er of s u bj e ct s p arti ci p ati n g i n t h e p o st o p e n -l a b el 
d e n o s u m a b e xt e n si o n  
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  0 1 A pril  2 0 1 9  
P a g e 2 of 3 3  
C O N FI D E N TI A L  
 
 
•   
Ad d a m a xi m u m of a p pr o xi m at el y 1 8  m o nt h s t o t h e st u d y d ur ati o n  
•  
A d d i n cl u si o n a n d e x cl u si o n crit eri a f or p o st o p e n -l a b el d e n o s u m a b z ol e dr o ni c a ci d 
e xt e n si o n  
•  
A d d e x cl u si o n crit eri a f or d o u bl e -bli n d p h a s e o f t h e st u d y 
•  
E xt e n d t h e e x p e ct e d ti m e o n st u d y  
•  
Cl arif y t h e E n d of St u d y d efi niti o n  
•  
Cl arif y t h at d uri n g t h e p o st o p e n -l a b el d e n o s u m a b e xt e n si o n, n o i n v e sti g ati o n al 
pr o d u ct will b e pr o vi d e d  
•  
M a k e e dit ori al a n d a d mi ni str ati v e c h a n g e s f or gr a m m ati c al r e a s o n s a s w ell a s f or 
i nt er n al c o n si st e n c y wit hi n t h e pr ot o c ol. 
A p pr o ve d
 
 
 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2 ) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9 / A B C S G-1 8  
D at e:  2 2  F e br u ar y 2 0 1 6  
P a g e 1 of 5 
C O N FI D E N TI A L  
 
S u p er s e di n g A m e n d m e nt 4  
Pr ot o c ol Titl e:  A R a n d o mi z e d, D o u bl e -bli n d , Pl a c e b o-c o ntr oll e d , M ulti-c e nt er 
P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s Wit h 
N o n -m et a st ati c Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
 
A m g e n Pr ot o c ol N u m b er 2 0 0 5 0 2 0 9/ A B C S G -1 8  
 
S u p er s e di n g A m e n d m e nt D at e:  
2 2  F e br u ar y  2 0 1 6  
R ati o n al e:  
S u p er s e di n g A m e n d m e nt 4 w a s writt e n t o:  
•  
c orr e ct i n c o n st a nt w or di n g a s it o c c ur s i n t h e d o c u m e nt  
•  
c orr e ct t y p o gr a p hi c al a n d f or m atti n g err or s 
•  
cl arif y e x pl or at or y a n al y si s w or di n g i n t h e st ati sti c al a n al y si s s e cti o n  
•  
cl arif y/ e x p a n d fi n al a n al y si s w or di n g i n t h e s y n o p si s   


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  2 5 J a n u ar y 2 0 1 6  
P a g e 1 of 3 6  
C O N FI D E N TI A L  
 
 
A m e n d m e nt 4 
Pr ot o c ol Titl e:  A R a n d o mi z e d, D o u bl e -bli n d , Pl a c e b o-c o ntr oll e d , M ulti-c e nt er 
P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s Wit h 
N o n -m et a st ati c Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
 
A m g e n Pr ot o c ol N u m b e r D e n o s u m a b  2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol N u m b er A B C S G 1 8  
 
A m e n d m e nt D at e:  
1 3 M ar c h 2 0 0 6 FI N A L  
2 7 A pril 2 0 0 6 S u p er s e di n g V er si o n  
1 2 J u n e 2 0 0 6 A m e n d m e nt 1  
0 6 A pril  2 0 1 0 A m e n d m e nt 2  
1 5 A u g u st 2 0 1 2 A m e n d m e nt 3  
0 2 N o v e m b er 2 0 1 2 S u p er s e di n g A m e n d m e nt 3  
2 7 N o v e m b er 2 0 1 2 S u p er s e di n g 2 A m e n d m e nt 3  
2 5 J a n u ar y 2 0 1 3 S u p er s e di n g 3 A m e n d m e nt 3  
2 5  J a n u ar y  2 0 1 6 A m e n d m e nt 4  
R ati o n al e:   
•  
T h e k e y pr ot o c ol c h a n g e i s t h e a d diti o n of a n o p e n -l a b el p h a s e d uri n g w hi c h 
d e n o s u m a b will b e off er e d t o s u bj e ct s w h o r e c ei v e d pl a c e b o pr e vi o u sl y d uri n g 
t h e st u d y a n d t h e e xt e n si o n of t h e l o n g -t er m f oll o w-u p t o 6 6 m o nt h s aft er 
P A D C D . 
T h e pri m ar y a n al y si s at pri m ar y a n al y si s d at a c ut -off d at e (P A D C D ) d e m o n str at e d a  
tr e at m e nt b e n efit wit h d e n o s u m a b tr e at m e nt a n d c o n s e q u e ntl y t h e D at a M o nit ori n g 
C o m m itt e e (D M C ) r e c o m m e n d e d t h at: 
o  T h e st u d y s h o ul d c o nti n u e o ut t o 6 6 m o nt h s aft er P A D C D  a s di s e a s e -fr e e 
s ur vi v al ( D F S ) i nt eri m r e s ult s di d n ot i n di c at e f utilit y. 
o   A n al y si s f or effi c a c y of t h e s e c o n d ar y e n d p oi nt s s h o ul d  b e c o n d u ct e d at or 
ar o u n d 1 8 m o nt h s aft er P A D C D b ef or e u n bli n di n g t o pr ot e ct t h e i nt e grit y of t h e 
s e c o n d ar y e n d p oi nt s.   
o  D e n o s u m a b  s h o ul d b e off er e d t o s u bj e ct s w h o  h a d pr e vi o u sl y r e c ei v e d pl a c e b o  
b ut n ot b ef or e 1 8 m o nt h s p o st P A D C D.  
C o n s e q u e ntl y , s u bj e ct s w h o  r e c ei v e d pl a c e b o o n st u d y will b e off er e d d e n o s u m a b 
6 0  m g e v er y 6 m o nt h s i n a d diti o n t o st a n d ar d of c ar e  f or 3 y e ar s ( 7 d o s e s). 
Pr e vi o u sl y , at y e arl y vi sit s aft er P A D C D , s u bj e ct s w o ul d h a v e b e e n i n l o n g-t er m 
f oll o w-u p wit h st a n d ar d of c ar e  f or a p eri o d of eit h er 1 8 or 6 6 m o nt h s aft er P A D C D 
(c h oi c e d e p e n d e nt o n D M C r e c o m m e n d ati o n)  a n d a n al y si s of  D F S , bo n e 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  2 5 J a n u ar y 2 0 1 6  
P a g e 2 of 3 6  
C O N FI D E N TI A L  
 
 
m et a st a s e s -fr e e s ur vi v al ( B M F S), a n d o v er all s ur vi v al  ( O S) w o ul d h a v e o c c urr e d at t h e 
e n d of t h e l o n g -t er m f oll o w-u p.   
•  
R ati o n al e  s e cti o n  
A pr e s e nt ati o n of t h e A u stri a n Br e a st a n d C ol or e ct al  C a n c er St u d y Gr o u p  (A B C S G ) 
1 8  pri m ar y a n al y si s  r e s ult s w a s a d d e d t o t h e r ati o n al e s e cti o n t o p ut t h e D M C 
r e c o m m e n d ati o n s i n c o nt e xt. 
•  
St u d y pr o c e d ur al  c h a n g e s  
St u d y pr o c e d ur al  c h a n g e s a p pli c a bl e t o t w o diff er e nt s u bj e ct gr o u p s (t h o s e w h o r e c ei v e 
o p e n -l a b el tr e at m e nt a n d t h o s e w h o d o n ot) ar e r e q uir e d t o ali g n wit h t h e a d diti o n of a n 
o p e n -l a b el p h a s e.   
Pl a c e b o -tr e at e d s u bj e ct s w h o d o n ot c h o o s e t o r e c ei v e o p e n-l a b el d e n o s u m a b will b e 
f oll o w e d o n c e a y e ar ( Q 1 2 M) b y cli ni c vi sit s or t el e p h o n e c o nt a ct s f or:  
•  
D F S, B M F S, a n d O S  
•  
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g s eri o u s a d v er s e e v e nt [ S A E ] r e p orti n g of 
s u s p e ct e d at y pi c al f e m or al fr a ct ur e c a s e s)  
•  
C o n c o mit a nt  b o n e aff e cti n g m e di c ati o n  
o  B o n e t ar g et e d t h er a p y ( e g , bi s p h o s p h o n at e or d e n o s u m a b)  
o  Gl u c o c orti c oi d s  
o  A nti e p il e pti c d r u g s 
o  A nti d e pr e s s a nt s  
o   In s uli n  
•  
A nti -c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y)  
•  
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m)  
S u bj e ct s w h o r e c ei v e o p e n -l a b el d e n o s u m a b will att e n d cli ni c vi sit s e v er y 6 m o nt h s f or 
( Q 6 M): 
•  
A d mi ni str ati o n of d e n o s u m a b ( 6 0 m g s u b c ut a n e o u sl y [ S C ]) 
•  
C oll e cti o n of s eri o u s a n d n o n s eri o u s a d v er s e e v e nt s [( S) A E s] of s p e ci al i nt er e st 
( or al e v e nt s) a n d S A E s 
•  
Cli ni c al fr a ct ur e r e c or di n g (i n cl u di n g S A E r e p orti n g of s u s p e ct e d at y pi c al f e m or al 
fr a ct ur e c a s e s) ( Q 1 2 M o nl y) 
•  
D F S, B M F S, a n d O S ( Q 1 2 M o nl y)  
•  
C o n c o mit a nt b o n e aff e cti n g m e di c ati o n ( Q 1 2 M o nl y)  
o  B o n e t ar g et e d t h er a p y ( e g bi s p h o s p h o n at e or d e n o s u m a b)  
o  Gl u c o c orti c oi d s  
o  A nti e pil e pti c d r u g s 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  2 5 J a n u ar y 2 0 1 6  
P a g e 3 of 3 6  
C O N FI D E N TI A L  
 
 
o  A nti d e pr e s s a nt s  
o  I n s uli n 
•  
A nti -c a n c er r el at e d t h er a p y ( e g, c h e m ot h er a p y or e n d o cri n e t h er a p y) 
( Q 1 2 M o nl y)  
•  
S u p pl e m e nt s ( vit a mi n D a n d c al ci u m) ( Q 1 2 M o nl y)  
I n a d diti o n, f or all s u bj e ct s, b o n e mi n er al d e n sit y (B M D ) d at a will  b e c oll e ct e d at a n y ti m e 
a d u al X -ra y a b s or pti o m etr y  (D X A ) s c a n  i s p erf or m e d f or B M D a n al y si s a s st a n d ar d of 
c ar e fr o m P A D C D t o e n d of st u d y . 
T h e e n d of o p e n -l a b el tr e at m e nt i s d efi n e d f or e a c h s u bj e ct a s t h e p oi nt i n ti m e t h e l a st 
d o s e of d e n o s u m a b i s a d mi ni st er e d.  
•  
E x pl or at or y  o bj e cti v e  
N e w e x pl or at or y r e s e ar c h w a s pl a n n e d:  
•  
I n cl u si o n/ E x cl u si o n Crit eri a t o R e c ei v e O p e n -l a b el P h a s e D e n o s u m a b 
T hr e e i n cl u si o n crit eri a a n d fi v e e x cl u si o n crit eri a w er e a d d e d t o m ai n st u d y 
i n cl u si o n/ e x cl u si o n t o d efi n e t h e p o p ul ati o n eli gi bl e t o r e cei v e tr e at m e nt i n t h e o p e n -l a b el 
p h a s e.  
•  
L o n g -t er m f oll o w-u p  
L o n g -t er m f oll o w-u p will b e a p pr o xi m at el y 6 6 m o nt h s aft er P A D C D f or all s u bj e ct s ( or 
c o m pl eti o n of tr e at m e nt, w hi c h e v er i s l o n g er ), f or s u bj e ct s w h o r e c ei v e o p e n -l a b el 
d e n o s u m a b , a s p er t h e D M C r ec o m m e n d ati o n , a n d t o e n s ur e t h at all s u bj e ct s ar e a bl e 
t o r e c ei v e t h e r e c o m m e n d e d s e v e n d o s e s of d e n o s u m a b.   
•  
U n bli n di n g  
U n bli n di n g i s n e c e s s ar y t o i d e ntif y s u bj e ct s w h o r e c ei v e d pl a c e b o d uri n g t h e 
d o u bl e -bli n d p h a s e.  T o m ai nt ai n s u bj e ct c o nfi d e nti alit y, u n bli n di n g of s u bj e ct s will b e 
d o n e b y a ut h ori z e d sit e p er s o n n el u si n g t h e u n bli n di n g ( c o d e br e a k) c all wit h t h e I V R S 
c all c e nt er.   T h e fir st d o s e of d e n o s u m a b m u st b e a d mi ni st er e d wit hi n 8 d a y s of 
u n bli n di n g.  


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  2 5 J a n u ar y 2 0 1 6  
P a g e 4 of 3 6  
C O N FI D E N TI A L  
 
 
•  
C o n c o mit a nt m e di c ati o n s  
A s e cti o n d e s cri bi n g u s e a n d d o c u m e nt ati o n of c o n c o mit a nt m e di c ati o n s w a s a d d e d t o 
t h e pr ot o c ol f or t h e o p e n-l a b el p h a s e t o e n s ur e t h at all c o n c o mit a nt m e di c ati o n s 
r e c o g ni z e d a n d d o c u m e nt e d t o h a v e a n i m p a ct o n b o n e m o d elli n g w er e c a pt ur e d. 
•  
Pr o hi bit e d th er a p y  
A s e cti o n d e s cri bi n g pr o hi bit e d t h er a p y (i e, bi s p h o s p h o n at e s) w a s a d d e d t o t h e  pr ot o c ol 
f or t h e o p e n-l a b el p h a s e.  B i s p h o s p h o n at e s l a n g u a g e w a s m ai nt ai n e d i n t h e o p e n-l a b el 
p h a s e t o pr ot e ct t h e st u d y e n d p oi nt.  
•  
D o si n g  
S e cti o n s d e s cri bi n g d o si n g, i n cl u di n g d e n o s u m a b d o s e, d o s i n g fr e q u e n c y a n d d ur ati o n, 
o v er d o s e, mi s s e d d o s e s, a n d d o s e a dj u st m e nt s w er e  a d d e d t o t h e pr ot o c ol f or t h e 
o p e n -l a b el p h a s e. 
•  
Cli ni c al fr a ct ur e s  
 
 
 
•  
D X A a n d b o n e mi n er al d e n sit y d at a  
A s e cti o n d e s cri bi n g d o c u m e nt ati o n of B M D d at a  fr o m D X A p erf or m e d a s st a n d ar d of 
c ar e d uri n g t h e o p e n -l a b el p h a s e w a s a d d e d t o t h e pr ot o c ol.  
•  
A d v er s e e v e nt s  
A  s e cti o n d e s cri bi n g d o c u m e nt ati o n of 
 
 w a s a d d e d t o t h e pr ot o c ol f or t h e 
o p e n -l a b el p h a s e t o all o w f or 
.  H a n dli n g of cli ni c al fr a ct ur e s 
d uri n g o p e n -l a b el tr e at m e nt a n d a n y s u s p e ct e d at y pi c al f e m or al fr a ct ur e , cl a s sifi e d a s a n 
S A E , w a s al s o d e s cri b e d. 
•  
E arl y wi t h dr a w al 
A d e s cri pti o n  of t h e f oll o w -u p r e q uir e d f or s u bj e ct s w h o wit h dr a w fr o m d e n o s u m a b 
d uri n g t h e o p e n -l a b el ph a s e w a s a d d e d t o t h e pr ot o c ol  f or o p er ati o n al r e a s o n s.  F or 
c o m pl et e n e s s, s ur vi v al d at a will b e c oll e ct e d e v er y 1 2 m o nt h s f or u p t o a p pr o xi m at el y 
6 6  m o nt h s aft er P A D C D .  
•  
E n d of o p e n -l a b el tr e at m e nt 
A s d uri n g t h e d o u bl e -bli n d p h a s e, s u bj e ct s will c o m pl et e a n e n d of o p e n -l a b el tr e at m e nt 
vi sit 3 0 t o 4 5 d a y s aft er t h e l a st d o s e of o p e n -l a b el d e n o s u m a b. 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8  
D at e:  2 5 J a n u ar y 2 0 1 6  
P a g e 5 of 3 6  
C O N FI D E N TI A L  
 
 
•  
L o n g -t er m f oll o w-u p  
A d e s cri pti o n of l o n g -t er m f oll o w-u p f or s u bj e ct s w h o d o a n d d o n ot r e c ei v e o p e n -l a b el 
d e n o s u m a b  w a s a d d e d si n c e t h er e ar e diff er e n c e s f or e a c h gr o u p of s u bj e ct s.  
•  
A d v er s e e v e nt s of s p e ci al int er e st a n d S A E re p orti n g  
F or o p er ati o n al r e a s o n s, s e cti o n s d e s cri bi n g r e p orti n g of all S A E s a n d a d v er s e e v e nt s  of 
s p e ci al i nt er e st w er e  a d d e d t o t h e pr ot o c ol f or t h e o p e n -l a b el p h a s e. 
•  
St ati sti c al  a n al y si s  
T h e st ati sti c al a n al y si s s e cti o n of t h e pr ot o c ol w a s alt er e d t o a d d a  ti m e-dri v e n a n al y si s 
f or effi c a c y of t h e s e c o n d ar y e n d p oi nt D F S, w hi c h will t a k e pl a c e a p pr o xi m at el y 
1 8  m o nt h s aft er P A D C D, b ef or e u n bli n di n g of s u bj e ct s at t h e i n v e sti g at or/ s u bj e ct l e v e l 
h a s o c c urr e d.  
Pri m ar y, s e c o n d ar y a n d s af et y e n d p oi nt s will b e a n al y z e d i n a fi n al a n al y si s at t h e e n d of 
t h e st u d y.  T h e D F S a n al y si s at a p pr o xi m at el y 1 8 m o nt h s aft er P A D C D will b e 
c o n si d er e d t h e m ai n D F S a n al y si s f or t h e hi er ar c hi c al t e sti n g str at e g y, w it h t h e 
 
 c o n si d er e d e x pl or at or y.   
T h e s u bj e ct i n ci d e n c e r at e s of 
 
 r e p ort e d d uri n g t h e o p e n -l a b el p h a s e wi ll b e t a b ul at e d s e p ar at el y b y 
s y st e m or g a n cl a s s a n d pr ef err e d t er m.   
•  
I n v e sti g ati o n al p r o d u ct 
A d e s cri pti o n of t h e d e n o s u m a b pr o d u ct t h at will b e s u p pli e d f or u s e d uri n g t h e 
o p e n -l a b el p h a s e w a s a d d e d.  
•  
A d mi ni str ati v e  
Mi n or t e xt cl arifi c ati o n s, a d diti o n s a n d c orr e cti o n s , a s w ell a s  t y p o gr a p hi c al, f or m at, a n d 
a d mi ni str ati v e  c h a n g e s w er e m a d e t hr o u g h o ut t h e pr ot o c ol.   T h e k e y s p o n s or c o nt a ct 
i nf or m ati o n w a s u p d at e d t o ali g n wit h c urr e nt p er s o n n el. 


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol  N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 3  
D at e:  2 5 J a n u ar y 2 0 1 3  
P a g e 7 3  of 1 2 0  
 
A m e n d m e nt  3 
A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, M ulti -C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h N o n -M et a st ati c 
Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
D e n o s u m a b  
A m g e n Pr ot o c ol N u m b er: 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol n u m b er: A B C S G -1 8  
A m e n d m e nt D at e:  
2 5 J a n u ar y 2 0 1 3  
R ati o n al e : 
T h e pri m ar y r e a s o n f or t hi s a m e n d m e nt i s t o cl arif y t h e d efi niti o n of p o st -m e n o p a u s al 
st at u s f or s u bj e ct s < 6 0 y e ar s of a g e.  T hi s c h a n g e will  cl arif y t h at f or s u bj e ct s < 6 0 y e ar s 
of a g e, F S H a n d e str a di ol m u st b e i n t h e p o st -m e n o p a u s al r a n g e a n d if t h e s u bj e ct h a s 
h a d a pr e vi o u s h y st er e ct o m y, t h er e i s n o r e q uir e m e nt f or a pr e g n a n c y t e st.   
T h e d efi niti o n of t er mi n ati o n d at e h a s b e e n u p d at e d t o a pri m ar y a n al y si s d at a c ut -off 
d at e ( P A D C D) a n d a 1 or 5  y e ar  f oll o w-u p h a s b e e n a d d e d.   
T h e i n v e sti g ati o n al pr o d u ct c urr e ntl y b ei n g u s e d o n t hi s st u d y will e x pir e a n d t h e 
i n v e sti g ati o n al pr o d u ct will b e s wit c h e d fr o m vi al s t o a pr e-fill e d s yri n g e.  
Ot h er C h a n g e s  
I n a d diti o n t h e f oll o wi n g a d diti o n al c h a n g e s ar e b ei n g pr o p o s e d: 
•  
Cl arif y eli gi bilit y crit eri a f or p o st -m e n o p a u s al st at u s  
•  
T o cl arif y t h e pr o c e d ur e s r e g ar di n g t h e E n d of Tr e at m e nt vi sit.  
•  
Cl arif y t h e r e q uir e m e nt f or r e p orti n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s , 
a n d u p d at e d t h e e x a m pl e of t h e S eri o u s A d v er s e E v e nt F or m i n A p p e n di x F  
•  
I n cl u d e i nf or m ati o n o n pr e-fill e d s yri n g e s a s t h e st u d y will c o n v ert fr o m si n gl e u s e 
vi al s t o pr e -fill e d s yri n g e s  
•  
Ot h er mi n or c h a n g e s a n d t y p o gr a p hi c al err or s h a v e b e e n c orr e ct e d t hr o u g h o ut  


S u perse de d  
 
 
Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 3  
D at e:  2 7 N o v e m b er  2 0 1 2  
P a g e 7 4  of 1 2 1  
 
A m e n d m e nt  3 
A R a n d o mi z e d, D o u bl e - Bli n d, Pl a c e b o-C o ntr oll e d, M ulti -
C e nt er P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct 
of D e n o s u m a b i n S u bj e ct s wit h N o n -M et a st ati c Br e a st 
C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
D e n o s u m a b  
A m g e n Pr ot o c ol N u m b er: 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol n u m b er: A B C S G -1 8  
A m e n d m e nt D at e:  
2 7 N o v e m b er  2 0 1 2  
R ati o n al e : 
T h e pri m ar y r e a s o n f or t hi s a m e n d m e nt i s t o  cl arif y t h e d efi niti o n of p o st -m e n o p a u s al 
st at u s f or s u bj e ct s < 6 0 y e ar s of a g e.  T hi s c h a n g e will  cl arif y t h at f or s u bj e ct s < 6 0 y e ar s 
of a g e, F S H a n d e str a di ol m u st b e i n t h e p o st -m e n o p a u s al r a n g e a n d if t h e s u bj e ct h a s 
h a d a pr e vi o u s h y st er e ct o m y, t h er e i s n o r e q uir e m e nt f or a pr e g n a n c y t e st.   
T h e d efi niti o n of t er mi n ati o n d at e h a s b e e n u p d at e d t o a pri m ar y a n al y si s d at a c ut -off 
d at e ( P A D C D) a n d a 1 or 5  y e ar  f oll o w-u p h a s b e e n a d d e d.   
T h e i n v e sti g ati o n al pr o d u ct c urr e ntl y b ei n g u s e d o n t hi s st u d y will e x pir e a n d t h e 
i n v e sti g ati o n al pr o d u ct will b e s wit c h e d fr o m vi al s t o a pr e-fill e d s yri n g e.  
Ot h er C h a n g e s  
I n a d diti o n t h e f oll o wi n g a d diti o n al c h a n g e s ar e b ei n g pr o p o s e d: 
•  
Cl arif y eli gi bilit y crit eri a f or p o st -m e n o p a u s al st at u s  
•  
T o cl arif y t h e pr o c e d ur e s r e g ar di n g t h e E n d of Tr e at m e nt vi sit.  
•  
Cl arif y t h e r e q uir e m e nt f or r e p orti n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s , 
a n d u p d at e d t h e e x a m pl e of t h e S eri o u s A d v er s e E v e nt F or m i n A p p e n di x  F 
•  
I n cl u d e i nf or m ati o n o n pr e-fill e d s yri n g e s a s t h e st u d y will c o n v ert fr o m si n gl e u s e 
vi al s t o pr e -fill e d s yri n g e s  
•  
Ot h er mi n or c h a n g e s a n d t y p o gr a p hi c al err or s h a v e b e e n c orr e ct e d t hr o u g h o ut  


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 3  
D at e:  0 2 N o v e m b er 2 0 1 2  
P a g e 7 3  of 1 2 0  
 
A m e n d m e nt  3 
A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, M ulti -C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h N o n -M et a st ati c 
Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
D e n o s u m a b  
A m g e n Pr ot o c ol N u m b er: 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol n u m b er: A B C S G -1 8  
A m e n d m e nt D at e:  
0 2 N o v e m b er  2 0 1 2  
R ati o n al e : 
T h e pri m ar y r e a s o n f or t hi s a m e n d m e nt i s t o cl arif y t h e d efi niti o n of p o st -m e n o p a u s al 
st at u s f or s u bj e ct s < 6 0 y e ar s of a g e.  T hi s c h a n g e will  cl arif y t h at f or s u bj e ct s < 6 0 y e ar s 
of a g e, F S H a n d e str a di ol m u st b e i n t h e p o st -m e n o p a u s al r a n g e a n d if t h e s u bj e ct h a s 
h a d a pr e vi o u s h y st er e ct o m y, t h er e i s n o r e q uir e m e nt f or a pr e g n a n c y t e st.   
T h e d efi niti o n of t er mi n ati o n d at e h a s b e e n u p d at e d t o a pri m ar y a n al y si s d at a c ut -off 
d at e ( P A D C D ) a n d a 1 or 5  y e ar  f oll o w-u p h a s b e e n a d d e d.   
T h e i n v e sti g ati o n al pr o d u ct c urr e ntl y b ei n g u s e d o n t hi s st u d y will e x pir e a n d t h e 
i n v e sti g ati o n al pr o d u ct will b e s wit c h e d fr o m vi al s t o a pr e-fill e d s yri n g e.  
Ot h er C h a n g e s  
I n a d diti o n t h e f oll o wi n g a d diti on al c h a n g e s ar e b ei n g pr o p o s e d:  
•  
Cl arif y eli gi bilit y crit eri a f or p o st -m e n o p a u s al st at u s  
•  
T o cl arif y t h e pr o c e d ur e s r e g ar di n g t h e E n d of Tr e at m e nt vi sit.  
•  
Cl arif y t h e r e q uir e m e nt f or r e p orti n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
•  
I n cl u d e i nf or m ati o n o n pr e-fill e d s yri n g e s a s t h e st u d y will c o n v ert fr o m si n gl e u s e 
vi al s t o pr e -fill e d s yri n g e s  
•  
Ot h er mi n or c h a n g e s a n d t y p o gr a p hi c al err or s h a v e b e e n c orr e ct e d t hr o u g h o ut  


Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2)  
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 3  
D at e:  1 5 A u g u st 2 0 1 2  
P a g e 7 3  of 1 1 7  
 
A m e n d m e nt  3 
A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, M ulti -C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h N o n -M et a st ati c 
Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y  
D e n o s u m a b  
A m g e n Pr ot o c ol N u m b er: 2 0 0 5 0 2 0 9  
A B C S G Pr ot o c ol n u m b er: A B C S G -1 8  
A m e n d m e nt D at e:  
1 5 A u g u st  2 0 1 2  
R ati o n al e : 
T h e pri m ar y r e a s o n f or t hi s a m e n d m e nt i s t o cl arif y t h e d efi niti o n of p o st -m e n o p a u s al 
st at u s f or s u bj e ct s < 6 0 y e ar s of a g e.  T hi s c h a n g e will  cl arif y t h at f or s u bj e ct s < 6 0 y e ar s 
of a g e, F S H a n d e str a di ol m u st b e i n t h e p o st -m e n o p a u s al r a n g e a n d if t h e s u bj e ct h a s 
h a d a pr e vi o u s h y st er e ct o m y, t h er e i s n o r e q uir e m e nt f or a pr e g n a n c y t e st.   
T h e d efi niti o n of t er mi n ati o n d at e h a s b e e n u p d at e d t o a pri m ar y a n al y si s d at a c ut -off 
d at e ( P A D C D) a n d a 1 or 5 y e ar  f oll o w-u p h a s b e e n a d d e d.   
T h e i n v e sti g ati o n al  pr o d u ct c urr e ntl y b ei n g u s e d o n t hi s st u d y will e x pir e a n d t h e 
i n v e sti g ati o n al pr o d u ct will b e s wit c h e d fr o m vi al s t o a pr e-fill e d s yri n g e.  
Ot h er C h a n g e s  
I n a d diti o n t h e f oll o wi n g a d diti o n al c h a n g e s ar e b ei n g pr o p o s e d: 
•  
Cl arif y eli gi bilit y crit eri a f or p o st -m e n o p a u s al st at u s  
•  
Cl arif y t h e r e q uir e m e nt f or r e p orti n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
•  
I n cl u d e i nf or m ati o n o n pr e-fill e d s yri n g e s a s t h e st u d y will c o n v ert fr o m si n gl e u s e 
vi al s t o pr e -fill e d s yri n g e s  
•  
Ot h er mi n or c h a n g e s a n d t y p o gr a p hi c al err or s h a v e b e e n c orr e ct e d t hr o u g h o ut  
D e s cri pti o n of C h a n g e s:  
T h e f oll o wi n g s p e cifi c u p d at e s h a v e b e e n m a d e t o t h e pr ot o c ol:  
Gl o b al C h a n g e:   
R e pl a c e “ A m e n d m e nt 2” wit h “ A m e n d m e nt 3” a n d “ 0 6 A pril 2 0 1 0” wit h “ 1 5  A u g u st 2 0 1 2 ” 


S u perse de d  
 
 
Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 2 
D at e:  0 6 A pril 2 0 1 0 
P a g e 7 0 of 1 0 2 
 
A m e n d m e nt  2 
A R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, M ulti- C e nt er P h a s e 3 St u d y t o 
D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h N o n- M et a st ati c 
Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y 
D e n o s u m a b 
A m g e n Pr ot o c ol N u m b er: 2 0 0 5 0 2 0 9 
A B C S G Pr ot o c ol n u m b er: A B C S G- 1 8 
A m e n d m e nt D at e: 
0 6 A pril 2 0 1 0 
R ati o n al e: 
S a m pl e si z e c al c ul ati o n 
I n a p h a s e 3 pi v ot al st u d y of d e n o s u m a b c o m p ar e d wit h pl a c e b o i n t h e tr e at m e nt of 
w o m e n wit h p o st m e n o p a u s al o st e o p or o si s ( A m g e n st u d y 2 0 0 3 0 2 1 6), d e n o s u m a b 
d e m o n str at e d a cli ni c al fr a ct ur e r e d u cti o n of 3 0 % c o m p ar e d wit h pl a c e b o ( N E n gl J M e d  
2 0 0 9; 3 6 1: 7 4 5- 5 5).  T hi s r e s ult i s a r e a s o n a bl e m e a s ur e b y w hi c h t o pr e di ct t h e cli ni c al 
fr a ct ur e r at e i n t h e st u d y p o p ul ati o n i n st u d y 2 0 0 5 0 2 0 9 w h er e p o st m e n o p a u s al s u bj e ct s 
wit h br e a st c a n c er ar e b ei n g tr e at e d wit h ar o m at a s e i n hi biti o n t h at i s k n o w n f or 
i n cr e a si n g b o n e t ur n o v er. 
T h e ori gi n all y a s s u m e d cli ni c al fr a ct ur e r e d u cti o n of 4 0 % b y d e n o s u m a b v er s u s pl a c e b o 
i n st u d y 2 0 0 5 0 2 0 9 m a y b e a n o v er e sti m ati o n a n d a c h a n g e t o t h e s a m pl e si z e t o 
a d e q u at el y p o w er t h e st u d y f or t h e p o s si bilit y t h at t h e r e s ult will b e si mil ar i s a p pr o pri at e.   
A s t h e h a z ar d r ati o h a s c h a n g e d fr o m 0. 6 t o 0. 7, t h e n u m b er of e v e nt s h a s i n cr e a s e d 
fr o m 1 2 8 s u bj e ct s t o 2 4 7 s u bj e ct s.  Gi v e n t h e c h a n g e i n h a z ar d r ati o a n d t h e i n cr e a s e i n 
t h e st u d y d ur ati o n t h e n u m b er of s u bj e ct s t o b e e nr oll e d h a s b e e n i n cr e a s e d fr o m 2 8 0 0 
t o 3 4 0 0.  B a s e d o n t h e r e cr uit m e nt fi g ur e s t o d at e a n d t h e pr e di cti o n s of f ut ur e 
r e cr uit m e nt, t h e o v er all st u d y d ur ati o n i s e sti m at e d t o b e 9 6 m o nt h s, w hi c h i n cl u d e s a n 
e nr oll m e nt p eri o d of a p pr o xi m at el y 7 1 m o nt h s.   
I nt eri m a n al y si s 
T h e i nt eri m a n al y si s will b e r e m o v e d b a s e d o n t h e f oll o wi n g r ati o n al e: 
•   
Si n c e t hi s tri al w a s st art e d i n D e c e m b er 2 0 0 6, n e w d at a h a v e e m er g e d fr o m p h a s e 3 
st u di e s e v al u ati n g d e n o s u m a b f or i m p a ct o n b o n e mi n er al d e n sit y ( B M D) a n d 
fr a ct ur e r at e.  T h e s e st u di e s h a v e d e m o n str at e d a c o n si st e nt a n d si mil ar 
i m pr o v e m e nt i n B M D a n d/ or i n cli ni c al fra ct ur e r at e a cr o s s all st u d y p o p ul ati o n s 
(J Cli n O n c ol  2 0 0 8; 2 6: 4 8 7 5- 8 2;  N E n gl J M e d  2 0 0 9; 3 6 1: 7 4 5- 5 5;  N E n gl J M e d 
2 0 0 9; 3 6 1: 7 5 6- 6 5).  T h er ef or e w e a nti ci p at e t h at B M D a n d fr a ct ur e r at e will di s pl a y a 
si mil ar eff e ct i n t hi s p o p ul ati o n a n d c o n s e q u e ntl y t h e i nt eri m a n al y si s i s n o l o n g er 
r e q uir e d.  
•   
A n i n d e p e n d e nt st u d y s p e cifi c d at a m o nit ori n g c o m mitt e e will c o nti n u e t o m o nit or t h e 
s af et y of t h e s u bj e ct s o n a n a n n u al b a si s.  
R e cl a s sifi c ati o n of t h e E x pl or at or y E n d p oi nt s a n d S e c o n d ar y E n d p oi nt s 
R e c o g ni zi n g t h at r e gi str ati o n tri al s f or a ntir e s or pti v e a g e nt s i n o st e o p or o si s i n di c ati o n s 
ar e t y pi c all y b a s e d o n a pri m ar y e n d p oi nt of s u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e 
o v er a 3 6 m o nt h s p eri o d ( N E n gl J M e d 2 0 0 9; 3 6 1: 7 4 5- 5 5), a n d al s o r e c o g ni zi n g t h e 
cli ni c al i m p ort a n c e of r e c e nt d at a a b o ut a p ot e nti al b e n efit of i n cl u di n g i ntr a v e n o u s 
bi s p h o s p h o n at e s i n t h e a dj u v a nt tr e at m e nt f or br e a st c a n c er o n br e a st c a n c er – r el at e d 


S u perse de d  
 
 
Pr o d u ct:  D e n o s u m a b ( A M G 1 6 2) 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 – A m e n d m e nt 2 
D at e:  0 6 A pril 2 0 1 0 
P a g e 7 1 of 1 0 2 
 
e n d p oi nt s ( N E n gl J M e d 2 0 0 9; 3 6 0: 6 7 9- 9 1), t h e s e c o n d ar y e n d p oi nt s w er e a d a pt e d t o 
a c c o u nt f or t h e s e cli ni c all y i m p ort a nt o ut c o m e s:  
•   
T h e e n d p oi nt s “ s u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e at 1 2 a n d 2 4 m o nt h s”, 
“ s u bj e ct i n ci d e n c e of n e w v ert e br al fr a ct ur e or w or s e ni n g of pr e- e xi sti n g v ert e br al 
fr a ct ur e s”, a n d “ c h a n g e i n b o n e mi n er al d e n sit y m e a s ur e m e nt o v er a 1 2 m o nt h a n d 
2 4 m o nt h p eri o d” w er e m o v e d t o e x pl or at or y e n d p oi nt s a n d e n d p oi nt s of “ s u bj e ct 
i n ci d e n c e of n e w v ert e br al fr a ct ur e o v er a 3 6 m o nt h p eri o d” a n d “ s u bj e ct i n ci d e n c e of 
a n e w or w or s e ni n g of pr e- e xi sti n g v ert e br al fr a ct ur e s at m o nt h 3 6” r e m ai n a s 
s e c o n d ar y e n d p oi nt s.   
•   
A s t h e tr e at m e nt wit h a nti-r e s or pti v e a g e nt s mi g ht h a v e a n i m p a ct o n c a n c er-r el at e d 
o ut c o m e s, t h e c a n c er e n d p oi nt s di s e a s e fr e e s ur vi v al, b o n e- m et a st a si s fr e e s ur vi v al, 
a n d o v er all s ur vi v al h a v e b e e n el e v at e d fr o m e x pl or at or y t o s e c o n d ar y e n d p oi nt s.  
T h e pri m ar y a n d s e c o n d ar y n ull h y p ot h e si s will b e t e st e d u si n g t h e hi er ar c hi c al a n al y si s 
str at e g y a n d t h e H o c h b er g pr o c e d ur e t o c o ntr ol t h e o v er all si g nifi c a n c e l e v el of 0. 0 5. 
Eli gi bilit y a s s e s s m e nt: D X A s c a n s 
T h e ti mi n g of t h e D X A s c a n a n d x-r a y s f or e v al u ati o n of i n cl u si o n t o t hi s st u d y i s b ei n g 
i n cr e a s e d fr o m 3 5 d a y s t o 1 2 0 d a y s.  
T h e c urr e nt pr ot o c ol sti p ul at e s t h at D X A s c a n s a n d x-r a y s at s cr e e ni n g s h o ul d b e 
p erf or m e d ≤ 3 5 d a y s fr o m r a n d o mi z ati o n or ≤ 6 0 d a y s wit h a p pr o v al fr o m t h e D M C.  T h e 
ti mi n g a s s o ci at e d wit h t hi s i n cl u si o n crit eri o n i s i m p a cti n g a c cr u al.  A d diti o n all y, si n c e 
B M D d e cli n e s i n t hi s p ati e nt p o p ul ati o n o c c ur o v er a l o n g p eri o d of ti m e a n d fr a ct ur e s 
b et w e e n s cr e e ni n g a n d b a s eli n e w o ul d o c c ur v er y i nfr e q u e ntl y, e xt e n di n g t h e ti m eli n e 
a s s o ci at e d wit h t h e s cr e e ni n g B M D i s n ot e x p e ct e d t o h a v e a n i m p a ct of t h e st u d y 
c o n d u ct or st u d y r e s ult s.   
Ot h er C h a n g e s 
I n a d diti o n t h e f oll o wi n g a d diti o n al c h a n g e s ar e b ei n g pr o p o s e d: 
•   
T h e b a c k gr o u n d s e cti o n h a s b e e n u p d at e d t o r efl e ct i nf or m ati o n a v ail a bl e i n t h e 
m o st r e c e nt v er si o n of t h e I n v e sti g at or’ s Br o c h ur e 
•   
T h e pr ot o c ol r ef er s t o t h e a n al y si s at 3 6 M o nt h s/ E n d of St u d y.  T h e t er m “ E n d of 
St u d y” w a s r e m o v e d a s t h e 3 6 m o nt h vi sit will b e a s s o ci at e d wit h t h e ti m e p eri o d it 
f all s i nt o r at h er t h e n b ei n g dir e ctl y a s s o ci at e d wit h E n d of St u d y vi sit 
•   
T h e e n d of st u d y a n d t er mi n ati o n d at e h a v e b e e n cl arifi e d t hr o u g h o ut 
•   
T h e l o c ati o n of t h e cli ni c al sit e s h a s b e e n g e n er ali z e d t o i n cl u d e sit e s o ut si d e of 
A u stri a 
•   
T h e c o n s e nt f or m h a s b e e n s e p ar at e d fr o m t h e pr ot o c ol s o t h at u p- d at e s o n t h e 
c o n s e nt will n ot r e q uir e a m e n di n g t h e pr ot o c ol   
•   
T h e d at a m a n a g e m e nt s y st e m h a d b e e n s p e cifi e d a s I n Tri al™ i n t h e pr ot o c ol a n d i s 
c urr e ntl y b ei n g r e pl a c e d wit h M A C R O.   
•   
Ot h er mi n or c h a n g e s a n d t y p o gr a p hi c al err or s h a v e b e e n c orr e ct e d t hr o u g h o ut 


 
Pri nte d c o p y is n ot offici al rec or d. 
                                         
S u perse de d  
Pr o d u ct:  D e n o s u m a b 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
A m e n d m e nt 1 D at e:  1 2 J u n e 2 0 0 6 
 
P a g e 1 of 3 
A m e n d m e nt 1 
Pr ot o c ol Titl e: A R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, M ulti- C e nt er 
P h a s e 3 St u d y t o D et er mi n e t h e Tr e at m e nt Eff e ct of D e n o s u m a b i n S u bj e ct s wit h 
N o n- M et a st ati c Br e a st C a n c er R e c ei vi n g Ar o m at a s e I n hi bit or T h er a p y 
 
A m g e n Pr ot o c ol N u m b er 2 0 0 5 0 2 0 9  
A B C S G- 1 8 
 
A m e n d m e nt D at e: 
1 2 J u n e 2 0 0 6 
 
R ati o n al e:   
 
 
Pr ot o c ol 2 0 0 5 0 2 0 9/ A B C S G- 1 8 i s b ei n g a m e n d e d f or t hr e e r e a s o n s: 
 
1. Eli gi bilit y a s s e s s m e nt: B o n e S c a n s, D X A s c a n s a n d X-r a y s.  
 
T h e c urr e nt pr ot o c ol sti p ul at e s t h at all s cr e e ni n g pr o c e d ur e s s h o ul d b e 
p erf or m e d ≤3 5 d a y s fr o m r a n d o mi z ati o n.  T h e A B C S G h a s n ot e d t h at f or m a n y 
p ati e nt s t h e s e r a di ol o gi c al a s s e s s m e nt s m a y h a v e r e c e ntl y b e e n p erf or m e d a s 
p art of t h eir r o uti n e cli ni c al c ar e.  R e p e ati n g t h e s e pr o c e d ur e s u n n e c e s s aril y 
w o ul d i n cr e a s e t h e r a di ati o n e x p o s ur e t o p ati e nt s wit h n o a d d e d cli ni c al b e n efit.  
I n t h e c a s e of t h e b o n e s c a n, it i s r e g ar d e d a s cli ni c all y a c c e pt a bl e t o i n cl u d e 
s c a n s t h at h a v e b e e n p erf or m e d wit hi n t h e l a st 6 m o nt h s t o d et er mi n e a n y 
e vi d e n c e of m et a st a si s.   
Wit h r e s p e ct t o t h e D X A s c a n s a n d X-r a y s, it i s i nt e n d e d t h at w h er e v er p o s si bl e 
t h e y ar e p erf or m e d wit hi n t h e 3 5 d a y s cr e e ni n g wi n d o w.  H o w e v er, if t h er e ar e 
a p pr o pri at e D X A s c a n s a n d/ or X-r a y fil m s a v ail a bl e wit hi n a 6 0 d a y wi n d o w fr o m 
t h e d at e of r a n d o mi z ati o n, t h e n t h e v ali dit y of t h e s e r e s ult s will b e a s s e s s e d o n a 
c a s e b y c a s e b a si s b y t h e D at a M o nit ori n g C o m mitt e e w h o will r e vi e w t h eir 
s uit a bilit y a s p art of a p ati e nt’ s eli gi bilit y t o p arti ci p at e i n t h e tri al. 
 
2. C h a n g e t o P ati e nt I nf or m ati o n S h e et  
D u e t o e m er gi n g d at a fr o m t h e o n g oi n g o st e o p or o si s pr o gr a m wit h D e n o s u m a b, 
t h e f oll o wi n g p ar a gr a p h i s b ei n g a d d e d t o p ati e nt i nf or m ati o n s h e et s: 
 
“ T h e eff e ct of d e n o s u m a b r e g ar di n g y o ur b o n e d e n sit y i s r e v er si bl e a n d a 
di s c o nti n u ati o n of d e n o s u m a b m a y l e a d t o a l o s s i n g ai n e d b o n e d e n sit y. Aft er 
di s c o nti n u ati o n, y o ur B M D- S c or e s s h o ul d b e f oll o w e d c ar ef ull y wit h r e g ar d t o a 
p o s si bl e l o s s of mi n er al d e n sit y. A s k y o ur p h y si ci a n f or alt er n ati v e tr e at m e nt s 
w hi c h c a n m ai nt ai n y o ur g ai n e d B M D”. 
 
3. D X A s c a n pr o c e d ur e s  
S e cti o n 7. 9. 2 of t h e pr ot o c ol c o nt ai n s a mi sl e a di n g p ar a gr a p h r e g ar di n g t h e u s e 
of st a n d ar d p h a nt o m s o n D X A m a c hi n e s.  E a c h t y p e of D X A m a c hi n e n e e d s t o 
b e c ali br at e d d ail y i n a c c or d a n c e wit h t h e m a n uf a ct ur er’ s g ui d eli n e s a n d i n li n e 
wit h t h e i n stit uti o n’ s p oli c y.  T h e p ar a gr a p h r ef erri n g t o t h e s c a n ni n g of st a n d ar d 
 
A m g e n T h o u s a n d O a k s 
C o nfi d e nti al 
A M G E N  
 


 
Pri nte d c o p y is n ot offici al rec or d. 
                                         
S u perse de d  
Pr o d u ct:  D e n o s u m a b 
Pr ot o c ol N u m b er:  2 0 0 5 0 2 0 9/ A B C S G 1 8 
A m e n d m e nt 1 D at e:  1 2 J u n e 2 0 0 6 
 
P a g e 2 of 3 
p h a nt o m s h a s t h er ef or e b e e n r e m o v e d fr o m t h e pr ot o c ol t o a v oi d b ot h a m bi g uit y 
a n d c o nf u si o n. 
 
D e s cri pti o n of C h a n g e s  ( all c h a n g e s t o t h e pr ot o c ol ar e i n di c at e d i n b ol d t e xt): 
 
C h a n g e s t o Pr ot o c ol i n C o n n e cti o n wit h P oi nt 1:  
P a g e:  3 1 
S e cti o n:  7. 1   S cr e e ni n g Vi sit 
E ntir e p ar a gr a p h 
R e pl a c e: 
All s cr e e ni n g pr o c e d ur e s m u st b e c o m pl et e d ≤ 3 5 d a y s b ef or e t h e d a y of r a n d o mi z ati o n. 
Wit h: 
Wit h t h e f oll o wi n g e x c e pti o n s , all s cr e e ni n g pr o c e d ur e s m u st b e c o m pl et e d ≤ 3 5 d a y s 
b ef or e t h e d a y of r a n d o mi z ati o n.  
F or eli gi bilit y p ur p o s e s, all s u bj e ct s m u st h a v e a b o n e s c a n t h at t h at h a s b e e n 
p erf or m e d wit hi n 6 m o nt h s of r a n d o mi z ati o n.   
D X A a n d X-r a y s s h o ul d b e p erf or m e d wit hi n t h e 3 5 d a y s cr e e ni n g wi n d o w. 
H o w e v er, if a p pr o pri at e D X A a n d/ or X-r a y a s s e s s m e nt s h a v e b e e n p erf or m e d 
wit hi n 6 0 d a y s of r a n d o mi z ati o n, t h e D at a M o nit ori n g C o m mitt e e will a s s e s s 
w h et h er t h e y ar e s uit a bl e f or d et er mi ni n g t h e s u bj e ct’ s eli gi bilit y or w h et h er t h e 
r a di ol o gi c al a s s e s s m e nt s n e e d t o b e r e p e at e d wit hi n t h e 3 5 d a y s cr e e ni n g 
wi n d o w. 
 
P a g e:  6 4 (t a bl e) a n d 6 5 (l e g e n d) 
S e cti o n:  A p p e n di x A – S c h e d ul e of A s s e s s m e nt s 
I n cl u si o n of s y m b ol s wit hi n t h e “ S cr e e ni n g P eri o d” c ol u m n of t h e t a bl e: 
¤  d e n ot e s X-r a y s a n d D X A s cr e e ni n g a s s e s s m e nt s 
§  d e n ot e s b o n e s c a n s cr e e ni n g a s s e s s m e nt 
 
A d d:  
At t h e b ott o m of t h e l e g e n d, o n p a g e 6 5, t h e f oll o wi n g t e xt h a s b e e n i n s ert e d: 
¤  
X-r a y s a n d D X A a s s e s s m e nt s p erf or m e d ≤6 0 d a y s of r a n d o mi z ati o n b ut o ut si d e t h e 
3 5 d a y s cr e e ni n g wi n d o w will b e a s s e s s e d b y t h e D at a M o nit ori n g C o m mitt e e f or 
d et er mi ni n g a s u bj e ct’ s eli gi bilit y. 
§  
A b o n e s c a n p erf or m e d ≤ 6 m o nt h s of d at e of r a n d o mi z ati o n will b e c o n si d er e d a s 
v ali d f or t h e p ur p o s e s of a s s e s si n g a s u bj e ct’ s eli gi bilit y. 
 
 
 
 
A m g e n T h o u s a n d O a k s 
C o nfi d e nti al 
A M G E N  
 

SAP_001.pdf: 
Statistical Analysis Plan
Product:
Denosumab
Protocol Number:
20050209 / ABCSG 18
Version No.:
6.0
Date:
December 10, 2019 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Phase 3 Study to Determine the Treatment Effect of 
Denosumab in Subjects with Non-Metastatic Breast Cancer 
Receiving Aromatase Inhibitor Therapy
Austrian Breast and Colorectal Cancer Study Group 
ABCSG  Protocol number 18
ABCSG Lead Statistician
Dr. 
Date
Coordinating Investigator
Univ.Prof. Dr. 
Date
NCT Number: NCT00556374
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
2
TABLE OF CONTENTS
PAGE
TITLE PAGE........................................................................................................................1
1
LIST OF ABBREVIATIONS / ACRONYMS ..........................................................................5
2
LIST OF STUDY TERMS.....................................................................................................8
3
1.
INTRODUCTION......................................................................................................11
4
2.
STUDY DETAILS .....................................................................................................12
5
2.1
Objectives .......................................................................................................12
6
2.1.1 Primary ..................................................................................................12
7
2.1.2 Secondary..............................................................................................12
8
2.1.3 Exploratory.............................................................................................12
9
2.2
Hypotheses .....................................................................................................13
10
2.2.1 Clinical Efficacy Hypothesis:...................................................................13
11
2.2.2 Clinical Safety Hypothesis:.....................................................................13
12
2.3
Overall Study Design.......................................................................................13
13
2.4
Number of Subjects and Sample Size Calculation...........................................15
14
2.4.1 Primary Endpoint....................................................................................15
15
2.4.2 Percent Change in Lumbar Spine BMD at Month 12 ..............................16
16
2.5
End of Treatment.............................................................................................16
17
2.6
Long-Term Follow-Up......................................................................................16
18
2.7
End of Open-label Treatment ..........................................................................17
19
2.8
End of Study....................................................................................................17
20
2.9
Study Termination ...........................................................................................17
21
3.
DATA SCREENING AND ACCEPTANCE ................................................................17
22
3.1
General Principles...........................................................................................17
23
3.2
Handling of Missing and Incomplete Data........................................................18
24
3.2.1 Early Withdrawal from Study and Lost-to-follow-up ................................18
25
3.2.2 Missed Visit or Non-evaluability of a Specific Clinical Measurement 
26
at its Planned Clinical Visit .....................................................................18
27
3.2.3 Dates .....................................................................................................18
28
3.3
Potential Outliers.............................................................................................19
29
3.4
Distributional Characteristics ...........................................................................20
30
3.5
Validation and Configuration Management......................................................20
31
4.
ANALYSIS SET........................................................................................................20
32
4.1
Definition of Analysis Sets...............................................................................20
33
4.1.1 Full Analysis Set (FAS) ..........................................................................21
34
4.1.2 OLP Denosumab (Dmab) Analysis Set ..................................................21
35
4.1.3 BMD Analysis Set ..................................................................................21
36
4.1.4 Vertebral Fracture Analysis Set..............................................................21
37


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
3
4.1.5 Per-Protocol (PP) Population .................................................................22
1
4.1.6 Safety Analysis Set (SAF)......................................................................22
2
4.1.7 OLP Denosumab (Dmab) Safety Analysis Set .......................................23
3
4.2
Subgroups.......................................................................................................23
4
5.
PRIMARY, SECONDARY, SAFETY AND EXPLORATORY ENDPOINTS................24
5
5.1
Primary Endpoint.............................................................................................24
6
5.2
Secondary Endpoints ......................................................................................24
7
5.3
Safety Endpoints .............................................................................................25
8
5.4
Exploratory Endpoints .....................................................................................25
9
5.5
Derived Endpoints...........................................................................................26
10
6.
PLANNED METHODS OF ANALYSIS......................................................................28
11
6.1
General Approach / Considerations.................................................................28
12
6.2
Handling of Incorrect Stratification...................................................................30
13
6.3
Analysis Windows ...........................................................................................30
14
6.3.1 Study Month...........................................................................................30
15
6.3.2 Incidence Endpoints...............................................................................30
16
6.3.3 Analysis at Specified Times....................................................................31
17
6.4
Analysis of Key Study Endpoints.....................................................................32
18
6.4.1 Efficacy Analysis ....................................................................................32
19
6.4.2 Safety Analyses .....................................................................................37
20
6.4.3 Exploratory Analyses..............................................................................39
21
6.4.4 Treatment Discontinuation and Lost-to-Follow-Up..................................41
22
6.4.5 Subgroup Analysis .................................................................................42
23
6.4.6 Covariates..............................................................................................42
24
6.4.7 SAS Code Fragments ............................................................................43
25
7.
FURTHER TABULAR SUMMARIES AND LISTINGS ...............................................45
26
8.
INTERIM ANALYSES AND EARLY STOPPING GUIDELINES ................................46
27
9.
DFS ANALYSIS RECOMMENDED BY DMC............................................................47
28
10.
DFS ANALYSIS 2018...............................................................................................48
29
11.
ZA SUBSTUDY ........................................................................................................48
30
11.1.1
Exploratory Objectives .......................................................................48
31
11.1.2
ZA Substudy design...........................................................................48
32
11.1.3
Number of Subjects and Sample Size Calculation..............................49
33
11.1.4
Estimated ZA Substudy Duration .......................................................50
34
11.1.5
End of ZA Substudy ...........................................................................50
35
11.1.6
Study Termination..............................................................................50
36
11.1.7
Exploratory Endpoints........................................................................50
37
11.1.8
Analysis Sets .....................................................................................51
38
11.1.9
Subgroups .........................................................................................51
39
11.1.10
Timepoint of Analysis.......................................................................52
40
11.1.11
Handling of Missing and Incomplete Data ........................................52
41


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
4
11.1.12
Analysis Windows ............................................................................53
1
11.1.13
Analysis Methods.............................................................................54
2
12.
AMENDMENTS TO THE STATISTICAL ANALYSIS PLAN ......................................55
3
13.
CHANGES FROM THE PROTOCOL PLANNED ANALYSES ..................................56
4
14.
LIST OF PLANNED TABLES AND FIGURES...........................................................58
5
15.
REFERENCES.........................................................................................................64
6
7
8
9


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
5
LIST OF ABBREVIATIONS / ACRONYMS
1
2
Abbreviation/Acronym 
Definition
ABCSG 
Austrian Breast and Colorectal Cancer Study Group
AE 
Adverse event
AI 
Aromatase inhibitor
AIT 
Aromatase inhibitor therapy
ALT 
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST 
Aspartate aminotransferase
ATAC 
Arimidex, Tamoxifen Alone or in Combination trial
AUC 
Area under the serum concentration-time curve
BIG 
Breast International Group
BMD 
Bone mineral density
BMFS
Bone metastases-free survival
CI 
Confidence interval
CDM
Clinical data management
CRF 
Case report form
CTCAE 
Common terminology criteria for adverse events
CTX
C-terminal telopeptide
DFS
Disease free survival
Dmab
Denosumab
DMC 
Data monitoring committee
DMP
Data management plan


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
6
Abbreviation/Acronym 
Definition
DXA 
Dual X-Ray Absorptiometry
ECOG 
Eastern Cooperative Oncology Group
EOOLT
End of open-label treatment
EOS 
End of study
EOT
End of treatment
ER 
Estrogen receptor
FAS 
Full Analysis Set
FDA 
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP 
Good Clinical Practice
HER-2
Human Epidermal growth factor Receptor 2
HIV 
Human immunodeficiency virus
ICF 
Informed consent form
ICH 
International conference on harmonization
IEC 
Independent ethics committee
IP 
Investigational product
IRB 
Institutional review board
IV 
Intravenous
IVRS 
Interactive voice response system
LTFU
Long-term follow-up
MedDRA 
Medical Dictionary for Regulatory Activities
OL
Open-label
OLP
Open-label phase


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
7
Abbreviation/Acronym 
Definition
OPG 
Osteoprotegerin
ORR 
Objective response rate
OS
Overall survival
PADCD
primary analysis data cut-off date
PgR
Progesterone receptor
PIN 
Personal identification number
PP 
Per protocol
Q6M 
Every 6 months
Q12M 
Every 12 months
RANKL 
Receptor activator for nuclear factor kappa B ligand
RPSFTM
Rank-preserving structural failure time model
SAE 
Serious adverse event
SAS
Statistical Analysis System
SERM 
Selective Estrogen Receptor Modulator
SC 
Subcutaneous
SD
Standard deviation
SOC
Standard of care
SOP
Standard Operating Procedure
TTP 
Time to progression
ULN 
Upper limit of normal per laboratory reference range
uNTX 
Urinary N-telopeptide
ZA
Zoledronic acid
1


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
8
LIST OF STUDY TERMS
1
2
Study Term 
Definition
Date of 
randomization
Date subject is randomized; enrollment date
Day 1 in double-blind 
phase and Open-
Label Phase (OLP)
First day investigational product is administered
Day 1 in Zoledronic 
Acid (ZA) substudy
Defined as 8 months (4 weeks) after the last OLP denosumab 
dose
For treatment arm: first day ZA is administered
For control arm (SOC treatment): SOC day 1 visit
End of Open-Label 
Treatment (EOOLT)
Last administration of open-label phase denosumab for each 
subject
EOOLT Visit
Subjects will complete an EOOLT visit 30 to 45 days after the last 
dose of open-label denosumab either by clinic visit or telephone 
contact
End of study (EOS)
The date when the last subject completes the last scheduled long-
term follow-up visit
EOS visit
A subject’s last formal visit or last formal contact or an unscheduled 
study visit in case of early withdrawal from study
End of ZA substudy
The date when the last subject participating in the ZA substudy 
completes the last formal visit or an unscheduled study visit in case 
of early withdrawal from the ZA substudy
End of ZA substudy 
visit
A subject’s last formal substudy visit or contact or an unscheduled 
substudy visit in case of early withdrawal from substudy
End of Treatment 
(EOT) in double-blind 
phase
Last administration of double-blind investigational product for each 
subject 
EOT visit in double-
blind phase
The visit at which the subject receives the last dose of double-blind 
IP; for all subjects, whose last regular study visit within 6 months
(+ 45 days time window) prior to the PADCD was a yearly visit (eg, 
months 12, 24, etc) and radiological assessments were performed, 


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
9
this visit will be considered an EOT visit. Those subjects, for whom 
the radiological assessments were not performed, will need to 
attend the next scheduled 6 months visit, when radiological 
assessments (vertebral x-rays, DXA) will take place and an antibody 
sample will be taken. For these subjects this visit will be considered 
as EOT visit.  For those whose last regular study visit within 6 
months (+ 45 day time window) prior to the PADCD was a 6 months 
visit (eg, month 6, 18, etc), the next regularly scheduled yearly study 
visit (eg, Q12M) within 6 months after PADCD will be considered an 
EOT visit
Fractures
Clinical fracture 
Clinically evident fracture with associated symptoms
Clinical Vertebral 
Fracture
Clinical vertebral fracture when there is ≥ 1 grade increase from a 
previous grade of 0 in any vertebra between T4 and L4 at any visit 
(scheduled or unscheduled) and the subject reported signs and/or 
symptoms indicative of a fracture.  Only fractures with low trauma 
severity will be included.
Low Trauma 
Severity
Assessed by the investigator and collected on the Clinical Fracture 
Summary CRF for each clinical fracture event and includes
- Fall from standing height or less
- Falls on stairs, steps or curbs
- Fall from the height of a stool, chair, first rung on a ladder or 
equivalent (about 0.5 metres)
- Minimal trauma other than a fall
- Moderate trauma other than a fall
- Unknown (including missing)
All asymptomatic vertebral fractures are considered of low trauma 
severity.
High Trauma 
Severity or 
pathologic
Assessed by the investigator and collected on the Clinical Fracture 
Summary CRF for each clinical fracture event and includes
- Fall from higher than the height of a stool, chair, first rung on a 
ladder or equivalent (> 0.5 metres)
- Severe trauma other than a fall
- Pathologic fractures
Morphometric 
fracture
A fracture in the vertebral column that is not clinically evident and 
that is asymptomatic
New Vertebral 
For the study a new vertebral fracture is defined as a fracture in a 


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
10
Fracture
previously undeformed vertebrae. New vertebral fractures will be 
classified as either clinical or morphometric depending on whether 
or not in the investigator’s opinion the symptom locality can be 
linked to the fracture.
Prevalent 
Vertebral 
Fracture
Prevalent vertebral fractures will be assessed and recorded at 
baseline.
Worsening 
Vertebral 
Fracture
Worsening is defined as an increase in fracture severity of at least 1 
grade on the semiquantitative scale.
New or 
Worsening 
Vertebral 
Fracture  
This is the combination of new vertebral fractures and worsening 
vertebral fractures.
Final analysis
Analysis performed after long-term follow up, and OLP,
approximately 66 months after PADCD, after review of the results of 
the interim analysis
Interim analysis
Analysis for futility for the secondary endpoint DFS to be performed 
after PADCD by an independent statistician.
DFS analysis
Analysis recommended by the DMC for the secondary endpoint 
DFS to be performed around 18 months after PADCD.
Long-Term Follow-
Up (LTFU) visit
All Q12M visits that are attended after EOT visit
Pre-selected (major) 
center
Centers were pre-selected (considered major) if they used the 
Hologic DXA device at site initiation
Primary analysis
Analysis after Primary Analysis Data Cut-off Date (PADCD)
Primary Analysis 
Data Cut-off Date 
(PADCD)
The date when approximately 247 subjects have experienced their 
first clinical fracture and all subjects have either withdrawn or had 
the opportunity to receive at least 2 doses of IP.
Screening period 
Begins with signed informed consent and ends on day 
investigational product is administered
1


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
11
1.
INTRODUCTION
1
The Austrian Breast & Colorectal Cancer Study Group (ABCSG) is a cooperative institution 
2
that was set up to conduct controlled clinical trials in breast and colorectal cancer and to 
3
facilitate communication and the dissemination of knowledge among scientists and others 
4
dedicated to the cancer problem. Since its establishment in 1984, more than 15,000 patients 
5
have been enrolled in ABCSG investigations. In certain patient risk groups, ABCSG is 
6
currently recruiting up to 40 per cent of all Austrian breast cancer patients to their clinical 
7
trials. The ultimate goal of the ABCSG is to enhance the standard of cancer treatment in this 
8
country and abroad by developing innovative approaches and testing increasingly more 
9
effective therapeutic strategies.
10
Prospectively randomized clinical investigations have come to be seen as the only instrument 
11
to generate valid and reliable clinical data, to gain insights into significant prognostic and 
12
predictive factors, and thus to enhance all aspects of evidence-based medicine. As a target 
13
of oncological research and practice, the ABCSG has selected two of the most common 
14
malignancies affecting women and men in the present-day western world: carcinoma of the 
15
breast and bowel.
16
As a whole, the ABCSG collaborates toward the common goal of controlling, effectively 
17
treating, and ultimately curing cancer by means of large, multicenter cancer trials in the (neo-)
18
adjuvant setting. Research results are provided to the medical community through scientific 
19
publications and professional meetings.
20
This Statistical Analysis Plan (SAP) is based on the Amended Clinical Study Protocol for 
21
ABCSG study 18 (Protocol Number: 20050209, Superseding Amendment 6, Date: 15 July 
22
2019) and gives a detailed description of all statistical analyses planned to be conducted 
23
within this trial at predefined time points. 
24
25
26


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
12
2.
STUDY DETAILS
1
2.1
Objectives
2
2.1.1
Primary 
3
To determine whether denosumab compared to placebo will reduce the rate of first (on-study) 
4
clinical fracture (ie, clinically evident fracture with associated symptoms) in women with non-
5
metastatic breast cancer receiving non-steroidal aromatase inhibitor therapy (AIT).
6
7
2.1.2
Secondary
8
To assess the effect of denosumab compared to placebo on:
9
10
Fracture-related secondary endpoints:
11

Bone mineral density (BMD) at lumbar spine, total hip and femoral neck in a subgroup of 
12
subjects with evaluable Dual X-Ray Absorptiometry (DXA) scans using the same Hologic 
13
device 
14

Incidence of new vertebral fractures (both clinical and morphometric [ie, a fracture in the 
15
vertebral column that is not clinically evident and that is asymptomatic])
16

Incidence of new or worsening of pre-existing vertebral fractures (both clinical and 
17
morphometric)
18
Disease outcome-related secondary endpoints:
19

Disease-free survival (DFS)
20

Bone metastasis-free survival (BMFS)
21

Overall survival (OS)
22
23
To assess the safety and tolerability of denosumab in this population.
24
25
2.1.3
Exploratory 
26


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
13
2.2
Hypotheses
8
2.2.1
Clinical Efficacy Hypothesis:
9
Denosumab, when administered subcutaneously (SC) at a dose of 60 mg every 6 months
10
(Q6M), will be considered efficacious in breast cancer subjects receiving AIT if the rate of first 
11
clinical fractures (clinical vertebral and non-vertebral - consistent with the ATAC trial) in 
12
denosumab-treated subjects is lower than that in placebo-treated subjects. It is anticipated 
13
that denosumab will reduce the rate by 30% compared with placebo (ie, the true hazard ratio 
14
of denosumab compared with placebo is 0.70).
15
16
2.2.2
Clinical Safety Hypothesis:
17
Denosumab, when administered SC at a dose of 60 mg every 6 months will be well tolerated 
18
in breast cancer subjects receiving AIT.
19
20
2.3
Overall Study Design
21
This is a multi-center phase 3, randomized, double-blind, placebo-controlled study to 
22
determine the treatment effect of denosumab in subjects with breast cancer treated with an 
23
approved non-steroidal aromatase inhibitor (AI), e.g. anastrazole. Approximately 3400 
24
subjects will be randomized in a 1:1 ratio to receive either double-blind:
25

Denosumab administered at a dose of 60 mg Q6M or 
26

Placebo SC Q6M 
27
28
The randomization schedule will use randomly permuted blocks, and will be stratified by 
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
14

Type of hospital (pre-selected [major] center or other center), 
1

Prior AI usage (Yes or No)
2

Total lumbar spine BMD score at baseline (T-score < –1.0 or T-score ≥ -1.0).
3
Subjects will be recruited over an estimated period of 82 months, and remain on 
4
investigational product (IP) until the required number of events (where an event is defined as 
5
first clinical fracture) is reached and all subjects had the opportunity to receive a minimum of 
6
at least 2 doses of IP, whichever occurs later. 
7
The primary analysis data cut-off date (PADCD) is defined as the time at which the required 
8
number of events is reached and all subjects have had the opportunity to receive at least 
9
2 doses of IP.  The actual timing of the primary analysis will depend on the subject enrollment 
10
rate, drop-out rate and the rate at which first clinical fractures are observed. When the 
11
PADCD is reached, all subjects will discontinue IP. 
12
Following the study PADCD, subjects will be followed for DFS, BMFS and OS every 12 
13
months (Q12M) by clinic visits or telephone contacts starting from their EOT visit until a 
14
maximum of either 18 or 66 months after the PADCD, depending on an interim DFS analysis 
15
after PADCD (see Section 8). Based on the Data Monitoring Committee (DMC)
16
recommendation, given that interim futility analysis of DFS did not indicate futility, it was 
17
decided to follow subjects until a maximum of approximately 66 months after PADCD. 
18
Additionally, a time-driven analysis for efficacy of the secondary endpoint DFS recommended 
19
by the DMC will take place approximately 18 months after PADCD, prior to any unblinding of 
20
subjects at the investigator/subject level.
21
Due to the statistically significant treatment effect in the primary endpoint and fracture-related 
22
secondary endpoints between the denosumab arm and the placebo arm, which were 
23
demonstrated at the primary analysis (Gnant et al.; Lancet 2015), willing and eligible subjects 
24
randomized to placebo during the double-blind phase may participate in an open-label phase 
25
(OLP) and receive denosumab 60 mg Q6M for up to 36 months (maximum of 7 doses), as 
26
recommended by the DMC. Subjects who do not fulfil the eligibility criteria or do not consent 
27
will complete LTFU assessments only.
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
15
The final analysis will be performed when all subjects have had the opportunity to attend 5 
1
long-term follow-up (LTFU) visits after approximately 66 months after PADCD or 7 OLP visits
2
after approximately 36 months after first OLP treatment.
3
A substudy has been added (see section 11) to evaluate the impact of a single intravenous 
4
(IV) zoledronic acid (ZA) administration on BMD, fracture incidence, and bone turnover 
5
markers. Subjects enrolled in the main study, who completed denosumab during the OLP
6
and are deemed eligible, may choose to participate in this ZA substudy. Subjects that are not 
7
included in the ZA substudy will end study as planned. Protocol-defined denosumab 
8
administration will complete at end of the open-label (OL) period no matter if subjects 
9
participate in the ZA substudy or not.
10
11
2.4
Number of Subjects and Sample Size Calculation
12
Participants enrolled in this clinical investigation shall be referred to as “subjects”.
13
14
2.4.1
Primary Endpoint
15
Approximately 3400 subjects will be enrolled into this trial (1700 per treatment group), which 
16
will conclude once approximately 247 subjects have experienced a clinical fracture. This is 
17
based on an 82-month accrual period and on a drop-out rate of 3.6% per year.
18
Approximately 247 subjects must experience a clinical fracture for this study to have 80% 
19
power to detect a hazard ratio of 0.70 (denosumab vs. control) with a two-sided significance 
20
level of 0.05.  A hazard ratio of 0.70 indicates that the fracture rate in the denosumab group is 
21
30% less than in the control group.
22
The incidence of clinical fracture in the ATAC trial (Jakesz et al, 2005) was 22.6 per 1000 
23
subject years. From this the fracture rate in the control group is estimated at 2.43% per year. 
24
In study 20050209, the observed total fracture rate of both arms combined after 61 months is 
25
1.7% per year. Assuming a hazard ratio of 0.70, the fracture rate in the control group is 
26
expected to be about 2.0% per year and 1.39% per year in the denosumab group. According 
27
to this fracture rate, 247 fractures will be reached after 103 months. All subjects will be 
28
followed until they have had the opportunity to receive at least 2 doses of IP, still in a blinded 
29
fashion. 
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
16
All clinical fractures, except those of the skull, face, fingers, and toes, which are typically not 
1
associated with osteoporosis, will be included in the analysis of clinical fractures.
2
3
2.4.2
Percent Change in Lumbar Spine BMD at Month 12
4
In addition to the primary endpoint, a comparison of the percent change of lumbar spine BMD 
5
between the denosumab treatment and placebo group is planned. In a subset of the ATAC 
6
data (Eastell and Adams, 2002) a 1.8% difference was observed between the change from 
7
baseline to 12 months in the tamoxifen and anastrozole groups. To have 90% power to 
8
detect a 1.8% difference (standard deviation [SD]=3.9%) between denosumab and placebo in 
9
the percentage of change of BMD for lumbar spine at 12 months with a two-sided 
10
significance level of 0.05, it will be necessary to have BMD data from 102 subjects per 
11
treatment arm.
12
13
2.5
End of Treatment
14
The end of treatment (EOT) is defined for each subject as the point in time when the last 
15
dose of blinded investigational product is administered.
16
In order to prevent a lengthy extension to the duration of the study, ABCSG and Amgen will 
17
monitor the rate of clinical fracture pooled by treatment group; if it is lower than expected, 
18
ABCSG and Amgen may choose to modify the sample size.
19
20
2.6
Long-Term Follow-Up
21
Subjects who do not receive OL denosumab will be followed for DFS, BMFS, and OS Q12M 
22
by clinic visits or telephone contacts starting from their EOT visit until approximately 66 
23
months after PADCD. 
24
Subjects who receive OL denosumab will have Q6M on-site visits for administration of 
25
denosumab (60 mg SC Q6M) and monitoring of serious adverse events (SAEs) and (serious)
26
adverse events (AEs) of special interest and will be followed Q12M by clinic visits or 
27
telephone contacts starting from their EOT visit for DFS, BMFS, and OS until either
28
approximately 66 months after PADCD or completion of treatment, whichever is longer. 
29
In addition, for all subjects, data on clinical fracture recording, concomitant bone affecting 
30
medication, anti-cancer related therapy and supplements will be assessed and BMD data will 
31


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
17
be collected at any time a DXA scan is performed for BMD analysis as SOCfrom PADCD to 
1
end of study (EOS).
2
To avoid extensive simultaneous visits or contacts each year, the EOT visit is chosen as 
3
starting point for the LTFU visits rather than the PADCD.
4
5
2.7
End of Open-label Treatment
6
The end of OL treatment (EOOLT) is defined for each subject as the point in time the last 
7
dose of OLP denosumab is administered.
8
9
2.8
End of Study
10
The patient individual EOS visit is defined as the last formal visit or contact for a subject or an 
11
unscheduled study visit in case of early withdrawal from study.
12
EOS reasons include 3 early EOS reasons (death, lost to follow-up, consent withdrawal) and 
13
per protocol EOS. At EOS, the EOS electronic Case Report Form (CRF) has to be completed 
14
for each subject.
15
16
2.9
Study Termination
17
Study termination will occur when the last subject has completed their last formal visit or last 
18
formal contact or an unscheduled study visit in case of early withdrawal from the study. This 
19
is expected to occur when the last subject completes their EOS visit or their end of ZA 
20
substudy visit (see section 11).
21
22
3.
DATA SCREENING AND ACCEPTANCE
23
3.1
General Principles
24
Data will be continually screened using data acceptance programs in a blinded fashion during 
25
the conduct of the study.  Before implementing data checks not specified in the Data 
26
Management Plan (DMP), the feasibility of adding the checks to the DMP will be discussed.  
27
Data issues identified by data acceptance programs will be communicated to ABCSG CDM 
28
for review and resolution.  
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
18
As part of the data acceptance procedure, all planned tables, listings, and graphs will be 
1
generated and reviewed to identify any additional data issues.  Any critical issues identified 
2
must be resolved with CDM before final acceptance of the data.
3
4
3.2
Handling of Missing and Incomplete Data
5
Subjects may have missing specific data points for a variety of causes.  In general, data may 
6
be missing due to a subject’s early withdrawal from study, a missed visit, or non-evaluability 
7
of a specific clinical measurement at its planned clinical visit.  The general procedures 
8
outlined below describe what will be done when a data point is missing.
9
10
3.2.1
Early Withdrawal from Study and Lost-to-follow-up
11
Reasons for withdrawals are described and censoring patterns are compared between 
12
treatment groups in an exploratory manner (see also Section 6.4.4). 
13
14
3.2.2
Missed Visit or Non-evaluability of a Specific Clinical Measurement at its 
15
Planned Clinical Visit
16
Only evaluable measurements are considered for the analyses. No values are imputed for 
17
missed or non-evaluable visits.
18
19
3.2.3
Dates
20
For fractures with a missing x-ray date, the fracture date captured on the eCRF will be used.  
21
If the fracture date or a date for an oncological event is completely missing, it will not be 
22
imputed.  If it is partially missing, imputed dates will be used to derive the time to event for the 
23
efficacy analyses.
24


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
19
Missing
Impute
Exception
Fracture 
Date
Day
01
Default to Day 1 of the study if an 
event started the same year and 
month as Day 1
Day /Month
01JAN
Default to Day 1 of the study if an 
event started the same year as Day 1
If a start or stop date for an AE or a concomitant medication use is completely missing, it will 
1
not be imputed. If it is partially missing, imputed dates will be used to derive the duration of 
2
the AE or the medication use.  If the medication is a proscribed therapy per protocol, the 
3
imputed start date will be used to identify at which point the data collected for this subject will 
4
be excluded from the per-protocol analysis set.  Missing years will not be estimated under 
5
any conditions.
6
Imputation Rules for Partial Adverse Event or Concomitant Medication Start and Stop 
7
Dates 
8
Missing
Impute
Exception
Start 
date
Day
01
Default to Day 1 of the study if an 
event started the same year and 
month as Day 1
Day /Month
01JAN
Default to Day 1 of the study if an 
event started the same year as Day 1
Stop 
date
Day
Last day of the 
month
Default to the EOS visit if the imputed 
event stop date is after the EOS visit
Day/Month
31Dec
9
3.3
Potential Outliers
10
Scatter plots will be examined to identify potential outliers in any of the continuous variables.  
11
Observations found to be due to data entry errors will be corrected by the study team before 
12
data freeze.  Potential outliers that are not due to data entry error will be included in the 
13
analyses.  The validity of any questionable values will be confirmed.  No valid measurement 
14
will be purposely excluded from descriptive or inferential analyses.  However, sensitivity 
15


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
20
analyses may be conducted to evaluate the influence of extreme values in the data.  These 
1
analyses will be documented in the study report.
2
3
3.4
Distributional Characteristics
4
The assumptions underlying the parametric models analyzed for continuous data will be 
5
checked.  In cases where residuals indicate marked departures from the assumptions,
6
additional sensitivity analyses will be performed using transformations or alternate methods 
7
such as nonparametric or robust procedures.
8
9
3.5
Validation and Configuration Management
10
Prior to freezing the database, CDM will perform data testing and ABCSG will run all planned 
11
tables, graphs and listings in a blinded fashion, the analysis file creation programs and the 
12
output programs. SAS® version 9.1 or higher will be used for all case report tabulations, 
13
tables, listings and graph creations. Validated departmental standard macros will be used 
14
whenever appropriate for the creation of these items. Output from these standard macros will 
15
not be validated further although they will be checked for quality. Output derived from non-
16
standard macros will be fully validated.
17
4.
ANALYSIS SET
18
4.1
Definition of Analysis Sets
19
The analyses for the primary, secondary and exploratory endpoints (except BMD and 
20
vertebral fracture endpoints) will be conducted on the full analysis set (FAS). Analysis of the 
21
BMD endpoints will be based on the BMD analysis set. The vertebral fracture endpoints will 
22
be based on the Vertebral fracture analysis set. In addition, exploratory analyses for 
23
will be performed on the FAS. Analysis of the per-protocol (PP) 
24
population will be considered supportive. OLP summaries of efficacy will be based on the 
25
OLP Denosumab (Dmab) Analysis Set.
26
Safety analyses will be conducted on the safety analysis sets, while OLP concomitant 
27
medication information will be based on the FAS.
28
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
21
4.1.1
Full Analysis Set (FAS)
1
The FAS is defined as all subjects who are randomized. Every patient will be analyzed 
2
according to the randomized (and not necessarily the actual) treatment.
3
4
4.1.2
OLP Denosumab (Dmab) Analysis Set
5
The OLP Dmab analysis set will consist of all subjects who joined the OLP phase. Hence, all 
6
patients received placebo during the double-blind phase (randomized treatment) and fulfill all 
7
OLP eligibility criteria.
8
9
4.1.3
BMD Analysis Set
10
This BMD analysis set includes subjects defined in Section 4.1.1 with evaluable DXA scan
11
values for the endpoint of interest (lumbar spine, total hip or femoral neck) at baseline and 
12
the post baseline timepoint under consideration (12, 24 or 36 months). DXA scans must be 
13
performed using the same Hologic device and be taken on the same side of the body (as the 
14
baseline measurement). Subjects in this subset will be analyzed according to their original 
15
treatment assignment, regardless of treatment received.
16
17
4.1.4
Vertebral Fracture Analysis Set 
18
The Vertebral fracture analysis set includes subjects defined in Section 4.1.1 who have a 
19
baseline and 1 post baseline evaluation of vertebral fracture at or prior to the time point 
20
under consideration. This analysis set will additionally include subjects who have vertebrae 
21
(T4 - L4) with missing Genant semi-quantitative scores at baseline and whose first post
22
baseline spinal radiograph shows no fracture on the same vertebrae because it can be 
23
inferred that the baseline scores would have also shown no fracture had they been available.
24
Note that this subset could potentially be different from endpoint to endpoint due to missing 
25
data. Subjects in this subset will be analyzed according to their original treatment 
26
assignment, regardless of treatment received. 
27
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
22
4.1.5
Per-Protocol (PP) Population
1
This PP population subset includes subjects defined in Section 4.1.1, who are compliant with 
2
the protocol, as characterized by the following criteria:
3

Subjects who received ≥ 1 dose of investigational product, where possible
4

The absence of violating any inclusion / exclusion criteria for subject eligibility
5
6
Subjects will be analyzed according to the randomized treatment. For subjects who deviate 
7
from the randomized treatment, all data collected on or after the first occurrence of incorrect 
8
treatment will be excluded from the analysis in the subset.
9
For subjects who received proscribed medications or therapy on study, all data collected on 
10
or after the first occurrence (for those indicated as any use) or after the 30th day of use (for 
11
those indicated as > 30 days cumulative) will be excluded from any analyses in the subset.
12
Proscribed therapies include commercially available denosumab (any use),IV 
13
bisphosphonates (any use), oral bisphosphonates (>30 days cumulative), fluoride (for 
14
osteoporosis; any use), strontium ranelate (any use), systemic estrogen (> 30 days 
15
cumulative), selective estrogen receptor modulators (SERM; e.g. raloxifene; >30 days 
16
cumulative), tibolone (> 30 days cumulative), calcitonin (> 30 days cumulative), anabolic 
17
steroids (any use), parathyroid hormone (or a derivative; any use), calcitriol (any use), 
18
tamoxifen (any use) and any other medication that is known or suspected to have activity on 
19
bone metabolism (except calcium and vitamin D; any use).
20
The time to first on-study clinical fracture will be re-defined as the time from Study Day 1 to 
21
the date of event or censoring.  Subjects who (i) deviated from randomized treatment or (ii) 
22
took prohibited medication, and have not yet had the event of interest, will be censored at 
23
PADCD, or the earliest violation date of either (i) or (ii).
24
25
4.1.6
Safety Analysis Set (SAF)
26
The SAF will consist of all subjects who are randomized and receive at least 1 dose of 
27
investigational drug. These subjects will be analyzed according to their actual treatment 
28
received, where subjects who received at least 1 dose of denosumab will be analyzed in the 
29
denosumab treatment group regardless of the randomized treatment.
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
23
1
4.1.7
OLP Denosumab (Dmab) Safety Analysis Set
2
The OLP Dmab safety analysis set will consist of all subjects who receive at least 1 dose of 
3
OLP denosumab. 
4
5
4.2
Subgroups
6
The primary endpoint will be analyzed in subgroups by randomization strata and other factors 
7
assessed at the screening phase:
8

Prior AI usage (Yes or No)*
9

Total lumbar spine BMD score at baseline (T-score < –1.0 or T-score ≥ -1.0)*
10
*Based on the randomized stratum (ie, from an Interactive Voice/Web Response System 
11
[IVRS]), regardless of the subject’s actual value.
12

Age (<50, 50-59, 60-69, 70-79 or ≥80 years)
13

T-stage (T0+Tis+T1 or T2+T3+T4)
14

pN-stage (positive (pN1 + pN≥2) or negative (pN0))
15

Grading (G1, G2+Gx or G3)
16

Primary Tumor (ductal invasive carcinoma, lobular invasive carcinoma or other)
17

Receptor status (ER+/PgR+ or other)
18

Chemotherapy (yes - adjuvant, yes - neoadjuvant or no)
19
20
Subgroups other than stratification variables will be re-examined for appropriateness and 
21
may be re-categorized or eliminated to ensure at least 10% of subjects within each subgroup
22
and an adequate number of events for analysis before unblinding.
23


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
24
5.
PRIMARY, SECONDARY, SAFETY AND EXPLORATORY ENDPOINTS
1
5.1
Primary Endpoint
2
The time to first on-study clinical fracture will be defined as the number of days from 
3
randomization to the date of the x-ray confirming the clinical fracture.  Subjects who die or 
4
withdraw without experiencing a clinical fracture will be censored at the date of last contact 
5
before PADCD (including date of scheduled and unscheduled, clinic and telephone visits, of 
6
early study termination and of deaths) or EOS visit whichever is earlier. If a subject does not 
7
have a post-randomization visit, the subject will be censored at randomization. Only clinical 
8
fractures which occur prior to or on PADCD will be included in the analysis for the primary 
9
endpoint.
10
A fracture is defined as clinical if CTCAE grade is greater than 1. Fractures with a missing 
11
CTCAE grade will not be considered clinical fractures. All clinical fractures, except those of 
12
the skull, face, fingers, and toes, which are typically not associated with osteoporosis, will be 
13
included in the analysis of clinical fractures. Clinical fractures of any trauma severity are 
14
subject to medical review and all exclusions of fractures as events will be documented prior 
15
to unblinding.
16
For the exploratory analysis of 
 
17
23
5.2
Secondary Endpoints
24
Fracture-related secondary endpoints:  
25

The percent change in total lumbar spine, total hip and femoral neck BMD from 
26
baseline to 36 months in subjects with evaluable DXA scans using the same Hologic 
27
device 
28

Subject incidence of new vertebral fractures (morphometric fractures identified from 
29
on study x-rays and clinical vertebral fractures confirmed by x-rays) at Month 36.
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
25

Subject incidence of a new or worsening of pre-existing vertebral fractures 
1
(morphometric vertebral fractures identified from on study x-rays and clinical vertebral 
2
fractures confirmed by x-rays) at Month 36. 
3
Disease outcome-related secondary endpoints:
4

DFS determined by the time from randomization to the first observation of disease 
5
recurrence or death from any cause
6

BMFS determined by the time from randomization to the first observation of bone 
7
metastasis or death from any cause
8

OS determined by the time from randomization to death from any cause
9
10
5.3
Safety Endpoints
11

Subject incidence of treatment-emergent AEs
12

Clinically significant changes in laboratory values
13

Subject incidence of anti-denosumab antibody (binding and neutralizing) formation
14
15
5.4
Exploratory Endpoints
16


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
26
5
5.5
Derived Endpoints
6
Baseline Value
7
Baseline value is the latest recorded measurement on or prior to the day of the first dose of 
8
IP. If there is no such baseline value available, BMD measurements recorded within 45 days 
9
after day 1 are also acceptable as a baseline measurement for BMD. In case of several 
10
candidates, the closest value to day 1 will be selected. If day 1 is missing, the measurement 
11
closest to randomization date within a window of 45 days is used as BMD baseline 
12
measurement.
13
If a subject doesn’t receive IP, baseline is the latest recorded measurement on or prior to the 
14
enrollment date.
15
Change from Baseline Value
16
The arithmetic difference between a value of interest and a baseline value: Change from 
17
baseline value = (value of interest - baseline value)
18
Percent Change from Baseline Value
19
The ratio of the arithmetic difference between a value of interest and the baseline value to the 
20
baseline value multiplied by 100: Percent change from baseline value = [(value of interest -
21
baseline value) / baseline value] * 100.
22
Subject Incidence Rate
23
The subject incidence rate for a given event is defined as the number of subjects with one or 
24
more reported occurrence of the event divided by the number of subjects who have the 
25
opportunity to report the event.  
26


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
27
Time to Event for Efficacy
1
Time interval (days) from the randomization date to the date of occurrence of the event or 
2
censorship during the given period:
3
Time interval = (date of occurrence of the event or censorship –
4
randomization date) +1
5
BMFS Time
6
Time interval (days) from the randomization date to the date of first occurrence of bone 
7
metastasis or death from any cause, whichever comes first.  Subjects last known to be alive,
8
who have not experienced bone metastasis, are censored at their last assessment (i.e., bone 
9
scan) date, or at the end of LTFU whichever comes first. Subjects who had their first 
10
occurrence of bone metastasis before randomization will be censored at their randomization 
11
date.
12
DFS Time
13
Time interval (days) from the randomization date to the date of first evidence of local or
14
distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any 
15
cause (whichever comes first).  Subjects last known to be alive, who have not experienced 
16
recurrence of disease, are censored at their last contact date (including date of scheduled 
17
and unscheduled, clinic and telephone visits, of early study termination and of deaths), or at 
18
the end of LTFU/PADCD (for the futility analysis)/interim data cut-off date (for the additional 
19
DFS analyses), whichever comes first. Subjects who had first disease recurrence before 
20
randomization will be censored at their randomization date.
21
OS Time
22
Time interval (days) from the randomization date to the date of death from any cause.  
23
Subjects last known to be alive are censored at their last contact date, or at the end of LTFU, 
24
whichever comes first.
25
Treatment Emergent Adverse Events
26
All AEs occurring on or after the first dose of IP through 30 days after the last dose of IP
27
(EOT) will be considered treatment emergent AEs. The following steps will be applied when 
28
AE onset date is partial or missing:
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
28

All cases where onset dates are partial, the AE will be considered treatment emergent 
1
unless it is impossible for this to be the case.
2

If onset date is missing, and outcome date is on or after first dose, the AE will be 
3
considered treatment emergent.
4

If onset date is missing, and outcome date is partial and does not clearly indicate that 
5
AE falls strictly before first dose, the AE will be considered treatment emergent.
6
Corrected Calcium
7
Calcium values need to be corrected when the serum albumin value is < 40 g/L. The 
8
corrective formula is indicated below; the raw calcium value is same as the corrected calcium 
9
value when the serum albumin is >=40 g/L.
10
Corrected Calcium (mmol/L) = Total Calcium (mmol/L) + 0.025 [40 (g/L) – Albumin (g/L)]
11
12
6.
PLANNED METHODS OF ANALYSIS
13
The analyses will be carried out using statistical analysis system (SAS) software (SAS®
14
version 9.1 or higher), by members of the biostatistics group at ABCSG. If necessary, 
15
selected other software will be used, e.g. StatXact (Version 8 or higher) for exact statistical 
16
tests not offered by SAS.
17
18
6.1
General Approach / Considerations
19
The primary analysis will take place after PADCD when all subjects attended their last study 
20
visit (considered as EOT visit). The primary analysis includes the primary endpoint, the first 
21
three secondary endpoints concerning the changes in BMD and vertebral fractures, 
22
exploratory endpoints and the safety endpoints.
23
Final analysis will be performed at the end of the main study, approximately 66 months after 
24
PADCD, when both the LTFU and the OLP are finalized for all patients. Hence, after the last 
25
LTFU-patients had their final visit in the LTFU and the last OLP-patients received their last 
26
treatment in the OLP. The final analysis will include an exploratory 
 analysis as well as 
27
the main analyses for efficacy of the secondary endpoints BMFS and OS. Additionally, 
28
 


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
29
 will be evaluated in a final exploratory analysis 
at this time point. BMD data, as well as data on 
, collected during 
2
LTFU, will be summarized descriptively. Data collected during the ZA substudy will not be 
3
used for the final analysis. Data from patients included to the ZA substudy will be censored at
4
the EOT Visit (OLP) or the EOS Visit (LTFU and OLP), whichever occurs later. 
5
The primary and secondary null hypotheses will be tested using the hierarchical analysis 
6
strategy and the Hochberg procedure (Westfall et al, 1999) to control the overall significance 
7
level of 0.05.
8
The primary null hypothesis will be tested first at a significance level of 0.05.  If the primary 
9
null hypothesis is rejected, the secondary null hypotheses will be tested in a stepwise fashion 
10
over 6 steps, in the order A to F as detailed below, at a significance level of 0.05. In case any 
11
one of the hypotheses is not rejected at a previous step, all subsequent endpoints will be 
12
analyzed in a descriptive manner only. Some steps involve single null hypothesis and some 
13
involve multiple null hypotheses (ie, BMD endpoint A).  If there are multiple null hypotheses, 
14
the Hochberg procedure will be used to control for multiplicity and the testing will proceed to 
15
the next step only if all null hypotheses are rejected.  The hierarchical analysis strategy will 
16
involve the secondary null hypotheses for the following endpoints in the order specified:
17
Fracture-related secondary endpoints:
18
A.
Percent change in total lumbar spine, total hip and femoral neck BMD from baseline to 
19
Month 36 in subjects with evaluable DXA using the same Hologic device (using the 
20
Hochberg procedure controlling for multiplicity)
21
B.
Subject incidence of new vertebral fractures (morphometric vertebral fractures 
22
identified from study x-rays and clinical vertebral fractures confirmed by x-ray) at 
23
Month 36
24
C.
Subject incidence of a new or worsening of pre-existing vertebral fractures 
25
(morphometric vertebral fractures identified from on study x-rays and clinical vertebral 
26
fractures confirmed by x-rays) at Month 36
27
Disease outcome-related secondary endpoints:
28
D.
DFS is defined as any evidence of disease recurrence or death from any cause
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
30
E.
BMFS determined by the time to first occurrence of bone metastasis (either 
1
symptomatic or asymptomatic) or death from any cause 
2
F.
OS
3
Statistical analysis procedures and techniques will be reviewed in the light of current practice 
4
and new techniques, prior to breaking treatment blind, and if appropriate alternative newer 
5
technical procedures will be adopted. 
6
7
6.2
Handling of Incorrect Stratification
8
For analyses where stratification needs to be adjusted for, the following general principles will 
9
be followed:
10

Stratified analyses that are intended to evaluate the treatment effect will be based on 
11
the randomized stratum (ie, from IVRS), regardless of the subject’s actual value. If the 
12
error rate is more than 5%, then a sensitivity analysis using the actual stratum will
13
also be performed for the primary and secondary endpoints.
14

Covariate analyses where covariates are stratification factors should be based on 
15
subject’s actual value.
16

For subgroup analyses, additionally
17
-
If the subgroup variable is a stratification factor, sensitivity analyses 
18
according to actual value may be needed.
19
20
6.3
Analysis Windows
21
6.3.1
Study Month
22
Study Month will be defined as:
23
CEIL(date of event – date of Study Day 1*))/30.44)
24
* If Study Day 1 is missing, the randomization date will be used instead
25
6.3.2
Incidence Endpoints
26
Incidence between periods of time will use the formula in Section 6.3.1 to derive month from 
27
Study Day 1 to event between Months 1 and 12, between Months 1 and 24 and between 
28
Months 1 and 36.  
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
31
6.3.3
Analysis at Specified Times
1
Per-protocol, all tests and procedures will aim to be performed within the specified windows
2
according to the definitions given in the tables below.  To allow for variations in scheduling 
3
the following visit windows will be used to assign evaluations to a most appropriate nominal 
4
visit for analysis and summarization.
5
One set of windows will be applied to endpoints that are measured semi-annually such as 
6
laboratory assessments (chemistry and hematology).  In order to get as many data points as 
7
possible for summarization, there will be no gaps between visit windows.  If more than one 
8
assessment is available within a window, the assessment closest to the target day at each
9
nominal visit (Month 6, Month 12, …) will be used. If Study Day 1 is missing, the 
10
randomization date will be used instead. BMD measurements recorded within 45 days after 
11
Day 1 are acceptable as baselines (see Section 6.1).
12
Nominal Visit 
Window
Target Day
Definition (Study Day)
Baseline
1
Last evaluation prior to or on Study Day 1
Month 6 
183
Study Day 2 to 274
Month 12
365
Study Day 275 to 456
Month 18
547
Study Day 457 to 634
Month 24
729
Study Day 635 to 821
Month 30 
911
Study Day 822 to 1003
Month 36 
1093
Study Day 1004 to 1186
Month 42 
1275
Study Day 1187 to 1368
Month 48
1457
Study Day 1369 to 1550
Month 54
1637
Study Day 1551 to 1735
Month 60
1821
Study Day 1736 to 1917
13
A different set of windows will be applied to endpoints that are measured annually such as 
14
DXA and antibody assay.  In order to get as many data points as possible for summarization, 
15
there will be no gaps between visit windows.  If more than one assessment is available within 
16
a window, the assessment closest to the target day at each nominal visit will be used.
17
Nominal Visit 
Window
Target Day
Definition (Study Day)
Baseline*
1
Last evaluation prior to or on Study Day 1
Month 12
365
Study Day 2 to 547
Month 24
729
Study Day 548 to 912
Month 36 
1093
Study Day 913 to 1277


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
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Month 48
1457
Study Day 1278 to 1642
Month 60
1821
Study Day 1643 to 2007
* If there is no such baseline value available, DXA (BMD) measurements recorded within 45 
1
days after day 1 are also acceptable as a baseline measurement for BMD.  In case of several 
2
candidates, the closest value to day 1 will be selected.  BMD values assigned as the baseline 
3
value cannot also be assigned to month 12.
4
5
6.4
Analysis of Key Study Endpoints
6
6.4.1
Efficacy Analysis
7
The efficacy analyses for the primary and the secondary endpoints will be based on the FAS 
8
and on PP population approach except for the BMD endpoints which are restricted to patients 
9
in the BMD analysis set and vertebral fracture secondary endpoints which will be based on 
10
the Vertebral fracture analysis set. The PP analyses will be considered supportive.  
11
Exploratory analyses will be conducted on the FAS unless otherwise specified.
12
OLP efficacy analyses will be based on the FAS, while descriptive summaries of OLP specific 
13
data will be based on the OLP Dmab Analysis Set. 
14
15
6.4.1.1
Primary Endpoint
16
The time to first on-study clinical fracture as defined in Section 5.1 will be analyzed using a 
17
Cox model (Cox, 1972) including treatment groups as the independent variable and stratified 
18
by the randomization stratification factors.   A supportive analysis will be performed using a 
19
log-rank test stratified by the randomization stratification factors.  
20
 
21
(see Section 6.4.6). Summary statistics from the Cox model will include 
22
the hazard ratio (95% CI) of denosumab compared with placebo. Furthermore clinical fracture 
23
rates (95% CI) and differences between clinical fracture rates (95% CI) at 36 months will be 
24
estimated using Kaplan-Meier methodology. The time to first clinical fracture will be estimated 
25
and graphically displayed for each treatment group by Kaplan-Meier curves.
26
The proportionality assumption of the Cox model will be investigated with a time-dependent 
27
exploratory variable, which is defined as treatment multiplied by the logarithm (base e) of the 
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
33
time-to-event. If there is evidence of a departure from the adjusted model assumptions the 
1
reason will be explored and reported.
2
Further sensitivity analyses based on different subgroups will be performed using the main 
3
analysis method as described in the first paragraph of Section 6.4.1.1. 
4

The first sensitivity analysis will consider the subjects who withdraw from the trial due to a 
5
>10% loss of BMD in the total hip or lumbar spine over any 1-year period as having had a 
6
clinical fracture at the time of withdrawal. This will assess if study monitoring has resulted 
7
in informative censoring of subjects within the trial.
8

A second sensitivity analysis will be conducted on the PP population to assess the effect 
9
of non-protocol compliant subjects. 
10

The main analysis will consider all available subject data regardless of the subject’s time 
11
since last treatment with study drug. A third sensitivity analysis will consider the influence 
12
of subject experience subsequent to discontinuation from study treatment. This will be 
13
assessed by including time varying covariates to the Cox model: A binary time dependent 
14
covariate is used to assess the effect of treatment discontinuation. This time dependent 
15
covariate has a value of zero during treatment application and it changes to one if the 
16
patient discontinues study treatment for any reason (except in case of study termination)
17
prior to PADCD. 
18
If any of the sensitivity analyses cause conflicting results to the main analysis then similar 
19
sensitivity analyses will be conducted for the secondary endpoints related to BMD and 
20
fractures.
21
The final exploratory analysis of clinical fractures will use the main analysis method as 
22
described in the first paragraph of Section 6.4.1.1.
23
Additionally, two sensitivity analyses will be performed to account for treatment cross-over 
24
associated with the OLP: 
25
First, a rank-preserving structural failure time model (RPSFTM) (Robins and Tsiatis, 1991) to 
26
correct the treatment effect estimate for bias introduced by cross-over from placebo to OLP 
27
Dmab will be conducted. The RPSFTM provides a randomization-based estimate of 
28
treatment effect assuming a multiplicative effect of treatment on time to event. The approach 
29
also allows reconstruction of the placebo time to event curve as if all patients initially 
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
34
randomized to placebo never switched to OLP Dmab. The RPSFTM adjusted HR (95% CI)
1
and the acceleration factor (95% CI) will be presented. Additionally a Kaplan-Meier curve 
2
may be used to display the RPSFTM estimate.
3
One of the key assumptions of the RPSFTM is the “common treatment effect”, ie, the 
4
treatment effect for the patient is the same regardless of when the patient started taking 
5
Dmab (double-blind phase or OLP). To check this key assumption, an analysis will be 
6
conducted for two groups of patients, looking at patients who received OLP Dmab on the one 
7
hand and who received Dmab during the double-blind phase on the other hand. In addition,
8
major baseline characteristics will be compared between the two groups of patients.
9
Second, the main analysis method will be repeated, but patients receiving OLP Dmab will be 
10
censored at the date of first receiving OLP treatment.
11
12
6.4.1.2
Secondary Endpoints
13
The BMD secondary endpoints will be based on the BMD analysis set. The vertebral fracture 
14
secondary endpoints will be based on the Vertebral fracture analysis set. The disease 
15
outcome-related secondary endpoints will be based on the FAS.
16
Sensitivity analyses will be conducted on the PP population to assess the effect of non-
17
protocol compliant subjects. If there are conflicts between the results of the main analysis and 
18
the sensitivity analyses of the primary endpoint, additional sensitivity analyses for the 
19
secondary endpoints similar to the primary endpoint will be performed.
20
21
Percent Change in Lumbar Spine, Total Hip and Femoral Neck Bone Mineral Density 
22
from Baseline to Month 36 
23
The percent change in lumbar spine (L1-L4, Vertebrae that are clearly fractured will be 
24
excluded), total hip and femoral neck BMD from baseline to 36 months will be calculated for 
25
the BMD analysis set. Missing data will not be imputed. There will be no distinction between 
26
left and right sides of the total hip and femoral neck BMD. The main analysis of these 
27
endpoints will employ an analysis of covariance (ANCOVA) including treatment group as the 
28
independent variable and adjusted for baseline value and the randomization stratification 
29
factors.
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
35
Summary statistics will include the observed and estimated percent changes, 95% 
1
confidence interval (CI), differences with 95% CI between the percent changes in the two 
2
groups at Month 36.  Model fit will be assessed by residual analysis and other diagnostic 
3
statistics. In case of heteroscedasticity, appropriate transformations will be performed to 
4
assess sensitivity to this violation of the model assumption.
5
Additional investigatory analyses of covariates will be conducted.
6
7
Incidence of new vertebral fractures at Month 36
8
The presence or absence of a new vertebral fracture (morphometric vertebral fractures 
9
identified from on study x-rays and clinical vertebral fractures confirmed by x-rays) will be 
10
noted at 36 months (over a 36 month evaluation period) and classified according to Genant 
11
semi-quantitative grades. 
12
There are 2 situations where Genant semi-quantitative grades can be missing:  either a spine 
13
radiograph is not taken or individual vertebrae on a radiograph are not evaluable.  Because a 
14
vertebral fracture can only get worse or at best remain at the same severity over time, the 
15
Genant semi-quantitative grade for a vertebra can only increase or remain the same.  This 
16
rationale will be used for handling missing data as follows and these imputations steps will be 
17
done before any analysis: 
18
If the Genant semi-quantitative grade on a given vertebra is 0 (ie, no fracture) at a later 
19
visit, it is reasonable to impute a grade of 0 for the same vertebra at previous visit(s) 
20
including baseline.  
21
If the Genant semi-quantitative grade on a given vertebra is > 0 at a later visit, any 
22
missing value for the same vertebra from previous visits will remain missing because 
23
it cannot be certain when the vertebral fracture occurred., i.e., the value > 0 is 
24
applicable at the time of first occurrence  
25
Note that baseline grades cannot be carried forward to impute missing post baseline values.
26
The independent assessment of vertebral fractures classified according to the Genant semi-
27
quantitative grading conducted by the Central Review Committee (CRC) will be used for the 
28
main analysis.  If two CRC assessments are available, the second reviewer’s assessment will 
29
be used.
30


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
36
The main analysis of this endpoint will use logistic regression models including treatment 
1
groups as the independent variable and stratified by the randomization stratification factors. 
2
Additional investigatory analyses of covariates may be conducted. 
3
Summary statistics will include the crude incidences at Month 36 and EOS, 95% CI, 
4
differences between incidences in the two groups and 95% CI.  Hosmer-Lemeshow tests will 
5
be calculated to assess the goodness-of-fit of the models.  Deviance and Pearson residuals 
6
and the diagonal elements of the hat matrix will be checked to detect outliers and influential 
7
observations. Deviations from the model assumptions will result in further sensitivity 
8
analyses.
9
10
Incidence of new or worsening vertebral fractures at Month 36
11
The analysis described above will be repeated considering new or worsening vertebral 
12
fractures.  
13
14
Disease-free survival 
15
Main and
analyses (DFS as defined in section 5.5) employ the same 
16
methods as the primary endpoint. Additional investigatory analyses of covariates (see section 
17
6.4.6) may be conducted.
 
18
 
An additional sensitivity analysis will be performed censoring subjects who received any
21
bisphosphonates or commercial available denosumab prior to EOT (with EOT reason 
22
‘requirements for alternative therapies’). Subjects who took an alternative therapy, and have 
23
not yet had a DFS event, will be censored at the time of EOT.
24
25


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
37
Bone metastasis-free survival 
1
BMFS as defined in section 5.5 will employ the same methods as the primary endpoint. 
2
Sensitivity analyses accounting for treatment cross-over associated with the OLP will be 
3
performed (as described for the primary endpoint). Additional investigatory analyses of 
4
covariates (see section 6.4.6) may be conducted.
5
6
Overall survival
7
OS as defined in section 5.5 will employ the same methods as the primary endpoint.
8
Sensitivity analyses accounting for treatment cross-over associated with the OLP will be 
9
performed (as described for the primary endpoint). Additional investigatory analyses of 
10
covariates (see section 6.4.6) will be conducted.
11
12
6.4.2
Safety Analyses
13
Safety analyses, prior to OLP, will be based on the SAF. Safety analyses in this study will 
14
evaluate the safety profile of denosumab as compared with placebo. No formal statistical 
15
testing will be conducted for the safety analyses. 
16
OLP AE data will be based on the OLP Dmab safety analysis set, OLP concomitant 
17
medication information will be based on the FAS. Both will further evaluate the safety profile 
18
of denosumab.
19
20
6.4.2.1
Adverse Events
21
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA version 
22
17.0 or higher). AEs will be classified as treatment emergent following rules outlined in 
23
Section 5.5. Only treatment emergent AEs will be tabulated.  AEs reported but not classified 
24
as treatment emergent will be listed.
25
The subject incidence rates of treatment-emergent AEs reported during the treatment period 
26
will be tabulated by system organ class and preferred term. 
27
Additional summary tables will be provided separately for 
28

all AEs
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
38

Common Terminology Criteria for AEs (CTCAE) grade 3, 4, or 5 AEs, 
1

AEs leading to investigational product discontinuation
2

AEs leading to study discontinuation
3

all investigational product related AEs
4

Investigational product related CTCAE grade 3, 4, or 5 AEs
5

Investigational product related AEs leading to investigational product discontinuation
6

Investigational product related AEs leading to study discontinuation
7

SAEs
8

Investigational product related SAEs
9

Fatal AEs
10
Narratives of deaths and SAEs will also be provided. 
12
An adjusted AE rate of treatment-emergent AEs reported during the treatment period will be 
13
presented as the number of AEs reported divided by subject years in the treatment period. 
14
The individual subject years in the treatment period are the number of days between a 
15
subject’s first dose date to the EOT date, inclusive, divided by 365.25 (ie, [EOT date – first 
16
dose date + 1]/365.25). The subject years for a treatment group in the treatment period are
17
the sum of individual subject years in the treatment period for all subjects in the treatment 
18
group. 
19
The final safety analysis, as well as safety analyses in an exploratory manner, will include 
20
23
6.4.2.2
Clinical Laboratory Assessments 
24
Laboratory parameters will be summarized over time using descriptive statistics for recorded 
25
values and change from baseline. Furthermore shifts tables will display the incidence of shift 
26


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
39
of toxicity grade (CTCAE version 3.0) in recorded values from baseline to “worst” on-study 
1
value. Graphs for other parameters of interest may also be presented.
2
3
6.4.2.3
Anti-denosumab Antibodies
4
The incidence and percentages of subjects who develop binding and neutralizing anti-
5
denosumab antibodies at any time will be tabulated by treatment group.
6
7
6.4.2.4
Concomitant Medication
8
For the final safety analysis, descriptive summary tables for concomitant bone affecting 
9
medication (including bone targeted therapy, glucocorticoids, antiepileptic drugs, 
10
antidepressants, insulin), as well as anti-cancer related therapy, will be provided. 
11
12
6.4.3
Exploratory Analyses
13


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
40


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
41
Translational endpoints
20
6.4.4
Treatment Discontinuation and Lost-to-Follow-Up
28
The basic assumption that censored (lost-to-follow-up) patients and treatment 
29
discontinuations will distribute equally to both treatment groups will be checked in an 
30
exploratory manner. For this purpose the numbers of a) censored patients and b) treatment 
31


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
42
discontinuations (except Completed Investigational Product) will be compared between both 
1
treatment groups. This will be described by Kaplan-Meier curves, where a) censoring and b) 
2
treatment discontinuations are handled as interesting events and other observations are 
3
censored at their last follow-up time or death time.
4
5
6.4.5
Subgroup Analysis
6
The primary endpoint will be analyzed using the Cox Model described in Section 6.4.1.1
7
within each subgroup indicated in Section 4.2 (if there are at least 10% of subjects within 
8
each sub-category). The primary endpoint will be summarized using descriptive statistics 
9
within each sub-category of the subgroup variables.
10
The treatment by subgroup interaction will be tested as follows: the Cox Model specified in 
11
Section 6.4.1.1 will have the subgroup variable and the interaction term of treatment-by-
12
subgroup added as covariates. If the p-value of interaction term is ≥ 0.05, the treatment-by-
13
subgroup interaction is not significant. Otherwise, if the interaction is significant, the Gail and
14
Simon test (Gail & Simon, 1985) will be used to test for qualitative interaction at the
15
significance level of 0.05. The interaction will be described graphically.
16
17
6.4.6
Covariates
18
The relationship of the following covariates to the primary and secondary efficacy endpoints
19
will be explored:
20

DXA device type (Hologic or other) [for analyses of BMD endpoints only]*
21

Prior AI usage (Yes or No)*
22

Total lumbar spine BMD score at baseline (T-score less than –1.0 or T-score ≥ -1.0)*
23
* Based on subject’s actual value.
24

Age (<50, 50-59, 60-69, 70-79 or ≥80 years)
25

T-stage (T0+Tis+T1 or T2+T3+T4)*
26

pN-stage (positive (pN1 + pN≥2) or negative (pN0)
27

Grading (G1, G2+Gx or G3)
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
43

Primary Tumor (ductal invasive carcinoma, lobular invasive carcinoma or other)
1

Receptor status (ER+/PgR+ or other)
2

Chemotherapy (yes - adjuvant, yes - neoadjuvant or no)
3

Neoadjuvant trastzumab therapy (yes or no)
4

Biphosphonate medication (yes or no)
5

Human Epidermal growth factor Receptor 2 (HER-2)-neu (positive, negative or 
6
missing)
7

Other covariates reported in literature as important or from other ongoing Amgen 
8
studies will be considered in the analysis if considered appropriate at the time of 
9
analysis.
10
*T-stage will be fitted along with the chemotherapy covariate to account for neo-adjuvant 
11
therapy.
12
The following covariate analyses will be conducted for the primary and secondary endpoints:
13

For the primary endpoint, the Cox model defined in Section 6.4.1.1 adding each 
14
above indicated covariate individually as a fixed (or continuous) effect will be used to 
15
obtain the 2-sided CIs for the covariate-adjusted estimates of the treatment and 
16
covariate effect with their respective p-values. The analysis set will be the same as 
17
used in the main analysis of the primary endpoint.
18

For the primary endpoint, the Cox  model defined in Section 6.4.1.1 adding all 
19
potential covariates listed above as fixed (or continuous) effects will be used to obtain 
20
the 2-sided CI for the covariate-adjusted estimate of the treatment effect and its p-
21
value. The analysis set will be the same as used in the main analysis of the primary 
22
endpoint.
23
24
6.4.7
SAS Code Fragments
25
The following statements are code fragments used for the main statistical analyses. They are
26
based on SAS® version 9.1. Italic words will be replaced by correct names of the datasets 
27
and variables (according to the database). In time-to-event data events are coded with 1 and 
28
non-events (censoring) with 0. 
29


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Version No.: 6.0
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Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
45
7.
FURTHER TABULAR SUMMARIES AND LISTINGS
36
Description of tabular summaries:
37
The following demographic information will be summarized by randomized treatment group:
38

Age: this summary will include number of observations, mean, SD, minimum, maximum 
39
and number of subjects with missing values in case of an approximately normal 
40


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
46
distribution. Otherwise, mean and SD are replaced by the median and minimum and 
1
maximum. 
2

Race: grouped into White/Caucasian and others
3
The following baseline, breast cancer history and BMD information will be summarized by 
4
randomized treatment group:
5

Stratification criteria for randomization
6

T-stage, pN-stage, Grading, primary tumor, estrogen receptor (ER) and progesterone 
7
receptor (PgR) expression: the number and percentage of subjects will be summarized.
8
The following withdrawal information will be summarized by randomized treatment group:
9

Subject disposition status (randomized, treated, withdrawn, completed); the number and 
10
percentage of subjects will be summarized.
11

Reason for withdrawal (according to “End of Treatment” CRF): the number and 
12
percentage of subjects will be summarized.
13

mean time under observation per patient from randomization to lost-to-follow up date or 
14
end-of-study visit
15
The following exposure / follow-up information will be summarized by randomized treatment 
16
group:
17

Number of doses
18
Any data collected relating to important protocol violations will be listed and summarized.
19
Accesses to individual subject treatment assignments (unblinding) and their reasons are 
20
summarized in a descriptive manner.
21
22
8.
INTERIM ANALYSES AND EARLY STOPPING GUIDELINES
23
An external DMC will be formed. Details regarding this DMC will be provided in a separate 
24
DMC charter. Selected Austrian Breast and Colorectal Cancer Group (ABCSG) and Amgen 
25
staff may serve as liaisons to the external DMC, but will not be voting members, and will not 
26
be unblinded to the results.  The DMC will have access to subject’s individual treatment 
27
assignments. To minimize the potential introduction of bias, these individuals will not have 
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
47
any direct contact with the study site personnel or subjects.  Members of this external DMC 
1
will include, at a minimum, physicians external to Amgen and appropriate statistical 
2
representation external to Amgen. The DMC will meet approximately annually. Records of all 
3
meetings will be archived. The DMC will communicate major safety concerns and 
4
recommendations regarding study modification or termination to Amgen senior management.
5
This DMC will review unblinded safety data.  Safety analyses provided to the DMC will be 
6
descriptive in nature.
7
There will be no interim analysis based on the primary endpoint. An interim analysis for futility 
8
for the secondary endpoint DFS will be based on the FAS and performed after PADCD, at the 
9
time of primary analysis, by an independent statistician. Only data captured prior to or on 
10
PADCD will be included in the futility analysis. This interim analysis will use an informal futility 
11
bound. Study termination may be recommended by the DMC if the observed hazard ratio 
12
exceeds the hazard ratio for futility (0.85). 
13
Following review of the interim DFS analysis results, the DMC determined that the hazard 
14
ratio did not indicate futility and that the study should continue further for approximately 66 
15
months. In addition, the DMC recommended that a time-driven analysis for efficacy of the 
16
secondary endpoint DFS should be performed at approximately 18 months after PADCD, 
17
before any investigator/subject level unblinding occurred for entry into the OLP.
18
In the event the study is terminated, it will be terminated when all subjects have had the 
19
opportunity to attend one LTFU visit after PADCD (approximately 18 months after PADCD). 
20
Otherwise the study will continue further 60 months.
21
22
9.
DFS ANALYSIS RECOMMENDED BY DMC
23
Based on the recommendation of the DMC from 28 April 2015 (DMC meeting on 7 April 
24
2015) a time-driven analysis for efficacy of the secondary endpoint DFS will be based on the 
25
FAS and performed around 18 months after PADCD. The DFS analysis data cut-off date will 
26
be 15 September 2015. Only data captured prior to or on this data cut-off date will be 
27
included in the analysis. The analysis must occur before any unblinding on 
28
patient/investigator level took place.
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
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Protocol Number 20050209 / ABCSG 18
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As the interim analysis for DFS did not indicate futility, the study continues until approximately 
1
66 months after PADCD. The DFS analysis around 18 months after PADCD will be 
2
considered the main DFS analysis for the hierarchical testing strategy (see section 6.1), with
3
. Analysis for efficacy
4
of the secondary endpoints BMFS and OS will not be affected and performed after 66 months 
5
after PADCD.
6
7
10.
DFS ANALYSIS 2018
8
Based on recommendation from the Study Steering Committee in early 2017 due to 
9
treatment crossover an additional, exploratory analysis of the secondary endpoint DFS will be 
10
performed early 2018. The data cut-off date will be 30 September 2017. Only data captured 
11
prior to or on this data cut-off date will be included in the analysis. The analysis will be based 
12
on the FAS and will include the main DFS analysis, as well as all above mentioned sensitivity 
13
analyses. 
14
15
11.
ZA SUBSTUDY 
16
11.1.1
Exploratory Objectives
17
21
11.1.2
ZA Substudy design
22
Subjects enrolled in the main study who received denosumab during the OLP may choose to 
25
participate in this substudy. 
26
Willing and eligible subjects who completed OL denosumab are randomized to 1 single 5 mg 
27
IV dose of ZA or to SOC in a 1:1 ratio by an IVRS. The randomization schedule will use 
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
49
randomly permuted blocks and will be stratified by AI use at the timepoint of OLP denosumab 
1
completion (Yes or No).
2
Follow up will continue for a total of 18 months after day 1. Day 1 for both arms should be 8 
3
months (± 4 weeks) from the last dose of OL denosumab. For the ZA arm, ZA will be 
4
administered on this visit.
5
Subjects who do not fulfill the eligibility criteria for or do not consent to the ZA substudy will 
6
complete OLP assessments only and will end the main study as planned.
7
8
11.1.3
Number of Subjects and Sample Size Calculation
9
For the ZA substudy, it is anticipated that approximately 200 subjects could be randomized.
10
Data is limited on BMD for subjects who discontinue denosumab 60 mg Q6M in the oncology 
11
setting. Therefore, data from postmenopausal osteoporosis was used in the sample size.
12
A phase 2 randomized blinded clinical trial in postmenopausal women with low bone mass 
13
assessed the effect of denosumab 60 mg Q6M on BMD and bone turnover markers (CTX 
14
and Osteocalcin) after long-term continued, discontinued, and restarting of therapy (Miller et 
15
al, 2008). One of the treatment cohorts received denosumab 210 mg Q6M for 24 months 
16
then placebo for the next 24 months. Based on this study, a 5% (SD = 4.3%), 5.2% (SD = 
17
2.6%), and 3.9% (SD = 3.8%) decrease in the lumbar spine, total hip, and femoral neck BMD 
18
was seen during the 2 years after denosumab discontinuation (data on file). A paper reporting 
19
22 case studies of postmenopausal women who received 5 injections (approximately 2.5 
20
years) of denosumab 60 mg Q6M and were then given a single dose of ZA 6 months after the 
21
fifth injection (Lehmann and Aeberli, 2017). A 3.8% (SD = 2.8%), 1.7% (SD = 3.3%), and 
22
0.6% (SD = 5%) decrease in the lumbar spine, total hip, and femoral neck BMD was seen 
23
during the 2.5 years after denosumab discontinuation.
24
A table showing the level of precision (ie, half width of 95% CI) for each treatment arm and 
25
each BMD type for different sample sizes, calculated based on the SD estimated from the 2 
26
studies mentioned above, is presented below.
27
Table 1.  Sample Sizes
28
Number of 
subjects in 
Precision (half width of 95% CI)
SOC
IV ZA


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each arm
Lumbar 
Spine
Total Hip
Femoral 
Neck
Lumbar 
Spine
Total Hip
Femoral 
Neck
75
1.0%
0.6%
0.9%
0.6%
0.8%
1.1%
100
0.9%
0.5%
0.7%
0.5%
0.7%
1.0%
125
0.8%
0.5%
0.7%
0.5%
0.6%
0.9%
IV = intravenous
1
2
11.1.4
Estimated ZA Substudy Duration
3
Subjects will be in the ZA substudy for a maximum duration of approximately 27 months 
4
(considering that the patient may enter the substudy 9 months after OLP denosumab 
5
completion and has a follow up of 18 months).
6
7
11.1.5
End of ZA Substudy
8
The patient individual end of ZA substudy visit is defined as the last formal substudy visit or 
9
contact for a subject or an unscheduled substudy visit in case of early withdrawal from the 
10
substudy. End of ZA substudy reasons include 3 early EOS reasons (death, lost to follow-up, 
11
and consent withdrawal) and per protocol EOS of ZA substudy.
12
The end of ZA substudy will therefor occur when the last subject participating in the ZA 
13
substudy has completed their last formal substudy visit or an unscheduled substudy visit in 
14
case of early withdrawal from the ZA substudy.
15
16
11.1.6
Study Termination
17
Study termination will occur when the last subject has completed their last formal visit or last 
18
formal contact or an unscheduled study visit in case of early withdrawal from the study. This 
19
is expected to occur when the last subject completes their EOS visit or their end of ZA 
20
substudy visit.
21
22
11.1.7
Exploratory Endpoints
23


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
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5
11.1.8
Analysis Sets
6
11.1.8.1
ZA Analysis Set
7
11.1.8.2
ZA Safety Analysis Set
11
11.1.9
Subgroups
16


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
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1
11.1.10
Timepoint of Analysis
2
8
11.1.11
Handling of Missing and Incomplete Data
9
For radiologic assessments x-rays should be performed for all patients. Nevertheless, for 
10
fractures with a missing x-ray date, the fracture date captured on the fracture recording eCRF 
11
will be used. If the fracture date is completely missing, it will not be imputed. If it is partially 
12
missing, imputed dates will be used to derive the incidence at each time point.
13
Missing
Impute
Exception
Fracture 
Date
Day
01
Default to Day 1 of ZA substudy if an 
event started the same year and 
month as Day 1
Day /Month
01JAN
Default to Day 1 of ZA substudy if an 
event started the same year as Day 1
If a start or stop date for an AE is completely missing, it will not be imputed. If it is partially 
14
missing, imputed dates will be used to derive the duration of the AE. Missing years will not be 
15
estimated under any conditions.
16
Missing
Impute
Exception
Start 
date
Day
01
Default to Day 1 of ZA substudy if an 
event started the same year and 
month as Day 1 of ZA substudy
Day /Month
01JAN
Default to Day 1 of ZA substudy if an 
event started the same year as Day 1
of ZA substudy
Stop 
Day
Last day of the 
Default to the end of ZA substudy visit 


Statistical Analysis Plan
Version No.: 6.0
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Protocol Number 20050209 / ABCSG 18
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date
month
if the imputed event stop date is after 
the end of ZA substudy visit 
Day/Month
31Dec
1
11.1.12
Analysis Windows
2
11.1.12.1 Study Month
3
Study Month will be defined as:
4
CEIL(date of event – date of ZA substudy Day 1*))/30.44)
5
* If ZA Substudy Day 1 is missing, the randomization date will be used instead
6
11.1.12.2 Incidence Endpoints
7
Incidence between periods of time will use the formula in Section 11.1.12.1 to derive month 
8
from ZA substudy Day 1 to event between Months 1 and 6, between Months 1 and 12 and 
9
between Months 1 and 18.  
10
11.1.12.3 Analysis at Specified Times
11
All tests and procedures will aim to be performed within the specified windows according to 
12
the definitions given in the tables below. To allow for variations in scheduling the following 
13
visit windows will be used to assign evaluations to a most appropriate nominal visit for 
14
analysis and summarization.
15
In order to get as many data points as possible for summarization, there will be no gaps 
16
between visit windows. If more than one assessment is available within a window, the 
17
assessment closest to the target day at each nominal visit (Month 6, Month 12, …) will be 
18
used. If ZA substudy Day 1 is missing, the randomization date will be used instead. BMD, 
19
CTX and Osteocalcin measurements recorded within 45 days after Day 1 are acceptable as 
20
baselines. In case of several candidates, the closest value to Day 1 will be selected.
21
Nominal Visit Window
Target Day
Definition (ZA substudy Day)
Baseline
1
Last evaluation prior to or on ZA substudy Day 1
Month 6 
183
ZA substudy Day 2 to 274
Month 12
365
ZA substudy Day 275 to 456
Month 18
547
ZA substudy Day 457 to 634
22


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Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
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11.1.13
Analysis Methods
1


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
55
12.
AMENDMENTS TO THE STATISTICAL ANALYSIS PLAN
1
Amendments to the Statistical Analysis Plan must include a description of and a rationale for 
2
changes to this original plan.
3
Version 1 of the SAP was issued on 27 April 2010 describing in detail the analysis per the 
4
original clinical study protocol for ABCSG study 18 (Protocol Number: 20050209, Date: 13 
5
March 2006).
6
Version 2 of the SAP was issued on 16 December 2014 updating the planned analysis per 
7
the amended clinical study protocol for ABCSG study 18 (Protocol Number: 20050209, 
8
Superseding 3 Amendment 3, Date: 25 January 2013).
9
Version 3 of the SAP was issued on 10 March 2015. The following specific updates were 
10
made:
11

The vertebral fracture endpoints will be based on the Vertebral fracture analysis set
12
(section 4.1.4) rather than the FAS.  Only approximately 60% of the FAS will have 
13
available data for analysis due to the high number of non-evaluable or missing 
14
independent assessments of vertebral fractures by the Central Review Committee 
15
(CRC). An additional exploratory analysis will be conducted on the FAS using time to 
16
event analysis methodology.
17

Treatment emergent AEs (section 5.5) will include AEs occurring on or after the first 
18
dose of IP reported through 30 days after the last dose of IP (EOT).  AEs reported but 
19
not classified as treatment emergent will be listed.
20

The proscribed therapies detailed in the per protocol population definition (section 
21
4.1.5) were updated in-line with the clinical study protocol (Protocol Number: 
22
20050209, Superseding 3 Amendment 3, Date: 25 January 2013), 
23
Version 4 of the SAP was issued on 22 October 2015 updating a DFS analysis per 
24
recommendation of the DMC and decision of the Study Steering Committee and the Study 
25
Sponsor.
26
Following review of the main DFS analysis results, version 4.1 of the SAP was issued on 24 
27
November 2015 adding a sensitivity analysis for the DFS analysis to account for treatment 
28
cross-over.
29


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Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
56
Version 5 of the SAP was issued on 15 January 2018 updating for OLP, including additional 
1
measurements and analyses, focusing on sensitivity analyses accounting for cross-over.
2
Furthermore, an additional exploratory 
 analysis in 2018 was introduced as 
3
recommended by the Study Steering Committee.
4
Due to inclusion of the ZA substudy Version 6 of the SAP was issued on 10 December 2019.
5
Details on the substudy, as well as clarifications regarding the final analysis of the main study 
6
and the analysis of the ZA substudy were included. Additionally, abbreviations were updated 
7
and made consistent throughout the document.
8
9
13.
CHANGES FROM THE PROTOCOL PLANNED ANALYSES
10
This SAP includes the following changes to the statistical analyses planned to be conducted 
11
within the amended clinical study protocol for ABCSG study 18 (Protocol Number: 20050209, 
12
Superseding 3 Amendment 3, Date: 25 January 2013):
13
The fracture-related secondary objective and associated endpoint has been updated from:
14

Objective: Bone mineral density (BMD) at total lumbar spine, total hip and femoral 
15
neck in a subgroup of subjects at pre-selected sites
16

Endpoint: The percent change in total lumbar spine, total hip and femoral neck bone 
17
mineral density (BMD) from baseline to 36 months (at pre-selected sites)
18
Revised with:
19

Objective: Bone mineral density (BMD) at total lumbar spine, total hip and femoral 
20
neck in a subgroup of subjects with evaluable DXA scans using the same Hologic 
21
device 
22

Endpoint: The percent change in total lumbar spine, total hip and femoral neck bone 
23
mineral density (BMD) from baseline to 36 months in a subgroup of subjects with 
24
evaluable DXA scans using the same Hologic device
25
The exploratory objective has been updated from:
26

Objective: 
 
27
28


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
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Revised with:
1

Objective: 
 
2
 
3
4
Background:
5
Sites were pre-selected at initiation if they used a Hologic DXA device. The original BMD 
6
related endpoints were to be subset on this stratum in order to limit variability across and 
7
within subjects. During the blinded review of the data it has become apparent that during the 
8
course of the study sites have changed their DXA devices and subjects may switch between 
9
DXA machines during the duration of the study. Therefore the stratification factor does not 
10
reflect the actual DXA machine type used. Consequently, the analyses of this endpoint will be 
11
based on the machine type reported on the subject’s eCRF. Subjects will be included in the 
12
main BMD analyses if the same Hologic DXA device was used (see Section 4.1.3, BMD 
13
analysis set).
14
An additional section regarding an analysis of DFS at 18 months after PADCD was included 
15
in Version 4 of the SAP (15 September 2015) based on a recommendation of the DMC and 
16
decision of the Study Steering Committee and the Study Sponsor.
17
Version 5 of this SAP includes the following changes to the statistical analyses planned to be 
18
conducted within the amended clinical study protocol for ABCSG study 18 (Protocol Number: 
19
20050209, Superseding Amendment 4, Date: 22 February 2016):
20
Based on recommendation from the Study Steering Committee, due to concerns of a 
21
potential dilution effect caused by treatment crossover, an additional, exploratory 
 
22
analysis will be conducted early 2018, including the main DFS analysis, as well as all above 
23
mentioned sensitivity analyses.
24
25


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Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
58
14.
LIST OF PLANNED TABLES AND FIGURES
1
List of Tables: 
2
1. Primary Endpoint for FAS - description: 
3
a) Number of analyzed patients and number of first clinical fractures by treatment 
4
groups in total and stratified by a) type of hospital, b) prior AI and c) total lumbar 
5
spine BMD score at baseline (Tscore <-1.0 or -1.0)
6
2. Primary Endpoint for FAS - modelling: 
7
a) Result of Cox regression analysis with treatment groups as covariate stratified by 
8
randomization stratification factors, description with hazard ratio and 95 % 
9
confidence interval and estimated fracture rates at 36 months and 95 % 
10
confidence intervals for each treatment group
11
b) Crude incidences at the end of study for each treatment group 
12
c) Results of Cox regression analyses including treatment and other covariates: age, 
13
prior AI usage, total lumbar spine BMD score at baseline (T-score <-1.0 or -1.0) 
14
and potential other covariates; description with hazard ratios and 95 % confidence 
15
intervals.  Univariate and multivariate analyses
16
3. Primary Endpoint sensitivity analyses - modelling: 
17
a) Result of Cox regression analysis with treatment groups as covariate stratified by 
18
randomization stratification factors using FAS, description with hazard ratio and 95 
19
% confidence interval; subjects who withdraw from the trial due to a > 10 % loss of 
20
BMD in the lumbar spine over any 1-year period are treated as having had a 
21
clinical fracture at the time of withdrawal 
22
b) Result of Cox regression analysis with treatment groups as covariate stratified by 
23
randomization stratification factors using per protocol population, description with 
24
hazard ratio and 95 % confidence interval
25
c) Result of Cox regression analysis with treatment groups as covariate and time 
26
from treatment discontinuation and first clinical fracture or date last seen as binary 
27
time dependent covariate stratified by randomization stratification factors using 
28
FAS, description with hazard ratios and 95 % confidence intervals
29
d) Result of RPSFTM using Cox regression analysis with treatment groups as 
30
covariate stratified by randomization stratification factors using FAS, description 
31
with hazard ratios (95% CI) and acceleration factor (95% CI) (final analysis)
32
4. Secondary Endpoint for FAS - description: 
33
a) Observed percent change and corresponding 95 % confidence interval in lumbar 
34
spine, total hip and femoral neck BMD from baseline to 36 months for each 
35
treatment group (BMD analysis set)
36
b) Number of patients, new vertebral fractures and number of new or worsening 
37
vertebral fractures at 36 months for each treatment group (Vertebral fracture 
38
analysis set)
39


Statistical Analysis Plan
Version No.: 6.0
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c) Crude incidences of new vertebral fractures at 36 months with 95 % confidence 
1
intervals for each treatment group and their difference with corresponding 95 % 
2
confidence interval (Vertebral fracture analysis set)
3
d) Crude incidences of new or worsening vertebral fractures at 36 months with 95 % 
4
confidence intervals for each treatment group and their difference with 
5
corresponding 95 % confidence interval (Vertebral fracture analysis set)
6
5. Secondary Endpoint for FAS (unless otherwise specified) - modelling:
7
a) Results of logistic regressions modelling the incidence of new vertebral fractures 
8
(odds-ratios and 95 % confidence intervals) with treatment group as covariate 
9
stratified by randomization stratification factors at 36 months (Vertebral fracture 
10
analysis set)
11
b) Results of logistic regressions modelling the incidence of new vertebral fractures 
12
with treatment group as covariate and other covariates found significant (odds-
13
ratios and 95 % confidence intervals) at 36 months (Vertebral fracture analysis 
14
set)
15
c) Results of logistic regressions modelling the incidence of new or worsening 
16
vertebral fractures (odds-ratios and 95 % confidence intervals) with treatment 
17
group as covariate stratified by randomization stratification factors at 36 months 
18
(Vertebral fracture analysis set)
19
d) Results of logistic regressions modelling the incidence of new or worsening 
20
vertebral fractures with treatment group as covariate and other covariates found 
21
significant (odds-ratios and 95 % confidence intervals) at 36 months, respectively
22
(Vertebral fracture analysis set)
23
e) Result of Cox regression analysis after around 18 months after PADCD for DFS; 
24
the model includes treatment as covariate and is stratified by the randomization 
25
stratification factors, description of the model by with hazard ratios and 95 % 
26
confidence intervals (IDMC recommended analysis)
27
f)
Result of Cox regression analysis for DFS analysis 2018; the model includes 
28
treatment as covariate and is stratified by the randomization stratification factors, 
29
description of the model by with hazard ratios and 95 % confidence intervals 
30
(Steering Committee recommended analysis)
31
g) Result of RPSFTM using Cox regression analysis for DFS analysis 2018; the 
32
model includes treatment groups as covariate stratified by randomization 
33
stratification factors using FAS, description with hazard ratios (95% CI) and 
34
acceleration factor (95% CI) (Steering Committee recommended analysis)
35
h) Result of Cox regression analysis after long-term-follow-up for a) DFS, b) BMFS
36
and c) OS; the model includes treatment as covariate and is stratified by the 
37
randomization stratification factors, description of the model by with hazard ratios 
38
and 95 % confidence intervals (final analysis)
39
i)
Result of RPSFTM using Cox regression analysis for a) DFS, b) BMFS and c) OS; 
40
the model includes treatment groups as covariate stratified by randomization 
41
stratification factors using FAS, description with hazard ratios (95% CI) and 
42
acceleration factor (95% CI) (final analysis)
43
6. Adverse Events for SAF: 
44


Statistical Analysis Plan
Version No.: 6.0
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Protocol Number 20050209 / ABCSG 18
60
a) Subject incidence rates of treatment emergent adverse events reported during 
1
treatment period are tabulated by system organ class and preferred term and split
2
by treatment and age categories and by treatment and race (White/Caucasian and 
3
others)
4
b) Investigational product related adverse events split by treatment and age 
5
categories and by treatment and race
6
c) Serious adverse events split by treatment and age categories and by treatment 
7
and race
8
d) Common Terminology Criteria for Adverse Events (CTCAE) grade 3, 4, or 5 
9
adverse events split by treatment and age categories and by treatment and race
10
e) Adverse events leading to investigational product discontinuation split by 
11
treatment and age categories and by treatment and race
12
f)
Adverse events leading to study withdrawal split by treatment and age categories 
13
and by treatment and race
14
g) Investigational product related serious adverse events split by treatment and age 
15
categories and by treatment and race
16
h) Fatal adverse events split by treatment and age categories and by treatment and 
17
race
18
i)
Narratives for death and serious adverse events 
19
7. Clinical Laboratory Assessments for SAF:
20
a) Summary of recorded values by minimum, maximum, median, mean and standard 
21
deviation for each nominal visit window (semi-annually) 
22
b) Summary of change from baseline by minimum, maximum, median, mean and 
23
standard deviation for each nominal visit window (semi-annually) 
24
c) Tables of shifts of toxicity grades (CTCAE: <3, 3, 4 , 5) for baseline and “worst” 
25
on-study values. For a selected subset both minimum and maximum are reported
26
8. Anti-denosumab Antibodies: incidence and percentages of subjects who develop binding 
27
and neutralizing anti denosumab antibodies split by treatment group and visit (SAF)
28
9. Exploratory Analyses for FAS (unless otherwise specified) – description:
29


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
61
11. Subgroup Analysis for FAS - modelling:
29
a) Result of Cox regression analysis with treatment groups as covariate separately 
30
for each sub-group combination of a) major academic site, b) Prior AI usage and 
31
c) Total lumbar spine BMD score at baseline (Tscore <-1.0 or -1.0); description 
32
of model results with hazard ratios and 95 % confidence intervals
33
b) Results of three Cox regression analyses with treatment and a subgroup variable 
34
(a) major academic site, b) Prior AI usage and c) total lumbar spine BMD score at 
35
baseline (Tscore <-1.0 or -1.0)) as covariates; interaction between treatment and 
36
corresponding subgroup variable is also included; description of model results 
37
with hazard ratios and 95 % confidence intervals
38
12. Further tabular summaries and listings for SAF unless otherwise specified
39
a) Demographic data of patients (age and race), stratification criteria (type of 
40
hospital, prior AI usage and total lumbar spine BMD score at baseline (Tscore <-
41
1.0 or -1.0)) and baseline and breast cancer history (T-stage, pN-stage, Grading, 
42


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
62
primary tumor, ER and PgR expression) split by randomized treatment groups
1
(FAS)
2
b) Withdrawal information (subject disposition status, reason for withdrawal and 
3
mean time under observation per patient from randomization to lost-to-follow up 
4
date or end-of-study visit) summarized by randomized treatment groups
5
c) Exposure / follow-up information (number of doses) summarized by randomized 
6
treatment group
7
d) Any data collected relating to important protocol violations
8
e) Accesses to individual subject treatment assignments (unblinding)
9
f)
Listing of Manufacturing Lot Numbers 
10
g) Listing of Unique Manufacturing Lot Numbers 
11
h) Listing of Laboratory Reference Ranges 
12
i)
Listing adverse events considered not treatment emergent
13
14
List of Tables for ZA substudy: 
15
1. Exploratory Endpoints for ZA analysis set - description: 
16
2. Exploratory Endpoints for ZA analysis set- modelling:
22


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
63
29
List of Figures:
30
1. Kaplan-Meier estimates for each treatment group for primary outcome
31
2. Kaplan-Meier estimates for each treatment group where censoring is the interesting 
32
outcome
33
3. Kaplan-Meier estimates for each treatment group where treatment discontinuation is the 
34
interesting outcome
35
4. Scatter plots to identify outliers in any of the continuous variables – including sensitivity 
36
analyses
37
5. Description of interactions
38
39


Statistical Analysis Plan
Version No.: 6.0
Product: Denosumab
Date: December 10, 2019
Protocol Number 20050209 / ABCSG 18
64
15.
REFERENCES
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Cox D.R. (1972) Regression models and life-tables (with discussion). Journal of the Royal 
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Statistical Society, Series B 34, 187-220.
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Eastell R. and Adams J.E. (2002) Effect of anastrozole on bone density and bone turnover: 
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Results of the “arimidex” (anastrozole), tamoxifen, alone or in combination (ATAC) trial 
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performed by the ATAC Trialists’ Group. Ann Oncol. 13, 32 (suppl5).
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Gail M. and Simon R. (1985) Testing for qualitative interactions between treatment effects 
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and patients subsets. Biometrics 41 (2): 361-372 
8
Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer(ABCSG-18): a
9
multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433-
10
43. Epub 2015 May 31.
11
Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-
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responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined 
13
results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005;366-455
14
Kaplan E.L. and Meier,P. (1958) Nonparametric estimation from incomplete observations. 
15
Journal of the American Statistical Association 53, 457-481.
16
Kenward, M.G. and Roger, J.H. (1997), Small Sample Inference for Fixed Effects from 
17
Restricted Maximum Likelihood, Biometrics, 53, 983 - 997. 
18
Lehmann T, Aeberli D. Possible protective effect of switching from denosumab to zoledronic 
19
acid on vertebral fractures. Osteoporos Int. 2017;28(10):3067-3068.
20
Miller PD, Bolognese MS, Lewiecki EM, et al. Effect of denosumab on bone density and 
21
turnover in postmenopausal women with low bone mass after long-term continued, 
22
discontinued, and restarting of therapy: a randomized blinding phase 2 clinical trial. Bone. 
23
2008;43(2):222-229.
24
Robins, J.M. and Tsiatis, A.A. (1991) Correcting for non-compliance in randomized trials 
25
using rank preserving structural failure time models. Commun Stat Theory Methods. 
26
1991;20:2609-2631.
27
Westfall, PH, Tobias, R.D., Rom, D. Wolfinger, R.D., Hochberg, Y. (1999) Multiple 
28
comparisons and multiple tests using the SAS system, SAS Institute Inc.
29