untitled h1
untitled h2

A M ulti dis ci pli n a r y T e a m -B as e d A p p r o a c h t o Miti g at e t h e I m p a ct of A n d r o g e n D e p ri v ati o n T h e r a p y i n P r ost at e C a n c e r: a R a n d o mi z e d P h as e 2 T h e " S T A N D " ( S u p p o rti v e T h e r a p y i n A n d r o g e n D e p ri v ati o n) Cli ni c P r ot o c ol N u m b e r C C \# 1 3 5 5 1 3 I N D \#: 1 2 1 8 4 6 ( E x e m pt)  
P ri n ci p al I n v esti g at o r R a h ul A g g a r w al M D  
Di visi o n of H e m at ol o g y/ O n c ol o g y, D e p art m e nt of M e di ci n e U ni v ersit y of C alif or ni a S a n Fr a n cis c o E m ail: R a h ul. A g g ar w al @ u csf. e d u
untitled h1
c o -i n v

Eri c J . S m all, M D  
T a m m y J. R o d v elt, N P  
C h arl es R y a n , M D  
M a c k R o a c h III, M D, F A C R  
Al b ert C h a n g, M D, P h D  
Al e x a n d er G otts c h al k, M D, P h D  
Gr et a M a c air e , R D  
G er o ni m a C ort es e -Ji m e n e z, R N, M P H  
R e g a n F e dri c, E x er cis e P h ysi ol o gist M a x w ell M e n g, M D  
J effr e y B el k or a, P h D  
K irst e n Gr e e n e, M D, M S  
P et er C arr oll, M D, M P H  
M att h e w C o o p er b er g, M D, M P H  
Mi c h a el R a b o w, M D  
A m y Li n, M D  
L a wr e n c e F o n g, M D  
T er e n c e Fri e dl a n d er, M D  
A n dr e w Hs i e h, M D  
W o n Ki m, M D  
D e a n n a Kr o et z, P h D  
J u n e C h a n, S c D  
Eri n Ri c h m a n, S c D  
S h ar mil a M aj u m d ar, P h D  
R a mi W ei n b er g, P T
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st atisti ci a n

Li Z h a n g, P h D, U C S F Bi ost atisti cs C or e R e visi o n Hist o r y V ersi o n 1 d at e d S e pt. 1 8, 2 0 1 3 V ersi o n 2 d at e d 1 2- 2 6, 2 0 1 3 V ersi o n 2. 1 d at e d 2- 1 2- 2 0 1 4 V ersi o n 3. 0 d at e d 0 7- 0 7- 2 0 1 5 P r ot o c ol Si g n at u r e P a g e Pr ot o c ol N o.: 3. 0 V er si o n D at e: 0 7 -0 7 -2 0 1 5 1. I a gr e e t o f oll o w t hi s pr ot o c ol v er si o n a s a p pr o v e d b y t h e U C S F Pr ot o c ol R e vi e w C o m mitt e e  
( P R C), C o m mitt e e o n H u m a n R e s e ar c h ( C H R), a n d D at a S af et y M o nit ori n g C o m mitt e e  
( D S M C).  
2. I will c o n d u ct t h e st u d y i n a c c or d a n c e wit h a p pli c a bl e C H R r e q uir e m e nt s, F e d er al r e g ul ati o n s, a n d st at e a n d l o c al l a w s t o m ai nt ai n t h e pr ot e cti o n of t h e ri g ht s a n d w elf ar e of st u d y p arti ci p a nt s.  
3. I c ertif y t h at I, a n d t h e st u d y st aff, h a v e r e c ei v e d t h e r e q ui sit e tr ai ni n g t o c o n d u ct t hi s r e s e ar c h pr ot o c ol.  
4. I h a v e r e a d a n d u n d er st a n d t h e i nf or m ati o n i n t h e I n v e sti g at or s' Br o c h ur e ( or M a n uf a ct ur er' s Br o c h ur e) r e g ar di n g t h e ri s k s a n d p ot e nti al b e n efit s. I a gr e e t o c o n d u ct t h e pr ot o c ol i n a c c or d a n c e wit h G o o d Cli ni c al Pr a cti c e s (I C H -G C P), t h e a p pli c a bl e et hi c al pri n ci pl e s, t h e St at e m e nt of I n v e sti g at or ( F or m F D A 1 5 7 2), a n d wit h l o c al r e g ul at or y r e q uir e m e nt s. I n a c c or d a n c e wit h t h e F D A M o d er ni z ati o n A ct, I will e n s ur e t h e r e gi str ati o n of t h e tri al o n t h e w w w. cli ni c altri al s. g o v w e b sit e.  
5. I a gr e e t o m ai nt ai n a d e q u at e a n d a c c ur at e r e c or d s i n a c c or d a n c e wit h C H R p oli ci e s, F e d er al, st at e a n d l o c al l a w s a n d r e g ul ati o n s.  
U C S F Pri n ci p al I n v e s ti g at or / St u d y C h air Pri nt e d N a m e  
Si g n at ur e D at e  
  
  
  
Pri n ci p al I n v e sti g at or Sit e  
  
  
  
  
| Pri nt e d N a m e   |
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Si g n at ur e D at e
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a b s t r

| Titl e                                                                                                                                   | A                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | M ulti dis ci pli n a r y T e a m -B as e d A p p r o a c h t o   | Miti g at e t h e I m p a ct of A n d r o g e n   |
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| D e p ri v ati o n T h e r a p y i n P r ost at e C a n c e r: a R a n d o mi z e d P h as e 2 St u d y of t h e " S T A N D "  Cli ni c |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                   |                                                   |
| P ati e nt                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                   |                                                   |
| p o p ul ati o n                                                                                                                         | 8 0 p ati e nts wit h pr ost at e c a n c er w h o h a v e r e c e ntl y st art e d ( wit hi n 6 m o nt hs of st u d y e ntr y) or  pl a n t o p urs u e a n dr o g e n d e pri v ati o n t h er a p y ( A D T), wit h a n e x p e ct e d d ur ati o n of t h er a p y of at  l e ast 1 2 m o nt hs f oll o wi n g st u d y e nr oll m e nt, will b e eli gi bl e t o p arti ci p at e i n t h e r a n d o mi z e d  st u d y. T w e nt y ( 2 0) p ati e nts c urr e ntl y r e c ei vi n g or pl a n ni n g t o st art c o m bi n e d c h e m o h or m o n al  t h er a p y will b e eli gi bl e t o p arti ci p at e i n t h e n o n-r a n d o mi z e d pil ot c o h ort.  K e y Eli gi bilit y C rit e ri a:  - Hist ol o gi c c o nfir m ati o n of a d e n o c ar ci n o m a of t h e pr ost at e  - R e c ei vi n g or pl a n ni n g t o r e c ei v e A D T wit h L H R H a g o nist or a nt a g o nist  - E x p e ct e d d ur ati o n of A D T at l e ast 1 2 m o nt hs fr o m st u d y e n tr y  - C o n c urr e nt a nti a n dr o g e n t h er a p y all o w e d b ut n ot r e q uir e d  - First d os e of L H R H a g o nist or a nt a g o nist n o m or e t h a n 6 m o nt hs pri or t o st u d y e ntr y  - Pri or/ c o n c urr e nt r a di ati o n t h er a p y all o w e d  - P h ysi c all y a bl e t o p arti ci p at e i n e x er cis e pr o gr a m  - Willi n g a n d a bl e t o tr a v el t o U C S F f or m o nt hl y visits  - R a n d o mi z e d c o h o rt o nl y:  o N o pri or c h e m ot h er a p y wit hi n 1 2 m o nt hs of st art d at e of st u d y   N o pl a n n e d c h e m ot h er a p y d uri n g t h e i niti al 1 2 m o nt h p eri o d of st u d y  p arti ci p ati o n  - N o n -r a n d o mi z e d pil ot c o h o rt:  o C o n c urr e nt c h e m ot h er a p y (i niti at e d wit hi n 3 m o nt hs of st u d y e ntr y) or pl a n n e d  c h e m ot h er a p y wit hi n 3 m o nt hs of st u d y e ntr y                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                   |                                                   |
| R ati o n al e f or  St u d y                                                                                                            | A n dr o g e n d e pri v ati o n t h er a p y ( A D T) is t h e m ost c o m m o n s yst e mi c t h er a p y a p pli e d i n pr ost at e  c a n c er. It is ass o ci at e d wit h i m pr o v e m e nt i n o v er all s ur vi v al, r e gr essi o n of t u m ors, a n d s y m pt o m  p alli ati o n i n v ari o us dis e as e st at es i n cl u di n g c o n c urr e ntl y wit h r a di ati o n t h er a p y, f oll o wi n g  s ur g er y, a n d f or p ati e nts wit h m et ast ati c dis e as e. H o w e v er, A D T is ass o ci at e d wit h n u m er o us  c h a n g es i n b o d y c o m p ositi o n a n d m et a b o li c p ert ur b ati o ns l e a di n g t o si g nifi c a nt i atr o g e ni c  m or bi dit y a n d m ort alit y . A D T is ass o ci at e d wit h t h e d e vel o p m e nt of t h e m et a b oli c s y n dr o m e,  i n cr e as es i n b o d y f at, d e cr e as e i n l e a n b o d y m a ss, w ei g ht g ai n, h y p erli pi d e mi a, i ns uli n  r esist a n c e/ di a b et es, a n d, p ot e nti all y, a n i n cr e as e d ris k of c ar di o v as c ul ar m or bi dit y a n d m ort alit y.  It als o i m p a cts q u alit y of lif e vi a m us cl e w asti n g, h ot fl as h e s, g y n e c o m a sti a, s e x u al d ysf u n cti o n,  m o o d, a n d r el ati o ns hi p c h a n g e s. Gi v e n t h e br o a d s p e ctr u m of A D T -ass o ci at e d t o xi citi es a cr oss  n u m er o us d o m ai ns, t h er e is a cl e ar u n m et m e di c al n e e d t o d e v el o p s yst e m ati c, m ulti -dis ci pli n ar y  a p pr o a c h t o p arti all y miti g at e t h e t o xi cit y of A D T.  M a n y of A D T -ass o ci at e d t o xi citi es ar e m o difi a bl e wit h c ar ef ul m a n a g e m e nt, alt h o u g h c urr e nt  pr a cti c e d at a s u g g est t h at t h e v ast m aj orit y of p h ysi ci a ns w h o pr es cri b e A D T d o n ot m a n a g e  t h es e si d e eff e cts in a c o nsist e nt w a y, if at all. M ulti pl e pri or st u di es i n t h e pri m ar y c ar e s etti n g  d e m o nstr at e t h at i nt e gr at e d, m ulti-dis ci pli n ar y eff orts as c o m p ar e d t o r o uti n e c o u ns eli n g d uri n g  p h ysi ci a n visits l e a d t o m or e s u bst a nti al c h a n g es i n lif est yl e h a bits, i n cl u di n g i m pr o v e d di et,  s m o ki n g c ess ati o n, a n d bl o o d pr ess ur e m a n a g e m e nt. T h er ef or e, c o m pr e h e nsi v e m a n a g e m e nt of  t h e p ot e nti al si d e eff e cts of A D T wit h t h e us e of a m ulti-dis ci pli n ar y cli ni c m a y i m pr o v e  o ut c o m es a n d p arti all y r e v er s e t h e si d e eff e cts of A D T, a s c o m p ar e d t o us u al st a n d ar d of c ar e.  T h e " S T A N D ( S u p p orti v e T h er a p y i n A N dr o g e n D e p ri v ati o n) " Cli ni c at U C S F w a s cr e at e d f or  p ati e nts tr e at e d wit h A D T t o a d dr ess a n d miti g at e t h e a d v ers e eff e cts of h or m o n e t h er a p y. T h e  i nt e nt is t o pr o vi d e " o n e st o p s h o p pi n g " a n d pr o vi d e p ati e nt n a vi g ati o n a cr oss a n u m b er of |                                                                   |                                                   |  
| diff er e nt di s ci pli n es, cli ni cs a n d s er vi c es .  D uri n g t h e c o urs e of a n i nt e gr at e d visit, t h e p ati e nt will h a v e t h e f oll o wi n g p ers o n ali z e d  ass ess m e nt a n d c o u ns eli n g :  - P ati e nt c ar e a n d c o u ns eli n g b y a tr ai n e d n urs e pr a ctiti o n er a n d/ or p h ysi ci a n  - T w el v e m o nt hl y e d u c ati o n al " m o d ul es " r e g ar di n g A D T si d e eff e ct m a n a g e m e nt  - M e di c ati o n m a n a g e m e nt i n cl u di n g L H R H a n al o g u e i nj e cti o ns d uri n g visit  - C ar di o v as c ul a r m o nit ori n g a n d ris k r e d u cti o n, i n cl u di n g h y p ert e nsi o n, h y p erli pi d e mi a,  gl u c o s e m o nit ori n g, a n d c ar di a c ris k str atifi c ati o n  - B o n e h e alt h m o nit ori n g a n d m a n a g e m e nt  - N utriti o n c o u ns eli n g  - E x er cis e tr ai ni n g  - E v al u ati o n a n d c o u ns eli n g f or r el ati o ns hi p a n d m o o d c h a n g e s b y tr ai n e d s o ci al w or k er  - Ass ess m e nt of q u alit y of lif e a n d si d e eff e cts of A D T wit h v ali d at e d q u esti o n n air es  ( p ati e nts will als o h a v e o p p ort u nit y t o fill o ut q u esti o n n air e s o n-li n e a h e a d of cli ni c visit)  T h e c urr e nt r a n d o mi z e d p h as e 2 cr oss-o v er st u d y is d esi g n e d t o pr eli mi n ar y e v al u at e t h e  l o n git u di n al i m p a ct of p arti ci p ati o n i n t h e " S T A N D " cli ni c ( as c o m p ar e d t o us u al st a n d ar d of  c ar e) o n k e y m et a b oli c p ar a m et ers, q u alit y of lif e, a n d p ati e nt s atisf a cti o n f or m e n r e c ei vi n g  h or m o n e t h er a p y f or pr ost at e c a n c er. St a n d ar d -of -c ar e t h er a p y will c o nsist of e v er y 3 -m o nt h  visits c o m pris e d of r e vi e w of m e di c al hist or y, t o xi cit y a ss e ss m e nt, a n d lif est yl e m o difi c ati o n  c o u ns eli n g pr o vi d e d b y i n di vi d u al h e alt h c ar e pr o vi d er, L H R H a n al o g i nj e cti o ns b y tr ai n e d  o n c ol o g y n ur s e. P ati e nts will h a v e a c c e ss t o e x er cis e, n utriti o n, a n d s o ci al w or k c o u ns eli n g if  r e q u est e d b y p ati e nt or d e e m e d n e c ess ar y aft er c o ns ult ati o n wit h h e alt h c ar e pr o vi d er. Aft er 1 2  m o nt hs o n st u d y, p ati e nts r a n d o mi z e d t o t h e us u al st a n d ar d -of - car e ar m will h a v e t h e o p p ort u nit y  t o cr oss-o v er a n d p arti ci p at e i n t h e S T A N D cli ni c f or t h e e ns ui n g 1 2 m o nt hs or f or t h e r e m ai n d er  of A D T d ur ati o n, w hi c h e v er is s h ort er. S h o ul d t h e r es ults i n di c at e a b e n efi ci al i m p a ct of  p arti ci p ati o n i n a m ulti -dis ci pli n ar y cli ni c i n miti g ati n g t h e s h ort - a n d i nt er m e di at e -t er m  t o xi citi e s of A D T, t his w o ul d f or m t h e j ustifi c ati o n f or l ar g er r a n d o mi z e d cli ni c al tri als t o ass ess  t h e i m p a ct of cli ni c p arti ci p ati o n o n l o n g er-t er m c o-m or bi diti es i n cl u di n g t h e i n ci d e n c e of  di a b e t es, c ar di o v as c ul ar m or bi dit y a n d m ort alit y, a n d o v er all i n ci d e n c e of n o n-pr ost at e c a n c er  s p e cifi c m ort alit y.   |                                |                                                               |                                                                               |               |
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| Pri m ar y  O bj e cti v e                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | R a n d o mi z e d c o h o rt: | T o c o m p ar e t h e                                        | m e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2                   | m o nt hs i n |
| p er c e nt a g e b o d y f at m ass                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | a m o n g                      | m e n                                                         | wit h pr ost at e c a n c er r e c ei vi n g a n dr o g e n d e pri v ati o n |               |
| t h er a p y r a n d o mi z e d t o p arti ci p at e i n t h e " S T A N D " cli ni c vs. us u al st a n d ar d of c ar e.  N o n -r a n d o mi z e d pil ot c o h o rt: T o d et er mi n e t h e f e asi bilit y of c o m pl eti n g m ulti -dis ci pli n ar y  S T A N D cli ni c vis its w hil e u n d er g oi n g c o n c urr e nt c h e m o h or m o n al t h er a p y f or pr ost at e c a n c er.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                |                                                               |                                                                               |               |
| S e c o n d ar y  O bj e cti v es                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | T o c o m p a r e t h e        | m e a n p e r c e nt c h a n g e f r o m b as eli n e t o 1 2 | m o nt hs a n d p att e r ns of c h a n g e                                   |               |
| o v e r ti m e d u ri n g p a rti ci p ati o n i n t h e S T A N D cli ni c vs. us u al st a n d a r d of c a r e wit h r es p e ct  t o:  M et a b oli c I m p a ct o n Di a b et es a n d C ar di o v as c ul ar Ris k F a ct ors:  - F asti n g bl o o d gl u c o s e  - F asti n g pl a s m a i ns uli n l e v el  - I ns uli n r esist a n c e as c al c ul at e d b y H O M A-I R  - H e m o gl o bi n A 1 c  - F asti n g li pi ds (t ot al c h ol est er ol, L D L, H D L, tri gl y c er ci d es)  - W aist cir c u mf er e n c e  - B o d y w ei g ht/ b o d y m ass i n d e x  - E x er cis e p att er ns as m e as ur e d b y v ali d at e d q u esti o n n air e a n d h o m e -b as e d a c c el er o m et er  ass ess m e nt  - Bl o o d pr ess ur e                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                |                                                               |                                                                               |               |  
| B o n e H e alt h:  - B o n e d e nsit y a s ass e ss e d b y D X A s c a n  - 2 5 -( O H) vit a mi n D s er u m l e v els  Q u a lit y of Lif e/ Ps y c h os o ci al I m p a ct:  - D e pr essi o n as m e as ur e d b y P H Q - 9  - C o g niti v e f u n cti o n a s m e a s ur e d b y t h e Att e nti o n al F u n cti o n al I n d e x  - O v er all q u alit y of lif e a s m e a s ur e d b y S F -1 2  - F ati g u e as m e as ur e d b y L e e F ati g u e S c al e  - Er e ctil e a n d uri n ar y f u n cti o n a s m e a s ur e d b y E PI C -2 6  - H ot fl as h s e v erit y a s m e a s ur e d b y H ot Fl a s h R el at e d D ail y I nt erf e r en c e S c al e  A m o n g m e n r a n d o mi z e d t o r e c ei v e us u al st a n d a r d of c a r e t h at c r oss -o v e r t o p a rti ci p at e i n  t h e S T A N D cli ni c aft e r m o nt h 1 2 of t h e st u d y:  T o m e as ur e t h e m e a n c h a n g e fr o m b as eli n e at st art of p arti ci p ati o n i n t h e S T A N D cli ni c aft er 1 2  m o nt hs of p arti ci p ati o n i n:  - M et a b oli c p ar a m et ers i n cl u di n g p er c e nt a g e b o d y f at, f asti n g i ns uli n/ gl u c os e, H O M A - I R, b o d y w ei g ht/ b o d y m ass i n d e x, w aist cir c u mf er e n c e  - B o n e h e alt h  - Q u alit y of lif e  A m o n g m e n i n t h e n o n -r a n d o mi z e d pil ot c o h o rt:  - T o d et er mi n e t h e m e a n c h a n g e fr o m b as eli n e t o 1 2 m o nt hs d uri n g S T A N D cli ni c  p arti ci p ati o n i n t h e pri m ar y a n d s e c o n d ar y m et a b oli c a n d q u alit y of lif e p ar a m et ers  list e d a b o v e.   |                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                   |        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|--------|
| C orr el ati v e  St u d y  O bj e cti v e s                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | -                                                                                                                                                                                                                                                                          | T o i n v esti g at e f or a r el ati o ns hi p b et w e e n i n h erit e d g e n eti c p ol y m or p his ms of f u n cti o n al  r el e v a n c e n e ar or wit hi n g e n es e n c o di n g pr ot ei ns wit h r ol es i n st er oi d h or m o n e tr a ns p ort  a n d a n dr o g e n r e c e pt or si g n ali n g wit h c h a n g es i n m et a b oli c p ar a m et ers a m o n g m e n  tr e at e d wit h a n dr o g e n d e pri v ati o n t h er a p y. |                   |        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | T o i n v esti g at e c h a n g es i n tr a b e c ul ar b o n e                                                                                                                                                                                                            | mi cr o -ar c hit e ct ur e as                                                                                                                                                                                                                                                                                                                                                                                                                               | m e as ur e d b y | Hi g h |
| R es ol uti o n P eri p h er al Q C T I m a gi n g of r a di us a n d ti bi a d uri n g a n dr o g e n d e pri v ati o n  t h er a p y.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                   |        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | T o i n v esti g at e f or r el ati o ns hi p b et w e e n 2 n d di git t o 4 t h di git l e n gt h r ati o n ( 2 D: 4 D r ati o)  a n d p er c e nt c h a n g e fr o m b as eli n e i n q u alit y of lif e m etri cs o n a n dr o g e n d e pri v ati o n  t h er a p y. |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                   |        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | T o i n v esti g at e f or a r el ati o ns hi p b et w e e n 2 n d di git t o 4 t h di git l e n gt h r ati o a n d b as eli n e  e m p at h y s c or e as m e as ur e d b y v ali d at e d q u esti o n n air e.                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                   |        |
| St u d y D esi g n                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | R a n d o mi z e d, p h as e 2 st u d y wit h cr oss -o v er d esi g n t o a ss ess t h e l o n git u di n al i m p a ct of t h e m ultidis ci pli n ar y S T A N D cli ni c o n c h a n g es i n k e y m et a b oli c p ar a m et ers, q u alit y of lif e, a n d p ati e nt  s atisf a cti o n a m o n g m e n r e c ei vi n g a n dr o g e n d e pri v ati o n t h er a p y f or pr ost at e c a n c er. A n o n - r a n d o mi z e d pil ot c o h ort of p ati e nts r e c ei vi n g c o n c urr e nt c h e m o h or m o n al t h er a p y will b e  e nr oll e d i n p ar all el t o ass ess t h e f e a si bilit y of S T A N D cli ni c p arti ci p ati o n i n t his p ati e nt  p o p u l ati o n.  R a n d o mi z e d st u d y s c h e m a:                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                   |        |  
  
  
| N u m b er of  p ati e nts                                                                                                                                                                                                                                                                                                                                                                                                            | 8 0 p ati e nts wit h p r ost at e c a n c er w h o ar e e x p e ct e d t o r e c ei v e at l e ast 1 2          | m o nt hs of a n dr o g e n   |       |
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| d e pri v ati o n t h er a p y fr o m t h e d at e of st u d y e nr oll m e nt will b e e nr oll e d .  A s e p ar at e n o n -r a n d o mi z e d p ati e nt c o h ort of 2 0 p ati e nts w h o ar e r e c ei vi n g c o n c urr e nt  c h e m o h or m o n al t h er a p y will b e e nr oll e d i n p ar all el.                                                                                                                    |                                                                                                                  |                               |       |
| D ur ati o n of  st u d y                                                                                                                                                                                                                                                                                                                                                                                                             | P ati e nts r a n d o mi z e d t o p arti ci p at e i n t h e S T A N D cli ni c will b e f oll o w e d f or 1 2 | m o nt hs.                    | M e n |
| i niti all y r a n d o mi z e d t o t h e us u al st a n d ar d-of -c ar e                                                                                                                                                                                                                                                                                                                                                            | will h a v e t h e o pti o n t o cr oss -o v er o nt o                                                           |                               |       |
| p arti ci p ati o n i n t h e S T A N D cli ni c aft er m o nt h 1 2, a n d will b e f oll o w e d i n t h e S T A N D cli ni c f or  a n a d diti o n al 1 2 m o nt hs or u ntil 6 m o nt hs f oll o wi n g l ast d os e of A D T, w hi c h e v er is s h ort er .  P ati e nts e nr oll e d i n t h e n o n -r a n d o mi z e d c h e m o h or m o n al c o h ort will p arti ci p at e i n S T A N D cli ni c  f or 1 2 m o nt hs. |                                                                                                                  |                               |       |
| St u d y                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                  |                               |       |
| Ass ess m e nts                                                                                                                                                                                                                                                                                                                                                                                                                       | I n t h e S T A N D cli ni c tr e at m e nt ar m, p ati e nts will h a v e e v er y 3 m o nt h visits wit h a h e alt h c ar e  pr o vi d er, al o n g wit h m o nt hl y e d u c ati o n al m o d ul es, a n d m ulti -dis ci pli n ar y a ss e ss m e nt a n d  c o u ns eli n g b y e x er cis e, n utriti o n, a n d s y m pt o m m a n a g e m e nt s er vi c e o n a r ot ati n g s c h e d ul e. I n  t h e us u al c ar e tr e at m e nt ar m, p ati e nts will h a v e e v er y 3 m o nt h visits wit h t h eir us u al h e alt h c ar e  pr o vi d er, a n d will h a v e u nr e stri ct e d a c c ess t o e x er cis e, n utriti o n, a n d s y m pt o m m a n a g e m e nt  s er vi c es u p o n p ati e nt r e q u est or as d e e m e d n e c ess ar y b y h e alt h c ar e pr o vi d er. I n t h e n o nr a n d o mi z e d c h e m o h or m o n al c o h ort, p ati e nts will h a v e s c h e d ul e m odifi e d a s n e c ess ar y t o fit wit h  c h e m ot h er a p y d osi n g s c h e d ul e b ut will h a v e o n a v er a g e e v er y 3 m o nt h c o u ns eli n g wit h p h ysi c al  t h er a pist, n utriti o n, a n d s y m pt o m m a n a g e m e nt.                                                                                                                  |                               |       |  
| St u d y       |                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
|----------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| E n d p oi nts | P ri m a r y E n d p oi nt  R a n d o mi z e d c o h ort:  M e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m a ss a s m e as ur e d b y  bi o el e ctri c al i m p e d a n c e a n al y z er.  N o n -r a n d o mi z e d c o h ort:  P er c e nt a g e of c o m pl et e d S T A N D cli ni c visits d uri n g t h e c o urs e of t h e 1 2 m o nt h S T A N D cli ni c  p arti ci p ati o n. |  
S e c o n d a r y E n d p oi nts M e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs a n d p att er ns of c h a n g e fr o m b as eli n e wit h r es p e ct t o t h e f oll o wi n g:  
M et a b oli c I m p a ct o n Di a b et es a n d C ar di o v as c ul ar Dis e as e Ris k F a ct ors:  
- F asti n g bl o o d gl u c o s e  
- F asti n g pl a s m a i ns uli n l e v el  
- I ns uli n r esist a n c e as c al c ul at e d b y H O M A-I R  
- H e m o gl o bi n A 1 c  
- F asti n g li pi ds (t ot al c h ol est er ol, L D L, H D L, tri gl y c er ci d es)  
- W aist cir c u mf er e n c e  
- B o d y w ei g ht/ b o d y m ass i n d e x  
- E x er cis e p att er ns as m e a s ur e d b y v ali d at e d q u esti o n n air e a n d a m b ul at or y a c c el er o m et er ass ess m e nt  
- Bl o o d pr ess ur e B o n e H e alt h:  
- B o n e d e nsit y at t h e l u m b ar s pi n e, f e m or al n e c k, a n d t ot al hi p as ass ess e d b y D X A s c a n a m o n g p ati e nts wit h o ut b o n e m et ast as es at t h e ti m e of st u d y e ntr y  
- S er u m 2 5 -( O H) vit a mi n D l e v els Q u alit y of Lif e/ Ps y c h os o ci al I m p a ct:  
- D e pr essi o n as m e as ur e d b y P H Q - 9  
- C o g niti v e f u n cti o n a s m e a s ur e d b y Att e nti o n al F u n cti o n al I n d e x  
- O v er all q u alit y of lif e a s m e a s ur e d b y S F -1 2  
- F ati g u e as m e as ur e d b y L e e F ati g u e S c al e  
- Er e ctil e a n d uri n ar y f u n cti o n a s m e a s ur e d b y E PI C -2 6  
- H ot fl as h s e v erit y a s m e a s ur e d b y H ot Fl a s h R el at e d D ail y I nt erf er e n c e S c al e  
| C o r r el ati v e St u d y E n d p oi nt s:  - Ass o ci ati o n b et w e e n i n h erit e d g e n eti c p ol y m or p his ms of f u n cti o n al r el e v a n c e n e ar or  wit hi n g e n es e n c o di n g pr ot ei ns wit h r ol es i n st er oi d h or m o n e tr a ns p ort a n d a n dr o g e n  r e ce pt or si g n ali n g wit h c h a n g es i n m et a b oli c p ar a m et ers a m o n g m e n tr e at e d wit h  a n dr o g e n d e pri v ati o n t h er a p y .  - M e a n c h a n g e fr o m b as eli n e i n tr a b e c ul ar b o n e ar c hit e ct ur e as m e a s ur e d b y tr a b e c ul ar  b o n e n u m b er ( T b N) a n d tr a b e c ul ar b o n e v ol u m e fr a cti o n ( B V/ T V) aft e r 1 2 m o nt hs of  a n dr o g e n d e pri v ati o n t h er a p y.   |
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untitled h1
li st of a b

| A E         | A d v ers e e v e nt                                                   |                                |
|-------------|------------------------------------------------------------------------|--------------------------------|
| C H R       | C o m mitt e e o n H u m a n R es e ar c h ( U C S F I R B)            |                                |
| C R C       | Cli ni c al R es e ar c h C o or di n at or                            |                                |
| C T M S     | Cli ni c al Tri al                                                     | M a n a g e m e nt S yst e m   |
| D S M C     | D at a a n d S af et y                                                 | M o nit ori n g C o m mitt e e |
| D S M P     | D at a a n d S af et y                                                 | M o nit ori n g Pl a n         |
| F D A       | F o o d a n d Dr u g A d mi nistr ati o n                              |                                |
| G C P       | G o o d Cli ni c al Pr a cti c e                                       |                                |
| H D F C C C | H el e n Dill er F a mil y C o m pr e h e nsi v e C a n c er C e nt er |                                |
| 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 R B       | I nstit uti o n al R e vi e w B o ar d                                 |                                |
| N CI        | N ati o n al C a n c er I nstit ut e                                   |                                |
| P R C       | Pr ot o c ol R e vi e w C o m mitt e e ( U C S F)                      |                                |  
| Table of Contents                                                                                                                                |                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| Protocol Signature Page ...................................................................................................................... 2 |                                                                                                               |
| ABSTRACT .                                                                                                                                       |                                                                                                               |
| L List of Abbreviations                                                                                                                          |                                                                                                               |
| 1. Background and Rationale                                                                                                                      |                                                                                                               |
| 1.1 Study Rationale and Clinical Significance ................................................................................................12 |                                                                                                               |
| 1.2 Rationale for the Clinical Study Endpoints                                                                                                   |                                                                                                               |
| 2. Hypothesis and Study Objectives                                                                                                               |                                                                                                               |
| 2.1 Hypothesis .                                                                                                                                 |                                                                                                               |
| 2 Study Objectives                                                                                                                               |                                                                                                               |
| 3. Study Design                                                                                                                                  |                                                                                                               |
| 3.1 Overall Study Characteristics                                                                                                                |                                                                                                               |
| 3.2 Study Endpoints                                                                                                                              |                                                                                                               |
| 3.3 Study Schema                                                                                                                                 |                                                                                                               |
| 4. Study Population                                                                                                                              |                                                                                                               |
| 4.1 Inclusion Criteria .                                                                                                                         |                                                                                                               |
| 4.2 Exclusion Criteria                                                                                                                           |                                                                                                               |
| 5.1  Lupron Depot (Leuprolide acetate for depot suspension) Description, Formulation                                                             |                                                                                                               |
| and  Storage                                                                                                                                     |                                                                                                               |
| 5.1.1 Description                                                                                                                                |                                                                                                               |
| 5.1.2 Formulation                                                                                                                                |                                                                                                               |
| 5.1.3 Storage                                                                                                                                    |                                                                                                               |
| 5.2.2 Formulation                                                                                                                                |                                                                                                               |
| 5.2.3 Storage                                                                                                                                    |                                                                                                               |
| 5.3.1 Description                                                                                                                                |                                                                                                               |
| 5.3.2 Formulation                                                                                                                                |                                                                                                               |
| 5.3.3 Storage                                                                                                                                    |                                                                                                               |
| 5.4                                                                                                                                              | Telstar Description, Formulation, and Storage ............................................................ 29 |
| 5.4.1 Description                                                                                                                                |                                                                                                               |
| 5.4.2 Formulation                                                                                                                                |                                                                                                               |
| 5.4.3 Storage                                                                                                                                    |                                                                                                               |
| 6. Drug Treatment Plan .                                                                                                                         |                                                                                                               |
| 6.1 LHRH Route of Administration, Primary Side Effects, and Dose Modifications and                                                               |                                                                                                               |
| Dosing Delays                                                                                                                                    |                                                                                                               |  
Protocol CC\# 135513  
| 6.1.1  Route of Administration .                                                                                                                                     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.1.2 Primary Side Effects .                                                                                                                                         |
| 7. Study Activities                                                                                                                                                  |
| 7.1 Study Schedule                                                                                                                                                   |
| 7.2 Screening Visit (within 6 weeks of Day 1 of Study) ...............................................................................33                             |
| 7.3 Randomization                                                                                                                                                    |
| 7.4 Day 1 Study Visit ............................................................................................................................................34 |
| 7.5 Day 1 and Monthly Study Visits (+/- 2 weeks) ........................................................................................34                          |
| 7.6 Every 3 Month Study Visits (+/- 2 weeks) .....................................................................................35                                 |
| 7.7 End of Month 12 Study Visit (+/- 2 weeks) ......................................................................................36                               |
| 7.8 Concomitant Medications ...........................................................................................................................37            |
| 7.9 Follow Up................................................................................................................................................37      |
| 7.10 Duration of Study .......................................................................................................................................37     |
| 8. Assessment of Study Variables .                                                                                                                                   |
| 8.1 Percent Body Fat Estimation ...............................................................................................................38                    |
| 8.2 Patient-Reported Outcomes .......................................................................................................................38              |
| 8.3 Germline Polymorphisms...........................................................................................................................38              |
| 8.4 High Resolution Peripheral Quantitative CT Imaging .....................................................................39                                       |
| 9. Planned Statistical Methods .                                                                                                                                     |
| 9.1 Study Design ...............................................................................................................................41                   |
| 9.2 Determination of Sample Size and Study Power .............................................................................41                                     |
| 9.3 Interim Analysis ..........................................................................................................................42                    |
| 9.4 Accrual.................................................................................................................................42                       |
| 9.5 Analysis Populations                                                                                                                                             |
| 9.6 Demographics and Baseline Characteristics ...................................................................................43                                  |
| 9.7 Study Endpoints ..........................................................................................................................43                     |
| 9.8 Methods for Analysis                                                                                                                                             |
| 10. Study Management .                                                                                                                                               |
| 10.1 Pre-study Documentation                                                                                                                                         |
| 10.2 Institutional Review Board Approval .........................................................................................47                                 |
| 10.3 Informed Consent                                                                                                                                                |
| 10.4 Changes in the Protocol ............................................................................................................48                          |
| 10.5 Case Report Forms (CRFs) ...........................................................................................................48                          |
| 10.6 Retention of Records ....................................................................................................................49                     |
| 1. References                                                                                                                                                        |
| Appendix 1. Selected Genetic Polymorphisms .                                                                                                                         |
| Appendix 2. Quality of Life Questionnaires                                                                                                                           |
| Appendix 3. Charlson Co-Morbidity Index                                                                                                                              |
| Appendix 4: Bioelectrical Impedance Device for Assessment of Percentage Body Fat ..... 67                                                                            |
| Appendix 5: Accelerometer For Ambulatory Recording of Activity Levels ........................ 68                                                                    |  
A p p e n di x 6. D at a a n d S af et y M o nit ori n g Pl a n f or a P h as e 2 I n stit uti o n al St u d y .............. 6 9 A p p e n di x 7. S p e ci m e n H a n dli n g a n d St or a g e .................................................................. 7 0
untitled h1
1. b a c k

A n dr o g e n d e pri v ati o n t h er a p y ( A D T), i n w hi c h t h e cir c ul ati n g s er u m t est ost er o n e is r e d u c e d t o a c ast rat e -r a n g e (l ess t h a n 5 0 n g/ d L), is a st a n d ar d tr e at m e nt o pti o n f or p ati e nts wit h pr ost at e c a n c er a cr oss a v ari et y of dis e as e st at es, i n cl u di n g a dj u v a nt t h er a p y f or l o c ali z e d dis e as e, a risi n g P S A aft er s u r g er y a n d/ or r a di ati o n t h er a p y, a n d f or r a di o gr a p hi c all y d et e ct a bl e m et ast ati c dis e as e t o t h e b o n es a n d ot h er or g a ns. A D T r e pr es e nts t h e m ost c o m m o n s yst e mi c t h er a p y a p pli e d i n pr ost at e c a n c er a n d n e arl y 4 0 % of m e n will r e c ei v e A D T wit hi n 6 m o nt hs of r e c ei vi n g pr ost at e c a n c er di a g n osis. T h o u g h i niti all y eff e cti v e i n t h e m aj orit y of p ati e nts i n l o w eri n g t h e s er u m P S A a n d c o ntr olli n g or pr e v e nti n g dis e as e pr o gr essi o n, A D T is ass o ci at e d wit h a m ultit u d e of c li ni c all y si g nifi c a nt y et p ot e nti all y tr e at a bl e t o xi citi es. T h es e i n cl u d e si d e eff e cts t h at c a n a d v ers el y a ff e ct q u alit y of lif e s u c h as h ot fl as h es, f ati g u e, d e cr e as e d li bi d o, er e ctil e d ysf u n cti o n ,  
g y n e c o m asti a, a n d m o o d/ c o g niti v e c h a n g es, w hi c h c a n a d v ers el y i m p a ct p ati e nts' r el ati o ns hi p wit h s p o us e, f a mil y m e m b ers, a n d c ar e gi v ers. A D T is ass o ci at e d wit h si g nifi c a nt m et a b oli c t o xiciti es i n cl u di n g i n cr e as e d ris k of i ns uli n r esist a n c e a n d di a b et es, i n cr e as e i n b o d y f at, l o w er b o d y m ass, a n d d e cr e as e d b o n e mi n er al d e nsit y , a n d i n cr e as e d ris k f or ost e o p or oti c fr a ct ur es [ 17 ]. T h e d e v el o p m e nt of t h e m et a b oli c a n d c ar di a c ris k f a ct ors o n A D T c a n p ar a d o xi c all y s h ort e n, r at h er t h a n e xt e n d, t h e lif e s p a n of m e n wit h pr ost at e c a n c er.  
M a n y of t h es e c h a n g es ar e m o difi a bl e wit h c ar ef ul m a n a g e m e nt, alt h o u g h c urr e nt pr a cti c e d at a s u g g est t h at t h e v ast m aj orit y of p h ysi ci a ns w h o pr es cri b e A D T d o n ot m a n a g e t h es e si d e eff e cts i n a c o nsist e nt w a y, if at all. A pri or pil ot st u d y i n w hi c h p ati e nts r e c ei v e d a n o n -i n di vi d u ali z e d e d u c ati o n al "t o ol -kit " c o nt ai ni n g i nf or m ati o n a n d r e c o m m e n d ati o ns wit h r es p e ct t o di et, e x er cis e, a n d ot h er lif est yl e m o difi c at i o ns a m o n g m e n st arti n g A D T i m pr o v e d p ati e nts s atisf a cti o n an d l e d t o p arti al lif est yl e c h a n g es; h o w e v er p ati e nt r et e nti o n o n t h e pr o gr a m w as i n c o m pl et e i n p art d u e t o l a c k of i n di vi d u ali z e d c o u ns eli n g [ 8]. I n di vi d u ali z e d, c o m pr e h e nsi v e m a n a g e m e nt of t h e p ot e nti al si d e eff e cts of A D T wit h t h e us e of a m ulti -dis ci pli n ar y cli ni c wit h  
"f a c e -t o-f a c e " c o u ns eli n g pr o vi d e d b y s p e ci alists a cr oss r el e v a nt dis ci pli n es m a y b e m or e eff e cti v e i n pr o m oti n g d ur a bl e c h a n g es i n lif est yl e f a ct ors a n d p ot e nti all y miti g ati n g th e si d e eff e cts of A D T, as c o m p a r e d t o us u al st a n d ar d of c ar e or n o n-i n di vi d u ali z e d e d u c ati o n al h a n do uts/ m at eri als. M ulti pl e pri or st u di es i n t h e pri m ar y c ar e s etti n g d e m o nstr at e t h at hi g h er i nt e nsit y, i n di vi d u ali z e d c o u ns eli n g, as c o m p ar e d t o l ess i nt e nsi v e c o u ns eli n g i n cl u di n g a ut o m at e d w e b - or t el e p h o n e -b as e d pr o gr a ms , l e a d t o m or e s u bst a nti al c h a n g es i n lif est yl e h a bits, i n cl u di n g i m pr o v e d di et, w ei g ht r e d u cti o n, a n d s m o ki n g c ess ati o n , a n d m a y i n f a ct b e m or e c ost -eff e cti v e w h e n c o nsi d eri n g t h e i m pr o v e m e nt i n r at es of c o -m or bi dit y ass o ci at e d wit h hi g h er i nt e nsit y c o u ns eli n g [ 9 - 1 1]. I n m e n i niti ati n g A D T, pr os p e cti v e p arti ci p ati o n i n a str u ct ur e d cli ni c f o c us e d o n miti g ati n g t h e m et a b oli c si d e eff e cts of t h er a p y h as pr o v e n t o b e f e asi bl e a n d t o p ot e nti all y l ess e n w ei g ht g ai n, pr e v e nt d e c a y i n b o n e d e nsit y/ b o n e h e alt h, a n d miti g at e a d v ers e eff e cts o n f asti n g li pi ds i n a r e c e ntl y r e p ort e d A ustr ali a n o bs er v ati o n al st u d y  
[ 1 2]. T h us, t h er e is a str o n g r ati o n al e t o dir e ctl y c o m p ar e p arti ci p ati o n i n a m ulti - dis ci pli n ar y cli ni c wit h st a n d ar d - of-c ar e p h ysi ci a n visits i n a r a n d o mi z e d f as hi o n a m o n g m e n r e c ei vi n g a n dr o g e n d e pri v ati o n t h er a p y, t o ass ess w h et h er cli ni c p arti ci p ati o n l e a ds t o i m pr o v e m e nts i n m et a b oli c t o xi citi es ass o ci at e d wit h t his t h er a p y.  
T h e " S T A N D ( S u p p orti v e T h er a p y i n A N dr o g e n D e pri v ati o n) " Cli ni c at U C S F w as cr e at e d f or p ati e nts tr e at e d wit h A D T t o a d dr ess a n d miti g at e t h e a d v ers e eff e cts of h or m o n e t h er a p y. T h e i nt e nt is t o pr o vi d e " o n e st o p s h o p pi n g " a n d i n di vi d u ali z e d c o u ns eli n g a n d t h er a p y a cr oss a n u m b er of diff er e nt dis ci pli n es, cli ni cs a n d s er vi c es. D uri n g t h e c o urs e of a n i nt e gr at e d visit, t h e p ati e nt will h a v e t h e f oll o wi n g p ers o n ali z e d ass ess m e nt a n d c o u ns eli n g:  
- P ati e nt c ar e a n d c o u ns eli n g b y tr ai n e d p h ysi ci a n or n urs e pr a ctiti o n er  
- N utriti o n c o u ns eli n g wit h tr ai n e d di etiti a n  
- E x er cis e tr ai ni n g wit h c ertifi e d e x er cis e tr ai n er wit h e x p ertis e i n c a n c er p ati e nts  
- M e di c ati o n m a n a g e m e nt i n cl u di n g L H R H a n al o g u e i nj e cti o ns  
- C ar di o v as c ul ar m o nit ori n g a n d ris k r e d u cti o n, i n cl u di n g h y p ert e n si o n, h y p erli pi d e mi a, gl u c os e m o nit ori n g, a n d c ar di a c ris k str atifi c ati o n  
- B o n e h e alt h m o nit ori n g a n d m a n a g e m e nt  
- E v al u ati o n a n d c o u ns eli n g f or r e g ar di n g s y m pt o ms a n d r el ati o ns hi p a n d m o o d c h a n g es b y s y m pt o m m a n a g e m e nt s er vi c e  
- Ass ess m e nt of q u alit y of lif e a n d si d e eff e cts of A D T wit h v ali d at e d q u esti o n n air es T h e c urr e nt r a n d o mi z e d p h as e 2 cr oss -o v er st u d y is d esi g n e d t o pr eli mi n ar y e v al u at e t h e l o n git u di n al i m p a ct of p arti ci p ati o n i n t h e " S T A N D " cli ni c ( as c o m p ar e d t o us u al st a n d ar d of c ar e) o n k e y m et a b oli c p ar a m et ers, q u alit y of lif e, a n d p ati e nt s atisf a cti o n f or m e n r e c ei vi n g h or m o n e t h er a p y f or pr ost at e c a n c er. Aft er 1 2 m o nt hs o n st u d y, p ati e nts r a n d o mi z e d t o t h e us u al st a n d ar d- of-c ar e tr e at m e nt ar m will h a v e t h e o p p ort u nit y t o cr oss -o v er a n d p arti ci p at e i n t h e S T A N D cli ni c f or t h e e ns ui n g 1 2 m o nt hs or f or t h e r e m ai n d er of A D T d ur ati o n, w hi c h e v er is s h ort er. S h o ul d t h e r es ults i n di c at e a b e n efi ci al i m p a ct of p arti ci p ati o n i n a m ulti -dis ci pli n ar y cli ni c i n miti g ati n g t h e s h ort - a n d i nt er m e di at e -t er m t oxi citi es of A D T, t his w o ul d f or m t h e j ustifi c ati o n f or l ar g er r a n d o mi z e d cli ni c al tri als t o ass ess t h e i m p a ct of cli ni c p arti ci p ati o n o n l o n g er-t er m c o-m or bi diti es i n cl u di n g t h e i n ci d e n c e of di a b et es, c ar di o v as c ul ar m or bi dit y a n d m ort alit y, a n d o v er all i n ci d e n c e of n o n- pr ost at e c a n c er s p e cifi c m ort alit y.  
A s e p ar at e n o n -r a n d o mi z e d c o h ort of p ati e nts r e c ei vi n g c o n c urr e nt c h e m o h or m o n al t h er a p y will b e e nr oll e d t o ass ess t h e f e asi bilit y of S T A N D cli ni c p arti ci p ati o n a m o n g p ati e nts r e c ei vi n g c h e m ot h er a p y f or pr ost at e c a n c er.
untitled h1
1. 2 r ati o

T h e pri m ar y e n d p oi nt of t h e c urr e nt st u d y will b e t h e m e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m ass as c al c ul at e d b y bi o el e ctri c al i m p e d e n c e a n al y z er. Pri or l o n git u di n al st u di es h a v e d e m o nstr at e d a c o nsist e nt m e a n p er c e nt a g e i n cr e as e i n p er c e nt a g e f at m as s of 1 1- 1 2% ( +/- 1. 5 %) aft er 1 y e ar of a n dr o g e n d e pri v ati o n t h er a p y [ 1 3]. Cr oss- s e cti o n al i m a gi n g st u di es h a v e s h o w n a str o n g c orr el ati o n wit h p er c e nt a g e b o d y f at i n cr e as es o n A D T wit h i n cr e as es i n pr e d o mi n a ntl y s u b c ut a n e o us a di p os e tiss u e. I n cr e as es i n b o d y f at m ass d uri n g A D T  
ar e str o n gl y ass o ci at e d wit h ot h er ris k f a ct ors f or d i a b et es a n d c ar di o v as c ul ar dis e as e, i n cl u di n g d ysli pi d e mi a, i ns uli n r esist a n c e, a n d o b esit y . R es ults o bt ai n e d vi a us e of a bi o el e ctri c al i mp e d e n c e a n al y z er c orr el at e wit h t h e us e of ot h er p er c e nt b o d y f at ass ess m e nts, i n cl u di n g d u al e n er g y X -r a y a bs or pti o m etr y ( D E X A) a n d u n d er w at er w ei g hi n g m et h o d ol o gi es, a n d i ntr a-p ati e nt v ari a bilit y is l o w [ 1 4].  
M e as uri n g p er c e nt a g e b o d y f at wit h h a n d h el d bi o el e ctri c al i m p e d a n c e d e vi c e t h us r e pr es e nts a r e a dil y o bt ai n a bl e, f e asi bl e, a n d cli ni c all y r el e v a nt m ar k er of t h e m et a b oli c i m p a ct of a n dr o g e n d e pri v ati o n t h er a p y. It is h y p ot h esi z e d t h at c o m pr e h e nsi v e m ulti -dis ci pli n ar y c o u ns eli n g m a y pr o m ot e s ust ai n e d lif est yl e c h a n g es wit h r es p e ct t o di et a n d e x er cis e w hi c h m a y p arti all y miti g at e t h e a d v ers e m et a b oli c i m p a ct of A D T o n p er c e nt b o d y f at, a n d i n t ur n, d e cr e as e t h e ris k of l o n g er t er m m et a b oli c d er a n g e m e nts i n cl u di n g i n ci d e n c e of di a b et es a n d c ar di o v as c ul ar m or bi dit y a n d m ort alit y.
untitled h1
1. 2 . 2 r

Pri or pr os p e cti v e l o n git u di n al st u di es h a v e c h ar a ct eri z e d t h e p ot e nti al i m p a ct of a n dr o g e n d e pri v ati o n t h er a p y o n m et a b oli c ris k f a ct ors f or c ar di o v as c ul ar dis e as e a n d di a b et es. A m o n g t h es e i n cl u d e c o nsist e nt i n cr e as es i n f asti n g pl as m a i ns uli n a n d i ns uli n r esist a n c e as m e as ur e d b y t h e H o m e ost ati c M o d el ( H O M A-I R), i n cr e as es i n h e m o gl o bi n A 1 c, d ysli pi d e mi a i n cl u di n g i n cr e as es i n t ot al c h ol est er ol a n d s er u m tri gl y c eri d es, as w ell as c h a n g es i n b o d y c o m p ositi o n i n cl u di n g i n cr e as e i n b od y w ei g ht, w aist cir c u mf er e n c e [ 1 3, 1 5]. I n cr e as es i n h e m o gl o bi n A 1 c a n d ot h er m ar k ers of i ns uli n r esist a n c e d uri n g A D T ar e oft e n cli ni c all y si g nifi c a nt; a n dr o g e n d e pri v ati o n t h er a p y w as ass o ci at e d wit h a n i n cr e as e d ris k of t h e d e v el o p m e nt of di a b et es o n m ulti v ari at e a n al ysis i n pri or l ar g e r etr os p e cti v e st u d y [ 7]. E v er y 1 % i n cr e as e i n h e m o gl o bi n A 1 C w as ass o ci at e d wit h i n cr e as e d ris k of mi cr o v as c ul ar c o m pli c ati o ns i n cl u di n g r eti n o p at h y, n e p hr o p at h y, a n d n e ur o p at h y [ 1 6 ]. T h e H O M A-I R i n d e x is str o n gl y ass o ci at e d wit h s u bs e q u e nt ris k of d e v el o pi n g di a bet es a n d c ar di o v as c ul ar dis e as e i n pri or pr os p e cti v e st u di es [ 1 7] . W h et h er or n ot t h e i m p a ct of A D T o n t h es e m et a b oli c p ar a m et ers tr a nsl at es i nt o a n i n cr e as e d ris k of c ar di o v as c ul ar m ort alit y is u n cl e ar wit h pri or st u di es pr o vi d e d mi x e d e vi d e n c e. M e as uri n g t h es e a d diti o n al e n d p oi nts is li k el y t o pr o vi d e a m or e c o m pr e h e nsi v e ass ess m e nt of t h e i m p a ct of p arti ci p ati o n i n t h e S T A N D cli ni c o n t h e m et a b oli c t o xi citi es of a n dr o g e n d e pri v ati o n, as c o m p ar e d t o m e as ur e m e nt of c h a n g es i n p er c e nt a g e b o d y f at al o n e.
untitled h1
1 . 2. 3 b

F or m e n wit h o ut b o n e m et ast as es at t h e ti m e of st u d y e ntr y, t h e m e a n c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n b o n e mi n er al d e nsit y as ass ess e d b y D X A s c a n will b e a s e c o n d ar y st u d y e n d p oi nt i n t h e c urr e nt o bs er v ati o n st u d y. N u m er o us pri or st udi es h a v e c h ar a ct eri z e d t h e d e c li n e i n b o n e mi n er al d e nsit y o bs er v e d wit h a n dr o g e n d e pri v ati o n t h er a p y. I n a pri or r a n d o mi z e d tri al c o m p ari n g st a n d ar d A D T t o hi g h -d os e bi c al ut a mi d e ( a n o n -c astr ati n g A R a nt a g o nist), t h e m e n r a n d o mi z e d t o t h e A D T tr e at m e nt ar m h a d a m e a n d e cli n e fr o m b as eli n e i n l u m b ar s pi n e b o n e mi n er al d e nsit y of 2. 5 % aft er 1 2 m o nt hs of t h er a p y [ 1 8]. R e d u cti o ns i n b o n e mi n er al d e nsit y wit h A D T ar e cli ni c all y r el e v a nt - pri or o bs er v ati o n al st u di es h a v e als o d e m o nstr at e d a n i n cr e as e d ris k of ost e o p or oti c fr a ct ur es wit h a n dr o g e n d e pri v ati o n t h er a p y [ 1 9].
untitled h1
1. 3. 4 q u

A n dr o g e n d e pri v ati o n t h er a p y is ass o ci at e d wit h a n a d v ers e i m p a ct o n o v er all q u alit y of lif e as t y pi c al si d e eff e cts i n cl u di n g h ot fl as h es, er e ctil e d ysf u n cti o n, f ati g u e, a n d d e pr essi o n.
untitled h1
1. 3. 4. 1 o

A v ali d at e d m e as ur e of g e n er al q u alit y of lif e is t h e S F - 1 2 Q O L s ur v e y , a n a b br e vi at e d f or m of t h e S F-3 6 wit h w hi c h it is ti g htl y c orr el at e d [ 2 0]. I n a pri or pr os p e cti v e st u d y of m e n u n d er g oi n g A D T, t h er e w as a st atisti c all y a n d cli ni c all y si g nifi c a nt m e a n d e cr e as e fr o m b as eli n e i n t h e s c or es of s e v er al d o m ai ns wit hi n t h e S F -3 6 pr ofil e, i n cl u di n g g e n er al h e alt h, vit alit y, a n d c o m p osit e p h ysi c a l h e alt h [ 2 1].
untitled h1
1. 3. 4. 2 h

H ot fl as h es ar e a c o m m o n a n d b ot h ers o m e s y m pt o m ass o ci at e d wit h a n dr o g e n d e pri v ati o n t h er a p y, t h o u g h t h e ex a ct m e c h a nis m r e m ai ns u n cl e ar. Pri or st u di es e x a mi ni n g t h e i m p a ct of A D T o n h ot fl as h es h a v e us e d a v ari et y of s c al es t o m e as ur e t h e i n ci d e n c e a n d s e v erit y of h ot fl as h es, i n cl u di n g t h e H ot Fl as h S c or e. T h e c urr e nt st u d y will us e t h e H ot Fl as h R el at e d D ail y R el at e d I nt erf er e n c e S c al e ( H F R DI S), w hi c h h as pr e vi o usl y b e e n v ali d at e d i n a st u d y p o p ul ati o n of br e ast c a n c er s ur vi v ors c o m p ar e d t o a g e - mat c h e d c o ntr ols [ 2 2 ]. I n t his st u d y, t h e H F R DI S  
w as i nt er n all y c o nsist e nt, d e m o nstr at e d c orr el ati o ns wit h ot h er h ot fl as h v ari a bl es, c orr el at e d wit h m e as ur es of aff e ct a n d m o o d, a n d d e m o nstr at e d s e nsiti vit y t o c h a n g e o v er ti m e.
untitled h1
1. 3. 4 . 3

Er e ctil e d ysf u n cti o n is a w ell -c h ar a ct eri z e d c o m pli c ati o n of a n dr o g e n d e pri v ati o n t h er a p y, b ot h i n m e n wit h a n d t h os e wit h o ut pri or r a di c al pr ost at e ct o m y or r a di ati o n t h er a p y t o t h e pr ost at e gl a n d . E PI C - 2 6 is a w ell-v ali d at e d m e as ur e m e nt of er e ctil e a n d uri n ar y f u n cti o n w hi c h h as b e e n st u di e d i n v ari o us dis e as e s etti n gs i n cl u d e d pri or pr ost at e c a n c er st u di es a n d will b e us e d t o m e as ur e er e ctil e f u n cti o n i n t h e c urr e nt st u d y [ 2 3].
untitled h1
1. 3. 4. 4 f

F ati g u e is a c o m m o n a n d b ot h ers o m e si d e eff e ct of a n dr o g e n d e pri v ati o n t h er a p y w hi c h c a n h a v e a n a d v ers e i m p a ct o n q u alit y of lif e f or s o m e m e n r e c ei vi n g a n dr o g e n d e pri v ati o n t h er a p y. I n a pri or cr oss -s e cti o n al st u d y c o m p ari n g 5 7 m e n r e c ei vi n g A D T wit h 5 1 a g e -m at c h e d c o ntr ols, m or e m e n i n t h e A D T gr o u p h a d s e v er e f ati g u e c o m p ar e d t o t h e c o ntr ol c o h ort ( 1 4 % vs. 4 %, p =  
0. 0 3) . T h e L e e F ati g u e s c al e is a w ell -v ali d at e d vis u al a n al o g m e as ur e of f ati g u e, w hi c h h as d e m o nstr at e d hi g h r eli a bilit y a n d v ali dit y c o m p ar e d t o t h e St a nf or d Sl e e pi n ess S c al e [ 2 4]. T h e L e e F ati g u e S c al e will b e us e d t o m e as ur e t h e d e gr e e of f ati g u e a n d c h a n g e i n e n er g y l e v el e x p eri e n c e d b y p ati e nts r e c ei vi n g A D T i n t h e c urr e nt st u d y.
untitled h1
1. 3. 4 . 5

D e pr essi o n is c o m m o n a n d fr e q u e ntl y u n d er di a g n os e d a m o n g m e n r e c ei vi n g A D T f or pr ost at e c a n c er. Pri or st u di es i n di c at e a r at e of d e pr essi o n i n t his p ati e nt p o p ul ati o n t h at f ar e x c e e ds t h e e x p e ct e d pr e v al e n c e a m o n g a g e -m at c h e d c o ntr ols. I n a pri or cr oss -s e cti o n al st u d y of 4 5 m e n r e c ei vi n g A D T ( m e di a n d ur ati o n of A D T w as 3. 3 y e ars), t h e pr e v al e n c e of d e pr essi o n as s cr e e n e d f or b y t h e str u ct ur e d cli ni c al i nt er vi e w usi n g t h e D S M -I V crit eri a w as 1 2. 8 %, 8 ti m es t h at of t h e n ati o n al a v er a g e i n m e n [ 2 5]. I n t h e c urr e nt st u d y, t h e P H Q - 9, a w ell -v ali d at e d s cr e e ni n g m etri c f or d e pr essi o n c o nsisti n g of 9 it e ms, will b e us e d t o m e as ur e t h e c h a n g e i n d e pr essi v e s y m pt o ms a m o n g m e n b ei n g tr e at e d wit h a n dr o g e n d e pri v ati o n t h er a p y f or h or m o n e s e nsiti v e pr ost at e c a n c er. P H Q -9 r es ults m ust b e r e vi e w e d b y tr e ati n g h e a lt h-c ar e pr o vi d er d uri n g t h e c o urs e of p ati e nt's st u d y visit.
untitled h1
1. 3. 4. 6 c

T h er e is mi x e d e vi d e n c e r e g ar di n g t h e i m p a ct of a n dr o g e n d e pri v ati o n t h er a p y o n c o g niti o n.  
S e v er al st u di es h a v e d e m o nstr at e d d e cr e m e nts i n ps y c h o m ot or s p e e d/ pr o c essi n g s p e e d, r e a cti o n ti m es, a n d w or ki n g m e m or y. V er b al m e m or y a n d fl u e n c y h a v e s h o w n m or e mi x e d eff e cts i n pri or st u di es. T h e Att e nti o n al F u n cti o n I n d e x is a w ell -v ali d at e d m etri c of w or ki n g m e m or y a n d pr o c essi n g s p e e d t h at w as c h os e n f or t h e c urr e nt st u d y t o b ett er c a pt ur e t h e s p e cifi c c o g niti v e as p e cts p ot e nti all y aff e ct e d b y A D T.
untitled h1
1. 3. 5. 1 g

I n c o ntr ast t o m e as uri n g t h e ass o ci ati o n b et w e e n effi c a c y of A D T a n d g er mli n e p ol y m or p his ms, t he ass o ci ati o n b et w e e n A D T t o xi cit y a n d g er mli n e v ari ati o n i n g e n es e n c o di n g pr ot ei ns i n v ol v e d i n st er oi d bi os y nt h esis or dr u g m et a b olis m is l ar g el y u n e x pl or e d. I n m et ast ati c h or m o n e- r e c e pt or p ositi v e br e ast c a n c er, c ert ai n p ol y m or p his ms wit hi n t h e estr o g e n r e c e pt or g e n e w er e ass o ci at e d wit h i n cr e as e d i n ci d e n c e of h ot fl as h es i n p ati e nts tr e at e d wit h t a m o xif e n  
[ 2 6].  
Wit h r es p e ct t o pri m ar y a n dr o g e n d e pri v ati o n t h er a p y wit h L H R H a g o nists, t h er e h a v e b e e n s e v er al st u di es i n v esti g ati n g t h e ass o ci ati o n of S N Ps i n g e n es b el o n gi n g t o t h e a n dr o g e n s y nt h esis p at h w a y a n d dis e as e o ut c o m e. I n a pri or st u d y i n v esti g ati n g t h e ass o ci ati o n b et w e e n g e n ot y p es fr o m 1 2 7 S N Ps i n 2 0 diff er e nt g e n es wit hi n t h e a n dr o g e n s y nt h eti c p at h w a y wit h dis e as e o ut c o m es i n m e n tr e at e d wit h A D T f or a d v a n c e d pr ost at e c a n c er, t hr e e p ol y m or p his ms i n s e p ar at e g e n es ( C Y P 1 9 A 1, H S D 3 B 1, a n d H S D 1 7 B 4) w er e ass o ci at e d wit h ti m e t o pr o gr essi o n o n m ulti v ari at e a n al ysis [ 2 7]. L ess is k n o w n, h o w e v er, a b o ut t h e ass o ci ati o n b et w e e n p ol y m or p his ms wit hi n c a n di d a t e g e n es t h at mi g ht pr e di ct f or s o m e of t h e p ot e nti al t o xi citi es of A D T, i n cl u di n g t h e m et a b oli c t o xi citi es dis c uss e d a b o v e. Pr e di cti n g p ot e nti al t o xi cit y of A D T  
m a y b e ulti m at el y us e d t o g ui d e cli ni ci a ns i n a v ari et y of cli ni c al s c e n ari os, i n cl u di n g ti mi n g of i niti ati o n of A D T i n m e n wit h bi o c h e mi c all y r el a ps e d dis e as e.  
T h e c urr e nt st u d y s a m pl e si z e will p er mit o nl y a n e x pl or at or y a n al ysis of t h e ass o ci ati o ns b et w e e n f u n cti o n al, n o n -s y n o n y m o us g er mli n e p ol y m or p his ms a n d t h e m et a b oli c t o xi cit y of A D T. T h e h y p ot h esis is t h at p ol y m or p his ms of f u n cti o n al r el e v a n c e w hi c h d e pl et e i ntr a -c ell ul ar a n dr o g e ns m a y b e ass o ci at e d wit h a n i n cr e as e d li k eli h o o d of m et a b oli c t o xi citi es r el at e d t o a n dr o g e n d e pri v ati o n t h er a p y, i n cl u di n g i n cr e asi n g ris k of i ns uli n r esist a n c e.  
1. 3. 5. 2 T r a b e c ul a r B o n e Mi c r o- A r c hit e ct u r e C h a n g es i n B M D, es p e ci all y t h os e m e as ur e d usi n g D X A d o n ot r efl e ct t h e c h a n g es t a ki n g pl a c e i n t h e c orti c al a n d tr a b e c ul ar b o n e c o m p art m e nts a n d d o n ot e ntir el y e x pl ai n b o n e str e n gt h a n d fr a ct ur e ris k. W e h a v e r e c e ntl y s h o w n, usi n g hi g h-r es ol uti o n p eri p h er al c o m p ut e d t o m o gr a p h y  
( H R p Q C T), t h at a g e a n d m et a b olis m r el at e d c h a n g es i n t h es e c o m p art m e nts diff er a n d r e gi o n al c h a n g es i n mi cr o -ar c hit e ct ur e h a v e pr of o u n d i m p a ct o n bi o m e c h a ni c al c h ar a ct eristi cs of b o n e.  
M a g n eti c r es o n a n c e i m a gi n g m a y b e us e d t o q u a ntif yf att y i nfiltr at i o n i n m us cl e o r s a r c o p e ni a t h us m a y b e a p ot e nti al s urr o g at e f or ass essi n g l oss of str e n gt h. I n a p ri o r st u d y of 2 6 m e n wit h m et ast ati c pr ost at e c a n c er o n A D T t h e l oss i n t h e c orti c al b o n e c o m p art m e nt is gr e at er t h a n i n tr a b e c ul ar b o n e, a n d t h at t h e l oss i n tr a b e c ul ar b o n e is r es p o nsi bl e f or t r a b e c ul a r b o n e d e c r e as es . T h es e diff er e nti al eff e cts i n c orti c al a n d tr a b e c ul ar b o n e, a n d l oss of tr a b e c ul ar n u m b er h as pr of o u n d eff e cts o n b o n e str e n g t h. F urt h er m or e, t h e diff er e n c es b et w e e n b o n e l oss i n m e n wit h m et ast ati c dis e as e m a y b e diff er e nt t h a n t h os e o n pri m ar y pr ost at e c a n c er a n d at t h e i niti ati o n of A D T t h er a p y. T h us, w e f e el a gr o u p of m e n wit h pri m ar y pr ost at e c a n c er st arti n g o n A D T w o ul d s er v e as a b ett er m o d el f or m al e ost e o p or osis, a n d assist i n d es cri bi n g t h e ti m e -  
c o urs e of m al e h or m o n e d efi ci e nt o ns et of ost e o p or osis. Hi g h -r es ol uti o n p eri p h er al c o m p ut e d t o m o gr a p h y is a l o w d os e t e c h ni q u e t h at pr o vi d es i m a g es d e pi cti n g c orti c al a n d tr a b e c ul ar b o n e str u ct ur e.  
R e gi o n al v ari ati o n i n tr a b e c ul ar str u ct ur e a cr oss a xi al s e cti o ns is oft e n o bs c ur e d b y t h e c o n v e nti o n al gl o b al a n al ysis, w hi c h t a k es a n a v er a g e v al u e f or t h e e ntir e c o m p art m e nt. W e h a v e c h ar a ct eri z e d s p ati al v ari a bilit y i n tr a b e c ul ar str u ct ur e wit hi n a cr oss -s e cti o n at t h e dist al r a di us a n d ti bi a, a n d g e n d er a n d a g e eff e cts usi n g i n vi v o hi g h -r es ol uti o n p eri p h er al q u a ntit ati v e c o m p ut e d t o m o gr a p h y ( H R -p Q C T) i n 1 4 6 h e alt h y i n di vi d u als a g e d 2 0 -7 8 y e ars. Tr a b e c ul ar b o n e v ol u m e fr a cti o n ( B V/ T V), n u m b er ( T b. N), t hi c k n ess ( T b. T h), s e p ar ati o n ( T b. S p), a n d h et er o g e n eit y ( T b. 1/ N. S D) w er e o bt ai n e d i n a t ot al of 1 1 r e gi o ns -t h e e ntir e tr a b e c ul ar c o m p art m e nt (t h e gl o b al m e a ns), i n n er, o ut er, a n d ei g ht d efi n e d s u br e gi o ns. R e gi o n al v ari ati o ns w er e e x a m i n e d wit h r es p e ct t o t h e gl o b al m e a ns, a n d c o m p ar e d b et w e e n w o m e n a n d m e n, a n d b et w e e n y o u n g ( 2 0 -2 9 y e ars ol d) a n d el d erl y ( 6 5 -7 9 y e ars ol d) a d ults. S u bst a nti al r e gi o n al v ari ati o ns i n tr a b e c ul ar b o n e str u ct ur e at t h e dist al r a di us a n d ti bi a w er e r e v e al e d ( e. g. B V/ T V  
v ari e d -4 0 % t o + 5 7 % a n d -5 9 % t o + 1 0 0 % of t h e gl o b al m e a ns, r es p e cti v el y, f or el d erl y w o m e n).  
T h e i n n er -l at er al (I L) s u br e gi o n h a d l o w B V/ T V, T b. N, a n d T b. T h, a n d l o w T b. S p a n d T b. 1/ N. S D at b ot h sit es; t h e o p p osit e w as tr u e i n t h e o ut er -a nt eri or ( O A) s u br e gi o n at t h e dist al r a di us a n d t h e o ut er-m e di al ( O M) a n d -p ost eri or ( O P) s u br e gi o ns at t h e dist al ti bi a. G e n d er diff er e n c es w er e m ost pr o n o u n c e d i n t h e i n n er -a nt eri or (I A) s u br e gi o n c o m p ar e d t o t h e ot h er r e gi o ns or t h e gl o b al m e a n diff er e n c es at bot h sit es. Tr a b e c ul ar str u ct ur e ass o ci at e d wit h a g e a n d diff er e d b et w e e n y o u n g a n d el d erl y a d ults pr e d o mi n a ntl y i n t h e i n n er -p ost eri or (I P) s u br e gi o n at t h e dist al r a di us a n d i n t h e I L a n d I A s u br e gi o ns at t h e dist al ti bi a; o n t h e ot h er h a n d, it r e m ai n e d u n c h a n g e d i n t h e O A s u br e gi o n at t h e dist al r a di us a n d i n t h e O M s u br e gi o n at t h e dist al ti bi a f or b ot h w o m e n a n d m e n. W e d e m o nstr at e d t h at n ot o nl y t h e c o n v e nti o n al gl o b al a n al ysis c a n o bs c ur e r e gi o n al diff er e n c es, b ut als o ass u mi n g b o n e st at us fr o m t h at o f s m all er s u br e gi o n m a y i ntr o d u c e a c o nf o u n di n g s a m pli n g err or. T h er ef or e, a c o m bi n e d a p pr o a c h of i n v esti g ati n g t h e e ntir e r e gi o n, e a c h s u br e gi o n, a n d t h e c orti c al c o m p art m e nt m a y off er m or e c o m pl et e i nf or m ati o n.
untitled h1
1. 3. 5. 3 s

T h e r ati o b et w e e n t h e l e n gt h of t h e 2 n d a n d 4t h di gits, t y pi c all y m e as ur e d o n t h e ri g ht h a n d, is a p h ysi c al tr ait t h at c orr el at es wit h f et al t est ost er o n e e x p os ur e. T h e fi n di n g c a n b e m e as ur e d t hr o u g h o ut lif e a n d c orr elat es wit h p h ysi c al m a nif est ati o ns a n d dis e as e pr o c ess es t h at ar e ass o ci at e d wit h a n dr o g e n e x c ess es s u c h as a utis m, m y o c ar di al i nf ar cti o n a n d pr ost at e c a n c er. It h as als o b e e n ass o ci at e d wit h b e h a vi or al tr aits t h at ar e c o m m o nl y ass o ci at e d wit h a n dr o g e n e x c e ss, s u c h as ris k t a ki n g.  
Alt h o u g h t h e li n k b et w e e n 2 d: 4 d r ati o a n d pr ost at e c a n c er h as b e e n est a blis h e d i n o n e st u d y p ati e nt wit h a p ositi v e 2 d: 4 d r ati o (i n d e x fi n g er l o n g er t h a n t h e ri n g fi n g er o n t h e ri g ht h a n d) h a d a 3 3 % r e d u c e d ris k of pr ost at e c a n c er .  
Gi v e n t h at it is a m ar k er of br ai n ' pri mi n g' b y t est ost er o n e, w e h y p ot h esi z e t h at p ati e nts wit h a hi g h er 2 d: 4 d r ati o ( gr e at er t est ost er o n e e x p os ur e i n ut er o) will b e m or e s e nsiti v e t o c h a n g es i n s er u m t est ost er o n e at a n y p oi nt i n lif e a n d t h er ef or e will e x p eri e n c e a gr e at er d e gr e e of t y pi c al a n dr o g e n d e pri v ati o n t o xi citi es ( h ot fl us h es, d e cr e as e d q u alit y of lif e, m o o d s wi n gs et c.) t h a n t h os e wit h a l o w er r ati o.  
T h e r ati o is m e as ur e d o n t h e ri g ht h a n d a n d c a n b e p erf or m e d at a n y p oi nt i n st u d y e ntr y.
untitled h1
2. h y p ot

T h e pri m ar y h y p ot h esis of t h e st u d y is t h at a cti v e p arti ci p ati o n i n a m ulti-dis ci pli n ar y cli ni c wit h i n di vi d u ali z e d c o u ns eli n g r e g ar di n g e x er cis e a n d di et ar y h a bits, as c o m p ar e d t o st a n d ar d- of-c ar e wit h p h ysi ci a n c o u ns eli n g d uri n g t h e fr a m e w or k of f oll o w -u p visits, will l e a d t o di mi nis h e d i m p a ct of a n dr o g e n d e pri v ati o n t h er a p y usi n g o bj e cti v e m e as ur es a n d s urr o g at e m ar k ers of i ns uli n r esist a n c e a n d c ar di o v as c ul ar dis e as e ris k f a ct ors, i n cl u di n g g ai ns i n b o d y f at m ass, f asti n g i ns uli n/ gl u c os e l e v els, w ei g ht g ai n a m o n g m e n wit h pr ost at e c a n c er. W e f urt h er h y p ot h esi z e t h at i n di vi d u ali z e d e d u c ati o n al s essi o ns a n d c o u ns eli n g r e g ar di n g ps y c h os o ci al as p e cts of a n dr o g e n d e pri v ati o n will l e a d t o i m pr o v e d p ati e nt u n d erst a n di n g a n d s atisf a cti o n a n d o v er all l ess a d v ers e i m p a ct o n q u alit y of lif e usi n g v ali d at e d p ati e nt -r e p ort e d m etri cs a d dr essi n g t h e s p e cifi c iss u es r ais e d wit h a n dr o g e n d e pri v ati o n t h er a p y. S h o ul d t h e st u d y r es ults fr o m t his pr eli mi n ar y p h as e 2 st u d y pr o vi d e e vi d e n c e s u p p orti n g p arti ci p ati o n i n t h e S T A N D cli ni c, t his will pr o vi d e t h e j ustifi c ati o n f or a c o nfir m at or y r a n d o mi z e d cli ni c al tri al a cr oss m ulti pl e i n v esti g ati o n al sit es t o ass ess t h e g e n er ali z a bilit y a n d r e pr o d u ci bilit y of t h e m ulti- dis ci pli n ar y cli ni c, a n d t o ass ess l o n g -t er m i m p a ct of m ulti -dis ci pli n ar y cli ni c p arti ci p ati o n o n i n ci d e n c e of di a b et es, c ar di o v as c ul ar dis e as e, a n d n o n -pr ost at e c a n c er r el at e d m ort alit y. Ulti m at el y, e nr oll m e nt i nt o a m ulti -dis ci pli n ar y cli ni c f or m e n r e c ei vi n g A D T m a y b e c o m e a r o uti n e as p e ct of pr ost at e c a n c er m a n a g e m e nt as a m e a ns t o miti g at e t h e p ot e nti al l y si g nifi c a nt t o xi cit y of a n dr o g e n d e pri v ati o n t h er a p y.
untitled h1
2 . 2 st u

R a n d o mi z e d c o h o rt: T o c o m p ar e t h e m e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m ass a m o n g m e n wit h pr ost at e c a n c er r e c ei vi n g a n dr o g e n d e pri v ati o n t h er a p y r a n d o mi z e d t o p arti ci p at e i n t h e " S T A N D " cli ni c vs. us u al st a n d ar d of c ar e.  
N o n -r a n d o mi z e d pil ot c o h o rt: T o d et er mi n e t h e f e asi bilit y of c o m pl eti n g m ulti -dis ci pli n ar y S T A N D cli ni c visits wit hi n c o nt e xt of c o n c urr e nt c h e m o h or m o n al t h er a p y f or pr ost at e c a n c er.
untitled h1
2. 2. 2 s e

T o c o m p a r e t h e m e a n p e r c e nt c h a n g e f r o m b as eli n e t o 1 2 m o nt hs a n d p att e r ns of c h a n g e o v e r ti m e d u ri n g p a rti ci p ati o n i n t h e S T A N D cli ni c vs. us u al st a n d a r d of c a r e wit h r es p e ct t o:  
M et a b oli c I m p a ct o n Di a b et es a n d C ar di o v as c ul ar Ris k F a ct ors:  
- F asti n g bl o o d gl u c os e  
- F asti n g pl as m a i ns uli n l e v el  
- I ns uli n r esist a n c e as c al c ul at e d b y H O M A -I R  
- H e m o gl o bi n A 1 c  
- F asti n g li pi ds (t ot al c h ol est er ol, L D L, H D L, tri gl y c er ci d es)  
- W aist cir c u mf er e n c e  
- B o d y w ei g ht/ b o d y m ass i n d e x  
- E x er cis e p att er ns as m e as ur e d b y v ali d at e d q u esti o n n air e a n d a m b ul at or y a c c el er o m et er ass ess m e nt (s e e A p p e n di c es 2 a n d 5 r es p e cti v el y)  
- Bl o o d pr ess ur e B o n e H e alt h:  
- B o n e d e nsit y as ass ess e d b y D X A s c a n  
- 2 5- ( O H) vit a mi n D s er u m l e v els Q u alit y of Lif e/ Ps y c h os o ci al I m p a ct:  
- D e pr essi o n as m e as ur e d b y P H Q - 9  
- C o g niti v e f u n cti o n as m e as ur e d b y t h e Att e nti o n al F u n cti o n al I n d e x  
- O v er all q u alit y of lif e as m e as ur e d b y S F - 1 2  
- F ati g u e as m e as ur e d b y t h e L e e F ati g u e S c al e  
- Er e ctil e a n d uri n ar y f u n cti o n as m e as ur e d b y E PI C - 2 6  
- H ot fl as h s e v erit y as m e as ur e d b y H ot Fl as h R el at e d D ail y I nt erf er e n c e S c al e
untitled h1
a m o n g

T o m e as ur e t h e m e a n c h a n g e fr o m b as eli n e at st art of p arti ci p ati o n i n t h e S T A N D cli ni c aft er 1 2 m o nt hs of p arti ci p ati o n i n:  
- M et a b oli c p ar a m et ers i n cl u di n g p er c e nt a g e b o d y f at, f asti n g i ns uli n/ gl u c os e, H O M A -I R,  
b o d y w ei g ht/ b o d y m ass i n d e x, w aist cir c u mf er e n c e  
- B o n e h e alt h  
- Q u alit y of lif e  
- P ati e nt s atisf a cti o n
untitled h1
a m o n g

- T o d et er mi n e t h e m e a n c h a n g e fr o m b as eli n e t o 1 2 m o nt hs d uri n g S T A N D cli ni c p arti ci p ati o n i n t h e pri m ar y a n d s e c o n d ar y m et a b oli c a n d q u alit y of lif e p ar a m et ers list e d a b o v e.
untitled h1
2. 2. 3 c o

- T o i n v esti g at e f or a r el ati o ns hi p b et w e e n i n h erit e d g e n eti c p ol y m or p his ms of f u n c ti o n al r el e v a n c e n e ar or wit hi n g e n es e n c o di n g pr ot ei ns wit h r ol es i n st er oi d h or m o n e tr a ns p ort a n d a n dr o g e n r e c e pt or si g n ali n g wit h c h a n g es i n m et a b oli c p ar a m et ers a m o n g m e n tr e at e d wit h a n dr o g e n d e pri v ati o n t h er a p y.  
- T o i n v esti g at e c h a n g es i n tr a b e c ul ar b o n e mi cr o -ar c hit e ct ur e as m e as ur e d b y Hi g h R es ol uti o n P eri p h er al Q C T I m a gi n g of r a di us a n d ti bi a d uri n g a n dr o g e n d e pri v ati o n t h er a p y.  
- T o i n v esti g at e f or r el ati o ns hi p b et w e e n 2 n d di git t o 4 t h di git l e n gt h r ati o ( 2 D: 4 D r ati o) a n d q u alit y of lif e o n a n dr o g e n d e pri v ati o n t h er a p y.  
- T o i n v esti g at e f or a r el ati o ns hi p b et w e e n 2 n d di git t o 4 t h di git l e n gt h r ati o a n d b as eli n e e m p at h y s c or e as m e as ur e d b y v ali d at e d q u esti o n n air e .
untitled h1
3. st u d y

R a n d o mi z e d, p h as e 2 st u d y wit h cr oss -o v er d esi g n t o ass ess t h e l o n git u di n al i m p a ct of p arti ci p ati o n i n t h e m ulti -dis ci pli n ar y S T A N D cli ni c vs. r e c ei pt of us u al st a n d ar d of c ar e o n c h a n g es i n k e y m et a b oli c p ar a m et ers, q u alit y of lif e, a n d p ati e nt s atisf a cti o n a m o n g m e n r e c ei vi n g a n dr o g e n d e priv ati o n t h er a p y f or pr ost at e c a n c er. St a n d ar d -of -c ar e t h er a p y will c o nsist of e v er y 3- m o nt h visits c o m pris e d of r e vi e w of m e di c al hist or y, t o xi cit y ass ess m e nt, a n d lif est yl e m o difi c ati o n c o u ns eli n g pr o vi d e d b y i n di vi d u al h e alt h c ar e pr o vi d er, L H R H a n al o g i nj e cti o ns b y tr ai n e d o n c ol o g y n urs e. P ati e nts i n t h e us u al c ar e tr e at m e nt ar m will h a v e u nr estri ct e d a c c ess t o e x er cis e, n utriti o n, a n d s y m pt o m m a n a g e m e nt s er vi c e u p o n p ati e nt r e q u est or as d e e m e d n e c ess ar y b y h e alt h c ar e pr o vi d er. M e n r a n d o mi z e d t o p arti ci p ati o n i n t h e S T A N D cli ni c will h a v e e v er y 3 m o nt h visits wit h h e alt h c ar e pr o vi d ers a n d L H R H a n al o g i nj e cti o ns, m o nt hl y s elf -  
dir e ct e d e d u c ati o n al " m o d ul es " c o v eri n g t h e v ari o us as p e cts of h or m o n e t h er a p y as w ell as e v er y 3- m o nt h i n di vi d u ali z e d c o u ns eli n g pr o vi d e d b y r e gist er e d di etiti a n, e x er cis e tr ai n er, a n d s y m pt o m m a n a g e m e nt s er vi c e . At t h e e n d of 1 2 m o nt hs of st u d y p arti ci p ati o n, p ati e nts i niti all y r a n d o mi z e d t o r e c ei v e st a n d ar d-of -c ar e, will h a v e t h e o pti o n of cr ossi n g -o v er t o p arti ci p at e i n t h e S T A N D cli ni c f or t h e e ns ui n g 1 2 m o nt hs.  
A n o n -r a n d o mi z e d pil ot c o h ort of p ati e nts r e c ei vi n g c o n c urr e nt c h e m o h or m o n al t h er a p y will b e e nr oll e d i n p ar all el t o ass ess t h e f e asi bilit y of S T A N D cli ni c p arti ci p ati o n i n t his p ati e nt p o p ul ati o n.
untitled h1
3. 2 st u d

R a n d o mi z e d c o h o rt: M e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m ass as m e as ur e d b y bi o el e ctri c al i m p e d a n c e a n al y z er (s e e A p p e n di x 4).  
N o n -r a n d o mi z e d c h e m o h o r m o n al c o h o rt: P er c e nt a g e of c o m pl et e d S T A N D cli ni c visits d uri n g t h e c o urs e of t h e 1 2 m o nt h S T A N D cli ni c p arti ci p ati o n.
untitled h1
3. 2. 2 s e

M e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs a n d p att er ns of c h a n g e fr o m b as eli n e wit h r es p e ct t o t h e f oll o wi n g:  
M et a b oli c I m p a ct o n Di a b et es a n d C ar di o v as c ul ar Dis e as e Ris k F a ct ors:  
- F asti n g bl o o d gl u c os e  
- F asti n g pl as m a i ns uli n l e v el  
- I ns uli n r esist a n c e as c al c ul at e d b y H O M A-I R  
- H e m o gl o bi n A 1 c  
- F asti n g li pi ds (t ot al c h ol est er ol, L D L, H D L, tri gl y c er ci d es)  
- W aist cir c u mf er e n c e  
- B o d y w ei g ht/ b o d y m ass i n d e x  
- E x er cis e p att er ns as m e as ur e d b y v ali d at e d q u esti o n n air e a n d a m b ul at or y a c c el er o m et er ass ess m e nt ( A p p e n di c es 2 a n d 5 r es p e cti v el y)  
- Bl o o d pr ess ur e B o n e H e alt h:  
- B o n e d e nsit y at t h e l u m b ar s pi n e, f e m or al n e c k, a n d t ot al hi p as ass e ss e d b y D X A s c a n a m o n g p ati e nts wit h o ut b o n e m et ast as es at t h e ti m e of st u d y e ntr y  
- S er u m 2 5- ( O H) vit a mi n D l e v els Q u alit y of Lif e/ Ps y c h os o ci al I m p a ct:  
- D e pr essi o n as m e as ur e d b y P H Q - 9  
- C o g niti v e f u n cti o n as m e as ur e d b y Att e nti o n al F u n cti o n al I n d e x  
- O v er all q u alit y of lif e as m e as ur e d b y S F - 1 2  
- F ati g u e as m e as ur e d b y t h e L e e F ati g u e S c al e  
- Er e ctil e a n d uri n ar y f u n cti o n as m e as ur e d b y E PI C - 2 6  
- H ot fl as h s e v erit y as m e as ur e d b y H ot Fl as h R el at e d D ail y I nt erf er e n c e S c al e P ati e nt S atisf a cti o n:  
- P ati e nt s atisf a cti o n as m e as ur e d b y a v ali d at e d q u esti o n n air e  
- P ati e nt i nsi g ht a n d u n d erst a n di n g of tr e at m e nt a n d dis e as e- r el at e d iss u es as m e as ur e d b y a s elf -a d mi nist er e d ass ess m e nt
untitled h1
3. 2. 3 c o

- Ass o ci ati o n b et w e e n i n h erit e d g e n eti c p ol y m or p his ms of f u n cti o n al r el e v a n c e n e ar or wit hi n g e n es e n c o di n g pr ot ei ns wit h r ol es i n st er oi d h or m o n e tr a ns p ort a n d a n dr o g e n r e c e pt or si g n ali n g wit h c h a n g es i n m et a b oli c p ar a m et ers a m o n g m e n tr e at e d wit h a n dr o g e n d e pri v ati o n t h er a p y.  
- M e a n c h a n g e fr o m b as eli n e i n tr a b e c ul ar b o n e ar c hit e ct ur e as m e as ur e d b y tr a b e c ul ar b o n e n u m b er ( T b N) a n d tr a b e c ul ar b o n e v ol u m e fr a cti o n ( B V/ T V) aft er 1 2 m o nt hs of a n dr o g e n d e pri v ati o n t h er a p y.  
- Ass o ci ati o n b et w e e n 2 D: 4 D r ati o wit h c h a n g e i n q u alit y of lif e o n a n dr o g e n d e pri v ati o n t h er a p y.  
- A ss o ci ati o n b et w e e n 2 D: 4 D r ati o wit h b as eli n e e m p at h y s c or e as m e as ur e d b y v ali d at e d q u esti o n n air e.
untitled h1
3.3.1 primary completion

Study accrual is anticipated to be approximately 2 patients per month, leading to an accrual duration of approximately 40 months. Anticipated time from last patient enrolled to primary study completion and analysis of primary and secondary endpoints equals approximately 12 months, leading to the primary completion of study in approximately 52 months from first patient enrolled.  
Study accrual of the 20 patient non-randomized chemohormonal cohort will be completed in parallel and is estimated to be approximately 0.8 patients/month, leading to an approximate 24 patient accrual period.
untitled h1
3.3.2 study completion

The total study duration including follow up is estimated to be 5 years.
untitled h1
4. st u d y

8 0 e v al u a bl e p ati e nts wit h pr ost at e c a n c er wit h c o n c urr e nt or pl a n n e d tr e at m e nt wit h a n dr o g e n d e pri v ati o n t h er a p y will b e eli gi bl e f or st u d y p arti ci p ati o n . P ati e nts m ust h a v e i niti at e d A D T  
wit hi n 6 m o nt hs pri or t o d a y 1 of st u d y e ntr y, a n d t h e e x p e ct e d d ur ati o n of A D T m ust b e at l e ast 1 2 m o nt hs fr o m st u d y e ntr y.  
2 0 p ati e nts w h o ar e r e c ei vi n g or pl a n ni n g t o r e c ei v e c o n c urr e nt c h e m o h or m o n al t h er a p y will b e e nr o ll e d i n a p ar all el n o n-r a n d o mi z e d c o h ort, t o est a blis h t h e f e asi bilit y of c o m pl eti n g S T A N D  
cli ni c visits i n t his p ati e nt p o p ul ati o n.
untitled h1
4. 1 i n cl

- Hist ol o gi c c o nfir m ati o n of a d e n o c ar ci n o m a of t h e pr ost at e  
- R e c ei vi n g or pl a n ni n g t o r e c ei v e A D T wit h L H R H a g o nist or a nt a g o nist  
- E x p e ct e d d ur ati o n of A D T at l e ast 1 2 m o nt hs fr o m d at e of st u d y c o ns e nt  
- C o n c urr e nt a nti a n dr o g e n t h er a p y all o w e d b ut n ot r e q uir e d  
- First d os e of L H R H a g o nist or a nt a g o nist n o m or e t h a n 6 m o nt hs pri or t o d at e of st u d y c o ns e nt  
- Pri or/ c o n c urr e nt r a di ati o n all o w e d  
- Ot h er i n v esti g ati o n al a g e nts i n a d diti o n t o L H R H a g o nist/ a nt a g o nist ar e all o w e d ( e. g.  
n o v el a nti- a n dr o g e ns, a n dr o g e n s y nt h esis i n hi bit ors)  
- Pri or a n dr o g e n d e pri v ati o n t h er a p y all o w e d, pr o vi d e d t h er e is d o c u m e nt e d e vi d e n c e of t est ost er o n e r e c o v er y t o > 1 5 0 n g/ d L a n d gr e at er t h a n 1 2 m o nt hs d ur ati o n b et w e e n l ast  
" eff e cti v e " d at e of A D T a n d d at e of st u d y c o ns e nt  
- R a n d o mi z e d c o h o rt o nl y:  
o N o pri or c h e m ot h er a p y wit hi n 1 2 m o nt hs of st art d at e of st u d y o N o pl a n n e d c h e m ot h er a p y at l e ast 1 2 m o nt hs fr o m st u d y e ntr y  
- N o n -r a n d o mi e d pil ot c o h o rt:  
o C o n c urr e nt c h e m ot h er a p y (i niti at e d wit hi n 3 m o nt hs of st u d y e ntr y) or pl a n n e d c h e m ot h er a p y wit hi n 3 m o nt hs of st u d y e ntr y  
- E C O G p erf or m a n c e st at us of 0 - 2  
- A bili t y t o si g n writt e n i nf or m e d c o ns e nt  
- Willi n g t o att e n d m o nt hl y cli ni c visits at U C S F
untitled h1
4. 2 e x cl

- P h ysi c all y u n a bl e or u n willi n g t o p arti ci p at e i n r e c o m m e n d e d e x er cis e pr o gr a ms or tr a v el t o U C S F o n a m o nt hl y b asis  
- Pr es e n c e of p er m a n e nt p a c e m a k e r or i m pl a nt a bl e m e di c al d e vi c e.  
o Artifi ci al j oi nt pr ost h es es a n d v e n o us filt ers ar e all o w e d.
untitled h1
5 . st u d

5. 1 L u pr o n D e p ot ( L e u pr oli d e a c et at e f or d e p ot s us p e nsi o n) D es cri pti o n, F or m ul at i on a n d St or a g e
untitled h1
5. 1. 1 d es

L u pr o n D e p ot ( L e u pr oli d e a c et at e ) is a s y nt h eti c n o n a p e pti d e a n al o g of n at ur all y o c c urri n g g o n a d otr o pi n r el e asi n g h or m o n e ( G n R H or L H- R H).
untitled h1
5. 1. 2 f or

L u pr o n D e p ot ( L e u pr oli d e a c et at e ) f or i nj e cti o n is a st eril e, a q u e o us s ol uti o n i nt e n d e d f or s u b c ut a n e o us i nj e cti o n. It is a v ail a bl e i n a 2. 8 m L m ulti pl e- d os e vi al c o nt ai ni n g l e u pr oli d e a c et at e ( 5 m g/ m L), s o di u m c hl ori d e, U S P ( 6. 3 m g/ m L) f or t o ni cit y a dj ust m e nt, b e n z yl al c o h ol, N F as a pr es er v ati v e ( 9 m g/ m L), a n d w at er f or i nj e cti o n, U S P. T h e p H m a y h a v e b e e n a dj ust e d wit h s o di u m h y dr o xi d e, N F a n d/ or a c eti c a ci d, N F. T h e p H r a n g e is 4. 0 t o 6. 0.  
T h e vi al is p a c k a g e d as a 4 D a y P ati e nt A d mi nistr ati o n Kit wit h 1 4 dis p os a bl e s yri n g es a n d 2 8 al c o h ol s w a bs, N D C 0 1 8 5- 7 4 0 0- 8 5.
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5. 1. 3 st or

St or e b el o w 7 7° F ( 2 5° C). D o n ot fr e e z e. Pr ot e ct fr o m li g ht; st or e vi al i n c art o n u ntil us e.  
G ui d eli n es f or A d mi nistr ati o n: S e e Tr e at m e nt a n d D os e M o difi c ati o n s e cti o n of pr ot o c ol 5. 2 Eli g ar d D es cri pti o n, F or m ul ati o n, a n d St or a g e 5. 2. 1 D es cri pti o n Eli g ar d is a st eril e p ol y m eri c m atri x f or m ul ati o n of l e u pr oli d e a c et at e, a G n R H a g o nist .  
5. 2. 2 F or m ul ati o n Eli g ar d is pr efill e d a n d s u p pli e d i n t w o s e p ar at e, st eril e s yri n g es w h os e c o nt e nts ar e mi x e d i m m e di at el y pri or t o a d mi nistr ati o n. T h e t w o s yri n g es ar e j oin e d a n d t h e si n gl e d os e pr o d u ct is mi x e d u ntil it is h o m o g e n o us.  
Eli g ar d is a d mi nist er e d s u b c ut a n e o usl y, w h er e it f or ms a s oli d dr u g d eli v er y d e p ot.  
5. 2. 3 St or a g e St or e at 2 - 8 ° C ( 3 5. 6 - 4 6. 4 ° F)  
G ui d eli n es f or A d mi nistr ati o n: S e e Tr e at m e nt a n d D os e M o difi c ati o n s e cti o n of pr ot o c ol.  
5. 3 Z ol o d e x D es cri pti o n, F or m ul ati o n a n d St or a g e
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5. 3. 1 d es

Z ol a d e x ( g os er eli n a c et at e) is a s y nt h eti c d e c a p e pti d e a n al o g of g o n a d otr o pi n r el e asi n g h or m o n e ( G n R H or L H R H).
untitled h1
5. 3. 2 f or

Z ol a d e x ( g os er eli n a c et at e) d e p ot is s u p pli e d as a c yli n dri c al r o d of bi o d e gr a d a bl e a n d bi o c o m p ati bl e D- L L a cti d e - gl y c oli d e c o p ol y m er. E a c h Z O L A D E X d e p ot c o nt ai ns g os er eli n a c et at e e q ui v al e nt t o 3. 6 m g of g os er eli n. T his d e p ot is pr es e nt e d i n a st eril e r e a d y- t o- us e s yri n g e wit h a 1 6 g a u g e n e e dl e f or a si n gl e s u b c ut a n e o us i nj e cti o n. T his si n gl e- d os e s yri n g e is ass e m bl e d wit h a pr ot e cti v e sl e e v e ( S af e S yst e m ™) i n a s e al e d, st eril e p o u c h t h at c o nt ai ns a d esi c c a nt.
untitled h1
5. 3. 3 st or

Pr ot e ct fr o m li g ht a n d m oist ur e. St or e i n t h e i nt a ct p a c k a g e b et w e e n 2° C a n d 2 5° C.  
G ui d eli n es f or A d mi nistr ati o n: S e e Tr e at m e nt a n d D os e M o difi c ati o n s e cti o n of pr ot o c ol 5. 4 T elst ar D es cri pti o n, F or m ul ati o n, a n d St or a g e 5. 4. 1 D es cri pti o n 5. 4. 1 Tr elst ar is a s y nt h eti c d e c a p e pti d e a g o nist a n al o g u e of g o n a d atr o pi n r el e as e h or m o n e  
( G n R H).
untitled h1
5. 4. 2 f or

Tr elst ar is a d mi nist er e d as a si n gl e i ntr a m us c ul ar i nj e cti o n i n eit h er b utt o c k. T h e l y o p hili z e d mi cr o gr a n ul es ar e t o b e r e c o nstit ut e d i n st eril e w at er. N o ot h er dil u e nt s h o ul d b e us e d. D u e t o diff er e nt r el e as e c h ar a ct eristi cs, t h e d os a g e str e n gt hs ar e n ot a d diti v e a n d m ust b e s el e ct e d b as e d o n t h e d esir e d d osi n g s c h e d ul e: 3. 7 5 m g e v er y 4 w e e ks, 1 1. 2 5 e v er y 1 2 w e e ks or 2 2. 5 m g e v er y 2 4 w e e ks.
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5. 4. 3 st or

St or e at 2 0 - 2 5° C ( 6 8- 7 7° F). [ S e e U S P C o ntr oll e d R o o m T e m p er at ur e.] D o n ot fr e e z e Tr elst ar wit h MI XJ E C T.  
G ui d eli n es f or A d mi nistr ati o n: S e e Tr e at m e nt a n d D os e M o difi c ati o n s e cti o n of pr ot o c ol
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6 . d r u

6. 1 L H R H R o ut e of A d mi nistr ati o n , Pri m ar y Si d e Eff e cts, a n d D os e M o difi c ati o ns a n d D osi n g D el a ys 6. 1. 1 R o ut e of A d mi nistr ati o n T h e L H R H a i nj e cti o ns will b e d eli v er e d eit h er s u b c ut a n e o usl y ( Eli g ar d ®, Z ol a d e x ®) or i ntr a m us c ul arl y ( L u pr o n D e p ot ® or Tr elst ar ®) b y a tr ai n e d h e alt h c ar e pr o vi d er w hil e o n pr ot o c ol t h er a p y.  
6. 1. 2 Pri m ar y Si d e Eff e cts H ot fl as h es, d e cr e as e d li bi d o, br e ast p ai n, g y n e c o m asti a, h y p er gl y c e mi a, h y p er c h ol est er ol e mi a, d e cr e as e d b o n e mi n er al d e nsit y, f ati g u e, a n e mi a, m o o d c h a n g es.  
6. 1. 3 Dr u g S u p pl y T h e dr u gs will b e c o m m er ci all y s u p pli e d.  
F or a c o m pl et e d es cri pti o n of t h es e dr u gs, pl e as e s e e t h e p a c k a g e i ns erts.
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7 . st u d

| F oll o w U p  Visit  (6 m o nt hs  aft e r  c o m pl eti o n  of S T A N D  cli ni c )   |                                                                                      |                               |    |    |    |
|-------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|-------------------------------|----|----|----|
| P h ysi c al E x a m  wit h H e alt h C ar e  Pr o vi d er  ( B ot h st u d y ar ms)      | P r e -St u d y/  S c r e e ni n g  ( wit hi n 6  w e e ks of  D a y 1 of  St u d y) | E n d of  E v e r y  M o nt h |    |    |    |
| ( +/- 2 w e e k s)                                                                        | E n d of  E v e r y 3  M o nt hs                                                     |                               |    |    |    |
| ( +/- 2 w e e ks)                                                                         | E n d of                                                                             |                               |    |    |    |
| M o nt h 1 2  St u d y Visit  ( +/- 2 w e e ks)                                           |                                                                                      |                               |    |    |    |
| D a y 1                                                                                   |                                                                                      |                               |    |    |    |
| St u d y Visit                                                                            |                                                                                      |                               |    |    |    |
| X                                                                                         | X                                                                                    | X                             | X  | X  |    |
| L H R H A n al o g u e a                                                                  | X                                                                                    | X                             |    |    |    |
| E x er cis e,  N utriti o n,  S y m pt o m                                                |                                                                                      |                               |    |    |    |
| M a n a g e m e nt  c o u ns eli n gb                                                     | X                                                                                    | X                             |    |    |    |
| E d u c ati o n al                                                                        |                                                                                      |                               |    |    |    |
| M o d ul es ( S T A N D                                                                   | X                                                                                    | X                             |    |    |    |
| cli ni c ar m o nl y )  C o u ns eli n g,  r e vi e w t ests a n d                        | X                                                                                    | X                             | X  |    |    |
| q u esti o n n air es                                                                     |                                                                                      |                               |    |    |    |
| I nf or m e d C o ns e nt                                                                 | X                                                                                    |                               |    |    |    |
| R a n d o mi z ati o n                                                                    | X                                                                                    |                               |    |    |    |
| D e m o gr a p hi cs                                                                      | X                                                                                    |                               |    |    |    |
| P ast M e di c al  Hist or y                                                              | X                                                                                    |                               |    |    |    |
| C o n c o mit a nt  M e di c ati o ns                                                     | X                                                                                    | X                             | X  | X  |    |
| Q O L / e m p at h y  Q u esti o n n air es c                                             | X                                                                                    | X                             | X  | X  |    |
| C o -m or bi dit y  Ass ess m e nt d                                                      | X                                                                                    |                               |    |    |    |
| R ati o of 2 n d t o 4t h di git fi n g er l e n gt h                                     | X                                                                                    |                               |    |    |    |
| W ei g ht/ B o d y  M ass  I n d e x/ P er c e nt  B o d y F at                           | X                                                                                    | X                             | X  | X  | X  |
| E C O G                                                                                   |                                                                                      |                               |    |    |    |
| P erf or m a n c e                                                                        | X                                                                                    | X                             |    |    |    |  
| D X A S c a n g                                                                                                                                                                                                                                                                                                            | X   | X   |    |    |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|-----|----|----|----|
| H R p Q C T  ( o pti o n al)                                                                                                                                                                                                                                                                                               | X   | X   |    |    |    |
| S er u m P S A                                                                                                                                                                                                                                                                                                             | X   | X   | X  | X  | X  |
| S er u m t est ost er o n e                                                                                                                                                                                                                                                                                                | X   | X   |    |    |    |
| S er u m 2 5 -( O H)  vit a mi n D l e v el                                                                                                                                                                                                                                                                                | X   | X   | X  |    |    |
| F asti n g                                                                                                                                                                                                                                                                                                                 |     |     |    |    |    |
| gl u c o s e/li pi d  p a n el, H g b A 1 c,  i ns uli n l e v el                                                                                                                                                                                                                                                          | X   | X   | X  | X  |    |
| H e m o gl o bi n A 1 c                                                                                                                                                                                                                                                                                                    | X   | X   | X  | X  |    |
| Pl as m a/s er u m f or  b a n ki n g k                                                                                                                                                                                                                                                                                    | X   | X   | X  | X  |    |
| P B M Cs f or  g er mli n e                                                                                                                                                                                                                                                                                                | X   |     |    |    |    |
| p ol y m or p his ms  ( o pti o n al)k                                                                                                                                                                                                                                                                                     |     |     |    |    |    |
| a. P ati e nts w h o h a v e st art e d A D T pri or t o st u d y e nr oll m e nt will b e k e pt o n s a m e s c h e d ul e f or n e xt d os e of L H R H  a n al o g a n d pr o vi d er visit w hil e o n st u d y. O n st u d y p ati e nts will r e c ei v e L H R H a g o nist e v er y 3 m o nt hs ( +/- 1 w e e k), |     |     |    |    |    |  
o n s a m e d a y a s h e alt h c ar e pr o vi d er visits w h e n e v er p ossi bl e.  
b : P ati e nts r a n d o mi z e d t o t h e S T A N D cli ni c will visit wit h o n e of t hr e e s p e ci alti es ( e x er cis e, n utriti o n, s y m pt o m m a n a g e m e nt ) at e a c h m o nt hl y visit. T h e t ot al n u m b er of visits wit h e a c h s p e ci alt y will b e f o ur o n a n e v er y 3-m o nt h b asis. T h e r ot ati o n of t h e s c h e d ul e of pr o vi d ers m a y b e a dj ust e d d e p e n di n g u p o n a v ail a bilit y of pr o vi d er a n d p ati e nt.  
P ati e nts r a n d o mi z e d t o t h e us u al c ar e st u d y ar m will b e r ef err e d t o n utriti o n, e x er cis e, a n d s y m pt o m m a n a g e m e nt s er vi c es u p o n p ati e nt r e q u est or as d e e m e d n e c e ss ar y b y h e alt h c ar e pr o vi d er.  
c : Q u alit y of lif e q u e sti o n n air e s t o b e c o m pl et e d i n cl u d e S F -1 2, E PI C -2 6 , H ot Fl as h R el at e d D a il y I nt erf er e n c e S c al e , L e e F ati g u e S c al e, P H Q -9, At t e nti o n al F u n cti o n al I n d e x, E x er cis e q u esti o n n air es , a n d e m p at h y q u oti e nt- 8  
(s e e A p p e n di x 2). T h es e q u esti o n n air es m a y b e c o m pl et e d o nli n e a h e a d of s c h e d ul e d visit or at t h e ti m e of cli ni c visit, eit h er e l e ctr o ni c all y or o n p a p er. T h e P H Q-9 s c al e m ust b e c o m pl et e d o n p a p er o n t h e s a m e d a y as st u d y visit, a n d r e vi e w e d a n d si g n e d b y h e alt h c ar e pr o vi d er pri or t o p ati e nt dis c h ar g e fr o m cli ni c.  
d : Ass ess e d wit h C h arls o n C o m or bi dit y I n d e x (s e e A p p e n di x 3)  
e: M e as ur e d b y c ali p er (s e e S e cti o n 1). F or p ati e nts alr e a d y e nr oll e d o n st u d y w h o di d n ot c o m pl et e at b as eli n e, t his m e as ur e m e nt will b e p erf or m e d at t h e n e xt pl a n n e d st u d y visit.  
f: P er c e nt b o d y f at t o b e m e as ur e d usi n g bi oi m p e d a n c e d e vi c e o n C 1 D 1, e v er y 3 m o nt hs, a n d e n d of m o nt h 1 2 o n st u d y ( s e e A p p e n di x 4)  
g : B o n e mi n er al d e nsit y m e a s ur e 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 ( p erf or m e d wit hi n 1 2 w e e ks of d a y 1 of st u d y)  
h: Hi g h r es ol uti o n q u a ntit ati v e p eri p h er al C T of t h e r a di us a n d ti bi a ( o p ti o n al)  
i: B as eli n e P S A d et er mi n e d d uri n g s cr e e ni n g if n ot alr e a d y t a ki n g A D T  
j: I n cl u d e s cr e e ni n g ass ess m e nt or s er u m t est ost er o n e of pri or r e c ei pt of A D T  
k: S e e A p p e n di x 6 f or c oll e cti o n a n d pr o c essi n g i nstr u cti o ns l: F oll o wi n g c o m pl eti o n of S T A N D cli ni c p arti ci p ati o n, p ati e nts will b e f oll o w e d b y t el e p h o n e visit aft er 2 a n d 4 m o nt hs t o ass ess a d h er e n c e t o r e c o m m e n d e d di et/ e x er cis e pl a ns. At 6 m o nt hs, p ati e nts will r et ur n f or cli ni c ass ess m e nt .
untitled h1
7 . 2 s c

S cr e e ni n g pr o c e d ur es a n d i nf or m e d c o ns e nt as w ell as writt e n h e alt h i nf or m ati o n a ut h ori z ati o n m ust b e c o m pl et e d wit hi n 6 w e e ks of d a y 1 of st u d y. All r es e ar c h -r el at e d pr o c e d ur es will b e c o n d u ct e d aft er p ati e nt h as si g n e d writt e n c o ns e nt t o p arti ci p at e i n t h e st u d y.  
T h es e pr o c e d ur es i n cl u d e:  
- P h ysi c al e x a m a n d m e di c al hist or y  
- D e m o gr a p hi cs a n d dis e as e c h ar a ct eristi cs:  
o D at e of pr ost at e c a n c er di a g n osis o Gl e as o n gr a d e a n d P S A at t h e ti m e of di a g n osis o T y p e a n d d at e of pri or l o c al t h er a p y (if a n y)  
o D at e of A D T i ni ti ati o n a n d i n di c ati o n ( a dj u v a nt, bi o c h e mi c al r el a ps e, or m et ast ati c dis e as e)  
o C o n c urr e nt us e of a nti- a n dr o g e n ( y es/ n o)  
o C o n c urr e nt r a di ati o n t h er a p y ( y es/ n o)  
o M et ast ati c st at us at ti m e of st u d y e ntr y ( n o n e, b o n e o nl y, s oft tiss u e, a n y vis c er al)  
Cli ni c al Ass e ss m e nt  
- C o - m or bi dit y ass ess m e nt b y C h arls o n C o- m or bi dit y S c al e ( A p p e n di x 3)  
- Q u alit y of lif e q u esti o n n air es (s e e A p p e n di x 2):  
o S F -1 2, E PI C -2 6, H F R DI S, L e e F ati g u e S c al e, P H Q -9, Att e nti o n al F u n cti o n al I n d e x, e x er cis e p att er ns, e m p at h y s c al e  
- C o n c o m it a nt m e di c ati o n  
- W ei g ht a n d b o d y m ass i n d e x  
- Ass ess m e nt of r ati o of 2 n d di git t o 4 t h di git fi n g er l e n gt h usi n g c ali p er ass ess m e nt
untitled h1
r a di o g

- D X A B o n e D e nsit y S c a n ( c o m pl et e d wit hi n 1 2 w e e ks of D a y 1 of st u d y)  
- Hi g h r es ol uti o n p eri p h er al q u a ntit ati v e C T s c a n of t h e dist al ti bi a a n d r a di us ( o pti o n al)
untitled h1
l a b o r

- B as eli n e P S A m e as ur e m e nt  
- S er u m t est ost er o n e (if pri or r e c ei pt of a n dr o g e n d e pri v ati o n t h er a p y)
untitled h1
7 . 3 r a

O n c e eli gi bilit y is c o nfir m e d a n d p ati e nt h as si g n e d i nf or m e d c o ns e nt , p ati e nts will b e str atifi e d a c c or di n g t o d ur ati o n of A D T pri or t o st u d y e ntr y ( ≤ 3 m o nt hs vs. 3- 6 m o nt hs) a n d b o d y m ass i n d e x at st u d y e ntr y ( ≤ 3 0 vs. > 3 0). T h e y will b e r a n d o mi z e d wit h e q u al pr o b a bilit y t o o n e of t h e t w o st u d y ar ms fr o m wit hi n e a c h of t h e si x str at a. B al a n c e i n tr e at m e nt assi g n m e nt will b e a c hi e v e d usi n g a r a n d o mi z e d bl o c k d esi g n. R a n d o mi z ati o n will b e c arri e d o ut vi a c o m p ut er g e n er at e d r a n d o m assi g n m e nt. R a n d o mi z ati o n m ust b e c o m pl et e d wit hi n 6 w e e ks of d a y 1 of st u d y.  
A n o n -r a n d o miz e d pil ot c o h ort of p ati e nts r e c ei vi n g c o n c urr e nt c h e m o h or m o n al t h er a p y will b e e nr oll e d i n p ar all el t o ass ess t h e f e asi bilit y of S T A N D cli ni c p arti ci p ati o n i n t his p ati e nt p o p ul ati o n.
untitled h1
7 . 4 d a

- P h ysi c al e x a mi n ati o n  
- C o n c o mit a nt m e di c ati o ns  
- E C O G P erf or m a n c e St at us  
- H ei g ht, w ei g ht, b o d y m ass i n d e x, a n d p er c e nt b o d y f at b y bi oi m p e d a n c e m e as ur e m e nt  
(s e e A p p e n di x 6)  
- L H R H A n al o g u e
untitled h1
7 . 4. 2 l

- O pti o n al P eri p h er al bl o o d c oll e cti o n f or g e n ot y pi n g  
- E xtr a s er u m a n d P B M Cs c oll e cti o n f or b a n ki n g  
- F asti n g li pi d p a n el (t ot al c h ol est er ol, tri gl y c eri d es, L D L, H D L), gl u c os e, i ns uli n l e v els  
- H e m o gl o bi n A 1 c  
- S er u m 2 5- ( O H) vit a mi n D l e v el  
- S er u m P S A  
- S er u m t est ost er o n e
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7 . 5 d a

P ati e nts r a n d o mi z e d t o t h e S T A N D cli ni c will r et ur n t o cli ni c o n a m o nt hl y b asis. D uri n g t h e c o urs e of t h es e m o nt hl y visits, t h er e will b e a s eri es of s elf -g ui d e d e d u c ati o n al m o d ul es dis c ussi n g v ari o us as p e cts of a n dr o g e n d e pri v ati o n t h er a p y a n d m a n a g e m e nt o f si d e eff e cts.  
T h es e m o d ul es will b e c o m pris e d of P o w er P oi nt sli d e pr es e nt ati o ns w hi c h t h e p ati e nts will vi e w o n a s elf -dir e ct e d m a n n er d uri n g t h eir cli ni c visit, wit h t h e o p p ort u nit y t o as k q u esti o ns b ef or e a n d aft er t h e pr es e nt ati o n. I n a d diti o n, o n a r ot ati ng s c h e d ul e, p ati e nts will m e et o n e -t o-o n e wit h a li c e ns e d e x er cis e tr ai n er, r e gist er e d di etiti a n, a n d s y m pt o m m a n a g e m e nt s er vi c e t o r e c ei v e i n di vi d u ali z e d c o u ns eli n g. T h e r ot ati o n of t h e s c h e d ul e of pr o vi d ers m a y b e a dj ust e d d e p e n di n g u p o n a v ail a bilit y of pr o vi d er a n d p ati e nt. I n t ot al, p ati e nts will m e et with e a c h s p e ci ali z e d s er vi c e f o ur ti m es o n a r ot ati n g e v er y 3 m o nt h-s c h e d ul e.  
P ati e nts e nr oll e d i n t h e n o n -r a n d o mi z e d c h e m o h or m o n al c o h ort will r et ur n t o cli ni c o n a n a p pr o xi m at el y m o nt hl y b asis f or r ot ati n g visits wit h e x er cis e, n utriti o n, a n d s y m pt o m m a n a g e m e nt, wit h s c h e d ul e of visits m at c hi n g w h e n e v er p ossi bl e t h e s c h e d ul e d d at es of i nf usi o n c e nt er a p p oi nt m e nts P ati e nts r a n d o mi z e d t o t h e st a n d ar d -of -c ar e ar m will b e r ef err e d t o n utriti o n, e x er cis e, a n d s y m pt o m m a n a g e m e nt s er vi c e u p o n p ati e nt r e q u est or if d e e m e d n e c ess ar y b y h e alt h c ar e pr o vi d er, as p er c urr e nt st a n d ar d - of-c ar e a n d pr a cti c e g ui d eli n es. P ati e nts w ill h a v e t h e o p p ort u nit y t o r e c ei v e t h e e d u c ati o n al m o d ul es f or r e vi e w o utsi d e t h e cli ni c s etti n g D uri n g t h e c o urs e of t h e visit wit h t h e e x er cis e tr ai n er, p ati e nts will r e vi e w e x er cis e p att er ns wit h t h e us e of q u estio n n air es fill e d o ut pri or t o visit a n d vi a t h e us e of a m b ul at or y a c c el er o m et er w hi c h q u a ntifi es a cti vit y l e v el . P ati e nts will r e c ei v e i n di vi d u ali z e d c o u ns eli n g r e g ar di n g s p e cifi c e x er cis es, a n d r ei nf or c e m e nt of est a blis hi n g r e g ul ar e x er cis e r o uti n e. D uri n g t h e c o urs e of t h e visit, p ati e nts w ill h a v e t h e o p p ort u nit y t o pr a cti c e a ct u al e x er cis e r o uti n es u n d er t h e s u p er visi o n of t h e e x er cis e tr ai n er, a n d will r e c ei v e i n -p ers o n ass ess m e nt of a er o bi c fit n ess l e v el.  
D uri n g t h e c o urs e of t h e visit wit h t h e r e gist er e d di etiti a n, p ati e nts will r e vi e w di et ar y h a bits wit h t h e us e of di et l o gs fill e d o ut pri or t o e a c h visit. P ati e nts will r e c ei v e i n di vi d u ali z e d c ou ns eli n g o n r e c o m m e n d e d f o o ds/ di et, a n d will r e c ei v e f e e d b a c k o n pr o gr ess o n a l o n git u di n al b asis.  
D uri n g t h e c o urs e of visit wit h s y m pt o m m a n a g e m e nt s er vi c e, p ati e nts p h ysi c al a n d ps y c h os o ci al iss u es will b e a d dr ess e d b y tr ai n e d h e alt h c ar e pr o vi d er. C o u ns eli n g a n d m e di c al m a n a g e m e nt will b e pr o vi d e d.
untitled h1
7. 6 e v e

- P h ysi c al e x a m  
- C o n c o mit a nt m e di c ati o ns  
- E C O G P erf or m a n c e St at us  
- Q u alit y of lif e q u esti o n n air es o S F - 1 2, E PI C - 2 6, H F R DI S, L e e F ati g u e S c al e, P H Q -9, Att e nti o n al F u n cti o n al I n d e x, e x er cis e p att er n ass ess m e nt, e m p at h y s c al e  
- W ei g ht, b o d y m ass i n d e x, a n d p er c e nt b o d y f at b y bi oi m p e d a n c e m e as ur e m e nt  
- P ati e nts will b e r ef err e d t o t h e S y m pt o m M a n a g e m e nt S er vi c e , n utriti o n s er vi c e, a n d/ or e x er cis e p h ysi ol o gist f or f urt h er e v al u ati o n at t h e dis cr eti o n of h e alt h c ar e pr o vi d er or p er p ati e nt r e q u est ( St a n d ar d- of-c ar e tr e at m e nt ar m o nl y)  
- L H R H a n al o g u e a d mi nistr ati o n  
- C o u ns eli n g r e g ar di n g lif est yl e m o difi c ati o ns a n d r e vi e w of t h e r es ults of t h e a b o v e l a b or at or y t ests a n d q u alit y of lif e q u esti o n n air es b y a tr ai n e d n urs e pr a ctiti o n er or p h ysi ci a n.  
o T h e P H Q -9 q u esti o n n air e s cr e e ni n g f or d e pr essi o n m ust b e c o m pl et e d i n p ers o n d uri n g t h e st u d y visit a n d m ust b e si g n e d b y tr e ati n g h e alt h c ar e pr o vi d er pri or t o p ati e nt dis c h ar g e fr o m cli ni c
untitled h1
7. 6 . 2 l

- S er u m a n d pl as m a c oll e cti o n f or b a n ki n g  
- F asti n g li pi d p a n el, gl u c os e, a n d i ns uli n l e v el  
- H e m o gl o bi n A 1 c  
- S er u m 2 5- ( O H) vit a mi n D l e v el  
- S er u m P S A
untitled h1
7. 7 e n d

- P h ysi c al e x a m  
- C o n c o mit a nt m e di c ati o ns  
- E C O G P erf or m a n c e S t at us  
- Q u alit y of lif e q u esti o n n air es o S F - 1 2, E PI C - 2 6, H F R DI S, L e e F ati g u e S c al e, P H Q -9, Att e nti o n al F u n cti o n al I n d e x, e m p at h y s c al e  
- W ei g ht, b o d y m ass i n d e x, a n d p er c e nt b o d y f at b y bi oi m p e d a n c e m e as ur e m e nt
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7. 7 . 2 l

- S er u m a n d pl as m a f or b a n ki n g  
- F asti n g li pi d p a n el, gl u c os e, a n d i ns uli n l e v els  
- H e m o gl o bi n A 1 c  
- S er u m 2 5- ( O H) vit a mi n D l e v els  
- S er u m P S A  
- S er u m t est ost er o n e
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7. 7 . 3 r

- D X A S c a n  
- Hi g h r es ol uti o n p eri p h er al q u a ntit ati v e C T s c a n of t h e dist al ti bi a a n d r a di us ( o pti o n al)
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7. 8 c o n

C o n c o mit a nt m e di c ati o ns will b e r e c or d e d at e a c h st u d y visit. T h e a d diti o n of m e di c ati o ns t o m a n a g e f asti n g bl o o d gl u c os e, li pi ds, b o n e d e nsit y, or bl o o d pr ess ur e will b e all o w e d a n d at t h e dis cr eti o n of t h e i n di vi d u al tr e ati n g p h ysi ci a n.
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7. 9 f oll o

P ati e nts r a n d o mi z e d t o t h e st a n d ar d - of-c ar e st u d y ar m will h a v e t h e o pti o n of cr ossi n g -o v er t o p arti ci p ati o n i n t h e S T A N D cli ni c at t h e e n d of m o nt h 1 2 st u d y visit. P ati e nts w h o o pt t o p arti ci p at e i n t h e S T A N D cli ni c will b e f oll o w e d f or a n a d diti o n al 1 2 m o nt hs. T h e S T A N D cli ni c s c h e d ul e will b e i d e nti c al t o t h at f oll o w e d b y p ati e nts i niti all y r a n d o mi z e d t o t h e S T A N D cli ni c.  
F oll o wi n g c o m pl eti o n of S T A N D cli ni c p arti ci p ati o n, p ati e nts will b e f oll o w e d b y t el e p h o n e visit aft er 2 a n d 4 m o nt hs t o ass ess a d h er e n c e t o r e c o m m e n d e d di et/ e x er cis e pl a ns. At 6 m o nt hs f oll o wi n g c o m pl eti o n of t h e S T A N D cli ni c, p ati e nts will r et ur n f or cli ni c ass ess m e nt, w hi c h will i n cl u d e a p h ysi c al e x a m, a m e as ur e m e nt of w ei g ht, b o d y m ass i n d e x, p er c e nt a g e b o d y f at, l a b or at or y t ests i n cl u di n g e v al u ati o n of f asti n g gl u c os e/li pi d/i ns uli n p a n els, h e m o gl o bi n A 1 c, pl as m a m et a b olit es, s er u m P S A, s er u m t est ost er o n e a n d c o m pl eti o n of q u alit y of lif e q u esti o n n air es as o utli n e d i n t h e A p p e n di x, a n d s er u m a n d pl as m a b a n ki n g.
untitled h1
7. 1 0 d u

T h e t ot al d ur ati o n of t h e st u d y i n cl u di n g f oll o w u p is e x p e ct e d t o b e a p pr o xi m at el y 5 y e ars fr o m t h e d at e t h e first p ati e nt is e nr oll e d o nt o st u d y.
untitled h1
8 . a s s

P er c e nt b o d y f at will b e esti m at e d at b as eli n e a n d e v er y 3 m o nt hs wit h t h e us e of st a n d ar d bi o el e ctri c al i m p e d a n c e m o nit or (s e e A p p e n di x 4). Pri or st u di es h a v e d e m o nstr at e d hi g h r eli a bilit y a n d str o n g c orr el ati o n wit h ot h er m o d aliti es i n cl u di n g D X A s c a ns.
untitled h1
8 . 2 p ati

At b as eli n e a n d e v er y 3 m o nt hs p ati e nts will c o m pl et e q u alit y of lif e a n d ot h er q u esti o n n air es as o utli n e d i n A p p e n di x 2. P ati e nts will c o m pl et e t h e q u esti o n n air es o nli n e wit hi n o n e w e e k of st u d y visit or at t h e ti m e of st u d y visit, eit h er el e ctr o ni c all y or o n p a p er. T h e P H Q -9 q u esti o n n air e m ust b e c o m pl et e d o n p a p er d uri n g t h e st u d y visit. It is m a n d at or y t h at t h e r es p o nsi bl e h e alt h c ar e pr o vi d er f or t h e st u d y visit r e vi e w a n d si g n t h e r es ults of t h e P H Q- 9 pri or t o p ati e nt dis c h ar g e fr o m cli ni c.
untitled h1
8 . 3 g e

C oll e cti o n of p eri p h er al bl o o d m o n o n u cl e ar c ells f or ass ess m e nt of g er mli n e p ol y m or p his ms a n d t h eir ass o ci ati o n wit h t h e r el e v a nt t o xi citi es of A D T is a n e x pl or at or y o bj e cti v e of t h e c urr e nt st u d y a n d p ati e nt p arti ci p ati o n i n t his as p e ct of t h e st u d y is o pti o n al.  
T h e g e n eti c p ol y m or p his ms s el e ct e d f or t his st u d y w er e b as e d o n a lit er at ur e r e vi e w of pri or st u di es w hi c h d e m o nstr at e d si g nifi c a nt ass o ci ati o ns b et w e e n p ol y m or p his ms n e ar or wit hi n s el e ct g e n es of i nt er est e n c o di n g pr ot ei ns i n v ol v e d i n st er oi d h or m o n e m et a b olis m, i ntr a- c ell ul ar tr a ns p ort, estr o g e n/ a n dr o g e n r e c e pt or si g n ali n g, a n d t h e I G F p at h w a y wit h cli ni c al o ut c o m es o n a n dr o g e n d e pri v ati o n t h er a p y. M ost pri or st u di es i n cl u d e d p ol y m or p his ms wit h a mi n or all el e fr e q u e n c y > 5 % i n t h e CE U ( C a u c asi a n) p o p ul ati o n. T h e f ull s et of p ol y m or p his ms t o b e a n al y z e d is list e d i n A p p e n di x 1.  
G e n o mi c D N A will b e pr e p ar e d fr o m p eri p h er al bl o o d usi n g a QI A a m p D N A Bl o o d Mi ni Kit  
( Q ui a g e n I n c, V al e n ci a, C A, U S A). D N A will b e st or e d at 4° C. G e n ot y pi n g wi ll b e c arri e d o ut usi n g S e q u e n o m i P L E X m atri x -assist e d l as er d es or pti o n/i o ni z ati o n ( M A L DI)-ti m e of fli g ht m ass s p e ctr o m etr y t e c h n ol o g y ( C arls b a d, C A; htt p:// w w w.s e q u e n o m. c o m/s e q _ g e n ot y pi n g. ht ml/).  
Ass a ys w ill b e d esi g n e d usi n g S e q u e n o m's M ass A R R A Y Assi g n D e si g n er a p pli c ati o n, v ersi o n 3. 0. P ol y m er as e c h ai n r e a cti o n ( P C R) a n d si n gl e b as e e xt e nsi o n ( S B E) oli g o n u cl e oti d es w ill b e s y nt h esi z e d b y I nt e gr at e d D N A T e c h n ol o gi es ( C or al vill e, I A). P C R a m plifi c ati o n will b e p erf or m e d usi n g a n i n p ut of 1 0 n g of D N A i n a fi n al v ol u m e of 6 L. T h e P C R pr o d u cts w ill b e s u bs e q u e ntl y tr e at e d wit h s hri m p al k ali n e p h os p h at as e, a n d t h e S B E r e a cti o ns w ill b e i niti at e d usi n g i P L E X e n z y m e a n d m ass -m o difi e d t er mi n at ors ( b ot h S e q u e n o m). Aft er d es alti n g, 7 n L of t h e S B E r e a cti o n will b e s p ott e d o nt o a S p e ctr o C HI P ( S e q u e n o m) pr el o a d e d wit h 7 n L of 3h y dr o x y pi c oli ni c a ci d m atri x. T h e S p e ctr o C HI P s w ill b e a n al y z e d i n a ut o m at e d m o d e b y a M ass Arr a y C o m p a ct s oli d p h as e l as er m ass s p e ctr o m et er s yst e m ( Br u k er D alt o ni cs, Bill eri c a, M A). T h e r es ul ti n g s p e ctr a will b e a n al y z e d a n d g e n ot y p es c all e d i n r e al -ti m e b y t h e S p e ctr o C all er al g orit h m, f oll o w e d b y a d diti o n al us er -i niti at e d a n al ysis wit h t h e S p e ctr o T y p er v. 3. 4 A ( S e q u e n o m). T h e err or r at e o n t his pl atf or m is esti m at e d t o b e l ess t h a n 0. 0 3 %.  
F or t h e mi cr os at ellit e a n al ysis, D N A s a m pl es will b e w h ol e g e n o m e a m plifi e d usi n g I ll ustr a G e n o mi P hi V 2 a c c or di n g t o t h e m a n uf a ct ur er's r e c o m m e n d e d pr ot o c ol ( G E H e alt h c ar e, C h alf o nt St Gill es, U K). T h e y will t h e n b e q u a ntifi e d usi n g R N As e P G e n e E x pr essi o n Ass a y a c c or di n g t o t h e m a n uf a ct ur er's r e c o m m e n d e d pr ot o c ol ( A p pli e d Bi os yst e ms, F ost er Cit y, C A,  
U S A). P ol y m er as e c h ai n r e a cti o n ( P C R) will b e p erf or m e d usi n g 2 μ M fi n al c o n c e ntr ati o n f or b ot h f or w ar d a n d r e v ers e pri m ers, 1. 5 m m ol/ L M g, a n d 0. 2 u nits of Pl ati n u m T a q D N A  
P ol y m er as e (I n vitr o g e n, C arls b a d, C A, U S A) i n a fi n al v ol u m e of 1 0 μ L. Aft er a n i niti al d e n at ur ati o n of 5 mi n at 9 4 °C, s a m pl es will b e t hr o u g h 3 5 c y cl es aft er 9 4° C f or 4 0 s, t h e pr o p er a n n e ali n g t e m p er at ur e f or 3 0 s, a n d 7 2° C f or 3 0 s, f oll o w e d b y a fi n al e xt e nsi o n st e p of 7 2° C f or 1 0 mi n. O n e mi cr olitr e of P C R pr o d u ct will b e a d d e d t o a mi xt ur e of Hi -Di F or m a mi d e ( A p pli e d Bi os yst e ms) a n d R O X 4 0 0 H D St a n d ar d ( A p pli e d Bi os yst e ms). S a m pl es will t h e n b e d e n at ur e d f or 5 mi n at 9 5° C a n d pl a c e d o n i c e f or 3 mi n, f oll o w e d b y c a pill ar y el e ctr o p h or esis o n a n A BI  
3 7 3 0 X L( A p pli e d Bi os yst e ms). G e n ot y p es will b e s c or e d usi n g G e n e M a p p er 4. 0 ( A p pli e d Bi os yst e ms).
untitled h1
8. 4 hi g h

T h e i m a g e c oll e cti o n will t a k e pl a c e at t h e C hi n a B asi n i m a gi n g f a cilit y at U C S F. 3 D tr a b e c ul ar b o n e d e nsit y a n d str u ct ur e, c orti c al b o n e d e nsit y, t hi c k n ess a n d p or osit y at t h e dist al r a di us a n d ti bi a will b e m e as ur e d usi n g hi g h -r es ol uti o n p eri p h er al q u a ntit ati v e c o m p ut e d t o m o gr a p h y  
( H R p Q C T).  
R e gi o n al of I nt er est D efi niti o n I n t h e s u p eri or-i nf eri or dir e cti o n w e will c oll e ct 1 8 m m of i m a g e d at a, w e will a n al y z e t his st a c k i n t w o st a g es, t h e dist al 9 m m, t h e n 9 m m-1 8 m m. I n a d diti o n r e gi o n al a n al ysis f or tr a b e c ul ar b o n e, i n 8 r e gi o ns will b e p erf or m e d. T h e tr a b e c ul ar c o m p art m e nt will b e di vi d e d i nt o t w o c o n c e ntri c r e gi o ns (i n n er a n d o ut er s u b -r e gi o ns), w h er e t h e ar e a of t h e i n n er s u b-r e gi o n will b e 6 0 % of t h e e ntir e tr a b e c ul ar r e gi o n. T h e v ol u m e will b e f urt h er di vi d e d i nt o a xi al q u a dr a nts. I n t h e l e g, a li ne c o n n e cti n g t h e a xi al c e ntr oi ds of t h e ti bi a a n d fi b ul a a n d it's ort h o g o n al c o m pli m e nt will d efi n e a p pr o xi m at el y m e di al -l at er al/ a nt eri or-p ost eri or q u a dr a nts. I n t h e f or e ar m, t h e m aj or a n d mi n or a x es of t h e a xi al cr oss s e cti o n of t h e r a di us will d efi n e t h e m e di al -  
l at er al/ a nt eri or-p ost eri or q u a dr a nts. E a c h s u b -r e gi o n d e n ot e d b y a t w o l ett er a cr o n y m b as e d o n l o c ati o n: I or O f or i n n er or o ut er s u b-r e gi o ns, r es p e cti v el y; a n d M, P, L, or A f or m e di al, p ost eri or, l at er al a n d a nt eri or, r es p e cti v el y. M e a n tr a b e c ul ar d e nsit o m etri c a n d mi cr o -  
ar c hit e ct ur al i n di c es will b e c o m p ut e d f or e a c h i n di vi d u al s u b -r e gi o n. T h e c orti c al a n al ysis will b e d o n e i n t h e 4 a xi al q u a dr a nts.
untitled h1
9 . pl a n

R a n d o mi z e d, p h as e 2 st u d y wit h cr oss -o v er d esi g n t o ass ess t h e l o n git u di n al i m p a ct of p arti ci p ati o n i n t h e m ulti -dis ci pli n ar y S T A N D cli ni c vs. r e c ei pt of us u al st a n d ar d of c ar e o n c h a n g es i n k e y m et a b oli c p ar a m et ers, q u alit y of lif e, a n d p ati e nt s atisf a cti o n a m o n g m e n r e c ei vi n g a n dr o g e n d e pri v ati o n t her a p y f or pr ost at e c a n c er. St a n d ar d -of -c ar e t h er a p y will c o nsist of e v er y 3- m o nt h visits c o m pris e d of r e vi e w of m e di c al hist or y, t o xi cit y ass ess m e nt, a n d lif est yl e m o difi c ati o n c o u ns eli n g pr o vi d e d b y i n di vi d u al h e alt h c ar e pr o vi d er, L H R H a n al o g i nj e cti o ns b y tr ai n e d o n c ol o g y n urs e. P ati e nts will h a v e a c c ess t o e x er cis e, n utriti o n, a n d s y m pt o m m a n a g e m e nt c o u ns eli n g if s o r e q u est e d b y t h e p ati e nt or d e e m e d n e c ess ar y b y h e alt h c ar e pr o vi d er . M e n r a n d o mi z e d t o p arti ci p ati o n i n t h e S T A N D cli ni c will r e c ei v e, i n a d diti o n t o st a n d ar d e v er y 3 m o nt h visits wit h h e alt h c ar e pr o vi d ers a n d L H R H a n al o g i nj e cti o ns, m o nt hl y s elf-dir e ct e d e d u c ati o n al " m o d ul es " c o v eri n g t h e v ari o us as p e cts of h or m o n e t h er a p y as w ell as e v er y 3 -m o nt h i n di vi d u ali z e d c o u ns eli n g pr o vi d e d b y r e gi st er e d di etiti a n, e x er cis e tr ai n er, a n d s y m pt o m m a n a g e m e nt s er vi c e . At t h e e n d of 1 2 m o nt hs of st u d y p arti ci p ati o n, p ati e nts i niti all y r a n d o mi z e d t o r e c ei v e st a n d ar d-of -c ar e, will h a v e t h e o pti o n of cr ossi n g -o v er t o p arti ci p at e i n t h e S T A N D cli ni c f or t h e e ns ui n g 1 2 m o nt hs.  
A n o n -r a n d o mi z e d pil ot c o h ort of 2 0 p ati e nts r e c ei vi n g c o n c urr e nt c h e m o h or m o n al t h er a p y will b e e nr oll e d i n p ar all el t o ass ess t h e f e asi bilit y of S T A N D cli ni c p arti ci p ati o n i n t his p ati e nt p o p ul ati o n.
untitled h1
9 . 2 d et

T h e s a m pl e si z e esti m at e is b as e d u p o n t h e pri m ar y e n d p oi nt of t h e st u d y, t h e m e a n p er c e nt c h a n g e i n p er c e nt a g e b o d y f at fr o m b as eli n e t o 1 2 m o nt hs. B as e d o n pri or pr os p e cti v e l o n git u di n al st u di es, it is esti m at e d t h at m e n r e c ei vi n g A D T a n d st a n d ar d- of-c ar e p h ysi ci a n c o u ns eli n g r e g ar di n g e x p e ct e d t o xi citi es will e x p eri e n c e a m e a n 1 2 % ( s d = 1 7 %) i n cr e as e i n p er c e nt a g e b o d y f at aft er 1 2 m o nt hs of A D T [ 1 3]. If m e n p arti ci p ati n g i n t h e S T A N D cli ni c, wit h i n di vi d u ali z e d e x er cis e/ n utriti o n c o u ns eli n g a n d l o n git u di n al ass ess m e nt, h a v e, o n a v er a g e, n o i n cr e as e i n p er c e nt a g e b o d y f at m ass aft er 1 2 m o nt hs of h or m o n e t h er a p y, t his w o ul d w arr a nt f urt h er e v al u ati o n of a m ulti-dis ci pli n ar y cli ni c i n a l ar g er r a n d o mi z e d cli ni c al tri al wit h l o n g -  
t er m e n d p oi nts of i nt er est, i n cl u di n g i n ci d e n c e of di a b et es a n d p ot e nti all y c ar di o v as c ul ar dis e as e.  
A n e nr oll m e nt t ar g et of 3 2 e v al u a bl e p ati e nts p er ar m will pr o vi d e p o w er of 8 0 % t o d et e ct a n eff e ct si z e of 0. 7 1 i n t h e diff er e n c e i n m e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m ass b et w e e n t h e t w o ar ms, usi n g a t w o -s a m pl e t t est a n d a t w o-t ail e d l e v el of si g nifi c a n c e = 0. 0 5. T h e t ot al pl a n n e d a c cr u al is 4 0 p ati e nts p er ar m a c c o u nti n g f or a n i n e v al u a bl e r at e of 2 0 %.  
A s a m pl e si z e of 2 0 p ati e nts is c h os e n f or t h e n o n-r a n d o mi z e d c h e m o h or m o n al c o h ort t o est a blis h t h e f e asi bilit y of a m ulti -dis ci pli n ar y cli ni c i n t his p ati e nt p o p ul ati o n. T h e pri m ar y e n d p oi nt f or t his pil ot c o h ort is t h e p er c e nt a g e of c o m pl et e d S T A N D cli ni c visits, wit h a t ar g et g o al of 8 0 %. A s a m pl e si z e of 2 0 p ati e nts ( 1 3 visits p er p ati e nt; 2 6 0 visits i n t ot al) pr o vi d es 1 7. 5 % pr e cisi o n t o d et er mi n e t h e p er c e nt a g e of c o m pl et e d visits at 9 5 % c o nfi d e n c e.
untitled h1
9 . 3 i nt

I nt eri m a n al ysis will b e p erf or m e d aft er 3 3 % of t h e pl a n n e d s a m pl e si z e of r a n d o mi z e d p ati e nts c o m pl et e 1 2 -m o nt h c ar e. T o pr es er v e t h e o v er all t y p e I err or r at e at < 0. 0 5, t h e L a n -D e M ets s p e n di n g f u n cti o n will b e us e d t o all o c at e n o mi n al al p h a -l e v els at t h e i nt eri m a n d fi n al a n al ys es.  
T h e effi c a c y st o p pi n g b o u n d ar i es f or t h e pri m ar y effi c a c y e n d p oi nt at t h e i nt eri m a n d fi n al a n al ys es ar e p < 0. 0 2 6 a n d p < 0. 4 7 4, r es p e cti v el y.  
A n i nt eri m a n al ysis f or t h e n o n -r a n d o mi z e d c o h ort will b e p erf or m e d aft er 1 0 p ati e nts h a v e b e e n e nr oll e d o n t h e S T A N D cli ni c f or a mi ni m u m of 6 m o nt hs. If t h e p er c e nt a g e of c o m pl et e d S T A N D visits is l ess t h a n 6 0 %, t h e st u d y s c h e d ul e will b e alt er e d t o e ns ur e hi g h er r at es of p ati e nt a d h er e n c e t o t h e cli ni c s c h e d ul e.
untitled h1
9. 4 a c c

A t ot al of 8 0 p ati e nts will b e e nr oll e d i n t h e r a n d o mi z e d p ati e nt c o h ort at t h e U ni v ersit y of C alif or ni a S a n Fr a n cis c o. St u d y a c cr u al is a nti ci p at e d t o b e a p pr o xi m at el y 2 p ati e nts p er m o nt h, l e a di n g t o t ot al st u d y a c cr u al d ur ati o n of 4 0 m o nt hs. A nti ci p at e d ti m e fr o m l ast p ati e nt e nr oll e d t o pri m ar y st u d y c o m pl eti o n a n d a n al ysis of pri m ar y a n d s e c o n d ar y e n d p oi nts e q u als a p pr o xi m at el y 1 2 m o nt hs, l e a di n g t o a n esti m at e d pri m ar y st u d y d ur ati o n of 5 2 m o nt hs. A t ot al of 2 0 p ati e nts will b e e nr oll e d i n t h e n o n -r a n d o mi z e d c h e m o h or m o n al c o h ort, at a n esti m at e d fr e q u e n c y of 0. 8 p ati e nts/ m o nt h, l e a di n g t o a n esti m at e d a c cr u al p eri o d of 2 4 m o nt hs.
untitled h1
9. 5 a n al

T h e pri m ar y a n al ysis f or t h e r a n d o mi z e d c o h ort will i n cl u d e all p ati e nts w h o h a v e a b o d y f at %  
m e as ur e m e nt at b as eli n e a n d at m o nt h 1 2 o n st u d y ( +/ - 2 w e e ks). If a p ati e nt c o m es off st u d y pri or t o o bt ai ni n g t h e e n d of m o nt h 1 2 b o d y f at % m e as ur e m e nt, t h e y will n ot b e i n cl u d e d i n t h e pri m ar y st u d y a n al ysis.  
All p ati e nts e nr oll e d i n t h e c h e m o h or m o n al n o n -r a n d o mi z e d c o h ort w h o c o m pl et e C 1 D 1 visit will b e i n cl u d e d i n t h e a n al ysis of t h e pri m ar y e n d p oi nt, t h e p er c e nt a g e of c o m pl et e d visits i n t h e S T A N D cli ni c.
untitled h1
9. 6 d e m

D e m o gr a p hi c v ari a bl es will i n cl u d e a g e, r a c e, a n d et h ni cit y. B as eli n e c h ar a ct eristi cs will i n cl u d e t h e f oll o wi n g:  
o H ei g ht, w ei g ht, b o d y m ass i n d e x, w aist cir c u mf er e n c e, p er c e nt a g e b o d y f at o Ass ess m e nt of c o - m or bi diti es i n cl u di n g di a b et es a n d h e art dis e as e ( A p p e n di x 3)  
o D at e of pr ost at e c a n c er di a g n osis o Gl e as o n gr a d e a n d P S A at t h e ti m e of di a g n osis o T y p e a n d d at e of pri or l o c al t h er a p y (if a n y)  
o D at e of A D T i niti ati o n a n d i n di c ati o n ( a dj u v a nt, bi o c h e mi c al r el a ps e, or m et ast ati c dis e as e)  
o B as eli n e P S A at t h e st art of A D T  
o C o n c urr e nt us e of a nti- a n dr o g e n o M et ast ati c st at us at ti m e of st u d y e ntr y ( n o n e, b o n e o nl y, s oft tiss u e, a n y vis c er al)
untitled h1
9. 7 st u d

R a n d o mi z e d c o h o rt: M e a n p er c e nt c h a n g e fr o m b as eli n e t o 1 2 m o nt hs i n p er c e nt a g e b o d y f at m ass as m e as ur e d b y bi o el e ctri c al i m p e d a n c e a n al y z er.  
N o n - r a n d o mi z e d c o h o rt: P er c e nt a g e of c o m pl et e d S T A N D cli ni c visits.
untitled h1
9. 7 . 2 s

M e a n p e r c e nt c h a n g e f r o m b as eli n e t o 1 2 m o nt hs a n d p att e r ns of c h a n g e f r o m b as eli n e wit h r es p e ct t o t h e f oll o wi n g :  
M et a b oli c I m p a ct o n Di a b et es a n d C ar di o v as c ul ar Dis e as e Ris k F a ct ors:  
- F asti n g bl o o d gl u c os e  
- F asti n g pl as m a i ns uli n l e v el  
- I ns uli n r esist a n c e as c al c ul at e d b y H O M A-I R  
- H e m o gl o bi n A 1 c  
- F asti n g li pi ds (t ot al c h ol est er ol, L D L, H D L, tri gl y c er ci d es)  
- W aist cir c u mf er e n c e  
- B o d y w ei g ht/ b o d y m ass i n d e x  
- E x er cis e p att er ns as m e as ur e d b y v ali d at e d q u esti o n n air e a n d p e d o m et er ass ess m e nt  
- Bl o o d pr ess ur e B o n e H e alt h:  
- B o n e d e nsit y at t h e l u m b ar s pi n e, f e m or al n e c k, a n d t ot al hi p as ass ess e d b y D X A s c a n a m o n g p ati e nts wit h o ut b o n e m et ast as es at t h e ti m e of st u d y e ntr y  
- S er u m 2 5- ( O H) vit a mi n D l e v els Q u alit y of Lif e/ Ps y c h os o ci al I m p a ct:  
- D e pr essi o n as m e as ur e d b y P H Q - 9  
- C o g niti v e f u n cti o n as m e as ur e d b y Att e nti o n al F u n cti o n al I n d e x  
- O v er all q u alit y of lif e as m e as ur e d b y S F - 1 2  
- F ati g u e as m e as ur e d b y t h e L e e F ati g u e S c al e  
- Er e ctil e a n d uri n ar y f u n cti o n as m e as ur e d b y E PI C - 2 6  
- H ot fl as h s e v erit y as m e as ur e d b y H ot Fl as h R el at e d D ail y I nt erf er e n c e S c al e
untitled h1
9. 7 . 3 c

- Ass o ci ati o n b et w e e n i n h erit e d g e n eti c p ol y m or p his ms of f u n cti o n al r el e v a n c e n e ar or wit hi n g e n es e n c o di n g pr ot ei ns wit h r ol es i n st er oi d h or m o n e tr a ns p ort a n d a n dr o g e n r e c e pt or si g n ali n g wit h c h a n g es i n m et a b oli c p ar a m et ers a m o n g m e n tr e at e d wit h a n dr o g e n d e pri v ati o n t h er a p y.  
- M e a n c h a n g e fr o m b as eli n e i n tr a b e c ul ar b o n e ar c hit e ct ur e as m e as ur e d b y tr a b e c ul ar b o n e n u m b er ( T b N) a n d tr a b e c ul ar b o n e v ol u m e fr a cti o n ( B V/ T V) aft er 1 2 m o nt hs of a n dr o g e n d e pri v ati o n t h er a p y.  
- Ass o ci ati o n b et w e e n 2 D: 4 D r ati o wit h c h a n g e i n q u alit y of lif e o n a n dr o g e n d e pri v ati o n t h er a p y.  
- Ass o ci ati o n b et w e e n 2 D: 4 D r ati o a n d b as eli n e a n d p er c e nt c h a n g e fr o m b as eli n e i n e m p at h y s c or e.
untitled h1
9. 8 m et h

G e n er all y, fr e q u e n c y distri b uti o ns, m e a ns, a n d st a n d ar d d e vi ati o ns will b e us e d t o d es cri b e s u bj e ct d e m o gr a p hi cs a n d b as eli n e c h ar a ct eristi cs. U ni v ari at e a n al ysis a m o n g v ari a bl es will b e ass ess e d usi n g t h e t w o -s a m pl e t-t est, Wil c o x o n-r a n k-s u m t est, C hi-s q u ar e t est, as a p pr o pri at e.  
St atisti c al si g nifi c a n c e will b e d e cl ar e d b as e d o n al p h a l e v el of 0. 0 5. F or t h e e n d p oi nts wit h missi n g l ess t h a n 2 5 % of v al u es, m ulti v ari at e i m p ut ati o n usi n g f ull y c o n diti o n al s p e cifi c ati o n ( R  
MI C E p a c k a g e) will b e i m pl e m e nt e d . F or e n d p oi nts missi n g m or e t h a n 2 5 % of v al u es, t h e e n d p oi nt will b e e x cl u d e d fr o m t h e fi n al a n al ysis.
untitled h1
9. 8 . 1 a

T w o -sa m pl e t -t est will b e us e d t o c o m p ar e t h e m e a n p er c e nt c h a n g e fr o m b as eli n e i n p er c e nt a g e b o d y f at aft er 1 2 m o nt hs of st u d y p arti ci p ati o n. T h e c h a n g es i n p er c e nt a g e b o d y f at a cr oss t h e diff er e nt ti m e p oi nts will b e e v al u at e d usi n g r e p e at e d m e as ur es a n al ysis of c o v ari a n c e. T o f urt h er c h ar a ct eri z e t h e p att er ns o v er t h e ti m e a n d i n v esti g at e t h e eff e ct of tr e at m e nt ar m assi g n m e nt, a li n e ar mi x e d m o d el will b e a p pli e d wit h a dj usti n g f or str atifi c ati o n f a ct ors a n d c o v ari at es i n cl u di n g C h arls o n c o- m or bi dit y i n d e x s c or e, a g e, a n d b as eli n e d e pr essi o n s c or e as m e as ur e d b y P H Q -9. P ati e nts w h o d o n ot h a v e a b as eli n e or e n d - of-m o nt h 1 2 p er c e nt a g e b o d y f at m e as ur e m e nt, or t h os e t h at st art m e di c ati o ns k n o w n t o aff e ct b o d y f at/ b o d y w ei g ht d uri n g t h e c o urs e of t h e 1 2 -m o nt h st u d y , i n cl u di n g m etf or mi n, i ns uli n, c orti c ost er oi ds, mirt a z a pi n e, or m e g estr ol , will b e e x cl u d e d fr o m t h e pri m ar y e n d p oi nt a n al ysis. I n a n e x pl or at or y a n al ysis, t h es e p ati e nts will b e r et ai n e d t o ass ess t h e i m p a ct of S T A N D cli ni c p arti ci p ati o n o n c h a n g es i n p er c e nt a g e b o d y f at o v er ti m e b ot h b ef or e a n d aft er i niti ati o n of m e di c al m a n a g e m e nt.  
F or t h e n o n -r a n d o mi z e d c h e m o h or m o n al c o h ort, t h e p oi nt esti m at e a n d 9 5 % c o nfi d e n c e i nt er v al of t h e p er c e nt a g e of c o m pl et e d S T A N D cli ni c visits will b e r e p ort e d.
untitled h1
9. 8 . 2 a

T w o -s a m pl e t t est will b e us e d t o c o m p ar e t h e m e a n c h a n g e fr o m b as eli n e t o 1 2 m o nt hs f or t h e s e c o n d ar y e n d p oi nts w hi c h h ol d t h e n or m alit y ass u m pti o n. F or e n d p oi nts t h at d o n ot h ol d t h e n or m alit y ass u m pti o n, as w ell as f or or di n al l e v el of m e as ur e m e nts, Wil c o x o n -r a n k-s u m t est will b e us e d. T o e v al u at e t h e c h a n g es i n s e c o n d ar y e n d p oi nts a cr oss t h e diff er e nt ti m e p oi nts, r e p e at e d m e as ur es a n al ysis of c o v ari a n c e will b e us e d f or c o nti n u o us e n d p oi nts ( a p pr o pri at e tr ansf or m ati o n will b e a p pli e d if n or m alit y ass u m pti o n d o es n't h ol d), w hil e r e p e at e d m e as ur es g e n er ali z e d esti m ati o n e q u ati o n wit h a c u m ul ati v e l o gi c c at e g ori c al will b e a p pli e d f or t h e or di n al l e v el of m e as ur e m e nts. G e n er ali z e d li n e ar mi x e d m o d els wit h a dj us tm e nt f or str atifi c ati o n f a ct ors a n d p ossi bl e c o v ari at es will b e a p pli e d t o f urt h er c h ar a ct eri z e t h e p att er ns o v er t h e ti m e a n d i n v esti g at e t h e eff e ct of t h e c ar e t y p e wit h a p pr o pri at e li n k f u n cti o n. R es ults will b e dis pl a y e d i n a gr a p hi c al f as hi o n. P ati e n ts w h o st art m e di c ati o ns k n o w n t o aff e ct e n d p oi nt b ei n g a n al y z e d ( e. g. st ati ns f or t h e li pi d p a n el m e as ur e m e nt) will b e e x cl u d e d fr o m t h e m ai n st atisti c al a n al ysis. I n a s e nsiti vit y a n al ysis t h es e p ati e nts will b e r et ai n e d t o ass ess i m p a ct of S T A N D cli ni c p arti ci p ati o n o n st u d y o ut c o m es. N o a dj ust m e nt f or m ulti pl e c o m p aris o ns will b e m a d e f or t h e a n al ysis of t h e s e c o n d ar y, e x pl or at or y o bj e cti v es.  
F or p ati e nts w h o cr oss -o v er fr o m st a n d ar d - of-c ar e t o p arti ci p at e i n t h e S T A N D cli ni c, t h e m e a n c h a n g e fr o m m o nt h 1 2 t o m o nt h 2 4 aft er t w el v e m o nt hs of p arti ci p ati o n i n t h e S T A N D cli ni c wit h r es p e ct t o t h e st u d y e n d p oi nts will b e d es cri pti v el y r e p ort e d.  
D uri n g t h e f oll o w -u p p h as e of t h e st u d y, t h e m e a n c h a n g e fr o m c o m pl eti o n of S T A N D cli ni c p arti ci p ati o n t o 1 2 m o nt hs aft er c o m pl eti o n wit h r es p e ct t o st u d y e n d p oi nts will b e d es cri pti v el y r e p ort e d.