A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of BHR-200 (0.36% Transdermal Estradiol Gel) for the Maintenance of Testosterone Suppression in Men With Advanced Androgen-Sensitive Prostate Cancer
Phase: PHASE2
Conditions: Cancer of the Prostate
Sponsor: BHR Pharma, LLC

Cli nical St u d y Pr ot oc ol  
 
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, D ose -Fi n di n g St u d y of  
B H R -2 0 0  ( 0. 3 6 % tra ns der mal estra di ol gel) f or Mai ntai ni n g  Test oster o ne 
S u p pressi o n i n Me n wit h A d va nce d A n dr o ge n -Se nsiti ve Pr ostate Ca ncer  
 
I n vesti g ati o n al Dr u g: 
B H R -2 0 0  (0. 3 6 % tra ns der mal estra di ol gel) 
Pr ot oc ol N u m ber:  
B H R -2 0 0 -2 0 1  
P h ase:  
2  
U S I N D N u m ber:  
Cli nic al Tri als. g o v I de ntifier : 
1 0 1, 2 8 8  
N C T 0 2 3 4 9 3 8 6  
 
 
Pr ot oc ol a n d A me n d me nt  D ate s: 
 
Versi o n 1. 0  
 
A me n d me nt 1  
 
A me n d me nt 2  
 
A me n d me nt 3  
 
A me n d me nt 4  
 
1 1 Fe br uar y 2 0 1 5  
2 1 A pril 2 0 1 5  
2 4 Se pte m ber 2 0 1 5  
2 6  A pril 2 0 1 6  
1 3  J u ne 2 0 1 6 
S p o ns or  
B H R P H A R M A,  L L C  
 
 
 
 
C o ntr act Rese arc h Or g a niz ati o n (s) 
Bi ostatistics & Data Ma na ge me nt  
 
 
 
 
M o nit ori n g  
 
 
 
 
  
Ce ntral La b orat or y  
 
 
 
 
Ce ntral  P har mac y  
 
 
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
 
T his pr ot oc ol c o ntai ns i nf or mati o n t hat is c o nfi de ntial a n d pr o prietar y t o B H R P H A R M A , 
L L C .  T his i nf or mati o n is bei n g pr o vi de d t o y o u f or t he p ur p ose of c o n d ucti n g a cli nical 
st u d y f or B H R P H A R M A , L L C .  Y o u ma y discl ose t he c o nte nts of t his pr ot oc ol t o st u d y 
pers o n nel u n der y o ur s u per visi o n w h o nee d t o k n o w t he c o nte nts f or t he p ur p ose, as well as 
t o y o ur I nstit uti o nal Re vie w B oar d(s) or Et hics C o m mittee(s). T he f ore g oi n g s hall n ot a p pl y 
t o discl ose re q uire d g o ver n me ntal re g ulati o ns or la ws; h o we ver, y o u will gi ve pr o m pt n otice 
t o B H R P H A R M A , L L C  of a n y s uc h discl os ure.  
 
A n y s u p ple me ntal i nf or mati o n t hat ma y be a d de d t o t his d oc u me nt is als o c o nfi de ntial a n d 
pr o prietar y t o B H R P H A R M A, L L C  a n d m ust be ke pt  i n c o nfi de nce i n t he sa me ma n ner as 
t he c o nte nts of t his pr ot oc ol. 
 
A n y pers o n w h o recei ves t his pr ot oc ol wit h o ut d ue a ut h orizati o n fr o m B H R P H A R M A , L L C  
is re q ueste d t o ret ur n it t o B H R P H A R M A , L L C  or t o pr o m ptl y destr o y it.  
 
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
S P O N S O R A P P R O V A L  
  
A ra n d o miz e d, bli n de d, place b o -c o ntr olle d, d ose -fi n di n g st u d y to e val uate t he safet y a n d 
efficac y of t hree differe nt d oses of B H R -2 0 0  ( 0. 3 6 % tra ns der mal estra di ol gel) c o m pare d t o 
place b o f or mai ntai ni n g  test oster o ne s u p pressi o n i n me n wit h a d va nce d a n dr o ge n-se nsiti ve 
pr ostate ca ncer.  
 
Versi o n: A me n d me nt 4  
Date:  1 3 J u ne 2 0 1 6  
 
 
B H R P H A R M A , L L C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
P RI N CI P A L I N V E S TI G A T O R A G R E E M E N T  
A ra n d o miz e d, d o u ble -b li n d, place b o -c o ntr olle d, d ose -fi n di n g st u d y to e val uate t he safet y 
a n d efficac y of t hree differe nt d oses of B H R -2 0 0  ( 0. 3 6 % tra ns der mal estra di ol gel) c o m pare d 
t o place b o f or mai ntai ni n g  test oster o ne s u p pressi o n i n me n wit h a d va nce d a n dr o ge n-se nsiti ve 
pr ostate ca ncer.  
 
Versi o n: A me n d me nt 4  
Date:  1 3 J u ne 2 0 1 6  
 
A s a n I n vesti gat or c o n d ucti n g t his st u d y, I a gree: 
• 
T o ass u me r es p o nsi bilit y f or t he pr o per c o n d uct of t he st u d y at t his site;  
• 
T o c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, wit h a n y f ut ure a me n d me nts, 
a n d wit h a n y ot her writte n st u d y c o n d uct pr oce d ures pr o vi de d a n d re vie we d a n d a p pr o ve d b y 
B H R P H A R M A , L L C ; 
• 
N ot t o i m ple me nt a n y de viati o ns fr o m or c ha n ges t o t his pr ot oc ol  wit h o ut a gree me nt 
fr o m t he S p o ns or a n d pri or re vie w a n d t he writte n a p pr o val fr o m t he I nstit uti o nal Re vie w 
B oar d, e xce pt w here necessar y t o eli mi nate a n i m me diate hazar d t o t he patie nts/ patie nts or 
f or a d mi nistrati ve as pects of t he st u d y ( w here per mitte d b y all a p plica ble re g ulat or y 
re q uire me nts); 
• 
T hat I a m t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he de vices, as descri be d i n 
t his pr ot oc ol, a n d a n y ot her i nf or mati o n pr o vi de d b y t he s p o ns or i ncl u di n g, b ut n ot li mite d t o 
t he c urre nt st u d y pr oce d ures or a n y e q ui vale nt d oc u me nts pr o vi de d b y B H R P H A R M A, 
L L C ; 
• 
T hat I a m a ware of, a n d will c o m pl y wit h G o o d Cli nical Practice a n d all a p plica ble 
re g ulat or y re q uire me nts; 
• 
T o e ns ure t hat all pers o ns assisti n g me wit h t he st u d y are a de q uatel y i nf or me d a b o ut 
the st u d y pr oce d ures a n d st u d y de vices, a n d t hat t he y are q ualifie d t o perf or m t heir st u d y -
relate d d uties a n d f u ncti o ns, as descri be d i n t his pr ot oc ol.  
 
P RI N CI P A L I N V E S TI G A T O R  
 
 
 
 
Na me  
 
 
 
 
 
 
 
 
Si g nat ure   
 
 
 
 
 
 
Date  
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 6  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  
he  is n o l o n ger c he micall y castrate d as de m o nstrate d b y test oster o ne 
le vels greater t ha n or e q ual t o 5 0 n g/d L ,  
•  
a rise i n P S A o ver baseli ne of  ≥0. 5 n g/ m L  is o bser ve d, 
•  
he has c o m plete d 2 4 wee ks of d o u ble bli n d treat me nt, a n d electe d n ot t o 
c o nti n ue i nt o t he e xte nsi o n peri o d, or 
•  
he has c o m plete d 5 2 wee ks of st u d y dr u g a d mi nistrati o n.  
At t he c o ncl usi o n of st u d y partici pati o n, patie nts will be a d vise d t o res u me 
sta n dar d of care treat me nt u n der t he s u per visi o n of t heir healt hcare pr o vi der.  
W hile o n treat me nt, patie nt s will be e valuate d at Da y 1  a n d e ver y 2 wee ks, 
f or t he first 2 4 wee ks a n d e ver y 4 wee ks t hereafter wit h a fi nal p ost-treat me nt 
f oll o w-u p visit 2 wee ks ( +/ - 2 da ys ) p ost last d ose a d mi nistrati o n. 
N u m ber of P atie nt s 
Pla n ne d sa m ple size is 1 2 0 male patie nts wit h a d va nce d a n dr o ge n -se nsiti ve 
pr ostate ca ncer , ra n d o mize d e q uall y t o o ne of f o ur treat me nt gr o u ps  ( N = 3 0 
per gr o u p) . 
I ncl usi o n Criteri a 
1.  Males, A ges 1 8 a n d ol der  
2.  B o d y Mass I n de x ( B MI) bet wee n 1 8 a n d 3 5 k g/ m 2 (i ncl usi ve) 
3.  N ot c urre ntl y h os pitalize d  
4.  Cli nical i n dicati o n of a de n ocarci n o ma of t he pr ostate e vi de nce d b y a 
bi o ps y re p ort o n rec or d  
5.  At prese nt recei vi n g A D T treat me nt wit h  
a. 
a G n R H a g o nist  
b.  f or at least 2 m o nt hs b ut n ot l o n ger t ha n 3 6 m o nt hs wit h o ut 
i nterr u pti o n 
N ote:  If t he patie nt recei ve d G n R H a g o nist treat me nt pri or t o t he treat me nt 
descri be d u n der 5a a n d b, t here m ust be e vi de nce of a peri o d wit h o ut G n R H 
a g o nist treat me nt f or a mi ni m u m of 2 m o nt hs pri or t o starti n g t he prese nt 
treat me nt as is see n, f or e xa m ple wit h i nter mitte nt treat me nt re gi me ns.  
6.  A ble t o i nitiate Scree ni n g pr oce d ures 2 wee ks pri or t o t he ne xt 
sc he d ule d i njecti o n wit h a G n R H a g o nist 
7.  Willi n g t o disc o nti n ue c urre nt A D T re gi me n f or t he d urati o n of t he 
st u d y 
8.  T le vel less t ha n 5 0 n g/ d L  at Scree ni n g 
9.  W H O/ E C O G perf or ma nce stat us of 0 or 1  
1 0.  Life e x pecta nc y of at least 1 year  
1 1.  A de q uate re nal f u ncti o n de m o nstrate d b y  n ot  ha vi n g ele vate d  bl o o d 
urea nitr o ge n ( B U N ) or  Creati ni ne Scree ni n g  la b val ues 
1 2.  Willi n g a n d a ble t o c o m m u nicate wit h t he I n vesti gat or a n d st u d y 
staff, a n d willi n g a n d a ble t o c o m plete all p hases a n d all pr oce d ures 
re q uire d of t he st u d y 
1 3.  Pr o vi de v ol u ntaril y c o nse nt t o partici pate i n t his st u d y a n d pr o vi de 
writte n i nf or me d c o nse nt pri or t o start of a n y st u d y -s pecific 
pr oce d ures  
E xcl usi o n Criteri a  
1.  Hist or y or prese nce of aller gic or a d verse res p o nse t o estra di ol 
2.  Prese nce of s y m pt o matic metastatic disease, ris k of s pi nal c or d 
c o m pressi o n or prese nce of cli nicall y si g nifica nt uri nar y o bstr ucti o n  as 
deter mi ne d b y t he Pri nci pal I n vesti gat or  
3.  Hist or y wit hi n t he past 2 years of dee p vei n t hr o m b osis ( D V T ), 
p ul m o nar y e m b olis m  (P E 2), a k n o w n t hr o m b o p hilic dis or der (e g. pr otei n 
C, pr otei n S, or a ntit hr o m bi n deficie nc y), or cere br o vasc ular acci de nt 
( C V A)  
4.  H ist or y wit hi n t he past 2 years  of m y ocar dial i nfarcti o n or a c or o nar y 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 8  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
uri nal ysis ) will be meas ure d at Scree ni n g, o n Da y 1 bef ore a d mi nistrati o n of 
st u d y dr u g, a n d t hereafter will be meas ure d e ver y 1 2 wee ks f or t he d urati o n 
of t he st u d y  wit h a fi nal c ollecti o n at t he E n d of St u d y Visit , if a b n or mal at 
t he pri or visit or if n ot perf or me d wit hi n t he last 4 wee ks. 
 
A Es  will be c ollecte d at eac h St u d y Visit be gi n ni n g wit h t he  first d ose of 
St u d y Dr u g ( St u d y Da y 1) . 
P h ar m ac o ki netic  
Ser u m estra di ol a n d estr o ne will be meas ure d o n Da y 1 bef ore a d mi nistrati o n 
of  st u d y dr u g, a n d t hereafter e ver y 2 wee ks t hr o u g h St u d y Wee k 2 4 a n d e ver y 
4 wee ks t hr o u g h St u d y Wee k 5 2 . 
S a m ple Size Deter mi n ati o n  
T he sa m ple size f or t his d ose -fi n di n g st u d y is a t otal of 1 2 0 patie nts. T he 
sa m ple size is base d o n t he f oll o wi n g ass u m pti o ns: 
•  
the res p o nse rate (t he pr o p orti o n of patie nt s mai ntai ni n g castrate 
le vels of T ( T < 5 0 n g/ d L) f or t he place b o gr o u p is 5 %,  
•  
t he res p o nse rate of t he l o w d ose gr o u p of B H R -2 0 0 is 5 0 % ,  
•  
t he res p o nse rate of t he mi d  d ose  gr o u p is 8 0 %, a n d  
•  
t he res p o nse rate of t he hi g h d ose  gr o u p  of B H R -2 0 0 is 9 5 %.  
T hirt y patie nt s per treat me nt gr o u p will pr o vi de at least 9 0 % p o wer t o detect 
t he differe nce i n pr o p orti o n of patie nt s mai ntai ni n g castrate le vels of T ( T < 
5 0 n g/ d L) bet wee n a n y d ose of B H R -2 0 0 -treate d patie nt s a n d t he place b o-
treate d patie nt s usi n g a t w o-si de d Fis her-E xact test wit h a 5 % si g nifica nce 
le vel. 
St atistic al Met h o ds  
T he pri mar y ef ficac y e n d p oi nt is t he res p o nse rate w hic h is defi ne d as t he 
pr o p orti o n of patie nt s mai ntai ni n g castrate le vels of T ( T < 5 0 n g/ d L). T he 
res p o n der rate will be c o m pare d f or  eac h of t he 3 B H R -2 0 0 d ose le vels 
a gai nst t he res p o n der rate f or t he place b o -treate d patie nt s at Wee k 1 2. 
T he C oc hra n – Ma ntel – Hae nszel ( C M H) statistics will be use d t o  c o m pare 2  
res p o n der rates of 2 treat me nt gr o u ps a dj uste d f or a p pr o priate  baseli ne 
c haracteristics.   
 
T he f oll o wi n g c o m paris o ns will be ma de bet wee n acti ve d ose le vels a n d 
place b o, a n d t he st u d y will be c o nsi dere d s uccessf ul if t he first c o m paris o n 
reac hes a si g nifica nce le vel of p < 0. 0 5. S u bse q ue nt c o m paris o ns will be 
c o nsi dere d si g nifica nt o nl y if t he y reac h a si g nifica nce le vel of p < 0. 0 5 i n 
a d diti o n t o t he c o m paris o n pri or t o it.  
•  
Hi g h d ose vs. place b o  
•  
M i d d ose vs. place b o  
•  
L o w d ose vs. place b o  
•  
L o w d ose vs. hi g h d ose  
•  
Mi d  d ose vs. hi g h d ose  
•  
L o w d ose vs. mi d  d ose  
Sec o n dar y efficac y e n d p oi nts will i ncl u de:  
( 1) T he pr o p orti o n of t he res p o n der rate at Wee k 2 4. T he sa me statistical 
a nal ysis met h o d t hat a p plie d t o Wee k 1 2 a nal ysis will be use d f or 
Wee k 2 4.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 9  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
( 2) T he Ka pl a n-Meier c ur ve f or ti me t o T   ≥ 5 0 n g/ d L at Wee k 1 2 f or 
eac h treat me nt gr o u p.  
( 3) T he Ka pla n -Meier c ur ve f or ti me t o T   ≥ 5 0 n g/ d L at Wee k 2 4 f or 
eac h treat me nt gr o u p.  
 
All ot her efficac y para meters (e. g., F S H, L H, S H B G, a n d P S A) will be 
s u m marize d b y treat me nt gr o u p at eac h st u d y visit usi n g descri pti ve statistics.  
Ser u m le vels of estra di ol a n d estr o ne will be s u m marize d b y treat me nt gr o u p 
at eac h st u d y visit usi n g descri pti ve statistics.  
 
Safet y varia bles will be s u m marize d f or eac h d ose le vel a n d o verall.  Safet y 
varia bles i ncl u de a d verse e ve nts ( A Es), la b orat or y tests, vital si g ns, a n d 
p h ysical e xa mi nati o n fi n di n gs.  Treat me nt -e mer ge nt a d verse e ve nts are 
defi ne d as t h ose A Es occ urri n g afte r t he first d ose of st u d y dr u g. 
 
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 0  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
T a ble of C o nte nts  
Ta ble of C o nte nts  ...........................................................................................................................1 0  
List of Fi g ures  ................................................................................................................................1 1  
List of A b bre viati o ns a n d Ter ms  ...................................................................................................1 2  
1. 0  
I ntr o d ucti o n a n d Rati o nale .................................................................................................1 4  
2. 0  
St u d y O bjecti ve  ..................................................................................................................1 7  
3. 0  
St u d y Desi g n  ......................................................................................................................1 8  
4. 0  
Patie nt Selecti o n a n d Wit h dra wal  ......................................................................................1 9  
4. 1  
I ncl usi o n Criteria ...............................................................................................................1 9  
4. 2  
E x cl usi o n Criteria  ..............................................................................................................1 9  
4. 3  
Earl y Wit h dra wal of Patie nts  .............................................................................................2 0  
4. 4  
Patie nt Re place me nt  ...........................................................................................................2 1  
5. 0  
St u d y Dr u g  .........................................................................................................................2 1  
5. 1  
Bli n di n g a n d U n bli n di n g ....................................................................................................2 1  
5. 2  
F or m ulati o n, Pac ka gi n g, a n d La beli n g  ..............................................................................2 2  
5. 3  
St ora ge  ...............................................................................................................................2 2  
5. 4  
Dis pe nsi n g ..........................................................................................................................2 2  
5. 5  
D osa ge a n d A d mi nistrati o n ................................................................................................2 2  
5. 6  
St u d y Dr u g A d mi nistrati o n Preca uti o ns  ............................................................................2 3  
5. 7  
Assess me nt of C o m plia nce  ................................................................................................2 4  
5. 8  
Dr u g Acc o u nta bilit y ...........................................................................................................2 4  
5. 9  
Pri or a n d C o nc o mita nt Me dicati o ns  ..................................................................................2 4  
5. 1 0  
Pr o hi bite d C o nc o mita nt Me dicati o ns/ T hera pies ................................................................2 5  
6. 0  
St u d y E val uati o ns  ..............................................................................................................2 6  
6. 1  
La b orat or y Tests  ................................................................................................................2 6  
6. 2  
Elec tr ocar di o gra m ..............................................................................................................2 7  
6. 3  
P h ysical E xa m  ....................................................................................................................2 7  
6. 4  
Vital Si g ns  ..........................................................................................................................2 7  
6. 5  
Q ualit y of Life Q uesti o n naire  ............................................................................................2 7  
7. 0  
St u d y Visits  ........................................................................................................................2 8  
8. 0  
Statistical Pla n  ....................................................................................................................3 7  
8. 1  
Statistical A nal ysis Pla n  .....................................................................................................3 7  
8. 2  
Sa m ple Size  ........................................................................................................................3 7  
8. 3  
Data Ma na ge me nt  ..............................................................................................................3 8  
8. 4  
St u d y P o p ulati o ns  ..............................................................................................................3 8  
8. 5  
Ha n dli n g of Missi n g a n d I nc o m plete Data  ........................................................................3 8  
8. 6  
Met h o d ol o g y a n d C o n ve nti o ns  ..........................................................................................3 8  
8. 7  
Efficac y A nal ysis  ...............................................................................................................3 9  
9. 0  
( Seri o us) A d verse E ve nt C ollecti o n a n d Re p orti n g ...........................................................4 0  
9. 1  
A d verse E ve nt C ollecti o n  ..................................................................................................4 0  
9. 2  
Re p orti n g of A d verse E ve nts  .............................................................................................4 1  
9. 3  
Assess me nt of A d verse E ve nt Se verit y  .............................................................................4 2  
9. 4  
Seri o us A d verse E ve nts  .....................................................................................................4 3  
1 0. 0  
Re g ulat or y a n d Pr oce d ural Re q uire me nts  .........................................................................4 4  
1 0. 1  
Et hical C o n d uct of t he St u d y  .............................................................................................4 4  
1 0. 2  
I nstit uti o nal Re vie w B oar d ................................................................................................4 4  
1 0. 3  
Patie nt I nf or me d C o nse nt  ..................................................................................................4 5  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 1  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
1 0. 4  
A d vis or y B oar d  ..................................................................................................................4 5  
1 0. 5  
I n vesti gat or O bli gati o ns .....................................................................................................4 5  
1 0. 6  
G C P c o m plia nce  ................................................................................................................4 5  
1 0. 7  
Pr ot oc ol a d here nce a n d i n vesti gat or a gree me nt  ................................................................4 6  
1 0. 8  
Pr ot oc ol de viati o ns  .............................................................................................................4 6  
1 0. 9  
M o nit ori n g of t he st u d y  .....................................................................................................4 6  
1 0. 1 0  Fi na ncial discl os ure  ...........................................................................................................4 6  
1 0. 1 1  D oc u me ntati o n a n d Rete nti o n of Rec or ds  .........................................................................4 7  
1 0. 1 2  Discl os ure of Data  ..............................................................................................................4 8  
1 0. 1 3  P u blicati o n  .........................................................................................................................4 8  
1 1. 0  
Refere nces  ..........................................................................................................................4 9  
A P P E N DI X 1:  P hase 2 Pr ot oc ol Sc he d ule of St u d y Assess me nts a n d Pr oce d ures: Scree ni n g 
–  St u d y Wee k 2 4  ................................................................................................................5 2  
A P P E N DI X 1 (c o nt.):  P hase 2 Sc he d ule of St u d y Assess me nts a n d Pr oce d ures: St u d y Wee k 
2 8 –  E n d of St u d y  ..............................................................................................................5 3  
A P P E N DI X 2:  P A TI E N T I N S T R U C TI O N S F O R U S E  ..............................................................5 4  
 
List of Ta bles  
Ta ble 1 Treat me nt  gr o u p all ocati o n f or st u d y B H R -2 0 0 -2 0 1  ........................................................1 8  
Ta ble 2 St u d y Dr u g D ose a n d A p plicati o n Sites  ...........................................................................2 3  
 
List of Fi g ures  
Fi g ure 1 C he mical Str uct ure of Estra di ol  ......................................................................................1 5  
Fi g ure 2 A p plicati o n Sites f or B H R -2 0 0 a n d Place b o gel  .............................................................2 3  
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 2  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
List of A b bre vi ati o ns  a n d Ter ms  
C  
Celsi us  
F  
Fa hre n heit  
A D T  
A n dr o ge n De pri vati o n T hera p y  
A E  
A d verse E ve nt  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne tra nsa mi nase  
A S T  
As partate tra nsa mi nase  
B H R  
B H R P har ma, L L C  
B H R -2 0 0  
T ra ns der mal 1 7- estra di ol gel (all stre n gt hs c urre ntl y i n de vel o p me nt)  
B MI  
B o d y Mass I n de x  
B S A P  
Al kali ne P h os p hatase, B o ne S pecific  
B U N  
Bl o o d urea nitr o ge n  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C M H  
C oc hra n – Ma ntel – Hae nszel  statistics 
C R F  
Case re p ort f or m  
C Y P 3 A 4  
C yt oc hr o me P 4 5 0 3 A 4  
C V A  
C ere br o vasc ular acci de nt  
D E S  
Diet h ylstil bestr ol  
d L  
Deciliter  
D V T  
Dee p Vei n T hr o m b osis  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E O S  
E n d of St u d y ( visit)  
E T  
Earl y Ter mi nati o n ( visit)  
F D A  
U. S. F o o d a n d Dr u g A d mi nistrati o n  
F S H  
F ollicle -Sti m ulati n g H or m o ne  
g  
Gra ms  
G C P  
G o o d Cli nical Practice  
G n R H  
G o na d otr o pi n -Releasi n g H or m o ne  
H b A 1c  
G l ycate d hae m o gl o bi n 
H T N  
H y perte nsi o n  
I C H 
Inter nati o nal C o nfere nce o n Har m o nisati o n  
I R B 
I nstit uti o nal Re vie w B oar d 
k g  
Kil o gra m  
L D H  
Lactate de h y dr o ge nase  
L H  
L utei nizi n g H or m o ne  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 3  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
m g  
Milli gra ms  
m L  
Milliliter  
m m H g  
Milli meter merc ur y  
N CI  
Nati o nal Ca ncer I nstit ute  
n g  
Na n o gra m  
O T C  
O ver t he c o u nter  
P A T C H  
Pr ostate A de n ocarci n o ma: Tra ns C uta ne o us H or m o nes st u d y  
P E 1  
P h ysical E xa m  
P E 2  
P ul m o nar y E m b olis m  
p g  
Pic o gra m  
P K  
P har mac o ki netic  
p m ol  
Pic o m ole  
P S A  
Pr ostate -S pecific A nti ge n  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical a nal ysis pla n  
S H B G  
Se x H or m o ne Bi n di n g Gl o b uli n  
T  
Test oster o ne  
g  
Micr o gra m  
U. S.  
U nite d States  
W H O  
W orl d Healt h Or ga nizati o n  
 
F or sa ke of c o nsiste nc y, t he f oll o wi n g u nits will be use d t hr o u g h o ut t his 
d oc u me nt:  
Estra di ol: p g/ m L ( 1 p m ol/ L = 0. 2 7 2 4 p g/ m L)  
Test oster o ne: n g/ d L ( 1 n m ol/ L = 2 8. 8 2 n g/ d L)  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 4  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
1. 0  
I ntr o d ucti o n a n d R ati o n ale 
B H R P H A R M A, L L C  has de vel o pe d a n i n vesti gati o nal tra ns der mal gel f or m ulati o n of 
estra di ol f or mai ntai ni n g  test oster o ne s u p pressi o n i n pr ostate ca ncer patie nts ha vi n g  ac hie ve d 
castrate test oster o ne le vels ( < 5 0 n g/ d L) o n  treat me nt wit h g o na d otr o pi n releasi n g h or m o ne 
( G n R H) a g o nists  or a nta g o nists . 
 
Estr o ge ns were use d f or ma n y years as t he ori gi nal n o ns ur gical h or m o ne s u p pressi o n t hera p y 
f or pr ostate ca ncer; t he y ha ve bee n use d i n vari o us f or m ulati o ns a n d d osa ges t o treat t he 
disease at all sta ges ( C o x a n d Cra wf or d 1 9 9 5 ). Estr o ge n q uic kl y a n d effecti vel y i n hi bits 
G n R H a n d l utei nizi n g h or m o ne ( L H) release via ne gati ve fee d bac k l o o ps at t he 
h y p ot hala m us a n d pit uitar y gla n d a n d, i n t ur n, i n hi bits test oster o ne release, res ulti n g i n 
test oster one s u p pressi o n. It is als o p ossi ble t hat  estr o ge n re place me nt i n patie nts u n der g oi n g 
G n R H t hera p y ( w hic h als o s u p presses estr o ge n) will pre ve nt s h ort  ter m a d verse e ve nts ( A Es) 
li ke h ot fl us hes, fati g ue a n d decrease d li bi d o, a n d l o n g ter m e ve nts li ke oste o por osis a n d 
decrease d m uscle mass , c o m m o nl y see n wit h G n R H t hera p y. 
 
E ve n t h o u g h estr o ge n was i nitiall y t he first c h oice f or test oster o ne s u p pressi o n i n pr ostate 
ca ncer patie nts, t he G n R H a g o nists, s uc h as le u pr oli de (le u pr oreli n), tri pt oreli n, a n d 
g osereli n, c urre ntl y d o mi nate t he mar ket ( Ka wa ka mi et al. 2 0 0 6 ). T his is d ue t o t he 
ass ociati o n of oral s y nt hetic estr o ge ns wit h a n i ncrease d ris k of car di o vasc ular t o xicit y, 
partic ularl y t hr o m b oe m b olis m, a n d t he t hera pe utic e q ui vale nc y of t he G n R H a g o nists i n 
test oster o ne s u p pressi o n. 
 
T his ass ociati o n ste m me d fr o m a n u m ber of st u dies c o n d ucte d wit h oral s y nt hetic estr o ge ns, 
n ota bl y diet h ylstil bestr ol ( D E S) i n t he 1 9 6 0s ( Melli n ger et al. 1 9 6 7 ) a n d 1 9 7 0s (B yar et al. 
1 9 7 3 ), w hic h were c o nfir me d i n t he 1 9 9 0s (R o bi ns o n et al. 1 9 9 5 ), s h o wi n g t hat, e ve n t h o u g h 
D E S t hera p y ca use d a m o dest decrease i n m ortalit y d ue t o pr ostate  ca ncer, it was ass ociate d 
wit h e xcessi ve ris k of car di o vasc ular m ortalit y, es peciall y i n t h ose wit h a pri or hist or y of 
car di o vasc ular disease.  
 
Gi ve n t he rece nt c o ncer ns raise d wit h t he safet y a n d t olera bilit y of G n R H a g o nists ( Hi ga n o 
2 0 0 3 , Oc kri m a n d A bel 2 0 0 8 , Efstat hi o u et al. 2 0 0 9 ), i nterest i n estr o ge n t hera p y is 
res ur gi n g.  Researc h i n me n wit h pr ostate ca ncer s h o ws pr o misi n g e vi de nce t hat w he n 
estr o ge n is deli vere d as 1 7 β-estra di ol rat her t ha n a s y nt hetic estr o ge n a n d b y a pare nteral or 
tra ns der mal r o ute rat her t ha n oral t he i ncrease i n t hr o m b oe m b olic ris k is a v oi de d a n d t he 
safet y a n d t olera bilit y pr ofile is i m pr o ve d relati ve b ot h t o oral estr o ge ns a n d G n R H a g o nists 
(Bla n d et al. 2 0 0 5 , Oc kri m et al. 2 0 0 5, P ur nell et al. 2 0 0 6 ). 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 5  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
B H R -2 0 0  gel c o ntai ns 1 7 -estra di ol i n 
 f or m ulate d t o 
pr o vi de c o nti n u o us release of 1 7 -estra di ol i nt o t he bl o o d. T he acti ve c o m p o ne nt of t he 
tra ns der mal gel is 1 7-estra di ol, i de ntical t o t he nat u rall y-occ urri n g estr o ge n i n t he b o d y. 
T he re mai ni n g c o m p o ne nts of t he gel are p har mac ol o gicall y i nacti ve. T he c he mical str uct ure 
of 1 7 -estra di ol is s h o w n i n Fi g ure 1.  
 
Fi g ure 1  
C he mic al Str uct ure of Estr a di ol  
 
 
C o m m o n na me:  
estra di ol 1 7 β -estra di ol 
C A S Re g. N o.:  
5 0 -2 8 -2  
C he mical Na me:  
estra-1, 3, 5( 1 0) -trie ne-3, 1 7 ß -di ol;  
                                    estra-1, 3, 4( 1 0) -trie ne-3, 1 7 -di ol, ( 1 7  β ) 
M olec ular F or m ula:  C 1 8H 2 4O 2 
M olec ular Wei g ht:  
2 7 2. 3 9  
 
Li mite d i nf or mati o n e xists o n t he use of estra di ol i n a p o p ulati o n of healt h y male v ol u nteers, 
as m ost, if n ot all, earl y sta ge cli nical w or k has bee n c o n d ucte d wit h fe male partici pa nts.  
Estra di ol has bee n gi ve n t o w o me n f or l o n g peri o ds of ti me as h or m o ne re place me nt t hera p y 
at a wi de ra n ge of d oses. I n a d diti o n, pil ot st u dies ha ve d oc u me nte d t he safe use of estra di ol 
i n me n wit h pr ostate ca ncer as a n dr o ge n de pri vati o n t hera p y usi n g tra ns der mal 
a d mi nistrati o n i n w hic h plas ma le vels of estra di ol were reac he d bet wee n 1 5 3 t o 5 2 7 p g/ m L 
f or a d urati o n u p t o 1 year (Bla n d et al. 2 0 0 5 ). Si milarl y, i n t he P A T C H st u d y, 1 6 9 me n ha ve 
bee n gi ve n estra di ol b y si m ulta ne o us a d mi nistrati o n of 3 -4 , 1 0 0 µ g/ da y tra ns der mal patc hes 
f or a mea n f oll o w-u p peri o d of 1 9 m o n t hs i n c o m paris o n wit h G n R H a g o nists, wit h a me dia n 
plas ma le vel of 2 3 9 p g/ m L ( La n gle y et al.  2 0 1 3, La n gle y et al . pers o nal c o m m u nicati o n  
1 5 Oct 2 0 1 3 ). Fi nall y, estra di ol s u p ple me ntati o n has bee n use d i n tra nsse x uals f or lifel o n g 
treat me nt at d ose le vels si gnifica ntl y hi g her ( M o ore et al. 2 0 0 3 ) t ha n pr o p ose d f or t his st u d y.  
Pr ol o n ge d e x p os ure i n me n a n d tra nsse x uals at hi g h d ose le vels has bee n ass ociate d wit h 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 6  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
g y nec o mastia, b ut n o safet y c o ncer ns ha ve bee n ass ociate d wit h  its use (Bla n d et al. 2 0 0 5 , 
M o ore et al. 2 0 0 3, Oc kri m et al. 2 0 0 3 ). 
 
T here are c o nsi dera ble p ote ntial be nefits wit h usi n g tra ns der mal estra di ol a d mi nistrati o n as 
mai nte na nce treat me nt i n A D T.  T hese c o ul d i ncl u de efficac y relate d be nefits  of a v oi da nce 
or dela y of t he necessit y f or re-treat me nt wit h G n R H ag o nists or a nta g o ni sts a n d l o wer or 
later occ urre nce of castrati o n resista nce.  P ossi ble safet y be nefits ma y i ncl u de t he  re d ucti o n 
i n G n R H- ass ociate d A Es  of s y m pt o ms li ke h ot fl us hes, s weati n g a n d fati g ue, car di o vasc ular 
para meters li ke fasti n g gl uc ose, fasti n g c h olester ol a n d diast oli c bl o o d press ure, a n d b o ne 
l oss.  I n a d diti o n, a rece nt st u d y (Fi n kelstei n et al. 2 0 1 3 ) s h o we d t hat i n me n ma de 
h y p o g o na dal wit h t he A D T g osereli n a n d treate d wit h test oster o ne gel i n t he prese nce or 
a bse nce of a nastraz ole, a c o m p o u n d w hic h pre ve nts t he c o n versi o n of test oster o ne t o 
estra di ol, t he s u bjects i nca pa ble of c o n verti n g test oster o ne e x perie nce d ne gati ve c ha n ges i n 
fat meas ures a n d ne gati ve effects o n li bi d o a n d erectile d ysf u ncti o n.  T heref ore, it is p ossi ble, 
t hat estra di ol-base d s u p p ressi o n w o ul d res ult i n fa v ora ble c ha n ges i n or mai nte na nce of b o d y 
c o m p ositi o n a n d se x ual f u ncti o n.  
 
Alt h o u g h estr o ge ns (a d mi nistere d b ot h ac utel y a n d c hr o nicall y) a n d G n R H a nal o gs (after 
c o nti n u o us c hr o nic a d mi nistrati o n) s u p press test oster o ne pr o d ucti o n  a n d testic ular f u ncti o n, 
t here are clear differe nces a n d a d va nta ges f or estr o ge ns use d f or A D T i n relati o n t o si de 
effect pr ofile a n d patie nt well -bei n g.  Estr o ge ns i n hi bit g o na d otr o pi n secreti o n acti n g b ot h at 
t he h y p ot hala mic a n d pit uitar y le vel, a n d b y acti n g o n h y p ot hala mic t her m ore g ulat or y a n d 
vas o m ot or ce nters t he y als o eli mi nate t he i nci de nce a n d ma g nit u de of h ot flas hes t hat e ns ues 
wit h t he l oss of g o na dal ster oi ds, b ot h i n p ost me n o pa usal w o me n a n d i n me n u n der g oi n g 
A D T wit h G n R H a nal o gs.  G n R H a na l o gs de plete e n d o ge n o us se x ster oi ds (e. g., test oster o ne 
a n d estra di ol) eli mi nati n g b ot h t he u n desira ble ( pr ostate ca ncer cell sti m ulati o n  b y 
test oster o ne) a n d t he be neficial (e. g. b o ne pr otecti ve estra di ol) effects of t he se x ster oi ds.  
E x o ge n o us estr o ge n s, i n a d diti o n t o s u p pressi n g test oster o ne dri ve of t he t u m or, pr o vi de a 
b uilt -i n b o ne s pari n g acti vit y b y decreasi n g t he n u m ber a n d acti vit y of oste oclasts (L o ose a n d 
Sta ncel, 2 0 0 5 ) a n d re d uci n g t he i nci de nce a n d fre q ue nc y of oste o p or osis a n d b o ne fract ures.  
Lar gel y d ue t o t hese si de effects, r esearc h si nce t he mi d -1 9 8 0s has l o o ke d at t he use of 
i nter mitte nt A D T  as a wa y t o re d uce t he si de effects of c o nti n u o us a n dr o ge n s u p pressi o n  
wit h G n R H a nal o gs ( B uc ha n a n d G ol d ber g, 2 0 1 0 ).  A d mi nistrati o n of estra di o l at hi g h le vels 
is ass ociate d wit h g y nec o mastia, a si de effect w h ose i m pact ca n be re d uce d b y pr o vi di n g 
pre ve nti ve breast ra diati o n. T he d oses pr o p ose d i n t he prese nt st u d y will res ult i n ser u m 
estra di ol le vels  well bel o w t h ose o bser ve d i n t he P A T C H st u d y, w hic h ma y res ult i n a 
re d ucti o n of t his b ot hers o me A E . Wit h t he use of B H R -2 0 0 , B H R P H A R M A, L L C  pr o p oses 
t o pr o vi de cli nicia ns wit h a mea ns t o pr o vi de c o nti n u o us a n dr o ge n s u p pressi o n t o patie nts 
w h o re q uire it, w hile p ote ntiall y alle viati n g t he ne gati ve si de effects ass ociate d wit h  A D T .  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 7  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
  
T h us far, t hree P hase 1 cli nical st u dies ha ve bee n c o n d ucte d t o assess t he safet y a n d 
p har mac o ki netic ( P K) pr ofile of m ulti ple d ose a d mi nistrati o n of tra ns der mal estra di ol gel i n 
healt h y male v ol u nteers ( St u dies B H R -2 0 0 -1 0 1 , B H R -2 0 0 -1 0 2 ), a n d i n 9 patie nts wit h 
pr ostate ca ncer recei vi n g A D T ( B H R -2 0 0 -1 0 3 ).  Base d o n t he P K res ults of St u d y B H R-2 0 0 -
1 0 1, B H R ref or m ulate d its tra ns der mal estra di ol gel t o i ncl u de l o wer c o nce ntrati o ns of t he 
pe netrati o n e n ha ncers pr o p yle ne gl y c ol, oleic aci d, a n d et h yl oleate.  T his ref or m ulate d 
pr o d uct was t he f or m ulati o n of t o pical estra di ol e val uate d i n st u d y B H R -2 0 0 -1 0 2  a n d st u d y 
B H R -2 0 0 -1 0 2 .  It is t his f or m ulati o n t hat will be use d i n t he c urre nt pr ot oc ol, B H R-2 0 0 -2 0 1.  
R es ults fr o m p hase  1 st u dies B H R -2 0 0 -1 0 1 a n d B H R -2 0 0 -1 0 2 i n dicate t hat b ot h 
f or m ulati o ns of tra ns der mal estra di ol gel at d oses  of 0. 2 5 g  a n d 1. 0 0 g of 0. 0 7 % were  well 
t olerate d b y healt h y male v ol u nteers. St u d y B H R -2 0 0 -1 0 3 was a P K st u d y i n w hic h a 0. 3 6 % 
f or m ulati o n was gi ve n  o nce dail y or t wice dail y f or 7 da ys. Mea n stea d y state plas ma le vels 
were reac he d of 5 3 a n d 1 0 4 p g/ m L, res pecti vel y. T he gel was well t olerate d . I n all s u bjects 
test oster o ne le vels re mai ne d bel o w 5 0 n g/ d L  a n d i n m ost patie nts t he le vels decrease d d uri n g 
t he treat me nt peri o ds.   W hile t his is a s mall gr o u p of patie nts, t hese data are e nc o ura gi n g a n d 
c o nsiste nt wit h fi n di n gs i n t he P A T C H st u d y  (La n gle y et al. 2 0 1 3 ).  
 
I n t his P hase 2 st u d y, ser u m estra di ol levels are e x pecte d t o be bet wee n  6 0 a n d 1 8 0 p g/ m L,  
wit h o nce dail y  d osi n g of B H R -2 0 0  gel at o ne of t hree d ose le vels: 3  m g estra di ol per 1 m L 
gel, 6  m g estra di ol per 2  m L gel or 9  m g estra di ol per 3  m L gel . 
 
I n vie w of t he a bse nce of a n y data i n dicati n g safet y iss ues, e ve n at hi g h d ose le vels, t he 
pla n ne d r o ute, d ose, a n d d urati o n of estra di ol a d mi nistrati o n i n t his P hase 2  st u d y are t h o u g ht 
t o p ose mi ni mal ris k t o me n wit h a d va nce d a n dr o ge n -se nsiti ve a d va nce d pr ostate ca ncer  
(Bla n d et al. 2 0 0 5 , M o ore et al. 2 0 0 3, Oc kri m et al. 2 0 0 3 ). I n a d diti o n, a patie nt w h ose  
test oster o ne le vels i ncrease a b o ve or e q ual t o 5 0 n g/ d L or w h o se P S A  rises > 0. 5 n g/ m L o ver 
basel i ne will be disc o nti n ue d fr o m t he st u d y  a n d will be a d vise d t o res u me sta n dar d of care 
treat me nt u n der t he s u per visi o n of t heir healt hcare pr o vi der . 
2. 0  
St u d y O bjecti ve  
T he o bjecti ve of t his st u d y is  to e val uate t he safet y a n d efficac y of t hree differe nt d oses  of 
B H R -2 0 0  c o m pare d t o place b o f or t he mai nte na nce of test oster o ne s u p pressi o n i n me n wit h 
a d va nce d a n dr o ge n -se nsiti ve pr ostate ca ncer i n or der t o select t he d ose (s) f or a s u bse q ue nt 
P hase 3  st u d y.  Fr o m t his P hase 2  st u d y, o ne or m ore  d osi n g re gi me n s will be selecte d f or t he 
mai nte na nce of test oster o ne s u p pressi o n bel o w 5 0 n g/ d L.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 8  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
3. 0  
St u d y Desi g n  
Patie nt s will partici pate i n a 2 4 wee k d o u ble -bli n d  treat me nt peri o d a n d will be all o we d t o 
c o nti n ue treat me nt wit h t heir assi g ne d st u d y dr u g f or u p t o 5 2 wee ks  as l o n g as t he y re mai n 
c he micall y castrate d. E ntr y criteria i ncl u de pr ostate ca ncer patie nts w h o are  c urre ntl y 
recei vi n g treat me nt wit h  a G n R H a g o nist de p ot i njecti o n  f or at least 2 m o nt hs b ut n ot l o n ger 
t ha n 3 6 m o nt hs wit h o ut i nterr u pti o n , a n d ha ve test o ster o ne le vels < 5 0 n g/ d L at Scree ni n g . 
At t he sc he d ule d ti me p oi nt f or t he ne xt G n R H a g o nist  de p ot  i njecti o n, p atie nts will be 
ra n d o mize d t o recei ve eit her place b o or l o w, mi d or hi g h d ose B H R -2 0 0. T he st u d y will 
e nr oll 1 2 0 patie nt s wit h 3 0 patie nt s ra n d omize d i nt o eac h of t he 4 treat me nt gr o u ps as s h o w n 
i n Ta ble 1 . 
T a ble 1  
Tre at me nt g r o u p a ll oc ati o n f or st u d y B H R -2 0 0 -2 0 1  
Tre at me nt Gr o u p  
N u m ber of 
P atie nts  
D ose  
N u m ber of P u m p 
Act u ati o ns *  
Place b o  
3 0  
1 0  
0  m g estra di ol  
1 act uati o n  
1 0  
0  m g estra di ol  
2 act uati o ns  
1 0  
0  m g estra di ol  
3 act uati o ns  
B H R -2 0 0 L o w D ose  
3 0  
3  m g estra di ol   
1 act uati o n  
B H R -2 0 0 Mi d D ose  
3 0  
6  m g estra di ol  
2 act uati o ns  
B H R -2 0 0  Hi g h D ose  
3 0  
9  m g estra di ol  
3 act uati o ns  
* 1 act uati o n  of t he p u m p  dis pe nses 
 
 
Patie nt s will be offere d o pti o nal l o w-d ose ra diati o n f or t he pre ve nti o n of g y nec o mastia  
(He dl u n d 2 0 0 0, Wi d mar k et. al. 2 0 0 3 ). Ti mi n g of t he a d mi nistrati o n of t he l o w -d ose 
ra diati o n will be at t he discreti o n of t he I n vesti gat or. 
 
Le vels of t otal T est oster o ne , estra di ol, a n d estr o ne will be assesse d e ver y 2 wee ks f or all 
patie nt s t hr o u g h Wee k 2 4 a n d t he n e ver y 4 wee ks t hr o u g h t he E n d of St u d y Visit at Wee k 5 4 
(see Sc he d ule of Assess me nts i n A p pe n di x  1 ).  Patie nt s will re mai n i n t he st u d y a n d 
a d mi nister dail y d oses of t he assi g ne d st u d y dr u g u ntil t he y are n o l o n ger c he micall y 
castrate d as i n dicate d b y a meas ure me nt of T  ≥5 0 n g/ d L  after 4 wee ks of d o u ble -bli n d 
treat me nt, a rise o ver baseli ne P S A  of  > 0. 5 n g/ m L is o bser ve d, or  if 5 2 wee ks of  st u d y dr u g 
a d mi nistrati o n ha ve bee n c o m plete d.  Patie nt s disc o nti n ued  fr o m t he st u d y will be a d vise d t o 
res u me sta n dar d of care treat me nt i n c o ns ultati o n wit h t heir healt hcare pr o vi der.  
 
Safet y assess me nts will i ncl u de  A Es as well as t he meas ure me nt of t y pical bl o o d c he mistr y , 
he mat ol o g y  a n d uri nal ysis para meters , as well as c oa g ulati o n fact ors, hor m o ne assess me nt s, 
b o ne bi o mar kers, a n d P S A ( Secti o n 6. 1 ).  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 1 9  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
4. 0  
P atie nt Selecti o n a n d Wit h dr a w al  
A t otal of 1 2 0 male patie nts w h o ha ve a d va nce d a n dr o ge n -se nsiti ve a d va nce d pr ostate ca ncer  
will be e nr olle d i n t his st u d y. Patie nts pr o vi di n g writte n i nf or me d c o nse nt a n d w h o meet t h e 
f oll o wi n g i ncl usi o n/e xcl usi o n criteria will be eli gi ble . 
4. 1  
I ncl usi o n Criteri a 
1.  Males, A ges 1 8 a n d ol der  
2.  B o d y Mass I n de x ( B MI) bet wee n 1 8 a n d 3 5 k g/ m 2 (i ncl usi ve) 
3.  N ot c urre ntl y h os pitalize d  
4.  Cli nical i n dicati o n of a de n ocarci n o ma of t he pr ostate e vi de nce d b y a bi o ps y re p ort o n 
rec ord  
5.  At prese nt recei vi n g A D T treat me nt wit h  
      a. a G n R H a g o nist  
b.  f or at least 2 m o nt hs b ut n ot l o n ger t ha n 3 6 m o nt hs wit h o ut i nterr u pti o n  
 
N ote:   If t he patie nt recei ve d G n R H a g o nist treat me nt pri or t o t he treat me nt descri be d u n der 
5a a n d b, t here m ust be e vi de nce of a peri o d wit h o ut G n R H a g o nist treat me nt f or a mi ni m u m 
of 2 m o nt hs pri or t o starti n g t he prese nt treat me nt as is see n, f or e xa m ple wi t h i nter mitte nt 
treat me nt re gi me ns.  
 
6.  A ble t o i nitiate Scree ni n g pr oce d ures 2 wee ks pri or t o t he ne xt sc he d ule d i njecti o n wit h a 
G n R H a g o nist  
7.  Willi n g t o disc o nti n ue c urre nt  A D T re gi me n f or t he d urati o n of t he st u d y 
8.  T le vel less t ha n 5 0 n g/ d L  at Scree ni n g  
9.  W H O/ E C O G perf or ma nce stat us of 0 or 1  
1 0.  Life e x pecta nc y of at least 1 year  
1 1.  A de q uate re nal f u ncti o n de m o nstrate d b y n ot ha vi n g ele vate d  bl o o d urea nitr o ge n ( B U N ) 
or  Creati ni ne Scree ni n g  la b val ues 
1 2.  Willi n g a n d a ble t o c o m m u nicate wit h t he I n vesti gat or a n d st u d y staff, a n d willi n g a n d 
a ble t o c o m plete all p hases a n d all pr oce d ures re q uire d of t he st u d y  
1 3.  Pr o vi de v ol u ntaril y c o nse nt t o partici pate i n t his st u d y a n d pr o vi de writte n i nf or me d 
c o nse nt pri or t o start of a n y st u d y -s pecific pr oce d ures 
4. 2  
E xcl usi o n Criteri a  
1.  Hist or y or prese nce of aller gic or a d verse res p o nse t o estra di ol  
2.  Prese nce of s y m pt o matic metastatic disease, ris k of s pi nal c or d c o m pressi o n or prese nce 
of cli nicall y si g nifica nt uri nar y o bstr ucti o n  as deter mi ne d b y t he Pri nci pal I n vesti gat or  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 0  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
3.  Hist or y wit hi n t he past 2 years of dee p vei n t hr o m b osis ( D V T ),  p ul m o nar y e m b olis m 
(P E 2), a k n o w n t hr o m b o p hilic dis or der  (e g. pr otei n C, pr otei n S, or a ntit hr o m bi n 
deficie nc y) , or cere br o vasc ular acci de nt ( C V A)  
4.  H ist or y wit hi n t he past 2 yea rs of m y ocar dial i nfarcti o n or a c or o nar y vasc ular pr oce d ure 
(e. g. perc uta ne o us c or o nar y i nter ve nti o n, c or o nar y arter y b y pass graft)  
5.  Hist or y of c o n gesti ve heart fail ure  
6.  Use of a n y i n vesti gati o nal dr u g, bi ol o gic, or de vice wit hi n 2 8 da ys pri or t o t he first d ose 
of st u d y dr u g  
7.  Use of a n y of t he f oll o wi n g k n o w n i n d ucers or i n hi bit ors of c yt oc hr o me P 4 5 0 3 A 4 
( C Y P 3 A 4):  p he n o bar bital, car ba maze pi ne, rifa m pi n, er yt hr o m yci n, clarit hr o m yci n, 
ket oc o naz ole, itrac o naz ole, rit o na vir, St. J o h n’s W ort pre parati o ns ( H y peric u m 
perf orat u m), a n d gra pefr uit j uice  
8.  He mat ol o gical para meters ( He mat ocrit or He m o gl o bi n) o utsi de 2 0 % of t he u p per or 
l o wer li mits of n or mal at Scree ni n g  
9.  Acti ve s ki n ras h, s u n b ur n, or ot her s ki n dis or der o n t he u p per ar m(s) t hat re q uires 
treat me nt or ma y affect s ki n a bs or pti o n of st u d y gel  
1 0.  Resti n g u nc o ntr olle d h y perte nsi o n ( H T N) ( 1 6 0/ 1 0 0 m m H g) at Scree ni n g 
1 1.  C o -e xiste nt mali g na nc y or a hist or y of mali g na nc y d uri n g t he past 5 years, wit h t he 
e xce pti o n of basal a n d/ or s q ua m o us cell carci n o ma of t he s ki n  
1 2.  A n y ot her  si g nifica nt c o nc urre nt ill ness or disease or c o n diti o n t hat i n t he o pi ni o n of t he 
I n vesti gat or mi g ht i nterfere wit h t he patie nt’s a bilit y t o recei ve t he treat me nt o utli ne d i n 
t he pr ot oc ol or mi g ht p ut hi m  at a d diti o nal ris k  
4. 3  
E arl y Wit h dr a w al of P atie nt s  
A  patie nt  is free t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n wit h o ut prej u dice t o 
t heir f ut ure me dical care b y t he p h ysicia n or at t he i nstit uti o n.  T he I n vesti gat or or S p o ns or 
ma y als o wit h dra w t he patie nt  at a n y ti me i n t he i nterest of patie nt  safet y.  T he pri mar y 
reas o n f or wit h dra wal m ust be rec or de d i n t he patie nt ’s me dical rec or d a n d o n t he wit h dra wal 
f or m i n t he Case Re p ort F or m ( C R F).  If a patie nt  is wit h dra w n f or m ore t ha n o ne reas o n, 
eac h reas o n s h o ul d be d oc u me nte d i n t he s o urce d oc u m e nt a n d t he m ost me dicall y 
si g nifica nt reas o n s h o ul d be e ntere d o n t he C R F.  T he wit h dra wal of a patie nt  fr o m t he st u d y 
s h o ul d be disc usse d w here p ossi ble wit h t he Me dical M o nit or bef ore t he patie nt  st o ps 
a d mi nistrati o n of t he st u d y dr u g .  If t he st u d y dr ug  is disc o nti n ue d, t he fi nal e val uati o ns will 
be perf or me d as c o m pletel y as p ossi ble.  A n y c o m me nts (s p o nta ne o us or elicite d) or 
c o m plai nts ma de b y t he patie nt  a n d t he reas o n f or ter mi nati o n, date of st o p pi n g st u d y dr u g 
a n d t he t otal a m o u nt of st u d y dr u g ad mi nistere d m ust be rec or de d i n t he C R F a n d s o urce 
d oc u me nts.  
T he f oll o wi n g are reas o ns t o ter mi nate t he partici pati o n of a patie nt  i n t he st u d y: 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 1  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  T he patie nt  is n o l o n ger c he micall y castrate d , after 4 wee ks of d o u ble-bli n d treat me nt  or 
a n yti me t hereafter, i n dicate d b y a meas ure me nt of T  ≥5 0 n g/ d L.  (tre at me nt f ail ure) 
•  T he patie nt’s P S A rises > 0. 5 n g/ m L a b o ve t he baseli ne meas ure me nt  (tre at me nt f ail ure) 
•  L ost t o f oll o w -u p: patie nt  fails t o ret ur n t o t he st u d y site f or sc he d ule d visits a n d d oes n ot 
res p o n d t o m ulti ple tele p h o ne or writte n atte m pts t o c o ntact (t hese atte m pts s h o ul d be 
d oc u me nte d) .  
•  Wit h dra wal of c o nse nt: patie nt  deci des t o st o p partici pati o n i n t he st u d y f or a n y reas o n or 
is u na ble t o c o m plete t he st u d y as descri be d i n t he st u d y pr ot oc ol.  Alt h o u g h a patie nt  is 
n ot o bli ge d t o gi ve his/ her reas o n f or wit h dra wi n g pre mat urel y, t he I n vesti gat or will 
ma ke a reas o na ble eff ort t o o btai n t he reas o n w hile f ull y res pecti n g t he patie nt ’s ri g hts.  
E ver y eff ort will be ma de t o c o ntact a patie nt  w h o fails t o atte n d a n y f oll o w -u p 
a p p oi nt me nts/c o ntacts i n or der t o c o m plete st u d y assess me nts.   
•  A d mi nistrati ve: t he S p o ns or deci des t o ter mi nate or disc o nti n ue t he st u d y (eit her at t he 
st ud y site or t he e ntire st u d y).  
4. 4  
P atie nt  Re pl ace me nt  
Ra n d o mize d patie nt s w h o d o n ot c o m plete t he st u d y f or a n y reas o n will n ot be re place d.  
5. 0  
St u d y Dr u g  
St u d y dr u g will o nl y be s hi p pe d t o I n vesti gat ors w h o ha ve pr o vi de d B H R P H A R M A, L L C 
( or a n a ut h orize d re prese ntati ve) all re q uire d st u d y d oc u me nts, i ncl u di n g I nstit uti o nal 
Re vie w B oar d  (I R B) a p pr o val, ha ve e xec ute d a cli nical trial a gree me nt ( C T A), a n d ha ve 
bee n a p pr o ve d b y B H R P H A R M A, L L C t o be gi n t he st u d y.  St u d y dr u g will be pr o vi de d b y 
B H R P H A R M A, L L C ( or a ut h orize d re prese ntati ve) as bli n d -la bele d rea d y-t o-use ca nisters 
c o ntai ni n g B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel) or place b o.  
5. 1  
Bli n di n g a n d U n bli n di n g  
All site pers o n nel will be bli n de d t o treat me nt assi g n me nt. T he I n vesti gat or (or desi g nee ) will 
be res p o nsi ble f or dr u g acc o u nta bilit y a n d dis pe nsi n g of t he st u d y dr u g.  
I n t he case of a n A E or seri o us a d verse e ve nt (S A E ) f or w hic h t he I n vesti gat or m ust k n o w a 
s pecific treat me nt all ocati o n t o e ns ure t he patie nt’s safet y, u n bli n di n g of treat me nt 
assi g n me nt is per mitte d. I nstr ucti o ns f or “ brea ki n g t he bli n d” will be pr o vi de d t o t he 
I n vesti gat or. It s h o ul d be stresse d t hat u n bli n di n g t he treat me nt all ocati o n is o nl y all o we d f or 
safet y c o ncer ns i n a n e mer ge nc y sit uati o n. If ti me all o ws, t he I n vesti gat or is e nc o ura ge d t o 
disc uss t he matter wit h t he st u d y Me dical M o nit or pri or t o “ brea ki n g t he bli n d” w he ne ver 
p ossi ble.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 2  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
If p ossi ble, t he relati o ns hi p of t he A E t o t he st u d y dr u g s h o ul d be assesse d bef ore t he 
treat me nt c o de is br o ke n. I n all cases, t he Me dical M o nit or m ust be n otifie d wit hi n 2 4 h o urs 
after t he c o de has bee n br o ke n.  
If t he treat me nt assi g n me nt is u n bli n de d, st u d y dr u g ma y  be dis c o nti n ued  at t he 
In vesti gat or’s discreti o n.  
5. 2  
F or m ul ati o n, P ac k a gi n g, a n d L a beli n g  
T he B H R -2 0 0 dr u g pr o d uct c o nsists of 
 
 
 
T he place b o dr u g pr o d uct is a n a bs or pti ve h y dr o -alc o h olic gel  pre parati o n of t he sa me 
i n gre die nts as B H R-2 0 0, b ut wit h o ut 1 7 β -estra di ol. 
B ot h dr u g pr o d ucts are pr o vi de d i n rea d y-t o-use , plastic ca nisters wit h a metere d -d ose p u m p  
ca pa ble  of deli veri n g 1 milliliter of gel , a n d la bele d ‘ F or I n vesti gati o nal Use O nl y’.  A 
reseala ble p ol y pr o p yle ne ca p t o ps t he ca nister t o pr otect t he p u m p. Eac h i n di vi d uall y 
pac ka ge d ca nister is ca pa ble of deli veri n g at least  9 0, 1 m L metere d d oses of gel.    
5. 3  
St or a ge  
All st u d y dr u g m ust be st ore d i n a sec ure li mite d -access area, at c o ntr olle d r o o m te m perat ure 
(2 0 –  2 5º C  [6 8° t o 7 7° F ]; e xc ursi o ns are per mitte d t o 1 5° t o 3 0° C [5 9° t o 8 6° F ]) i n 
acc or da nce wit h la bele d st ora ge re q uire me nts. Patie nt s will be i nstr ucte d t o st ore t he st u d y 
dr u g  at h o me at r o o m te m perat ure , a n d t o a v oi d e xtre me heat or c ol d d uri n g tra ns p ortati o n 
fr o m t he cli nic t o h o me. Patie nts will be pr o vi de d wit h a n i ns ulate d  ba g t o be use d w he n 
tra ns p orti n g t he st u d y dr u g fr o m t he cli nic t o t he patie nt’s h o me. I n vesti gati o nal la beli n g will 
i ncl u de i nstr ucti o ns t o kee p t he pr o d uct o ut of t he reac h of c hil dre n.  
5. 4  
Dis pe nsi n g  
T he I n vesti gat or ( or desi g nee) will o nl y dis pe nse t he s pecific n u m bere d ca nisters  of t he st u d y 
dr u g as all ocate d b y ce ntral p har mac y t o t he patie nt . T w o ( 2) ca nisters will dis pe nse d at a 
ti me.  
5. 5  
D os a ge a n d A d mi nistr ati o n  
Patie nt s will self-a p pl y eit her B H R -2 0 0  or place b o  as a metere d u nit d ose ( o ne act uati o n or 
m ulti ples t here of , Ta ble 2 ) of gel  dail y t o clea n, dr y, i ntact s ki n of t he u p per ar ms a n d 
s h o ul ders as s h o w n i n t he s ha de d areas i n Fi g ure 2 . T he gel s h o ul d n ot  be a p plie d t o a n y 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 3  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
ot her parts of t he b o d y, i ncl u di n g t he a b d o me n or ge nitals. T he area of a p plicati o n s h o ul d be 
li mite d t o t he area t hat w o ul d be c o vere d b y a s h ort slee ve t-s hirt. It is a d vise d t o a p pl y st u d y 
dr u g i n t he m or ni n g after s h o weri n g. Ni g ht -ti me a p plicati o n is acce pta ble, b ut ca uti o n s h o ul d 
be ta ke n t o li mit tra nsfer  t o ot her i n di vi d uals. A p plicati o n s h o ul d occ ur a p pr o xi matel y at t he 
sa me ti me dail y. A patie nt st u d y dr u g a d mi nistrati o n g ui deli ne is pr o vi de d i n A p pe n di x 2 . 
 
W he n a ca nister is use d f or t he first ti me, it m ust pri me d . T o pri me t he ca nister, r e m o ve t he 
ca p fr o m t he ca nister  a n d p us h t he p u m p all t he wa y d o w n u ntil gel is dis pe nse d. C o m plete 
t he pri mi n g pr ocess b y p us hi n g t he p u m p all t he wa y d o w n a n a d diti o nal t hree ( 3) ti mes. D o 
n ot u se a n y gel t hat ca me o ut w hile pri mi n g. Discar d t he gel b y w as hi n g it d o w n t he si n k t o 
a v oi d acci de ntal e x p os ure t o ot hers.  It is o nl y necessar y t o pri me t he p u m p bef ore t he first 
d ose is dis pe nse d. ( Re peat pri mi n g eac h ti me a ne w ca nister is o pe ne d.)  Aft er pri mi n g, t h e 
ca nister is rea d y t o use. O ne  c o m plete press of t he p u m p will deli ver  a p pr o xi matel y t he sa me 
a m o u nt of gel eac h ti me.  T he I n vesti gat or ( or desi g nee) will pri me t he st u d y dr u g ca nister(s) 
pri or t o dis pe nsi n g t o t he patie nt.  
T a ble 2  
St u d y Dr u g D ose a n d A p plic at i o n Sites 
T ot al N u m ber of P u m p Act u ati o ns *  
P u m p Act u ati o ns Per U p per Ar m a n d S h o ul der  
 
U p per Ar m a n d S h o ul der :  # 1  
U p per Ar m a n d S h o ul der :  # 2  
1 act uati o n  
1  
0  
2 act uati o ns  
1  
1  
3 act uati o ns  
2  
1  
* 1 act uati o n of t he p u m p dis pe nses 
 
 
Fi g ure 2  
A p plic ati o n Sites f or B H R -2 0 0 a n d Pl ace b o gel  
 
5. 6  
St u d y Dr u g  A d mi nistr ati o n  Prec a uti o ns   
•  O nl y t he patie nt  s h o ul d a p pl y t he st u d y dr u g .  Ot hers (st u d y staff a n d/ or patie nt ’s 
fa mil y me m bers) s h o ul d n ot a p pl y t he st u d y dr u g  t o t he patie nt . 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 4  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  T he patie nt  s h o ul d n ot ma ke c o ntact wit h t he area of s ki n w here t he  st u d y dr u g  was 
a p plie d f or at least 1 h o ur after t he a p plicati o n. 
If s o me o ne else is e x p ose d to t he st u d y dr u g  b y direct c o ntact wit h t he st u d y dr u g , t hat 
pers o n s h o ul d was h t he area of c o ntact wit h s oa p a n d water as s o o n as p ossi ble. T he l o n ger 
t he st u d y dr u g  is i n c o ntact wit h t he s ki n t he greater t he c ha nce t hat t he ot her pers o n will 
a bs or b s o me of t he estr o ge n h or m o ne. T his is es peci all y i m p ort a nt f or c hil dre n.  
N o s ki n -t o-s ki n tra nsfer st u dies wit h B H R-2 0 0 (estra di ol gel) ha ve bee n c o n d ucte d. 
H o we ver, a st u d y c o n d ucte d i n w o me n wit h a si milar F D A -a p pr o ve d  pr o d uct , Estr o Gel ®  
( 0. 0 6 % estra di ol gel), s h o we d t hat s ki n-t o-s ki n c o ntact bet wee n treate d a n d n o n-treate d 
w o me n  1 h o ur after a p plicati o n of t he gel , neit her res ulte d  i n a statisticall y si g nifica nt or 
cli nicall y i m p orta nt tra nsfer of estra di ol gel t o  t he n o n-treate d w o me n n or was t here 
s u bse q ue nt a bs or pti o n of estra di ol b y t he n o n-treate d w o me n ( Z u m Br u n ne n et al. 2 0 0 6 ). Use 
of l oti o ns a n d crea ms o n t he a p plicati o n site is  n ot all o we d. Use of s u nscree n pr o d ucts is 
all o we d 1 h o ur after a p plicati o n. Alt h o u g h n o st u dies ha ve bee n perf or me d wit h B H R -2 0 0, a 
st u d y wit h re peate d dail y a p plicati o n of s u nscree n f or 7 da ys at 1 h o ur after t he 
a d mi nistrati o n of Estr o Gel ® ( 0. 0 6 % estra di ol gel ) decrease d t he mea n A U C a n d C ma x of 
estra di ol b y n ot m ore t ha n 1 6 %  (Estr o Gel ® Pac ka ge I nsert Re v. 0 8/ 2 0 1 4).  
5. 7  
Assess me nt of C o m pli a nce  
St u d y dr u g c o m plia nce will be perf or me d at eac h st u d y visit. If t he st u d y dr u g is 
disc o nti n ue d or i nterr u pte d, t he reas o n(s) will be rec or de d.  
 
S t u d y dr u g ca nisters will be wei g he d after pri mi n g of t he ca nister  a n d w he n t he ca nister is 
ret ur ne d. T he ca nister wei g ht (s) will be rec or de d i n gra ms.  
5. 8  
Dr u g Acc o u nt a bilit y  
T he I n vesti gat or will mai ntai n acc urate rec or d s of t he dis p ositi o n of all cli nical dr u g s u p plies 
recei ve d d uri n g t he st u d y a n d t he dates o n w hic h dr u g s u p plies were recei ve d fr o m B H R 
P H A R M A, L L C  or a ut h orize d re prese ntati ve. At t he c o ncl usi o n of t he st u d y, a n y u n use d 
st u d y gel will be destr o ye d b y t he  site u p o n writte n a ut h orizati o n b y B H R P H A R M A, L L C  
a n d p urs ua nt t o a p plica ble fe deral a n d state re g ulati o ns  or ret ur ne d t o B H R P H A R M A , L L C 
or  t heir desi g nee. 
5. 9  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
A ll me dicati o ns, o n -g oi n g a n d ne w, a d mi nistere d or ta ke n b y t he patie nt  d uri n g t he st u d y 
(fr o m ti me of c o nse nt t hr o u g h Wee k 2 4 ) are t o be rec or de d o n t he C R F.  I nf or mati o n s h o ul d 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 5  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
be rec or de d f or: na me of dr u g, d ose, r o ute of a d mi nistrati o n, start a n d e n d dates a n d ti me  (f or 
i. v. dr u gs), a n d i n dicati o n. 
 
A n y t hera pe utic or s ur gical pr oce d ure perf or me d f or c o nc urre nt c o n diti o ns t hr o u g h St u d y 
Wee k 2 4 s h o ul d be rec or de d, i ncl u di n g t he date, descri pti o n of t he pr oce d ure, a n d cli nical 
fi n di n gs. 
5. 1 0  Pr o hi bite d C o nc o mit a nt Me dic ati o ns/ T her a pies  
I n vesti gati o nal dr u gs or t hera pies s h o ul d n ot be use d at a n y ti me d uri n g t he st u d y beca use of 
t heir p ote ntial t o c o nf o u n d t he res ults.  T he f oll o wi n g i nter ve nti o ns are pr o hi bite d d uri n g t he 
st u d y beca use of t heir p ote ntial t o c o nf o u n d t he res ults:  
•  A d mi nis trati o n of a n y of t he f oll o wi n g pr ostate ca ncer treat me nts: 
•  
I m m u n ot hera p y (e. g., a nti b o d y t hera pies, t u m or-vacci nes)  
•  
E xter nal ra di ot hera p y  
•  
Brac h yt hera p y  
•  
C he m ot hera p y  
•  
Bi ol o gical res p o nse m o difiers (e. g., c yt o ki nes)  
•  
G n R H a g o nists (e. g. L u pr o n ® , Eli gar d ® , Via d ur ® , Va ntas® , Trelstar® , Z ola de x® )  
•  
G n R H a nta g o nists (e. g. Fir ma g o n ® ) 
•  
A ntia n dr o ge ns (e. g. Cas o de x ® , E ule xi n® , Nila n dr o n® )  
•  
A n dr o ge n i n hi bit ors (e. g. Z yti ga ® , Xta n di® ) 
•  A n y of t he f oll o wi n g  pr ostatic  or ot her relate d  s ur ger y : 
•  
Tra ns ur et hral resecti o n of t he  pr ostate  
•  
Ra dical pr ostatect o m y  
•  
Orc hiect o m y  
•  
A dre nalect o m y  
•  
H y p o p h ysect o m y  
•  A p plicati o n of p rescri pti o n or o ver -t he-c o u nter  (O T C ) t o pical pr o d ucts (i ncl u di n g b ut 
n ot li mite d t o: gel, patc h, crea m, oi nt me nt, l oti o n , or s pra y) t o t he st u d y dr u g 
a p plicati o n site(s), i.e. o n t he u p per ar m(s)  a n d s h o ul der(s) . A n e xce pti o ns is t he use 
of s u nscree n  pr o d ucts  > 1 h o ur after a p plicati o n of t he st u d y dr u g.  
•  P rescri pti o n or O T C treat me nts t hat are k n o w n/s u g geste d t o ha ve a n estr o ge nic or 
anti -a n dr o ge nic effect.  
•  A n y of t he f oll o wi n g k n o w n i n d ucers or i n hi bit ors of c yt oc hr o me P 4 5 0 3 A 4 
( C Y P 3 A 4):  p he n o bar bital, car ba maze pi ne, rifa m pi n, er yt hr o m yci n, clarit hr o m yci n, 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 6  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
ket oc o naz ole, itrac o naz ole, rit o na vir, St. J o h n’s W ort pre parati o ns ( H y peric u m 
perf orat u m), a n d gra pefr uit j uice . 
 
6. 0  
St u d y E v al u ati o ns  
6. 1  
L a b or at or y Tests  
La b orat or y tests will be perf or me d b y a ce ntral la b orat or y. T he f oll o wi n g t est res ults  will be 
re p orte d t o t he I n vesti gat or: he mat ol o g y, bl o o d c he mistr y, uri nal ysis, c oa g ulati o n fact ors, 
h or m o nes (i ncl u di n g t otal Test oster o ne), a n d P S A . T he I n vesti gat or will assess all ab n or mal 
la b val ues f or cli nical si g nifica n ce; if cate g orize d as a d verse e ve nts , t he y will be c ollecte d 
a n d rec or de d si milarl y t o ot her A Es . All cli nicall y si g nific a nt a b n or mal la b val ues will  be 
f oll o we d u ntil res ol uti o n. If res ol uti o n is n ot see n, a j ustificati o n as t o t he ca use f or s uc h a n 
a b n or malit y, s uc h as d ue t o a n u n derl yi n g pre -e xisti n g c o n diti o n, ass ociate d c o -m or bi dit y, 
etc., will  be rec or de d. 
 
T he f oll o w i n g la b orat or y assess me nts will be perf or me d f or t his st u d y.  
He mat ol o g y:  
He mat ocrit, H e m o gl o bi n, W B C wit h differe ntial, R B C, P latelets  
 
Bl o o d  C he mistr y:   
Ala ni ne tra nsa mi nase ( A L T), Al b u mi n, Al kali ne p h os p hatase  ( A L P), 
As partate a mi n otra nsferase ( A S T), Bl o o d urea nitr o ge n ( B U N), 
Calci u m, Car b o n di o xi de, C hl ori de, t otal C h olester ol, C h olester ol 
H D L, C h olester ol L D L, Creati ni ne, Direct bilir u bi n, Gl uc ose,  Lactate 
de h y dr o ge nase ( L D H), P otassi u m, S o di u m, t otal B ilir u bi n, t otal 
P r otei n, Tri gl yceri des 
 
C oa g ulati o n Fact ors:  Pr otei n C -acti vit y a n d a nti ge n , P r otei n S-acti vit y, Pr otei n S -a nti ge n, 
A ntit hr o m bi n  III a nti ge n, a n d Acti vate d pr otei n C resista nce ( A P C R)  
 
E n d ocri ne:  
G l ycate d he m o gl o bi n ( H b A 1 C) 
 
H or m o nes:  
F ollicle sti m ulati n g h or m o ne ( F S H), L utei nizi n g h or m o ne ( L H), a n d 
S e x h or m o ne -bi n di n g gl o b uli n  ( S H B G) 
 
Uri nal ysis:  
A p peara nce , C ol or, Gl uc ose, Ket o nes, Micr osc o pic, Nitrites, Occ ult 
bl o o d, p H, Pr otei n, S pecific Gra vit y  
Bi o mar kers:   
 
B o ne :  
C -tel o pe pti de cr ossli n k of t y pe 1 c olla ge n (C T x)  –  b o ne res or pti o n  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 7  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
Al kali ne P h os p hatase, B o ne S pecific ( B S A P)  –  b o ne f or mati o n  
 
 
Pr ostate:  
Pr ostate s pecific a nti ge n ( P S A)  
 
Efficac y:  
t otal Test oster o ne 
 
P har mac o ki netic:  
Estra di ol, E str o ne 
 
6. 2  
Electr oc ar di o gr a m  
T he electr ocar di o gra m ( E C G) will be a c o m plete,  sta n dar dize d 1 2-lea d rec or di n g. E C Gs will 
be e val uate d b y t he I n vesti gat or or a q ualifie d desi g nee. A n y si g nifica nt fi n di n gs,  prese nt 
pri or t o t he first d ose of St u d y Dr u g ( St u d y Da y 1), m ust be re p orte d o n t he E C G C R F.  
Si g nifica nt fi n di n gs ma de after t he  start of st u d y dr u g w hic h meet t he defi niti o n of a n A E  
m ust be rec or de d o n t he A d verse E ve nt C R F.  
6. 3  
P h ysic al E x a m  
A n y  si g nifica nt fi n di n gs prese nt pri or t o t he first d ose of St u d y Dr u g ( St u d y Da y 1) m ust be 
re p orte d o n t he P h ysical E xa m C R F. Si g nifica nt fi n di n gs ma de after t he first d ose of St u d y 
Dr u g ( St u d y Da y 1)  w hic h meet t he defi niti o n of a n A E m ust be rec or de d o n t he A d verse 
E ve nt C R F. T he p h ysical e xa m (P E 1) will  i ncl u de a n assess me nt of all b o d y s yste ms as well 
as meas ure me nt of hei g ht a n d wei g ht.  T he e xa m s h o ul d i ncl u de i ns pecti o n of t he t h ora x f or 
t he prese nce of g y nec o mastia. 
6. 4  
Vit al Si g ns  
A n y  si g nifica nt fi n di n gs prese nt pri or t o t he first d ose of St u d y Dr u g ( St u d y Da y 1) m ust  be 
re p orte d o n t he Vital Si g ns  C R F . S itti n g vital si g ns t o be meas ure d are: heart rate  
( beats/ mi n ute), res pirati o n rate ( breat hs/ mi n ute), s yst olic a n d diast olic bl o o d press ure 
( m m H g), a n d b o d y te m perat ure. 
6. 5  
Q u alit y of Life Q uesti o n n aire  
T he  E x pa n de d Pr ostate ca ncer I n de x C o m p osite ( E PI C) was de vel o pe d b y researc hers at 
U ni versit y of Mic hi ga n a n d U C L A t o meas ure healt h relate d q ualit y of life a m o n g me n wit h 
pr ostate ca ncer ( Wei et.al. 2 0 0 0 ). E PI C has bee n vali date d i n me n wit h l ocalize d pr ost ate 
ca ncer w h o u n der we nt s ur ger y, e xter nal bea m ra diati o n, or brac h yt hera p y wit h or wit h o ut t he 
use of h or m o nal a dj u va nts. E PI C assesses t he disease -s pecific as pects of pr ostate ca ncer a n d 
its t hera pies a n d c o m prises f o ur s u m mar y d o mai ns ( Uri nar y, B o wel, Se x ual a n d H or m o nal). 
I n t his st u d y, o nl y t he Se x ual a n d H or m o nal d o mai ns of t he q uesti o n naire will be use d.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 8  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
Res p o nse o pti o ns f or eac h E PI C ite m f or m a Li kert scale, a n d m ulti -ite m scale sc ores are 
tra nsf or me d li nearl y t o a 0-1 0 0 scale, wit h hi g her sc ores r e prese nti n g better healt h relate d 
q ualit y of life ( H R Q O L).  
6. 5. 1  E PI C  –  H or m o n al C o m p o ne nt  
T he E PI C –  H or m o nal  Assess me nt is a 6 q uesti o n s ur ve y desi g ne d t o meas ure t he 
Q ualit y of Life ( Q o L) iss ues s pecific t o h or m o nal f u ncti o n i n patie nts wit h Pr ostate 
ca ncer. 
6. 5. 2  E PI C  –  Se x u al C o m p o ne nt  
T he E PI C –  Se x ual Assess me nt is a 9 q uesti o n s ur ve y desi g ne d t o meas ure t he 
Q ualit y of Life ( Q o L) iss ues s pecific t o se x ual f u ncti o n a n d se x ual satisfacti o n i n 
patie nts wit h Pr ostate ca ncer.  
7. 0  
St u d y Visits  
7. 1  
Scree ni n g   
T he assess me nts liste d bel o w will be c o n d ucte d n o m ore t ha n 1 4  da ys pri or t o t he first 
d ose of St u d y Dr u g ( St u d y Da y 1) .  
•  I nf or me d C o nse nt 
•  Re vie w of i ncl usi o n/e xcl usi o n criteria 
•  De m o gra p hics: ge n der, a ge, race, a n d, et h nicit y  
•  Re vie w of rele va nt me dical hist or y  wit hi n past 5 years   
•  Re vie w of rele va nt me dicati o n / pr oce d ure hist or y  wit hi n past 2 years   
•  E C G  
•  F ull p h ysical e xa mi nati o n i ncl u di n g: 
•  
Hei g ht  
•  
Wei g ht  
•  
B MI  
•  Vital S i g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  C e ntral  la borat or y  assess me nts (see Secti o n  6. 1  f or details): 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n F act ors 
•  
Efficac y Assess me nt  
7. 2  
St u d y D a y 1  ( Wee k 1):  B aseli ne  
T he e val uati o ns a n d  assess me nts liste d bel o w will be perf or me d wit hi n 2 h o urs pri or t o 
d osi n g wit h St u d y Dr u g o n Da y 1. A n o ver ni g ht fast  is re q uire d f or t he ce ntral 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 2 9  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d sa m ples i n t he m or ni n g ( 8-
1 0 A M).  
•  Reaffir mati o n of partici pati o n  
•  A ffir mati o n of eli gi bilit y criteria 
•  Re vie w of me dical hist or y  
•  P h ysical e xa m, i ncl u di n g:  
•  
Hei g ht  
•  
Wei g ht  
•  
B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d  A Es  
•  Rec or d  c o nc o mita nt me dicati o ns  & pr oce d ures  
•   Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n Fact ors  
•  
E n d ocri ne Assess me nt  
•  
H or m o ne Assess me nt  
•  
Bi o mar kers: B o ne & Pr ostate  
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  A d mi nister Q ualit y of Life Q uesti o n naires:  
•  
E PI C –  H or m o na l C o m p o ne nt  
•  
E PI C –  Se x ual  C o m p o ne nt  
•  Ra n d o mizati o n  
•  Dis pe nse  st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h  ca nister(s) 
•  Rec or d  st u d y dr u g a d mi nistrati o n  
•  Iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y 
•  O pti o n al  –  L o w D ose Ra diati o n f or t he pre ve nti o n of g y nec o mastia *  
* Ti mi n g is at t he discreti o n of t he I n vesti gat or.  
7. 3  
St u d y Wee k 2:  + 1 4 d a ys ( +/- 2 d a ys)  fr o m B aseli ne 
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or di n g   a d verse e ve nts ( A Es)  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 0  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 4  
St u d y Wee k 4:  + 2 8 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d  A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 5  
St u d y Wee k 6:  + 4 2 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.   
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es   
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 6  
St u d y Wee k 8 –  + 5 6 d a ys ( +/ - 2 d a ys) fr o m B aseli ne   
T he e val uati o ns a n d assess me nts liste d be l o w will be perf or me d. 
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y  te m perat ure 
•  Rec or d  A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe ns e st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g hi n g of ca nister(s)  
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 1  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
7. 7  
St u d y Wee k 1 0 :  + 7 0 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.   
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 8  
St u d y Wee k 1 2:  + 8 4 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d. A n  o ver ni g ht fast  is 
re q uire d f or t he ce ntral la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d 
sa m ples i n t he m or ni n g ( 8-1 0 A M).  
•  E C G  
•  Hei g ht, Wei g ht a n d B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es   
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n Fact ors  
•  
E n d ocri ne Assess me nt  
•  
H or m o ne Assess me nt  
•  
Bi o mar kers: B o ne & Pr ostate  
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  A d mi nister Q ualit y of Life Q uesti o n naires:  
•  
E PI C –  H or m o nal C o m p o ne nt  
•  
E PI C –  Se x ual C o m p o ne nt  
•  D is pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 9  
St u d y Wee k 1 4:  + 9 8 d a ys ( +/ - 2 d a y s) fr o m B aseli ne 
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 2  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 1 0  St u d y Wee k 1 6:  + 1 1 2 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y  te m perat ure 
•  Rec or d  A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h  ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 1  St u d y Wee k 1 8:  + 1 2 6 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d pre ss ure, heart rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 1 2  St u d y Wee k 2 0:  + 1 4 0 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce nt ral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi n istrati o n diar y 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 3  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
7. 1 3  St u d y Wee k 2 2:  + 1 5 4 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
7. 1 4  St u d y Wee k 2 4:  + 1 6 8 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  
T he e val uati o ns a n d assess me nts liste d bel o w will b e perf or me d. A n  o ver ni g ht fast  is 
re q uire d f or t he ce ntral la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d 
sa m ples i n t he m or ni n g ( 8-1 0 A M).  
•  E C G  
•  Hei g ht, Wei g ht a n d B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n Fact ors  
•  
E n d ocri ne Assess me nt  
•  
H or m o ne Assess me nt  
•  
Bi o mar k ers: B o ne & Pr ostate  
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  A d mi nister Q ualit y of Life Q uesti o n naires:  
•  
E PI C –  H or m o nal C o m p o ne nt  
•  
E PI C –  Se x ual C o m p o ne nt  
•  O btai n i nf or me d c o nse nt if patie nt c h o oses t o e nter t he st u d y e xte nsi o n p hase ( St u d y 
Wee k 2 8 –  St u d y Wee k 5 2 : E xte nsi o n St u d y) 
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 5  St u d y Wee k 2 8 :  + 1 9 6 d a ys ( +/ - 2 d a ys) fr o m B aseli ne –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 4  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  Rec or di n g A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Sec ti o n 6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 6  St u d y Wee k 3 2:  + 2 2 4 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nt s (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 7  St u d y Wee k 3 6:  + 2 5 2 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d. A n  o ver ni g ht fast is 
re q uire d f or t he ce ntral la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d 
sa m ples i n t he mor ni n g ( 8 -1 0 A M).  
•  E C G  
•  Hei g ht, Wei g ht a n d B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures   
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n Fact ors  
•  
E n d ocri ne Assess me nt  
•  
H or m o ne Assess me nt  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 5  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
•  
Bi o mar kers: B o ne & Pr ostate  
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  A d mi nister Q ualit y of Life Q uesti o n naires:  
•  
E PI C –  H or m o nal C o m p o ne nt  
•  
E PI C –  Se x ual C o m p o ne nt  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 8  St u d y Wee k 4 0 :  + 2 8 0 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 1 9  St u d y Wee k 4 4:  + 3 0 8 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m pli a nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 6  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
7. 2 0  St u d y Wee k 4 8:  + 3 3 6 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d. A n  o ver ni g ht fast is 
re q uire d f or t he ce ntral la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d 
sa m ples i n t he m or ni n g ( 8-1 0 A M).  
•  E C G  
•  Hei g ht, Wei g ht a n d B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y  te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
•  
C oa g ulati o n Fact ors  
•  
E n d ocri ne Assess me nt  
•  
H or m o ne Assess me nt  
•  
Bi o mar kers: B o ne & Pr ostate  
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  A d mi nister Q ualit y of Life Q uesti o n naires:  
•  
E PI C –  H or m o nal C o m p o ne nt  
•  
E PI C –  Se x ual C o m p o ne nt  
•  Dis pe nse st u d y dr u g 
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect /iss ue patie nt’s st u d y dr u g a d mi nistrati o n diar y  
7. 2 1  St u d y Wee k 5 2:  + 3 6 4 d a ys ( +/ - 2 d a ys) fr o m B aseli ne  –  E xte nsi o n St u d y  
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d.  
•  Vit al Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•  Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details) 
•  
Efficac y Assess me nt  
•  
P har mac o ki netic Assess me nt  
•  
Bi o mar kers: Pr ostate  
•  St u d y dr u g c o m plia nce – wei g h ca nister(s) 
•  C ollect patie nt’s st u d y dr u g a d mi nistrati o n diar y  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 7  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
7. 2 2  St u d y Wee k 5 4 :  + 3 7 8 d a ys ( +/ - 2 d a ys) fr o m B aseli ne or E n d of St u d y / E arl y 
Ter mi n ati o n   
T he e val uati o ns a n d assess me nts liste d bel o w will be perf or me d. A n  o ver ni g ht fast is 
re q uire d f or t he ce ntral la b orat or y assess me nts. It is rec o m me n de d t o c ollect bl o o d 
sa m ples i n t he m or ni n g ( 8-1 0 A M).   
•  E C G  
•  P h ysical e xa m, i ncl u di n g:  
•  
Hei g ht  
•  
Wei g ht  
•  
B MI  
•  Vital Si g ns: bl o o d press ure, heart  rate, res pirati o n rate, a n d b o d y te m perat ure 
•  Rec or d A Es  
•  Rec or d c o nc o mita nt me dicati o ns  & pr oce d ures  
•   Ce ntral la b orat or y assess me nts (see Secti o n  6. 1  f or details)*  
•  
He mat ol o g y  
•  
Bl o o d C he mistr y  
•  
Uri nal ysis  
* If a bn or mal or n ot  perf or me d wit hi n t he past  4 wee ks , t he y are t o be perf or me d . 
•  A d mi nister Q ualit y of Life Q uesti o n naires * : 
•  
E PI C –  H or m o nal C o m p o ne nt  
•  
E PI C –  Se x ual C o m p o ne nt  
* If less t ha n 4 wee ks ha ve passe d si nce t he E PI C q uesti o n naire s were last a d mi nistere d, 
t he y are t o be o mitte d. 
•  Res u me A D T of c h oice  
8. 0  
St atistic al Pl a n  
8. 1  
St atistic al A n al ysis Pl a n  
A statistical a nal ysis pla n ( S A P) will be writte n a n d fi nalize d pri or t o a n y l oc k of t he st u d y 
data base. T he S A P will gi ve a detaile d descri pti o n of t he s u m maries a n d statistical 
met h o d ol o gies f or a nal yses t hat will be perf or me d a n d clearl y descri be w he n t hese a nal yses 
will ta ke place.  S h o ul d a n y i nc o nsiste ncies e xist bet wee n t he a nal yses descri be d i n t his 
secti o n a n d t he a nal yses descri be d i n t he m ore detaile d S A P, t he S A P will ta ke prece de nce. 
8. 2  
S a m ple Size  
T he sa m ple size f or t his d ose -fi n di n g st u d y is a t otal of 12 0  patie nt s. Ass u mi n g t he res p o nse 
rate (t he pr o p orti o n of patie nt s mai ntai ni n g castrate le vels of T ( T < 5 0 n g/ d L)  f or t he 
place b o gr o u p is 5 % , t he res p o nse rate f or t he l o w d ose gr o u p of B H R -2 0 0 is 5 0 %, t he 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 8  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
res p o nse rate f or t he mi d  d ose  gr o u p  is 8 0 %, a n d t he res p o nse rate f or t he hi g h d ose gr o u p of 
B H R -2 0 0 is 9 5 % , 3 0 patie nt s per treat me nt gr o u p will pr o vi de at least 9 0 % p o wer t o detect 
t he difference i n pr o p orti o n of patie nt s mai ntai ni n g castrate le vels of T ( T < 5 0 n g/ d L)  
bet wee n a n y d ose of B H R -2 0 0 -treate d patie nt s a n d t he place b o-treate d patie nt s usi n g a t w o-
si de d Fis her-E xact test wit h a 5 % si g nifica nce le vel.  
8. 3  
D at a M a n a ge me nt  
A n electr o nic data  ca pt ure ( E D C) s y ste m will be use d t o c ollect t he bac k gr o u n d i nf or mati o n, 
safet y a n d efficac y data fr o m eac h s u bject. T his i nf or mati o n will be use d f or statistical 
a nal ysis. T he st u d y data base will be c o nst r ucte d base d o n t he E D C  data , pl us la b orat or y data 
i nf or mati o n. Data q ueries will be ge nerate d a n d res ol ve d acc or di n g t o t he pre-s pecifie d data 
ma na ge me nt pla n.  I n a d diti o n, ra n ge c hec ks, pla usi bilit y a n d c o nsiste nc y c hec ks will be 
perf or me d t o assess c o nsiste nc y, acc urac y a n d c o m plete ness of t he data c ol lecte d. Sta n dar d 
S A S datasets  will be ge nerate d fr o m t he fi nal st u d y data base f or a nal ysis.  A c o m plete a u dit 
trail of all c orrecti o ns will be ma de a n d ke pt as a part of E D C data base . 
8. 4  
St u d y P o p ul ati o ns  
T hree a nal ysis p o p ulati o ns will be defi ne d a n d a nal yze d: 
 
( 1) Safet y p o p ulati o n  will c o ntai n all patie nts  w h o recei ve at least o ne d ose of st u d y dr u g.   
All safet y para meters will be a nal yze d usi n g safet y p o p ulati o n.  
( 2) I nte nt-t o-treat (I T T) p o p ulati o n will c o ntai n all patie nts w h o are ra n d o mize d i nt o t he 
st u d y. All efficac y para meters will be a nal yze d usi n g t he I T T p o p ulati o n. I n t he case 
of a patie nt w h o was ra n d o mize d b ut di d n ot ta ke t he st u d y dr u g, t he a nal ysis will be 
d o ne f or t his patie nt usi n g t he ra n d o mize d treat me nt.  
( 3) Per -pr ot oc ol p o p ulati o n will c o ntai n all I T T patie nts  w h o d o n ot ha ve a n y maj or 
pr ot oc ol de viati o n. T he maj or pr ot oc ol de viat i o ns will be descri be d i n t he S A P a n d 
i de ntifie d b y B H R P H A R M A, L L C bef ore  t he data base is l oc ke d.  
8. 5  
H a n dli n g of Missi n g a n d I nc o m plete D at a  
T he S A P will descri be  h o w t o ha n dle missi n g efficac y data.  Missi n g date or ti me f or t he 
safet y date will be i m p ute d. T he statistical a nal ysis pla n ( S A P) will i ncl u de all detaile d 
i m p utati o n r ules.  
8. 6  
Met h o d ol o g y a n d C o n ve nti o ns  
Safet y a n d efficac y data will be s u m marize d a n d pr ese nte d b y treat me nt gr o u p a n d ti me p oi nt 
i n s u m mar y ta bles.   C o nti n u o us varia bles will be prese nte d b y descri pti ve statistics: n, mea n, 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 3 9  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m.  Cate g orical varia bles will be 
ta b ulate d b y fre q ue nc y c o u nt a n d perce nta ge. 
 
W he n t he act ual treat me nt recei ve d b y a patie nt  is differe nt fr o m t he ra n d o mize d treat me nt 
assi g ne d, t he patie nt  will be a nal yze d per t he ra n d o mize d treat me nt f or t he efficac y 
para meters  ( usi n g t he I T T p o p ulati o n); w hile t he y will be a nal yze d per act ual treat me nt t hat 
was ta ke n f or t he safet y para meters  ( usi n g t he safet y p o p ulati o n). 
 
U nless ot her wise state d, all statistical tests will be t w o -si de d h y p ot hesis tests perf or me d at 
t he 5 % le vel of si g nifica nce f or mai n effects a n d all c o nfi de nce i nter vals will be t w o-si de d 
9 5 % c o nfi de nce i nter vals . 
8. 7  
Effic ac y A n al ysis  
T he pri mar y efficac y e n d p oi nt is t he res p o nse rate (t he pr o p orti o n of patie nts  mai ntai ni n g 
castrate le vels of T ( T < 5 0 n g/ d L) ).  T he pri mar y a nal ysis o n t he pri mar y efficac y e n d p oi nt 
is t o c o m pare t he res p o nse  rate fr o m eac h of t he 3, B H R -2 0 0 d ose le vel s a gai nst t he res p o nse 
rate f or t he place b o-treate d patie nt s at Wee k 1 2 usi n g t he  C oc hra n – Ma ntel – Hae nszel ( C M H) 
statistics a dj uste d f or a p pr o priate baseli ne c haracteristics.  
 
T he f oll o wi n g c o m paris o ns  will be ma de bet wee n acti ve d ose le vels a n d place b o, a n d t he 
st u d y will be c o nsi dere d s uccessf ul if t he first c o m paris o n reac hes a si g nifica nce le vel of 
p < 0. 0 5. S u bse q ue nt c o m paris o ns will be c o nsi dere d si g nifica nt o nl y if t he y reac h a 
si g nifica nce le vel of p < 0. 0 5 i n a d diti o n t o t he c o m paris o n pri or t o it.  
 
•  Hi g h d ose vs. place b o  
•  Mi d  d ose vs. place b o  
•  L o w d ose vs. place b o  
•  L o w d ose vs. hi g h d ose  
•  Mi d  d ose vs. hi g h d ose  
•  L o w d ose vs. mi d  d ose  
 
Sec o n dar y efficac y e n d p oi nts will i ncl u de:  
( 4) T he pr o p orti o n of t he res p o nse rate at Wee k 2 4.  T he sa me statistical a nal ysis met h o d 
t hat a p plie d t o Wee k 1 2 a nal ysis will be use d f or Wee k 2 4.  
( 5) T he Ka pla n -Meier c ur ve f or ti me t o T  >  5 0 n g/ d L at Wee k 1 2 f or eac h treat me nt 
gr o u p.  
( 6) T he Ka pla n -Meier c ur ve f or  ti me t o T >  5 0 n g/ d L at Wee k 2 4 f or eac h treat me nt 
gr o u p.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 0  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
 
F or t he ti me -t o-e ve nt a nal ysis, t he l o g -ra n k test a n d t he Wilc o x o n test will be use d t o 
c o m pare t he me dia n ti me t o e ve nt.  I n a d diti o n, a C o x pr o p orti o nal hazar d m o del will be use d 
t o a nal yze t he ti me-t o-e ve nt , a n d t he m o del will be stratifie d b y t he a p pr o priate  baseli ne 
c haracteristics .  Treat me nt effect will be teste d f or t he hazar d rati o usi n g t he Wal d C hi -
s q uare d test.  I n a d diti o n, t he 9 5 % c o nfi de nce i nter val f or t he hazar d rati o ( H R) will be 
esti mate d  
 
All ot her efficac y para meters (e. g., F S H, L H, S H B G, a n d P S A) will be s u m marize d b y 
treat me nt gr o u p at eac h st u d y visit usi n g descri pti ve statistics. Ser u m le vels of estra di ol a n d 
estr o ne will be s u m mari ze d b y treat me nt gr o u p at eac h st u d y visit  usi n g descri pti ve statistics.  
T he E PI C -H or m o nal Ass ess me nt a n d t he E PI C -Se x ual Assess me nt will be s u m marize d b y 
treat me nt gr o u p at eac h st u d y visit usi n g descri pti ve statistics. 
 
9. 0  
( Seri o us) A d verse E ve nt C ollecti o n a n d Re p orti n g  
9. 1  
A d verse E ve nt C ollecti o n  
A Es will be ca pt ure d f or t he d urati o n of t he st u d y. T he re p orti n g peri o d be gi ns  wit h t he first 
d ose of St u d y Dr u g ( St u d y Da y 1)  a n d e n ds at Wee k 5 4 or t he E n d of St u d y.  F or t his st u d y, 
an A E is defi ne d as:  “ A n y u nfa v ora ble or  u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m, or disease, w het her or n ot ass ociate d wit h t he treat me nt a n d st u d y 
pr oce d ures .”  T his i ncl u des a n y ne wl y occ urri n g e ve nt or pre vi o us c o n diti o n t hat has 
i ncrease d i n se verit y or fre q ue nc y si nce t he a d mi nistrati o n of st u d y dr u g.  
 
A Es  ma y als o be re p orte d s p o nta ne o usl y at a n y ti me. Details of a n y a d verse or u ne x pecte d 
e ve nts, si g ns, a n d s y m pt o ms will be c ollecte d  i ncl u di n g details of o nset, res ol uti o n, 
fre q ue nc y, se verit y (as defi ne d bel o w), seri o us ness, relati o ns hi p t o t he dr u g, effect o n t he 
st u d y dr u g, treat me nts a d mi nistere d, a n d o utc o me. A n y A E  will be f oll o we d, w he ne ver 
p ossi ble, u ntil it ret ur ns t o t he baseli ne c o n diti o n or bec o mes sta ble wit h n o f urt her c ha n ge 
e x pecte d. 
T he safet y of B H R’s tra ns der mal estra di ol gel has bee n st u die d i n 2 5  healt h y v ol u nteers 
usi n g si n gle d oses a n d i n 9 patie nts i n t he tar get patie nt p o p ulati o n, me n wit h a n dr o ge n-
p ositi ve pr ostate ca ncer , usi n g o nce dail y d osi n g or t wice dail y d osi n g f or o ne wee k. T he 
t olera bilit y of t he dr u g was ver y g o o d  (f or f ull refere nce, see t he I n vesti gat or Br oc h ure). I n 
o t her f or m ulati o ns of tra ns der mal estr o ge ns ha ve bee n st u die d i n t his patie nt p o p ulati o n a n d 
t he res ults ha ve bee n p u blis he d i n peer-re vie we d literat ure. T he k n o w n si de effects of 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 1  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
tra ns der mal estra di ol i n t hese st u d y p o p ulati o n s, w here estra di ol was use d f or u p t o a year i n 
s o me cases, i ncl u de: 
•  g y nec o mastia ( Bla n d et al. 2 0 0 5, Ger ber et al. 2 0 0 0,  Oc kri m et al. 2 0 0 3 ),  
•  vas o m ot or s y m pt o ms (He dl u n d 2 0 0 0 , S petz et al. 2 0 0 1 ),  
•  l oss of li bi d o, a n d erectile d ysf u ncti o n ( C o x a n d Cra wf or d 1 9 9 5, He dl u n d 2 0 0 0 , 
L ycette et al. 2 0 0 6 , Oc kri m et al. 2 0 0 6, Sa ye d a n d Ta xel 2 0 0 3 ) 
 
Partic ular atte nti o n s h o ul d be pai d t o t he f oll o wi n g p ote ntial ris ks pre vi o usl y i de ntifie d as 
ass ociate d wit h a d mi nistrati o n of estra di ol i n p o p ulati o ns of p ost -me n o pa usal w o me n:  
•  m y ocar dial i nfarcti o n  
•  str o ke 
•  D V T  
•  p ul m o nar y e m b oli  
 
9. 2  
Re p orti n g of A d verse E ve nts  
9. 2. 1  Di a g n oses vs. si g ns/s y m pt o ms  
Eac h A E  s h o ul d be rec or de d t o re prese nt a si n gle dia g n osis. Acc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y val ues  if n ot c o nstit uti n g A Es t he msel ves or E C G fi n di n gs) or 
s y m pt o ms s h o ul d N O T be rec or de d as a d diti o nal A Es. If a dia g n osis is u n k n o w n, si g n(s) or 
s y m pt o m(s) s h o ul d be rec or de d as a n a d verse e ve nt(s). 
9. 2. 2  L a b or at or y v al ues  
C ha n ges i n la b orat or y val ues ma y be c o nsi dere d A Es if t he y are j u d ge d t o be cli nicall y 
si g nifica nt (i.e., if s o me acti o n or i nter ve nti o n is re q uire d or if t he I n vesti gat or j u d ges t he 
c ha n ge t o be be y o n d t he ra n ge of n or mal p h ysi ol o gical fl uct uati o n).  If a b n or mal la b orat or y 
val ues are t he res ult of pat h ol o g y f or w hic h t here is a n o verall dia g n osis (e. g., i ncrease d 
creati ni ne i n re nal fail ure), t he dia g n osis o nl y s h o ul d be re p orte d as a n A E . 
9. 2. 3  Pre -e xisti n g c o n diti o ns  
Pre -e xisti n g c o n diti o ns ( prese nt bef ore  t he start of t he A E  c ollecti o n peri o d) are c o nsi dere d 
c o nc urre nt me dical c o n diti o ns a n d s h o ul d N O T be rec or de d as A Es.  H o we ver, if t he patie nt  
e x perie nces a w orse ni n g or c o m plicati o n of s uc h a c o nc urre nt c o n diti o n, t he w orse ni n g or 
c o m plicati o n s h o ul d be rec or de d as a n A E. I n vesti gat ors s h o ul d e ns ure t hat t he A E  ter m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti o n (e. g., “ w orse ni n g of ….”). 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 2  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
9. 2. 4  Pre pl a n ne d s ur geries or pr oce d ures  
Pre pla n ne d pr oce d ures (s ur geries or t hera pies) t hat were sc he d ule d pri or t o t he start  of 
a d verse e ve nt c ollecti o n are n ot c o nsi dere d A Es. H o we ver, if a pre pla n ne d pr oce d ure is 
perf or me d earl y (e .g ., as a n e mer ge nc y) d ue t o a w orse ni n g of t he pree xisti n g c o n diti o n, t he 
w orse ni n g of t he c o n diti o n s h o ul d be ca pt ure d as a n A E . 
9. 2. 5  E lecti ve s ur geries or pr oce d ures  
Electi ve pr oce d ures perf or me d w here t here is n o c ha n ge i n t he patie nt ’s me dical c o n diti o n 
s h o ul d n ot be rec or de d as A Es, b ut s h o ul d be d oc u me nte d i n t he patie nt ’s s o urce d oc u me nts. 
9. 2. 6  O ver d ose  
Cases of dr u g o ver d ose wit h o ut ma nifeste d si de ef fects are N O T c o nsi dere d a d verse e ve nts. 
9. 3  
Assess me nt of A d verse E ve nt Se verit y  
T he I n vesti gat or will gra de  t he se verit y of eac h A E acc or di n g t o t he Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E). All A Es will be 
rec or de d o n t he A E case re p ort f or m. 
After caref ul me dical c o nsi derati o n, t he I n vesti gat or will assess t he relati o ns hi p of t he A E t o 
t he st u d y gel as f oll o ws: 
U nrelate d  - N o p ossi ble relati o ns hi p. T he te m p oral ass ociati o n bet wee n a d mi nistrati o n 
of t he st u d y pr o d uct a n d t he a d verse e ve nt is u nreas o na ble or i nc o m pati ble a n d/ or 
a n ot her ca use is c o nfir me d.  
 
P ossi ble  - T here is a reas o na ble te m p oral ass ociati o n a n d ca usal relati o ns hi p bet wee n t he 
i n vesti gati o nal pr o d uct a n d t he a d verse e ve nt. Ot her p ote ntial ca u ses ma y e xist t hat are 
j ust as li kel y or d o n ot f ull y e x plai n t he a d verse e ve nt. Dec halle n ge/rec halle n ge 
i nf or mati o n is u n k n o w n or u nclear. 
 
Pr o ba ble  - T here is a reas o na ble te m p oral ass ociati o n a n d ca usal relati o ns hi p bet wee n 
t he i n vesti gati o nal pr o d uct an d t he a d verse e ve nt. T he a d verse e ve nt res p o n ds 
a p pr o priatel y t o dec halle n ge. Rec halle n ge is n ot necessar y. Ot her ca uses ha ve bee n 
eli mi nate d or are u nli kel y.  
T he I n vesti gat or m ust deci de w het her t he A E meets t he defi niti o n of a n S A E.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 4  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
F or eac h S A E, t he I n vesti gat or a n d S p o ns or will i n de pe n de ntl y assess w het her t here is a 
reas o na ble p ossi bilit y t hat t he e ve nt ma y ha ve be e n ca use d b y t he st u d y dr u g (“ dr u g-
relate d”). T he S p o ns or will e val uate eac h dr u g-relate d S A E t o deter mi ne if t he e ve nt was 
u ne x pecte d. If t he S A E is assesse d t o be b ot h dr u g -relate d a n d u ne x pecte d, t he S p o ns or or 
desi g nee will n otif y all I n vesti gat ors, a n d will re p ort it t o t he a p pr o priate re g ulat or y 
a ut h orities as re q uire d b y a p plica ble l ocal re g ulati o ns.  T he S p o ns or or  desi g nee will re p ort 
S A Es, i ncl u di n g narrati ves, t o t he U nite d States ( U. S. ) F o o d a n d D r u g A d mi nistrati o n ( F D A)  
a n d l ocal re g ulat or y a ut h orities as re q uire d b y 2 1 C F R 3 1 2. 3 2 a n d I C H G ui deli ne f or G o o d 
Cli nical Practice. T he I n vesti gat or is res p o nsi ble f or  n otif yi n g his/ her res pecti ve I R B.  
 
1 0. 0  
Re g ul at or y a n d Pr oce d ur al Re q uire me nts  
1 0. 1  Et hic al C o n d uct of t he St u d y  
G o o d Cli nical Practice ( G C P) is a n i nter nati o nal et hical a n d scie ntific q ualit y sta n dar d f or 
desi g ni n g, c o n d ucti n g, rec or di n g, a n d re p orti n g st u dies t ha t i n v ol ve t he partici pati o n of 
h u ma n s u bjects . T h is st u d y will be c o n d ucte d i n c o m plia nce wit h G C P a n d t he a p plica ble 
nati o nal re g ulati o ns s o as t o ass ure t hat t he ri g hts, safet y, a n d well -bei n g  of t he partici pati n g 
st u d y s u bjects are pr otecte d c o nsiste nt wit h t he et hical pri nci ples t hat ha ve t heir ori gi n i n t he 
Declarati o n of Helsi n ki.   
1 0. 2  I nstit uti o n al Re vie w B o ar d 
T he S p o ns or ( or a n a ut h orize d re prese ntati ve) or t he I n vesti gat or (acc or di n g t o nati o nal 
pr o visi o ns) is res p o nsi ble f or f oll o wi n g t he re gi o nal la w w here t he st u d y is t o be c o n d ucte d 
t o o btai n writte n a p pr o val f or t he cli nical st u d y pr ot oc ol (i ncl u di n g all s u bsta ntial pr ot oc ol 
a me n d me nts), t he patie nt  i nf or me d c o nse nt, i nf or me d c o nse nt u p dates, patie nt  recr uit me nt 
pr oce d ures (e. g., a d vertise me nts) a n d a n y ot her i nf or mati o n t o be pr o vi de d t o patie nt s fr o m 
a n i nstit uti o nal re vie w b oar d ( I R B) t hat c o m plies wit h t he l ocal re g ulat or y re q uire me nts. 
Writte n a p pr o val of t he st u d y m ust be o btai ne d fr o m t he I R B pri or t o t he st u d y bei n g 
i m ple me nte d (i.e., s hi p me nt of cli nical s u p plies t o t he I n vesti gat or or scree ni n g of patie nt s). 
C o pies of t he a p pr o val d oc u me ntati o n will be mai ntai ne d b y b ot h t he I n vesti gat or a n d t he 
S p o ns or ( or a n a ut h orize d re prese ntati ve) i n t he desi g nate d st u d y d oc u me ntati o n files.  
T he S p o ns or ( or a n a ut h orize d re prese ntati ve) or t he I n vesti gat or (acc or di n g t o nati o nal 
pr o visi o ns) will s u b mit writte n re p orts of t he cli nical st u d y stat us t o t he I R B a n n uall y, or 
m ore fre q ue ntl y if re q ueste d b y t he I R B. A fi nal st u d y n otificati o n s h o ul d  be f or war de d t o 
t he I R B wit hi n 9 0 da ys after t he st u d y has c o m plete d, or i n t he e ve nt of pre mat ure 
ter mi nati o n of t he st u d y wit hi n 1 5 da ys, wit h t he rati o nale f or st u d y ter mi nati o n clearl y 
e x plai ne d. C o pies of all cli nical st u d y stat us re p orts (i ncl u di n g ter mi nati o n) will be 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 5  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
mai ntai ne d b y b ot h t he I n vesti gat or a n d t he S p o ns or ( or a n a ut h orize d re prese ntati ve) i n t he 
st u d y d oc u me ntati o n files. 
 
I n acc or da nce wit h nati o nal pr o visi o ns a n d t he r ules of t he F o o d a n d Dr u g A d mi nistrati o n 
( F D A), or a p plica ble natio nal or state la ws, t he S p o ns or ( or a n a ut h orize d re prese ntati ve) will 
i nf or m all partici pati n g I R Bs a n d a p plica ble nati o nal a ut h orities of all S A Es or ot her safet y -
relate d i nf or mati o n, w hic h occ ur d uri n g t he cli nical st u d y as a p pr o priate. 
1 0. 3  P atie nt  I nf or me d C o nse nt  
It is t he res p o nsi bilit y of t he I n vesti gat or t o o btai n writte n I nf or me d C o nse nt fr o m t he patie nt  
pri or t o i nitiati n g a n y st u d y pr oce d ures . All c o nse nt d oc u me ntati o n m ust be i n acc or da nce 
wit h a p plica ble re g ulati o ns a n d G C P. Eac h patie nt  is re q ueste d t o si g n t he Patie nt  I nf or me d 
C o nse nt F or m after t he patie nt  has recei ve d a n e x pla nati o n of w hat t he st u d y i n v ol ves, 
i ncl u di n g b ut n ot li mite d t o, t he f oll o wi n g: t he o bjecti ves, p ote ntial be nefits a n d ris k, 
i nc o n ve nie nces a n d t he patie nt ’s ri ghts a n d res p o nsi bilities. A c o p y of t he i nf or me d c o nse nt 
d oc u me ntati o n ( C o nse nt F or m) m ust be gi ve n t o t he patie nt .  
1 0. 4  A d vis or y B o ar d  
A n A d vis or y B oar d , c o m p ose d of e x perts i n t he fiel d of Pr ostate Ca ncer , will pr o vi de 
scie ntific a n d cli nical  lea ders hi p f or t his st u d y i n c o ns ultati o n wit h B H R P H A R M A, L L C . 
1 0. 5  I n vesti g at or O bli g ati o ns 
T he Pri nci pal I n vesti gat or a grees t o c o n d uct t he cli nical st u d y i n c o m plia nce wit h t his 
pr ot oc ol w hic h was a p pr o ve d b y t he I R B i n c o m plia nce wit h l ocal re g ulat or y re q uire me nts. 
T he I n vesti gat or a n d t he S p o ns or will si g n t he pr ot oc ol ( Pa ge 4 ) t o c o nfir m t his a gree me nt. 
1 0. 6  G C P c o m pli a nce  
T he I n vesti gat or m ust u n derta ke t o perf or m t he st u d y i n acc or da nce wit h I C H G C P 
G ui deli ne E 6  ( F D A 1 9 9 6) a n d t he a p plica ble re g ulat or y re q uire me nts. C o pies  of t hese 
g ui deli nes are a vaila ble at w w w.ic h. or g  a n d will be  pr o vi de d t o t he site b y B H R u p o n 
re q uest. 
 
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat a de q uate ti me a n d a p pr o priate res o urces 
are a vaila ble at t he st u d y site pri or t o c o m mit me nt t o partici pate i n t his st u d y. T he 
I n vesti gat or s h o ul d als o be a ble t o esti mate or de m o nstrate a p ote ntial f or recr uiti n g t he 
re q uire d n u m ber of s uita ble patie nt s wit hi n t he a gree d recr uit me nt peri o d. 
T he I n vesti gat or will mai ntai n a list of a p pr o priatel y q ualifie d pers o ns t o w h o m t he 
I n vesti gat or has dele gate d si g nifica nt st u d y-relate d tas ks. A n u p-t o-date c o p y of t he 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 6  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
c urric ul u m vit ae  f or t he I n vesti gat or, s u b-i n vesti gat or(s) a n d esse ntial st u d y staff, as 
a p pr o priate, will be pr o vi de d t o B H R ( or desi g nee) bef ore starti n g t he st u d y.  
1 0. 7  Pr ot oc ol a d here nce a n d i n vesti g at or a gree me nt  
T he I n vesti gat or m ust a d here t o t he pr ot oc ol as detaile d i n t his d oc u me nt. T he I n vesti gat or 
will be res p o nsi ble f or e nr olli n g o nl y t h ose patie nt s w h o ha ve met pr ot oc ol eli gi bilit y criteria. 
T he I n vesti gat ors will be re q uire d t o si g n a n I n vesti gat or A gree me nt t o c o nfir m acce pta nce 
a n d willi n g ness t o c o m pl y wit h t he st u d y pr ot oc ol.  
 
It is t he I n vesti gat or’s res p o nsi bilit y t o c o m m u nicate wit h t heir I RB t o e ns ure acc urate a n d 
ti mel y i nf or mati o n is pr o vi de d at all p hases d uri n g t he st u d y. I n partic ular, t he a p pr o priate 
a p pr o vals m ust be i n place pri or t o recr uit me nt, n otificati o n of a n y S A Es d uri n g t he st u d y 
m ust ta ke place a n d t he I R B m ust be i nf or me d o f st u d y c o m pleti o n. 
1 0. 8  Pr ot oc ol d e vi ati o ns 
T he I n vesti gat or will n ot de viate fr o m t he pr ot oc ol wit h o ut pri or writte n a p pr o val fr o m t he 
S p o ns or or desi g nee , e xce pt i n me dical e mer ge ncies. I n t he e ve nt of a me dical e mer ge nc y, 
t he Me dical M o nit or m ust be n otified as s o o n a s p ossi ble. T he g o ver ni n g I R B/ will be 
i nf or me d of all pr ot oc ol c ha n ges iss ue d b y t he S p o ns or b y t he i n vesti g at or i n acc or da nce 
wit h t he I R B ’s esta blis he d pr oce d ure. 
1 0. 9  M o nit ori n g of t he st u d y 
Site visits a n d i ns pecti o ns will be c o n d ucte d b y t he S p o ns or or desi g nee at re g ular i nter vals 
i n acc or da nce wit h F D A a n d I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H) g ui deli nes. 
T he I n vesti gat or will per mit re prese ntati ves of t he s p o ns or’s m o nit ori n g tea m, F D A or l ocal 
healt h a ut h orit y a u dit ors t o i ns pect f acilities a n d rec or ds rele va nt t o t his st u d y.  
1 0. 1 0  Fi n a nci al discl os ure  
T he I n vesti gat or will be re q uire d t o discl ose a n y fi na ncial arra n ge me nt w here b y t he val ue of 
t he c o m pe nsati o n f or c o n d ucti n g t he st u d y c o ul d be i nfl ue nce d b y t he o utc o me of t he st u d y. 
T he f oll o wi n g i nf or mati o n will be c ollecte d: a n y si g nifica nt pa y me nts of ot her s orts fr o m 
B H R P H A R M A, L L C , s uc h as a gra nt t o f u n d o n g oi n g researc h, c o m pe nsati o n i n t he f or m of 
e q ui p me nt, retai ner f or o n g oi n g c o ns ultati o n or h o n oraria; a n y pr o prietar y i nterest i n B H R -
2 0 0  or a n y si g nifica nt e q uit y i nterest i n B H R P H A R M A , L L C as defi ne d i n 2 1 C F R 5 4 2( b). 
 
I n c o nsi derati o n of partici pati o n i n t he st u d y, B H R P H A R M A , L L C, will pa y t he I n vesti gat or 
or n o mi nate d pa yee t he s u ms set o ut i n t he pa y me nt sc he d ule attac he d t o t he I n vesti gat or 
a gree me nt.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 7  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
1 0. 1 1  D oc u me nt ati o n a n d R ete nti o n of R ec or ds 
1 0. 1 1. 1  C ase Re p ort F or ms  
Data c ollecti o n f or t his pr ot oc ol ma y be acc o m plis he d usi n g pa per f or ms or electr o nic data 
rec or ds or b ot h. T heref ore, t he ter m C R F is u n derst o o d t o refer t o a pa per f or m, a n electr o nic 
data rec or d or b ot h.  
 
C R Fs are re q uire d a n d m ust be c o m plet e d f or eac h ra n d o mize d patie nt . It is t he 
I n vesti gat or’s res p o nsi bilit y t o e nsure t he acc urac y a n d c o m plete ness of t he data re p orte d o n 
t he patie nt ’s C R F. C R Fs s h o ul d be c o m plete d i n a ti mel y fas hi o n t o s u p p ort t he st u d y 
ti meli nes. S o urce d oc u me ntati o n s u p p orti n g t he C R F data s h o ul d i n dicate t he patie nt ’s 
partici pati o n i n t he st u d y a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr oce d ures, 
a d verse e ve nts, a n d stat us. T he I n ve sti gat or or desi g nee s h o ul d c o m plete a n d t he I n vesti gat or 
s h o ul d verif y t he s o urce d oc u me nts as t he i nf or mati o n is c ollecte d. C o m plete d case re p ort 
f or ms m ust be s u b mitte d f or eac h patie nt . T he I n vesti gat or will retai n a c o p y of all c o m plete d 
s o urce d oc u ments.  
1 0. 1 1. 2  Rec or di n g, access a n d rete nti o n of s o urce d at a  
S o urce data t o be re vie we d d uri n g t his st u d y will i ncl u de, b ut is n ot li mite d t o: patie nt ’s 
me dical file, ori gi nal la b orat or y re p orts, a n d hist ol o g y  a n d pat h ol o g y re p orts.  All ke y data 
m ust be rec or de d i n t he patie nt ’s me dical rec or ds. 
 
T he I n vesti gat or m ust per mit a ut h orize d re prese ntati ves of B H R P H A R M A , L L C, t he 
res pecti ve nati o nal, l ocal or f orei g n re g ulat or y a ut h orities, t he I R B, a u dit ors a n d i ntereste d 
c o m mercial parti es t o i ns pect facilities a n d rec or ds rele va nt t o t his st u d y.  
 
T he m o nit or, a u dit ors, I R B or re g ulat or y i ns pect ors, ma y c hec k t he C R F e ntries a gai nst t he 
s o urce d oc u me nts. T he c o nse nt f or m will i ncl u de a state me nt b y w hic h t he patie nt s all o w t he 
m o nit or/a u d it or/i ns pect or fr o m B H R P H A R M A , L L C or its re prese ntati ves, nati o nal or l ocal 
re g ulat or y a ut h orities or t he I R B access t o s o urce dat a (e. g., patie nt ’s me dical file), w hic h 
s u bsta ntiate i nf or mati o n rec or de d i n t he C R Fs.  
 
As descri be d i n t he I C H G C P G ui deli nes, ‘esse ntial d oc u me nts’, i ncl u di n g C R Fs, s o urce 
d oc u me nts, c o nse nt f or ms, la b orat or y test res ults a n d St u d y Dr u g  i n ve nt or y rec or ds, s h o ul d 
be retai ne d b y t he I n vesti gat or u ntil at least 2 years after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at least 2 years ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t he St u d y Dr u g . T hese d oc u me nts s h o ul d be 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 8  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
retai ne d f or a l o n ger peri o d h o we ver if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or 
b y a n a gree me nt wit h B H R P H A R M A , L L C. T he I n vesti gat or m ust  o btai n writte n 
per missi o n fr o m B H R P H A R M A, L L C  pri or t o t he destr ucti o n of a n y st u d y d oc u me nt.  
 
T hese rec or ds m ust be ma de a vai la ble at reas o na ble ti mes f or i ns pecti o n a n d d u plicati o n, if 
re q uire d, b y a pr o perl y a ut h orize d re prese ntati ve of t he U S F o o d a n d Dr u g A d mi nistrati o n 
( F D A) i n acc or da nce wit h t he U S C o de of Fe deral Re g ulati o ns 2 1 C F R 3 1 2. 6 8 or ot her 
nati o nal or f orei g n re g ulat or y a ut h orities  i n acc or da nce wit h re g ulat or y re q uire me nts. 
1 0. 1 2  Discl os ure of D at a  
I n di vi d ual patie nt s’ me dical i nf or mati o n o btai ne d as a res ult of t his st u d y is c o nsi dere d 
c o nfi de ntial a n d discl os ure t o t hir d parties ot her t ha n t h ose n ote d bel o w is pr o hi b ite d.  Patie nt  
c o nfi de ntialit y will be f urt her ass ure d b y utilizi n g patie nt  i de ntificati o n c o de n u m bers. If 
res ults of t his st u d y are re p orte d i n me dical j o ur nals or at meeti n gs, t he patie nt ’s i de ntit y will 
re mai n c o nfi de ntial. Me dical i nf or mati o n ma y be pr o vi de d t o t he patie nt ’s pers o nal p h ysicia n 
or t o ot her a p pr o priate me dical pers o n nel res p o nsi ble f or t he patie nt ’s welfare. 
 
Data ge nerate d as a res ult of t his st u d y are t o be a vaila ble f or i ns pecti o n o n re q uest b y 
F D A/l ocal healt h a ut h orit y a u dit ors, t he  s p o ns or’s m o nit ors, a n d b y t he I R Bs. If t he F D A or 
ot her re g ulat or y a ge nc y s h o ul d sc he d ule a n i ns pecti o n, t he Me dical M o nit or s h o ul d be 
a d vise d i m me diatel y.   
1 0. 1 3  P u blic ati o n  
B y si g ni n g t he st u d y pr ot oc ol, t he I n vesti gat or a grees t hat t he res ults of t he st u d y  ma y be 
use d f or t he p ur p oses of nati o nal a n d i nter nati o nal re gistrati o n, p u blicati o n, a n d i nf or mati o n 
f or me dical a n d p har mace utical pr ofessi o nals b y t he S p o ns or.  
 
P u blicati o ns or prese ntati o ns base d o n t he st u d y ma y n ot be ma de u ntil t he st u d y is 
c o m plete d, u nless s o deci de d b y t he S p o ns or. O nce t he S p o ns or or desi g nee p u blis hes t he 
fi nal re p ort a n d mai n st u d y ma n uscri pt, or if p u blicati o n has n ot occ urre d wit hi n 1 8  m o nt hs  
after c o m pleti o n of t he st u d y (fi nal data base l oc k), a n I n vesti gat or ma y i n di vi d uall y p u blis h 
or prese nt i nf or mati o n o n t his st u d y, prefera bl y pr o vi di n g t he ma n uscri pt t o t he S p o ns or f or 
re vie w pri or t o p u blicati o n.  T he Cli nical Trial A gree me nt be t wee n t he I n vesti gat or a n d t he 
S p o ns or ma y pr o vi de a d diti o nal ter ms re gar di n g p u blicati o n or prese ntati o n base d o n t he 
st u d y. 
 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 4 9  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
1 1. 0  
Refere nces  
Bla n d, L. B., Garz ott o, M., De L o u g her y, T. G., R y a n, C. W., Sc h uff, K. G., Wersi n ger, E. M., et al. 
( 2 0 0 5).  P hase II st u d y of tra ns der mal estra di ol i n a n dr o ge n-i n de pe n de nt pr ostate carci n o ma. 
Ca ncer. 1 0 3( 4), 7 1 7 -7 2 3.  
B uc ha n, N. C., & G ol de n ber g, S. L. ( 2 0 1 0). I nter mitt e nt vers us c o nti n u o us a n dr o ge n s u p pressi o n 
t hera p y: d o we ha ve c o nse ns us y et?. C urre nt O nc ol o gy ,1 7 ( S u p pl 2), S 4 5. 
B y ar, D. P. f or t he Vetera n's A d mi nistrati o n C o o perati ve Ur ol o gical Researc h Gr o u p.  ( 1 9 7 3). T he 
Vetera ns a d mi nistrati o n c o o perati ve ur ol o gical researc h gr o u p's st u dies of ca ncer of t he pr ostate.  
Ca ncer. 3 2, 1 1 2 6 -1 1 3 0.  
Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R) a n d Ce nter f or Bi ol o gics E val uati o n a n d 
Researc h ( C B E R), U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A).  1 9 9 6.  
I nter nati o nal C o nfere nce o n Har m o nisati o n of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Use (I C H), G ui da nce f or I n d ustr y, E 6 G o o d Cli nical Practice: 
C o ns oli date d G ui da nce.  A pril 1 9 9 6.  
C o x, R. L., a n d Cra wf or d, E. D. ( 1 9 9 5). Estr o ge ns i n t he treat me nt of pr ostate ca ncer. J. Ur ol., 
1 5 4( 6), 1 9 9 1 -1 9 9 8.  
Efstat hi o u, J. A., Bae, K., S hi ple y, W. U., Ha n ks, G. E., Pile pic h, M. V., Sa n dler, H. M., et al. ( 2 0 0 9). 
Car di o vasc ular m ortalit y after a n dr o ge n de pri vati o n t hera p y f or l ocall y a d va nce d pr ostate ca ncer: 
R T O G 8 5 -3 1. J. Cli n. O nc ol., 2 7( 1), 9 2 -9 9.  
Estr o Gel ®  Pac ka ge I nsert Re v. 0 8/ 2 0 1 4; Asce n d T hera pe utics, L L C.  
Fi n kelstei n, J. S., Lee, H., B ur nett -B o wie, S. A. M., Pallais, J. C., Y u, E. W., B or ges, L. F., ... & 
Le der, B. Z. ( 2 0 1 3). G o na dal ster oi ds a n d b o d y c o m p ositi o n, stre n gt h, a n d se x ual f u ncti o n i n 
me n.  Ne w E n gl a n d J o ur n al of Me dici ne , 3 6 9 ( 1 1), 1 0 1 1-1 0 2 2.  
Ger b er, G. S., Za gaja, G. P., Ra y, P. S., a n d R u kstalis, D. B. ( 2 0 0 0). Tra ns der mal estr o ge n i n t he 
treat me nt of h ot fl us hes i n me n wit h pr ostate ca ncer. Ur ol o g y., 5 5( 1), 9 7 -1 0 1.  
He dl u n d, P. O. ( 2 0 0 0). Si de effects of e n d ocri ne treat me nt a n d t heir mec ha nis ms: castr ati o n, 
a ntia n dr o ge ns, a n d estr o ge ns. Pr ostate S u p pl., 1 0, 3 2 -3 7.  
Hi ga n o, C. S. ( 2 0 0 3). Si de effects of a n dr o ge n de pri vati o n t hera p y: m o nit ori n g a n d mi ni mizi n g 
t o xicit y. Ur ol o g y., 6 1( 2 S u p p. 1), 3 2-3 8.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 5 0  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
Ka wa ka mi, J., C o wa n, J. E., El ki n, E. P., Lati ni, D. M., D u C ha ne, J., a n d Carr oll, P. R. f or t he 
Ca P S U R E I n vesti gat ors. 2 0 0 6. A n dr o ge n -de pri vati o n t hera p y as pri mar y treat me nt f or l ocalize d 
pr ostate ca ncer.  Ca ncer, 1 0 6, 1 7 0 8 -1 7 1 4.  
La n gle y R E, G o dsla n d I F, K y nast o n H, Clar ke N W, R ose n S D, M or ga n R C, et al. ( 2 0 0 8 ). Earl y 
h or m o nal data fr o m a m ultice ntre p hase II trial usi n g tra ns der mal o estr o ge n patc hes as first -li ne 
h or m o nal t hera p y i n patie nts wit h l ocall y a d va nce d or metastatic pr ostate ca ncer. BJ U I nt. 1 0 2( 4), 
4 4 2 -4 4 5.  
La n gle y R E, Caffert y F H, Al hass o A A, R ose n S D, S u n dara m S K, Free ma n S C, P oll oc k P, Ji n ks 
R C, G o dsla n d I F, K oc kel ber g h R, Clar ke N W, K y nast o n H G, Par mar, M K, A bel P D ( 2 0 1 3). 
Car di o vasc ular o utc o mes i n patie nts wit h l ocall y a d va nce d a n d metastatic pr ostate ca ncer treate d 
wit h l utei nisi n g -h or m o ne -releasi n g -h or m o ne a g o nists or tra ns der mal oestr o ge n: t he ra n d o mise d, 
p hase 2 M R C P A T C H trial ( P R 0 9). La ncet O nc ol. 1 4( 4), 3 0 6 -1 6.  
L o ose D S a n d Sta ncel G M ( 2 0 0 5). Estr o ge ns a n d pr o gesti ns. I n Br u nt o n, L. B., Laz o, H. S., a n d 
Par ker, K. L., E ds. G o o d ma n & Gil ma ns’s T he P har mac ol o gical Basis of T hera pe utics., 1 1t h e d. 
( p ps. 1 5 4 1-1 5 7 1). Ne w Y or k, N Y: Mc Gra w -Hill.  
L y cette, J. L., Bla n d, L. B., Garz ott o, M., a n d Beer, T. M. ( 2 0 0 6). Pare nteral estr o ge ns f or pr ostate 
ca ncer: ca n a ne w r o ute of a d mi nistrati o n o verc o m e ol d t o xicities? Cli n. Ge nit o uri n. Ca ncer., 5( 3), 
1 9 8 -2 0 5.  
Melli n ger, G. T. as me m b er of t he Vetera n's A d mi nistrati o n C o o perati ve Ur ol o gical Researc h 
Gr o u p. ( 1 9 6 7). Treat me nt a n d s ur vi val of patie nts wit h ca ncer of t he pr ostate.  S ur g. G y nec ol. 
O bstet. 1 2 4, 1 0 1 1 -1 0 1 7.  
M o ore, E., Wis nie ws ki, A., a n d D o bs, A. ( 2 0 0 3). E n d ocri ne treat me nt of tra nsse x ual pe o ple: a 
re vie w of treat me nt re gi me ns, o utc o mes, a n d a d verse effects. J. Cli n. E n d ocri n ol. Meta b.. 8 8( 8), 
3 4 6 7 -3 4 7 3.  
Oc kri m, J. L., Lala ni, E. N., La nia d o, M. E., Carter, S. S., a n d A bel, P. D. ( 2 0 0 3). Tra ns der mal 
estra di ol t hera p y f or a d va nce d pr ostate ca ncer --f or war d t o t he past?  J. Ur ol., 1 6 9( 5), 1 7 3 5-1 7 3 7.  
Oc kri m, J. L., Lala ni, el -N, Ka k kar, A. K., a n d A bel, P. D. ( 2 0 0 5). Tra ns der mal estra di ol t hera p y f or 
pr os tate ca ncer re d uces t hr o m b o p hilic acti vati o n a n d pr otects a gai nst t hr o m b oe m b olis m.  J. Ur ol., 
1 7 4( 2), 5 2 7 -5 3 3.  
Oc kri m, J. L., a n d A bel, P. D. ( 2 0 0 8). L o n g ter m a n dr o ge n de pri vati o n t hera p y i n pr ostate ca ncer. 
Britis h Me dical J o ur nal. 2 0 0 8 Se p 2 2;  3 3 7:  a 1 3 6 1. 
Oc kri m, J., Lala ni, E. N., a n d A bel, P. ( 2 0 0 6). T hera p y I nsi g ht: pare nteral estr o ge n treat me nt f or 
pr ostate ca ncer --a ne w da w n f or a n ol d t hera p y.  Nat. Cli n. Pract. O nc ol.,  3( 1 0), 5 5 2 -5 6 3.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
Pa ge 5 1  of 5 6  
A me n d me nt 4 : 1 3  J u ne 2 0 1 6 
P ur nell, J. Q., Bla n d, L. B., Garz ott o, M., Le m m o n, D., Wersi n ge r, E. M., R y a n, C. W., et al. ( 2 0 0 6).  
Effects of tra ns der mal estr o ge n o n le vels of li pi ds, li pase acti vit y, a n d i nfla m mat or y mar kers i n 
me n wit h pr ostate ca ncer. J. Li pi d Res., 4 7( 2), 3 4 9 -3 5 5.  
R o bi ns o n, M. R., S mit h, P. H., Ric har ds, B., Ne wli n g, D. W., de Pa u w, M., a n d S yl vester, R. ( 1 9 9 5). 
T he fi nal a nal ysis of t he E O R T C Ge nit o -Uri nar y Tract Ca ncer C o -O perati ve Gr o u p p hase III 
cli nical trial ( pr ot oc ol 3 0 8 0 5) c o m pari n g orc hi dect o m y, orc hi dect o m y pl us c y pr oter o ne acetate a n d 
l o w d ose stil b oestr ol i n t he ma na geme nt of metastatic carci n o ma of t he pr ostate. E ur. Ur ol., 2 8( 4), 
2 7 3 -2 8 3.  
Sa y e d, Y. a n d Ta xel, P. ( 2 0 0 3). T he use of estr o ge n t hera p y i n me n. C urr. O pi n. P har mac ol., 3( 6), 
6 5 0 -6 5 4.  
S petz, A. C., Ha m mar, M., Li n d ber g, B., S på n g ber g, A., a n d Vare n h orst, E. f or t he Sca n di na via n 
Pr ostatic Ca ncer Gr o u p -5 Trial St u d y. ( 2 0 0 1). Pr os pecti ve e val uati o n of h ot flas hes d uri n g 
treat me nt wit h pare nteral estr o ge n or c o m pl ete a n dr o ge n a blati o n f or metastatic carci n o ma of t he 
pr ostate. J. Ur ol., 1 6 6( 2), 5 1 7 -5 2 0.  
Wei, J. T ., D u n n, R. L., Lit wi n, M. S., Sa n dler, H. M., & Sa n da, M. G. ( 2 0 0 0). De vel o p me nt a n d 
vali dati o n of t he e x pa n de d pr ostate ca ncer i n de x c o m p osite ( E PI C) f or c o m pre he nsi ve assess me nt 
of healt h -relate d q ualit y of life i n me n wit h pr ostate ca ncer. Ur ol o g y,  5 6( 6), 8 9 9 -9 0 5.  
Wi d mar k, A., F osså, S. D., L u n d m o, P., Da m ber, J. E., Vaa ge, S., Da m ber, L., ... & Kle p p, O. 
( 2 0 0 3). D oes pr o p h ylactic breast irra diati o n pre ve nt a ntia n dr o ge n-i n d uce d g y nec o mastia? 
E val uati o n of 2 5 3 patie nts i n t he ra n d o mize d Sca n di na via n tri al S P C G-7/ S F U O -3. Ur ol o g y, 6 1( 1), 
1 4 5 -1 5 1.  
Z u m Br u n ne n, T. L., Me u wse n, I., de Vries, M., a n d Bre n na n, J.J. ( 2 0 0 6) T he Effect of Was hi n g a n d 
t he A bse nce of I nteri n di vi d ual Tra nsfer of Estra di ol Gel: A Direct S ki n-t o-S ki n C o ntact St u d y i n 
P ost me n o pa usal W o me n. A m J Dr u g Deli v 4 ( 2), 8 9 -9 5.  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
 
 
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
 
 
 
 
Pa ge 5 3  of 5 6  
A me n d me nt 4 :  1 3  J u ne 2 0 1 6 
 
 
  
A P P E N DI X 1 (c o nt.):  P h ase 2 Sc he d ule of St u d y Assess me nts a n d Pr oce d ures: St u d y Wee k 2 8 –  E n d of St u d y  
St u d y Assess me nt or Pr oce d ure  
W k 2 8  
W k 3 2  
W k 3 6  
W k 4 0  
W k 4 4  
W k 4 8  
W k 5 2  
E T/ E O S   
W k 5 4  
 
E C G  
 
 
X  
 
 
X  
 
X  
Hei g ht a n d Wei g ht/ B MI  
 
 
X  
 
 
X  
 
X  
P E / B o d y S yste ms Re vie w  
 
 
 
 
 
 
 
X  
Vital Si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
A Es  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt Me dicati o ns & Pr oce d ures  
X  
X  
X  
X  
X  
X  
X  
X  
Dis pe nse St u d y Dr u g: B H R -2 0 0  Gel/ Place b o  
X  
X  
X  
X  
X  
X  
 
 
St u d y Dr u g c o m plia nce : wei g h ca nisters; c ollect/iss ue d osi n g diar y  
X  
X  
X  
X  
X  
X  
X  
 
C oa g ulati o n Fact ors  (pr otei n C -acti vit y a n d a nti ge n , pr otei n S-acti vit y, pr otei n S -a nti ge n , a ntit hr o m bi n III a nti ge n , 
a n d A P C resista nce) 
 
 
X  
 
 
X  
 
 
La b orat or y Meas ure me nts  (bl o o d c he mistr y, he mat ol o g y a n d uri nal ysis )5  
 
 
X  
 
 
X  
 
X 7 
E n d ocri ne ( H b A 1C ) & H or m o ne assess me nt  ( F S H, L H, S H B G) 
 
 
X  
 
 
X  
 
 
B i o mar kers: B o ne ( C T x  a n d B S A P )5 
 
 
X  
 
 
X  
 
 
P S A  
X  
X  
X  
X  
X  
X  
X  
 
Efficac y  assess me nt  (ser u m t otal T) 
X  
X  
X  
X  
X  
X  
X  
 
P har mac o ki netic  assess me nt  (ser u m estra di ol a n d estr o ne) 
X  
X  
X  
X  
X  
X  
X  
 
Q ualit y of  Life Q uesti o n naires  
 
 
X  
 
 
X  
 
X 8 
R es u me A D T of c h oice  
 
 
 
 
 
 
 
X  
1 U p t o 2 wee ks pri or t o t he ne xt sc he d ule d i njecti o n wit h a G n R H a g o nist treat me nt.  
2 Wit hi n 2 h o urs of St u d y Dr u g A d mi nistrati o n ( Wee k 1:  Da y 1: H o ur 0).  
3 Ti mi n g of a d mi nistrati o n at I n vesti gat or’s discreti o n 
4 I nitial St u d y Dr u g a d mi nistrati o n will ta ke place i n t he cli nic ( Wee k 1:  Da y 1:  h o ur 0) u n der t he s u per visi o n of t he PI/ Desi g nee, after A L L bl o o d sa m ples are ta ke n.  
5 A n  o ver ni g ht fast is re q uire d. C ollect s peci me n i n t he m or ni n g ( 8-1 0 a m.)  
P E = p h ysic al e xa m; E C G =el ectr ocar di o gra m;  B MI = b o d y mass i n de x; A Es =a d verse e ve nts; C o n Me ds =c o nc o mita nt me dicati o ns; A P C =acti vate d pr otei n c;  F S H =f ollicle sti m ulati n g h or m o ne , L H =l utei nizi n g 
h or m o ne; S H B G = Se x h or m o ne -bi n di n g gl o b uli n; C T x = C -tel o pe pti de crossli n k of t y pe 1 c olla ge n; B S A P =al kali ne p h os p hatase, b o ne s pecific ( B S A P) ; P S A = pr ostate s pecific a n dr o ge n; A D T =a n dr o ge n 
de pri vati o n t hera p y; E T =earl y ter mi n ati o n; E O S =e n d of st u d y  
6 I nf or me d c o nse nt will a gai n be o btai ne d pri or t o t he  patie nt c o nti n ui n g wit h t he e xte nsi o n p hase of t he st u d y ( Wee k 2 8 -Wee k 5 2)  
7  La b orat or y Assess me nt will o nl y be d o ne if a b n or mal at pre vi o us visit  or if perf or me d m ore t ha n 4 wee ks a g o.  
8  O mit  E PI C q uesti o n naires if less t ha n 4 wee ks ha ve passe d si nce last a d mi nistrati o n 
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
 
Pa ge 5 4  of 5 6  
A me n d me nt 4 :  1 3  J u ne 2 0 1 6 
 
A P P E N DI X 2:  P A TI E N T I N S T R U C TI O N S F O R U S E  
B H R -2 0 0 gel is pr o vi de d i n a rea d y -t o-use ca nister wit h a 1 m L metere d -d ose p u m p.  
 
B H R -2 0 0 gel c o ntai ns 3  m g of estra di ol per d ose of 1 m L of  gel.  
  
T he c lear, c ol orless gel pr o vi des deli ver y of estra di ol t hr o u g h t he s ki n of t he s h o ul ders a n d u p per ar ms.   
 
B H R -2 0 0 gel  is f or t o pical use o nl y. D o n ot s wall o w. 
 
F or I n vesti gati o nal Use O nl y  
P R E C A U TI O N S : 
1.  B H R -2 0 0 is f l a m m a ble u ntil dr y. D o n ot a p pl y B H R -2 0 0 gel ne ar fire, fl a me or he at.  
2.  Be s ure t o f oll o w y o ur d oct or’s i nstr ucti o ns caref ull y t hr o u g h o ut t he c o urse of t he st u d y.  
3.  I nf or m y o ur d oct or a b o ut a n y  ne w me dici ne y o u ta ke d uri n g t he st u d y (i ncl u di n g d ose(s), d urati o n 
a n d reas o n), or a n y c ha n ge(s) t o me dici nes y o u ta ke re g ularl y.  
4.  I nf or m y o ur d oct or a b o ut a n y u n us ual s y m pt o ms or si de effects occ urri n g d uri n g t he st u d y. 
 
I N S T R U C TI O N S F O R U S E: 
 
Ste p 1 . A p pl yi n g B H R -2 0 0 gel  
 
D o n ot all o w ot her pe o ple t o a p pl y B H R -2 0 0  t o y o ur s ki n f or y o u. 
A p pl y B H R -2 0 0 gel o nce d ail y prefer a bl y  i n t he m or ni n g  
A p pl y B H R -2 0 0 gel o nce d ail y at t he s a me ti me of d a y . 
Y o ur st u d y d oct or will tell y o u t he n u m ber of ti mes t o press t he p u m p.  
 
•  A p pl y B H R -2 0 0 gel t o clea n, dr y, u n br o ke n s ki n  after y o ur bat h or s h o wer .  
•  Re m o ve t he ca p fr o m t he ca nister . H ol d  t he ca nister i n o ne ha n d a n d place t he pal m of y o ur ot her 
ha n d u n der t he p u m p t o catc h t he gel; see Fi g ure A .  Be s ure t o press d o w n c o m pletel y o n t he 
p u m p a n d release it c o m pletel y t o dis pe nse o ne d ose of gel. Re peat t o dis pe nse prescri be d d ose.  
 
Fi g ure A  
 

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
 
Pa ge 5 5  of 5 6  
A me n d me nt 4 :  1 3  J u ne 2 0 1 6 
 
•  Usi n g y o ur  ha n d, a p pl y t he B H R -2 0 0 gel per t he g ui de i n Ta ble 1  a n d as s h o w n i n Fi g ure B . 
S prea d t he gel as t hi nl y as p ossi ble. D o n ot massa ge or r u b i n B H R -2 0 0 gel. All o w t he gel t o dr y 
f or 5 mi n utes*  bef ore y o u get dresse d  ( B H R-2 0 0  gel is c ol orless a n d will n ot stai n y o ur 
cl ot hi n g) . Use t he s a me a p plicati o n met h o d e ver y ti me y o u a p pl y t he gel.  
 
*  If it ta kes m ore t ha n 5 mi n utes f or t he gel t o air-dr y or a stic k y resi d ue re mai ns o n y o ur s ki n 
after  5 mi n utes, y o u nee d t o s prea d t he ge l o ver a lar ger area of s ki n. 
 
T a ble 1: D ose a n d A p plic ati o n G ui de  
* 1 act uati o n of  t he p u m p dis pe nses 1 m L of gel. 
 
Fi g ure B   
 
 
 
Ste p 2 . After a p pl yi n g B H R -2 0 0 gel  
 
•  Re place  t he ca p o n t o p of t he ca nister after eac h B H R -2 0 0 gel a p plicati o n t o pr otect t he p u m p. 
•  Was h y o ur ha n ds ri g ht a wa y wit h s oa p a n d water after a p pl yi n g t he B H R -2 0 0 gel.  
•  D o n ot let ot hers t o ma ke c o ntact  wit h t he area of s ki n w here y o u a p plie d t he B H R -2 0 0 gel  f or at 
least 1 h o ur after a p pl yi n g t he B H R -2 0 0 gel .  
•  A v oi d water acti vities (i.e. s wi m mi n g) after y o u a p pl y  t he B H R -2 0 0 gel.  If n ot p ossi ble, tr y t o 
wait at least o ne ( 1 ) h o ur after a p pl yi n g t he B H R -2 0 0 gel  bef ore partici pati n g i n t he water 
acti vit y. 
•  D o n ot a p pl y a n y crea ms, l oti o ns or s pra ys (i.e. m oist urizer ) or tra ns der mal patc hes (i.e. nic oti ne 
patc h) t o y o ur u p per ar m(s) or s h o ul der(s)  at a n y ti me  d uri n g t he st u d y.  
•  S u nscree n  pr o d ucts  ca n be a p plie d o ne h o ur after a p plicati o n of t he B H R -2 0 0 gel . 
Prescri be d D ose *  
 
P u m p Act u ati o ns Per U p per Ar m a n d  S h o ul der  
U p per Ar m a n d  S h o ul der  
# 1  
U p per Ar m a n d  S h o ul der  
# 2  
1 act uati o n  
1  
0  
2 act uati o ns  
1  
1  
3 act uati o ns  
2  
1  

B H R -2 0 0 ( 0. 3 6 % tra ns der mal estra di ol gel)   
 
 
 
 
 
 
P hase 2 Pr ot oc ol  
B H R P H A R M A, L L C  
 
 
 
 
 
 
 
 
 
B H R -2 0 0 -2 0 1  
C o nfi de ntial  
 
 
 
Pa ge 5 6  of 5 6  
A me n d me nt 4 :  1 3  J u ne 2 0 1 6 
 
 
R E C O M M E N D A TI O N S : 
•  F or t he d urati o n of t he st u d y, a v oi d c o ntact bet wee n t he a p plicati o n area a n d t he s ki n of ot her 
i n di vi d uals (i.e., y o ur c hil d, y o ur se x ual part ner or ot her pers o ns).  T he f oll o wi n g preca uti o ns are 
rec o m me n de d t o mi ni mize p ote ntial tra nsfer: 
o  Was h y o ur ha n ds i m me diatel y after gel a p plicati o n.  
o  C o ver t he a p plicati o n site wit h cl ot hi n g after t he gel has drie d.  
o  I n t he e ve nt t hat u n was he d or u ncl othe d s ki n t o w hic h st u d y gel has bee n a p plie d d oes c o me 
i n direct c o ntact wit h t he s ki n of a n ot her pers o n, t he ge neral area of c o ntact o n t he ot her 
pers o n s h o ul d be was he d wit h s oa p a n d water as s o o n as p ossi ble.  
•  If y o u f or get t o a p pl y a d ose, d o n ot d o u ble t he ne xt d ose t o “catc h u p.”  If y o u ha ve a st u d y visit 
sc he d ule d t hat da y, tell t he st u d y staff a b o ut y o ur misse d d ose a n d t he y will i nstr uct y o u o n w hat t o 
d o.  If y o u d o n ot ha ve a st u d y visit sc he d ule d t hat da y, c o ntact y o ur St u d y C o or di nat or a b o ut y o ur 
misse d d ose.  
 
S T O R A G E : 
•  
Kee p B H R -2 0 0  gel at r o o m te m perat ure  6 8° F t o 7 7° F ( 2 0° C t o 2 5° C) . 
•  
Kee p o ut of t he reac h of c hil dre n.  
•  
A v oi d e x p os ure t o e xtre me heat or c ol d d uri n g tra ns p ortati o n fr o m t he cli nic t o h o me.  
R E M E M B E R T O:   Rec or d t he date, ti me, a n d l ocati o n ( w hic h ar m/s h o ul der) y o u a p plie d t he gel t o  i n 
y o ur  d osi n g  diar y . Bri n g t his diar y a n d t he st u d y dr u g  wit h y o u t o eac h cli nic visit.  
T his is ver y i m p ort a nt f or t he c o ncl usi o n of t he st u d y:  
After treat me nt, be s ure t o ta ke all  of t he u n use d st u d y gel bac k t o y o ur d oct or.  D o n ot discar d y o ur 
u n use d st u d y gel.