Clinical trial NCT02349386
Conditions: Cancer of the Prostate
Sponsor: BHR Pharma, LLC
Start date: 2015-07-01; Completion date: 2018-01-10
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study is to evaluate the safety and efficacy of three different doses of BHR-200 (0.36% transdermal estradiol gel) compared to placebo for the maintenance of testosterone (T) suppression in men with advanced androgen-sensitive prostate cancer.

Detailed description:
This is a multi-center, randomized, double-blind, placebo-controlled, dose finding study in men with advanced androgen-sensitive prostate cancer. Patients who give informed consent will have screening evaluations, and if fulfilling the entry criteria, will be randomized to one of 4 treatment groups: 1mL, 2mL or 3mL of 0.36% BHR-200 (transdermal estradiol gel) or Placebo. Study drug will be initiated on the day they were scheduled to receive next depot GnRH agonist injection. Patients will be offered low-dose radiation to aid in the prevention of gynecomastia. Patients will apply the study drug once per day. The first dose of study gel will be applied under the supervision of the PI/designee. Subsequent doses will be self-administered daily by the patient until he is no longer chemically castrated (testosterone levels increase above 50 ng/dL), a rise over baseline PSA of \> 0.5 ng/mL is observed, or he has completed 52 weeks of study drug administration. At the conclusion of study participation, patients will be advised to resume standard of care treatment under the supervision of their healthcare provider. While on treatment, patients will be evaluated at Day 1 and every 2 weeks, for the first 24 weeks and every 4 weeks thereafter with a final post-treatment follow-up visit 2 weeks (+/- 1 week) post last dose administration.

Arms: arm 1: 3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. arm 2: 6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. arm 3: 9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. arm 4: 1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks.
Interventions: intervention 1: BHR-200 (0.36% transdermal 17β-estradiol gel) intervention 2: Placebo
Intervention descriptions: intervention 1: An absorptive hydroalcoholic gel preparation containing 17β-estradiol. intervention 2: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.

Protocol documents:
Prot_000.pdf: 
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.  
 

SAP_001.pdf: 


BHR Confidential 
Page 2 of 17 
Statistical Analysis Plan Revision History 
 
Version 
Date 
Author(s) 
Summary of Changes/Comments 
Version 0.1 
June 15, 2017 
  
First version 
Version 1.0 
August 19, 2017 
 
Final version 
 




BHR Confidential 
Page 4 of 17 
 
Table of contents 
Table of contents .................................................................................................................. 4 
1 
LIST OF ABBREVIATIONS AND TERMS ...................................................................... 6 
2 
INTRODUCTION ............................................................................................................... 8 
3 
STUDY OBJECTIVES ........................................................................................................ 8 
3.1 
Primary objective ..................................................................................................... 8 
3.2 
Secondary objectives................................................................................................ 8 
4 
STUDY OVERVIEW .......................................................................................................... 8 
4.1 
Study design ............................................................................................................. 8 
4.2 
Study Drug Administration ...................................................................................... 9 
4.3 
Sample Size and Power Analysis ............................................................................. 9 
4.4 
Randomization and Blinding ................................................................................... 9 
5 
ANALYSIS ENDPOINTS ................................................................................................ 10 
5.1 
Efficacy Endpoints ................................................................................................. 10 
Primary Efficacy Endpoint: ............................................................................................... 10 
Secondary Efficacy Endpoints: .......................................................................................... 10 
Exploratory Endpoints: ...................................................................................................... 10 
5.2 
Safety Endpoints .................................................................................................... 10 
5.3 
Pharmacokinetic Endpoints .................................................................................... 10 
6 
ANALYSIS POPULATIONS ........................................................................................... 11 
6.1 
Intent-to-treat (ITT) population ............................................................................. 11 
6.2 
Safety population ................................................................................................... 11 
7 
DATA AND ANALYSIS CONVENTIONS .................................................................... 11 
7.1 
Visit windows ........................................................................................................ 12 
7.2 
Missing Data .......................................................................................................... 12 
7.3 
Post-baseline repeated or unscheduled data ........................................................... 12 
8 
SUBJECT ACCOUNTING AND STUDY DISPOSITION ............................................. 12 
9 
BASELINE SUBJECT DATA .......................................................................................... 13 
9.1 
Demographic and Other Baseline Characteristics ................................................. 13 
9.2 
Medical History...................................................................................................... 13 
10  PRIOR AND CONCOMITANT MEDICATIONS/NON-DRUG THERAPIES AND 
PROCEDURES ................................................................................................................. 13 
11  EFFICACY ........................................................................................................................ 14 
12  SAFETY ............................................................................................................................ 14 
12.1 
Exposure to Study Drug ......................................................................................... 14 
12.2 
Vital Signs .............................................................................................................. 14 
12.3 
12-Lead Electrocardiogram (ECG) ........................................................................ 14 
12.4 
Physical Examination ............................................................................................. 15 


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12.5 
Adverse Events ...................................................................................................... 15 
12.6 
Clinical Laboratory Parameters ............................................................................. 16 
13  QUALITY OF LIFE QUESTIONNAIRE ......................................................................... 16 
14  OPTIONAL LOW-DOSE RADIATION .......................................................................... 17 
15  REFERENCES .................................................................................................................. 17 
13  QUALITY OF LIFE QUESTIONNAIRE  .............................................................................. 15 
 
13.1      EPIC – Hormonal Component .............................................................................. 16 
 
13.2      EPIC – Sexual Component ................................................................................... 16 
14  OPTIONAL LOW-DOSE RADIATION .......................................................................... 16 
15 REFERENCES .................................................................................................................. 16 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
LIST OF ABBREVIATIONS AND TERMS 
 
Abbreviation 
Term 
C 
Celsius 
F 
Fahrenheit 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BHR 
BHR Pharma, LLC 
BHR-200 
Transdermal 17- estradiol gel (all strengths currently in development) 
BMI 
Body Mass Index 
BSAP 
Alkaline Phosphatase, Bone Specific 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
dL 
Deciliter 
ECG 
Electrocardiogram 
EOS 
End of Study (visit) 
EPIC 
Expanded Prostate Cancer Index Composite 
ET 
Early Termination (visit) 
FDA 
U.S. Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
g 
Gram 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-Releasing Hormone 
HbA1c 
Glycated haemoglobin 
ICH 
International Conference on Harmonisation 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing Hormone 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
ng 
Nanogram 
OTC 
Over the counter 
pg 
Picogram 


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PK 
Pharmacokinetic 
pmol 
Picomole 
PSA 
Prostate-Specific Antigen 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SHBG 
Sex Hormone Binding Globulin 
g 
Microgram 
U.S. 
United States 
WHO 
World Health Organization 
 
 
 
For the purpose of consistency, the following units will be used throughout 
this document: 
 
Estradiol: pg/mL (1 pmol/L= 0.2724 pg/mL) 
Testosterone: ng/dL (1 nmol/L = 28.82 ng/dL) 
 
 
 


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2 
INTRODUCTION  
This document presents the statistical analysis plan (SAP) for Study BHR200-201, 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.  A total of 34 study subjects were randomized at 7 centers in the US before study 
termination. 
The planned analyses identified in this SAP may be included in regulatory submissions and/or future 
manuscripts.  Exploratory analyses, not identified in this SAP, may be performed to support the 
clinical development program.  Any post-hoc, or unplanned, analyses that are performed but not 
identified in this SAP will be clearly identified in the clinical study report (CSR).  The structure and 
content of this SAP provides sufficient detail to meet the requirements identified by the Food and 
Drug Administration ( FDA) and International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical 
Principles in Clinical Trials  
Hedlund, P.O. (2000). Side effects of endocrine treatment and their mechanisms: castration, 
antiandrogens, and estrogens. Prostate Suppl., 10, 32-37. 
 [ICH, 2005]. 
This study was discontinued prematurely by the sponsor because of slow enrollment.   
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
 To evaluate the safety and efficacy of three different doses of BHR-200 (0.36% transdermal 
estradiol gel) compared to placebo for the maintenance of testosterone (T) suppression in men 
with advanced androgen-sensitive prostate cancer. 
3.2 
Secondary objectives 
 To select the dose(s) for a subsequent Phase 3 trial. 
 
4 
STUDY OVERVIEW 
4.1 
Study design 
This was a multi-center, randomized, double-blind, placebo-controlled, dose-finding study in men 
with advanced androgen-sensitive prostate cancer. Patients participated in a 24-week double-blind 
treatment period and were allowed to continue treatment with their assigned study drug for up to 52 
weeks as long as they remained chemically castrated. Patients who gave informed consent had 
screening evaluations, and if fulfilling the entry criteria, were randomized to one of 4 treatment 
groups: 1mL, 2mL or 3mL of 0.36% BHR-200 (transdermal estradiol gel) or placebo. Study drug 
was initiated on the day (+/- 5 days) they would be scheduled to receive the next GnRH agonist 
depot injection. Patients were offered low-dose radiation to aid in the prevention of gynecomastia. 
Patients applied the study drug once per day. The first dose was applied under the supervision of the 


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PI/designee. Subsequent doses were self-administered daily by the patient until one of the following 
occurred: 
 he was no longer chemically castrated as demonstrated by testosterone levels greater than or 
equal to 50 ng/dL,  
 a rise in PSA over baseline of ≥0.5 ng/mL was observed, 
 he had completed 24 weeks of double blind treatment, and elected not to continue into the 
extension period, or 
 he had completed 52 weeks of study drug administration. 
 
At the conclusion of study participation, patients were advised to resume standard of care treatment 
under the supervision of their healthcare provider. While on treatment, patients were evaluated at 
Day 1, every 2 weeks, for the first 24 weeks, and every 4 weeks thereafter, with a final post-
treatment follow-up visit 2 weeks (+/- 2 days) post last dose administration. 
 
4.2 
Study Drug Administration 
 
The 0.36% BHR-200 gel formulation contains 3.6 mg/g estradiol in a clear, colorless, absorptive 
hydroalcoholic gel base formulated to provide continuous release of estradiol. BHR-200 was 
supplied in a non-aerosol canister with a 1mL metered-dose pump. A single pump actuation 
delivered 3 mg of estradiol in 0.87 g of gel. The gel was applied to clean, dry, intact skin of the upper 
arms and shoulders. 
4.3 
Sample Size and Power Analysis 
 
The planned sample size was 120 male patients. Assuming the response rate (the proportion of 
patients maintaining castrate levels of T (T < 50 ng/dL) for the placebo group was 5%, the response 
rate for the low dose group of BHR-200 was 50%, the response rate for the mid dose group was 
80%, and the response rate for the high dose group of BHR-200 was 95%, 30 patients per treatment 
group provided at least 90% power to detect the difference in proportion of patients maintaining 
castrate levels of T (T < 50 ng/dL) between any dose of BHR-200-treated patients and the placebo-
treated patients using a two-sided Fisher-Exact test with a 5% significance level. 
 
However, this study was discontinued prematurely by the sponsor. A final total of 34 study subjects 
will be included in the analyses.   
4.4 
Randomization and Blinding 
 
All site personnel were blinded to treatment assignment. The Investigator (or designee) was 
responsible for drug accountability and dispensing of the study drug. In the case of an AE or serious 
adverse event (SAE) for which the Investigator must know a specific treatment allocation to ensure 
the patient’s safety, unblinding of treatment assignment was permitted. Instructions for “breaking the 
blind” were provided to the Investigator. It should be stressed that unblinding the treatment 
allocation was only allowed for safety concerns in an emergency situation. If time allowed, the 
Investigator was encouraged to discuss the matter with the study Medical Monitor prior to “breaking 
the blind” whenever possible. If possible, the relationship of the AE to the study drug was to be 
assessed before the treatment code was broken. In all cases, the Medical Monitor was to be notified 
within 24 hours after the code had been broken. If the treatment assignment was unblinded, study 
drug was permitted to be discontinued at the Investigator’s discretion. Please note that patient 110-
001 withdrew from the study and was unblinded on 5/13/16.   


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5 
ANALYSIS ENDPOINTS 
5.1 
Efficacy Endpoints 
Primary Efficacy Endpoint: 
 
The primary efficacy endpoint is the response rate (the proportion of patients maintaining castrate 
levels of T (T < 50 ng/dL)). The primary analysis on the primary efficacy endpoint is to compare the 
response rate from each of the 3 BHR-200 dose levels against the response rate for the placebo-
treated patients at Week 12. 
Secondary Efficacy Endpoints: 
 
(1) The response rate at Week 24. The same statistical analysis method that applied to Week 12 
analysis will be used for Week 24. 
(2) The Kaplan-Meier curve for time to T > 50 ng/dL through Week 12 for each treatment group. 
(3) The Kaplan-Meier curve for time to T > 50 ng/dL through Week 24 for each treatment group. 
Exploratory Endpoints: 
 
All other efficacy parameters (e.g., FSH, LH, SHBG, and PSA) will be summarized by treatment 
group at each study visit using descriptive statistics. Serum levels of estradiol and estrone will be 
summarized by treatment group at each study visit using descriptive statistics. The Expanded 
Prostate Cancer Index Composite (EPIC)-Hormonal Assessment and the EPIC-Sexual Assessment 
will be summarized by treatment group at each study visit using descriptive statistics. 
 
5.2 
Safety Endpoints 
The following safety data was collected and evaluated at pre-specified time points: 
 
Vital signs: blood pressure, heart rate, respiration rate, and body temperature. 
 
ECG. 
 
Biomarkers: bone biomarkers and prostate-specific antigen (PSA). 
 
Central laboratory assessments for blood chemistry, hematology, and urinalysis, as well as 
coagulation factors, and hormone assessments. 
 
Post-treatment events (adverse events [AEs] and serious AEs [SAEs]).  
Please note that 2 SAEs have been reported from the 34 enrolled patients:  
(1) Patient 102-001 reported an unrelated SAE of Worsening of Patient Small Bowel 
Obstruction on 1/15/16 and resolved on 1/16/16. The patient completed the study on 
01/27/2016. 
(2) Patient 106-004 reported an unrelated SAE of Robotic Assisted Right Lymphocelectomy 
on 5/11/17 and resolved on 5/12/17. The patient withdrew consent on 05/16/2017. 
 
5.3 
Pharmacokinetic Endpoints 
The following pharmacokinetic data was collected and evaluated at each visit: serum estradiol and 
estrone.   
 


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6 
ANALYSIS POPULATIONS  
6.1 
Intent-to-treat (ITT) population 
 
The Intent-to-treat (ITT) population will contain all patients who are randomized into the study. All 
efficacy parameters will be analyzed using the ITT population. In the case of a patient who was 
randomized but did not take the study drug, the analysis will be done for this patient using the 
randomized treatment. 
 
6.2 
Safety population 
 
The Safety population will contain all patients who receive at least one dose of study drug. 
All safety parameters will be analyzed using the Safety population.   
 
7 
DATA AND ANALYSIS CONVENTIONS 
Post-text tables and listings will be prepared in accordance with the current ICH Guidelines.  The 
information and explanatory notes to be provided in the “footer” or bottom of each table and listing 
will include the following information: 
1. Date and time of output generation; 
2. SAS program name, including the path that generates the output; 
3. Any other output-specific details that require further elaboration. 
In general, tables will be formatted with a column for each treatment group.  The tables for baseline 
data will be formatted with an additional column displaying the findings for all subjects combined. In 
general, Row entries in tables are made only if data exists for at least one subject (i.e., a row with all 
zeros will not appear).  The exception to this rule applies to tables that list the termination status of 
subjects (e.g., reasons for not completing the study).  In this case, zeros will appear for study 
termination reasons that no subject satisfied.  The summary tables clearly indicate the number of 
subjects to which the data apply and unknown or not performed are distinguished from missing data. 
Specific algorithms are discussed for imputing missing or partially missing dates, if deemed 
appropriate, under specific data topics.  Imputed or derived data are flagged in the individual subject 
data listings.  Imputed data are not incorporated into any raw or primary datasets.  These data are 
retained in derived (or analysis) datasets. 
This section details general conventions to be used for the statistical analyses.  The following 
conventions will be applied to all data presentations and analyses. 
 Summary statistics will consist of the number and percentage of responses in each level for 
categorical variables, and the sample size (n), mean, median, standard deviation (SD) and 
range (i.e. minimum and maximum values) for continuous variables. 
 All mean and median values will be formatted to one more decimal place than the measured 
value.  Standard deviation values will be formatted to two more decimal places than the 
measured value.  Minimum and maximum values will be presented with the same number of 
decimal places as the measured value. 
 The number and percentage of responses will be presented in the form XX (XX.X). 


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 All p-values will be rounded to 4 decimal places.  All p-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.0000 will be presented as ‘>0.9999’.     
 All summary tables will include the analysis population sample size (i.e., number of 
subjects). 
 Study Day 1 is defined as the date at which the subject receives the first application of the 
study drug.  All study days are determined relative to Day 1.  Relative days will be calculated 
as: 
 
Relative Day = Assessment Date – First Application Date+1. 
 
 Baseline values will be defined as those values recorded closest to, but prior to, the study 
drug on Day1 unless otherwise specified in the protocol.  
 Change from baseline will be calculated as follows:  
Change = Post-baseline value  baseline value. 
 
 Date variables will be formatted as YYYY-MM-DD for presentation. 
 Tables, figures, and listings will be presented in landscape orientation. 
 SAS Version 9.4 or higher will be the statistical software package used for all data analyses.   
 All data from this study will be presented in a listing.  All listings will be sorted by subject 
number and visit date, as applicable.   
 Table and listing numbering will follow ICH guidelines for post-text table and listing 
numbering.   
7.1 
Visit windows 
 For the statistical analyses, data will be analyzed by their target date and time.   
7.2 
Missing Data 
Missing values will not be imputed by estimated values, but treated as missing in the statistical 
evaluation.  All data from all subjects dosed in the study will be included in all listings, plots, 
summary tables, and statistical analyses when appropriate. 
7.3 
Post-baseline repeated or unscheduled data 
Repeated or unscheduled data post study drug administration will not be used for data analysis, 
except for summary tables of the numbers of subjects with notable values of vital signs, physical 
examination data, and ECG data.  All repeated or unscheduled data will be reported in data listings. 
8 
SUBJECT ACCOUNTING AND STUDY DISPOSITION 
A complete accounting of subject participation in the study will be summarized in a table.  The 
purpose of this table is to provide an accounting of subjects from their entrance into the study (after 
signing informed consent) through their final visit and to account for subject evaluation in major 
analyses of safety, including reasons for early study termination.  The table will display the number 
of subjects that were enrolled in the study and the number and percentage of subjects who: 
 withdrew prior to dosing, 


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Page 13 of 17 
 are included in the safety population  
 completed or did not complete the study.   
 For those subjects who did not complete the study, the reason for their non-completion, 
noting the number and percentage of subjects for each reason.   
 
9 
BASELINE SUBJECT DATA 
9.1 
Demographic and Other Baseline Characteristics 
Demographic information and other baseline characteristics will be presented using descriptive 
statistics for the Safety population.  Demographic variables will include age, gender, race and 
ethnicity.  Age will be calculated as the age in years from the birth date to the informed consent date 
and will be rounded down to the nearest integral value.  Other baseline characteristics will include 
height, weight, and body mass index (BMI).  
9.2 
Medical History 
Medical history will be summarized using counts and percentages for the Safety population, and will 
be mapped to preferred terms and System Organ Class (SOC) using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary.  The terms will be presented in alphabetical 
order.  Subjects reporting more than one condition in a category will be counted only once for that 
category.   
The subject’s ADT history will be summarized.  
 
10 
PRIOR AND CONCOMITANT MEDICATIONS/NON-DRUG 
THERAPIES AND PROCEDURES  
Prior medications are medications that are taken and stopped prior to the first application of the study 
drug.  Concomitant medications are those medications that are ongoing at or started after the first 
application of the study drug.  Prior and concomitant medications will be coded using the 
Anatomical-Therapeutic-Chemical (ATC) classification text from the WHO Drug Dictionary.  
Medications will be presented by ATC Class and Preferred Term.  Prior and concomitant 
medications will be summarized for the Safety population.  Subjects will only be counted one time in 
each unique ATC Class and Preferred Term category.   
If the medication start date is completely missing then the medication will be considered concomitant 
unless it can be determined that the medication end date occurred prior to the start of the study.  If 
the medication start date is partially missing and the partial date is not sufficient to determine if the 
medication was taken after the start of the study, then the medication will be considered concomitant 
for the study unless it can be ruled out by the partial date and/or medication end date. 
The non-drug therapies and procedures will be mapped to preferred terms and SOC using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary.  
   


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11 
EFFICACY 
Since the study was stopped prematurely, no planned inferential efficacy analyses will be performed 
for all of the efficacy parameters.  However, the all efficacy endpoints including primary, secondary 
and exploratory parameters (e.g., FSH, LH, SHBG, and PSA) will be summarized by treatment 
group at each study visit using descriptive statistics. Serum levels of estradiol and estrone will also 
be summarized by treatment group at each study visit using descriptive statistics. The Expanded 
Prostate Cancer Index Composite (EPIC)-Hormonal Assessment and the EPIC-Sexual Assessment 
will be summarized by treatment group at each study visit using descriptive statistics. 
  
12 
SAFETY  
Safety will be measured by the incidence of AEs, changes in vital signs and clinical safety laboratory 
results, and electrocardiogram results.  All safety analysis will be conducted in the Safety population. 
For safety data, the last non-missing pre-administration observation will be used as the baseline 
value for calculating post-administration changes from baseline.  In all summary tables the data will 
be presented by study dose group.  
12.1 
Exposure to Study Drug 
The number of applications of study drug administered and the total weight of gel applied to each 
subject will be summarized descriptively by dose group for the Safety population.  
12.2 
Vital Signs 
Vital sign parameters include systolic and diastolic blood pressure, body weight, height, BMI, 
respiration rate, temperature, and heart rate.  Vital sign values and changes from baseline in these 
parameters will be presented using descriptive summaries by visit.   
A shift from baseline analysis of abnormalities (normal, abnormal/clinically significant, and 
abnormal/ not clinically significant) will also be presented by counts and percentages at each post-
administration visit and in an overall view regardless of post-administration assessment time point. 
In addition, at each time point, the sums of subjects with normal, abnormal CS, and abnormal NCS 
values at that time point will be summarized. Also, at each time point the sums of subjects with 
normal, abnormal CS, and abnormal NCS values at baseline and values at that time point will be 
summarized.   
  
12.3 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG was to be performed at Screening and at Week 12, 24, 36, 48, 52, 54/EOS. 
ECG parameters include PR interval (msec), QRS interval (msec), RR interval (msec), QT interval 
(msec), and QTc interval (msec).  ECG values and changes from baseline will be presented using 
descriptive summaries by visit.   
A shift from baseline analysis of abnormalities (normal, abnormal/clinically significant, and 
abnormal/ not clinically significant) will also be presented by counts and percentages at each post-
administration visit and in an overall view regardless of post-administration assessment time point. 
In addition, at each time point, the sums of subjects with normal, abnormal CS, and abnormal NCS 
values at that time point will be summarized. Also, at each time point the sums of subjects with 


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normal, abnormal CS, and abnormal NCS values at baseline and values at that time point will be 
summarized.   
   
12.4 
Physical Examination  
Physical examination results will be summarized at each visit as normal, abnormal/clinically 
significant or abnormal/not clinically significant, and compared in a shift analysis to the baseline 
result for each physical examination category and in an overall view regardless of post-
administration assessment time point. In addition, at each time point, the sums of subjects with 
normal, abnormal CS, and abnormal NCS values at that time point will be summarized. Also, at each 
time point the sums of subjects with normal, abnormal CS, and abnormal NCS values at baseline and 
values at that time point will be summarized.   
  
12.5 
Adverse Events 
Adverse events (AEs) will be mapped to preferred terms and SOC using the MedDRA coding 
dictionary.  
Summaries of AEs will be also presented based on treatment-emergent AEs (TEAEs), defined as 
AEs that begin (or if preexisting medical conditions that worsen) after receiving the first application 
of the study drug. If the adverse event start date is partially or completely missing then the adverse 
event will be considered treatment-emergent.   
The number and percentage of subjects experiencing AEs will be summarized by SOC and preferred 
term.  Subjects will be counted only once at the SOC level and will be counted once for each 
applicable preferred term; multiple occurrences of the same preferred term for a subject will be 
counted only once.  SOCs, and preferred terms within SOC, will be displayed alphabetically.  
Similarly, AEs leading to discontinuation from the study will be presented by SOC and preferred 
term as well.  The treatment-related AEs, defined as AEs with relationship of ‘Possibly’ or 
‘Probably’ related to the study treatment, will be summarized by SOC and preferred term.   
Summaries by SOC and preferred term and maximum intensity or relationship to study treatment 
will also be provided for AEs. A summary by SOC and preferred term and maximum intensity will 
be provided for treatment-related AEs as well. Subjects with multiple occurrences of the same SOC 
or preferred term will be summarized at the maximum intensity or the strongest relationship to study 
treatment reported for that adverse event.  If a subject has an AE with unknown intensity, then the 
subject will be counted in the intensity category of “Severe”.  If a subject has an AE with unknown 
relationship to study treatment, then the subject will be counted in the relationship category of 
“Related” even if the subject has another occurrence of the same event with a relationship to study 
treatment. 
Additionally, the number and percentage of subjects experiencing AEs will be summarized by 
preferred term in an order of decreasing frequency. 
The number and percentage of subjects experiencing serious AEs will be summarized by SOC and 
preferred term.   
An overall summary table of the adverse events will be produced.  This table displays the number 
and percentage of subjects who: 
 have any treatment emergent adverse events 
 have any treatment emergent adverse events at least possibly related to the study drug  


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 have any treatment emergent adverse events presented by maximum intensity 
 have any treatment emergent serious adverse events 
 have any treatment emergent serious adverse events at least possibly related to the 
administration of the study drug 
 have any treatment emergent adverse events leading to discontinuation from the study 
 have any treatment emergent adverse events leading to death 
 have any treatment emergent adverse events leading to death that are at least possibly related 
to administration of the study drug. 
 
12.6 Clinical Laboratory Parameters 
 
Shift analysis (High/Normal/Low), compared to the baseline result, at each visit and an overall view 
regardless of post-administration assessment time point, and descriptive statistics for the central 
laboratory values and changes from baseline at each visit will be presented by treatment group, for 
laboratory parameters collected in the study that include: 
 
Hematology: Hematocrit, Hemoglobin, WBC with differential, RBC, Platelets 
 
Blood Chemistry: Alanine transaminase (ALT), Albumin, Alkaline phosphatase (ALP), Aspartate 
aminotransferase (AST), Blood urea nitrogen (BUN), Calcium, Carbon dioxide, Chloride, total 
Cholesterol, HDL Cholesterol, LDL Cholesterol, Creatinine, Direct bilirubin, Glucose, Lactate 
dehydrogenase (LDH), Potassium, Sodium, total Bilirubin, total Protein, Triglycerides 
 
Coagulation Factors: Protein C-activity and antigen, Protein S-activity, Protein S-antigen, 
Antithrombin III antigen, and Activated protein C resistance (APCR)  
 
Endocrine: Glycated hemoglobin (HbA1C) 
 
Hormones: Follicle stimulating hormone (FSH), Luteinizing hormone (LH), and Sex hormone-
binding globulin (SHBG) 
 
Urinalysis: Appearance, Color, Glucose, Ketones, Microscopic, Nitrites, Occult blood, pH, Protein, 
Specific Gravity 
 
Biomarkers: 
o Bone: C-telopeptide crosslink of type 1 collagen (CTx) – a marker of bone resorption; 
           Alkaline Phosphatase, Bone Specific (BSAP) – a marker of bone formation 
o Prostate: Prostate specific antigen (PSA) 
 
Pharmacokinetic: Estradiol, Estrone (no shift analysis will be performed for Estradiol and Estrone 
data). 
 
 
 
13 
QUALITY OF LIFE QUESTIONNAIRE 
The Expanded Prostate Cancer Index Composite (EPIC) was developed by researchers at the 
University of Michigan and UCLA to measure health related quality of life among men with prostate 


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cancer (Wei et.al. 2000). Response options for each EPIC item form a Likert scale, and multi-item 
scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health 
related quality of life (HRQOL). The EPIC-Hormonal Assessment and the EPIC-Sexual Assessment 
will be summarized by treatment group at each study visit using descriptive statistics.  
 
13.1 EPIC – Hormonal Component 
The EPIC – Hormonal Assessment is a 6-question survey designed to measure the Quality of Life 
(QoL) issues specific to hormonal function in patients with prostate cancer. 
 
13.2 EPIC – Sexual Component 
The EPIC – Sexual Assessment is a 9-question survey designed to measure the Quality of Life (QoL) 
issues specific to sexual function and sexual satisfaction in patients with prostate cancer. 
 
14 
OPTIONAL LOW-DOSE RADIATION 
Patients were offered optional low-dose radiation for the prevention of gynecomastia (Hedlund 2000, 
Widmark et. al. 2003). Timing of the administration of the low-dose radiation was at the discretion 
of the Investigator. Data collected on the CRF will be presented in a data listing.  
 
15 
REFERENCES 
 
Hedlund, P.O. (2000). Side effects of endocrine treatment and their mechanisms: castration, 
antiandrogens, and estrogens. Prostate Suppl., 10, 32-37. 
 [ICH, 2005] 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: The Clinical Evaluation Of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (E14). 
2005. 
 
Wei, J. T., Dunn, R. L., Litwin, M. S., Sandler, H. M., & Sanda, M. G. (2000). Development and 
validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment 
of health-related quality of life in men with prostate cancer. Urology, 56(6), 899-905. 
 
Widmark, A., Fosså, S. D., Lundmo, P., Damber, J. E., Vaage, S., Damber, L., ... & Klepp, O. 
(2003). Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation 
of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3. Urology, 61(1), 145-151.