Conditions: Gout
Keywords: Biological Markers Cardiovascular disease Humans Pulse Wave Velocity Cardiovascular risk factors Allopurinol Pulse Wave Analysis Thiazoles Inflammation Uric acid Febuxostat Oxidative stress Tumor Necrosis Factor Arthritis Hyperuricemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 196
Healthy volunteers: no

Brief summary:
There is a mounting and clear association between hyperuricaemia, gout and the presence of traditional cardiovascular (CV) risk factors and CV event-equivalent conditions such as chronic kidney disease, metabolic syndrome, and diabetes. Gout is associated with increased risk of CV events such as myocardial infarction and CV death. Furthermore hyperuricaemia is clearly associated with an increased arterial stiffness, a marker of pre-clinical atherosclerosis. Carotid-femoral pulse wave velocity (PWV) is the "gold standard" measurement of arterial stiffness and it is considered, in this trial, as a valid surrogate endpoint with clearly established relevance to predict cardiovascular disease (CVD) clinical outcome In this randomised trial conducted on adult subjects with a history of gout, we use surrogate endpoints to investigate the efficacy of febuxostat compared with allopurinol to predict (CVD) clinical outcome.

Eligible subjects were randomised in a 1:1 ratio to the following treatment groups:

* Test product: febuxostat 80 mg or 120 mg once daily (120 mg daily, if serum urate was \>6 mg/dL after 2 weeks of treatment at 80 mg daily).
* Active comparator: allopurinol 100 mg once daily (up to a maximum dose of 600 mg daily escalated in 100 mg increments every 2 weeks, if serum urate acid (sUA) was \>6 mg/dL after 2 weeks of treatment at the previous dose).

The study duration was 39 weeks, which included the:

* Run-in/screening period: 1 week (extendable up to a maximum of 30 days according to variability of sUA levels);
* Treatment period: 36 weeks;
* Safety follow-up period: 2 weeks.

Detailed description:
The study physician, responsible for randomization and drug supply handling, is unblinded to study medications and therefore will not be involved in the main efficacy evaluations of each patient randomized in the study.

Conversely, the study physician/s responsible for the main efficacy evaluation (Pulse Wave Velocity) will be blind to study treatments.

Key efficacy variables will be performed by an independent centralized laboratory.

Trial was conducted in a detailed and orderly manner in accordance with established research principles, International Conference on Harmonization (ICH), Good Clinical Practice (GCP) Guidelines and with Clinical Research Organization (CRO) Standard Operating Procedures (SOPs). As part of a concerted effort to fulfill these obligations, the authorised CRO study monitor visited investigative sites prior to and during the trial in addition to maintaining telephone and written communication. Data from each subject were reviewed and source verified as the study progressed.

In accordance with audit plans, this trial may have been selected for audits. The investigators committed to permit independent audits by auditors assigned by the Sponsor at a reasonable notice. Audits included, but were not limited to, drug supply, presence of required documents, the informed consent process, protection of rights and well-being of subjects and verification of Electronic case report form (eCRF) entries against source documents.

Regulatory authorities worldwide had the right to inspect the investigative sites during or after the trial. In such cases, the investigators were required to contact the Sponsor immediately and to fully cooperate with the inspectors.

Copies of written correspondence between the investigators, CRO, Sponsor, Competent Authorities, Institutional Review Board (IRB) and Independent Ethic Committee (IEC) are on file with the Sponsor and investigators.

Adverse events were according to the Medical Dictionary for Regulatory Activities (MedDRA, version 18.0) thesaurus.

Statistical analysis were conducted according the Statistical Analysis Plan (SAP) describing the analytical principles and statistical techniques employed in order to address the objectives specified in the Protocol.

A Data Management Plan was present for missing data, to address situations where variables are reported as missing, unavailable, non-reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results.

Arms:
arm 1: Febuxostat 80/120 mg film coated tablets.The initial daily dose is 80 mg given orally. In case a patient has serum urate level 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained during the study treatment period.

To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg quaque die (QD ) or in case of colchicine intolerance, Naproxen 550 mg bis in die (BID) with Omeprazole (20-40 mg once daily), if indicated to be used. arm 2: Allopurinol 100/300 mg tablets.The initial daily allopurinol dose is 100 mg given orally, to be escalated of 100 mg every 2 weeks in patients with serum urate concentration \>6 mg/dl.

The maximum dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg daily.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD or in case of colchicine intolerance, Naproxen 550 mg BID with Omeprazole (20-40 mg once daily), if indicated to be used.

Interventions: intervention 1: Febuxostat 80/120mg/day intervention 2: Allopurinol 100 up to 600mg/day intervention 3: Colchicine intervention 4: Naproxen intervention 5: Omeprazole
Intervention descriptions: intervention 1: Starting dose and dose regimen of Febuxostat : the initial daily dose is 80 mg. In case the patient has the serum urate concentration \> 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained for the duration of the study. intervention 2: Starting dose and dose regimen of allopurinol : the initial daily allopurinol dose is 100 mg, to be increased by 100 mg every 2 weeks in patients with serum urate concentration \>6 mg/dl. The maximum daily dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg. intervention 3: Colchicine 0.5 mg tablets.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD intervention 4: Naproxen sodium 550 mg film coated tablets. In case of colchicine intolerance patients will be treated for at least 6 months with Naproxen 550 mg BID and Omeprazole (20-40 mg once daily), if indicated to be used. intervention 5: Omeprazole 20 mg capsules, co-administered to patients for gastric protection.

Protocol document:
Prot_001.pdf: 
  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 1 of 68
	


	 !"	#$%&'( 
 &)&*+&	&,*)(-).
)"!($/
#

	
,0120$34/50661
	
	

	
	

			
		
&4.(&45

5$7182.()(9
:686:8961;8

	


	
	


	
 
!"#$%&'()

	""#*" ! $!#
+,	""#*"#*# "





 
- .
+/0
'10
/
23
12- 4)5-6

	""!!%!$#&"# "
+,	""!%!$#&#"4* *



!		
		

	72
(8.(,9

	""#  .!*4.
+,	""#  .!*4.!*


:;+5<;'(')''<<;'
	

		

		
			

				
	


	
	
		
		

 		  	      	 	
       
		



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 2 of 68
&((!()(1

	
		

	
	

		 
 	!	 	
"		#	
$!%
&'!
	
	 
 
 		   
  	! 	 '	
  "	  	 # 	
 $
!%


(
	
		
))
* 
 '+	 ,
  -
  
 #	'	 
	   .  	 	
!'	/
'	0,		
' #


	

12  		  
 
	 #
#
 # ! 	
  
 3 ,"  !

 	
%
	

	
			
	
			
				 !

•

		!	

	!
•
	
"


!
•
	#$%!
•
#$&!
•



•
			'	
			!
•
'

#			
!


	()*+,-.(/

4	


 
			


	

1   	 
  			  	
 ,
	 	 # !   	

		
#
5
	

6 *7%

3
1
	!',#	
	#




8
0(((1(2,#%(((/
	

031(24%/





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 3 of 68
 !"#$%&!!%

(
+5
&	6	7'8
#	
9	:		
&	%&69:
"		
:	;'	
;(
+;5;<2;	2&	7	
=(((>$?@	(((0	
	=(((($>.
?@	(((0
A(
+A&	7	
7&		
(
+AB
		&	%
7
				
A1	$(
&		'		8-###4;12
111<($	C-CD##4;1?
111<()
2(
+&	-		&	%	A<	E
(<(!
&	'		F		
!
?(
+F	
	A!7';
						.
-D(				#
#G
				'
	 		
#'		!

'	
=*-/>*-9
	6		
#
'	
!#!	
'
 		,#	#
=	!
*-/>*-9  
•
"	
+	'		!
#"	'		!

	!
•
2 #	#	
+!'
 	!,#	#,

= 
#
F(
+;;	;A
8	"	
<(
+;F2(
)	>			>	
		11?11	'	A11?11	!
5(
+AA(F(A
>					#6-@B#6-
		
1( +A<(<(
				E-'	
-D@->	
		.
*#!	 		
#
'
			

	#	!

 	
 	

#
 		,#	#,
	#*-/  
=	!,
	=	!	
 			
	#!*
	

		

(


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 4 of 68
>+D	'<((
( +A<(<(
&	'		A1		
$
>			()'(<(		
4#		
#

,"	+		

4#

,	
 ,	'#"#		#	
 
		
>	

		 	#	
!

 	 		
#!	 		
#	#'
!
,	# 
#!		(+7? 
'

! 2	
9				!'

!	 
"	
#

 	


*#!	 		
#
'
			

	#	!

 	
 	

#
 		,#	#,
	#*-/  
=	!,
	=	!	
 			
	#!*
	

		

(

	'		!
29			
	

		
#29	 
	!
#
	' 	
		
#
	
		,	#	

 			
		
@

@		
,###	#
'
+
294#	 !'+
29
!

	
#29
#
'
'	,	#	)!	


 	A	

;( +(<(
#		
	
	

	"	()		C%C	

	E	+
(
	
	'

 
	
			 	
 				
	
'		'	
"	#
#
	 #
		 
	 ' 	.'.&07-07
		
9649B4C?446.B.7*D7+&	
	

	
*4>
1&	!	E		'



	
A( +(1((2
%>7		=0=0


 "		 
	'

 
				F	
'

!
,##		 
'
 	!
( +2(1(;
>
			

99
				
 
,	'

	7&;
2( +2(1(A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 5 of 68
$			&>7(-	
	
'

(+	
'	
(
B-D%&	

?( +F(1(
		
		(-	H=6
	B&>7!	@

/
	
06	B&>7!/
F( +F		(1((6


8				
%

#6-
	
!		

-
	
.	#6-
	!	
	>7(+
	

<(A!
		+8
	
			(
I	
			
+*	&

(

<( +F1(2
-			
			G
!
5( +<((A
0)6

/	0)7&G
0
;1( +2F(
8	
=8	

		&&		*-	G&*-!
.(/











  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 6 of 68







  3    $          
  
"
 #
$%&''""

	
 ........................................................................................................................................................... 21
2.2
STUDY FLOW CHART .............................................................................................................................................. 22
(
$)
)
*%&& $+


	 ................................................................................................................................. 26


 ................................................................................................................................ 27
,
!-.%&'$/

	
 .................................................................................................................................................. 27


	
 ............................................................................................................................................. 27
+
  $0

	 .............................................................................................................................................. 28


	 ............................................................................................................................. 28



 .................................................................................................................................................... 29

 

 .................................................................................................................................................... 30
/
 !& &%("
!



"#$%&
&
 ...................................................................................................................................................... 31
!
$ ......................................................................................................... 32
!


'
 .............................................................................. 33
!

 ................................................................................................................................................. 34
!


 ........................................................................................................................................... 34
!


	 ............................................................................................................................................... 34
!!
 .............................................................................................................................................................. 34


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 7 of 68
!(

 .................................................................................................................................................... 35
!)

$
$ .............................................. 35
!*
 .................................................................................................................................................. 35
!

 .......................................................................................................... 36
!



 ................................................................................................................... 36
!



 ................................................................................................................ 36
!


 ................................................................................................................................................... 37
!
 ............................................................................................................................... 37
0
%&'&%&!---'&-'(/
(
	
 .......................................................................................................................................... 37
(
	"

	# .................................................................................................................................. 40
(

	

	 .............................................................................................................................. 40
(
	 ................................................................................................................................................... 41
#
1.&1 -&&-!. )$
"2
&)$
*
................................................................................................................................................................. 42
*
"# ........................................................................................................................................................ 42
*
	
 .......................................................................................................................................................... 43
*
	
"# ...................................................................................................................................... 43
*
	 .................................................................................................................................................................... 44
*
"#+	
"# ............................................................................................ 44
*
"#+	
"# ...................................................................................... 44
*!
		
"# ....................................................................................................... 45
*

 ................................................................................................. 45
*

	 .......................................................................................................................... 45
*

	
 .............................................................................................................................. 45
*

	 ..................................................................................................................................... 46
*

,	"# ....................................................................................................... 47
*

 ...................................................................................................................... 47
*


	
 ..................................................................................................................... 47
""
&3% '!!)0
""" %&'&%!4&  )0
""""-!)0
""$ &4%&&%!)0
""( &3% ' 4%&'!)0


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 8 of 68
"") 3% '%)#
"$
)#

	"# .................................................................................................... 49

- ............................................................................................................................... 50

	 .............................................................................................................................................. 50

	 .................................................................................................................................................... 51


	 ................................................................................................................................................. 51


% .............................................................................................................. 55
!

	 ........................................................................................................................................ 55
"(
!4%&4% ',+
13.1
  MONITORING ............................................................................................................................................................... 56
13.2
  AUDITS ........................................................................................................................................................................ 56
13.3 
REGULATORY INSPECTIONS ........................................................................................................................................... 56
")
.,/
14.1
ETHICS COMMITTEES..................................................................................................................................................... 57
14.2
   INFORMED CONSENT.................................................................................................................................................... 57

.	 ........................................................................................................................................................ 58
",
-& '&& 1! ,0
"+
&+2
"/
 !&-+2
"0
-+$





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 9 of 68
18 3


 
 
	6#*C'
&(>(
>	JC?C'

 

11A2;;?5F? 


 
	11A2;;?5F?5

 ,),",,#
	%(-8
EE
>(68#E
D&&K21A8E8#!#


  !" ###$% &#"


	  !" ###$% ""$'

&)!,)' ",#  
	%(7>	6
>(68#E
D&&K21A8E8#!#



11A51222?<1521?


	11A51222?<1;1

&)!
&!,"
,#
	()*		+
		
 
6#*C'
&(>(
>	JC?C'




  !#,,$&"-$% 


	11A2;;?5F?5

4)
 
	.)/	0

 
D>
2K-	(;
1A<,,*!#

 
  !" #'$!$,%&!



	  !" #'!"'!, 


 
	12
	3425	*	
	6

 
 +)))

 

%32	

3	42! '!&


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 10 of 68



  &%5',6$,,&&- 


	  &%5',6$,,&&$ 


 
	%(6*

 
74894',
'&   		&
/
*	
):	;) 

  &, $ &#$%!'&




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 11 of 68
98	


<


<...

	2
	57=<62	

	
2	

			4
	
2

		4		

	)




<:>(<	

/
*+1?'&?+0>@?  '
1
	
	

.

<	

	% ', ?	5(+71/A6						)


<+@'  $  ?	
						)
(




)))(%&'
<
		% )1
		
		


	
 B$ ? 	. , 24 . 	
   2 
		', 	
.	2	
	
.	

.)

)))( &
<
			
'   
	'  
,24
	
2	

	
B$?)
 ('(&( )! )   & %   &)! 
) )*)!&)%!.%&');66(8

< 
 .	 
  
	 	 . 	
 	
 2 
	.		$
2
 )#'C(5	D	

	)+7=


(E,  $6
	.


	
 	
 ##   01( 2 :	 5, &   

	6.
	)
F.	2	
2	
## 01(
.
.1(
	.	

	
		
	
	 	
 2 F1 ) 1
 	 . 1(

	
?
	
	
  	4 . ..	 	 
 	
?
5	
			
G
6
		
	
	
:G
•
>	@



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 12 of 68


	
G


•
>	
	
•
0	
 
	  	
 
	 
 . 	


	50	
<06
•
*	4.
.		
5/<H		.

6
•
*	4 . 
	 		
 5@/* 1/*> 

6
•
:			*(*::=(=:'	
:,
•
7F	

	

	
	

	
•
=.
•
	.	
	

	
+


/	
.....		
	

>	
@5>@6	.!$24.	
)

	
+


•
/	

0	
<0		.',,&	
!$24.
	
E
•
/	
 
 
.		
 	4 5/ <α 7 	
 		
.

6	.',,&	
!$24.	
E
•
/	
 
 	  		 I*	
	 5*(6
*	 5*:6 : 2
 
 5:=(=6
		
	 ' 	
 , 5:' :,6J 	. ', ,& 	
 !$ 24 .
	
E
•
/	

.	.',,&	
!$24.	
E
•

	.	
2		

	
.
	
K	$?	.',,&	
!$24.	
)
•
<	7	.	
	..7
		
	.2%)'%)%?%)"")$?")-' )!?
' )&'') ?B''?E
•
/	

F2/3(+1.		.',,&	
!$24.
	
E
•
/	
 
 
 	
 
 	 		  . 



	
?	

	 5?6 	. ', ,& 	
!$ 24.
	
E
•

	.	
	7		>4',>4


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 13 of 68
,&	
>4!$	.	
	7		>4,E
•
<
	
2
G

E
•
 >	 
	 5

 .	
 . >@ 		
..

		
	
	

6	.',
,&	
!$24.	
E
•
/	


			
?	
	45@/*1/*
> 
6  	. ', ,& 	
 !$ 24 . 	
 5
		 2  		 
 	  . 	
 
 



6
•
	.	
	2	.2
		
			

5@'6>4,5@'.+
6>4',5@,6
>4,&5@!6	
>4!$5@&6
o
:	

.	
5+6)
o
+
.		
	

o
@	
5?	
2			6)
o
=		 		 5  		

	 
 . / <0/ 	

 	4	

		<=<
FF<<L	
6
	
1@
(

	
 	
 
 	 		 
 		


	
		1@	)
	
2	
''.		
)

	

		.
	

	

 	 
 . 	
 	
 '%, 5"'  	

	6)
	
22	.	
	
5G
K6
	
	
	
.	
>			)5
	
	 .  	.	
 .  	 	 . 	 E
'"--6M	


!)	
	
.	.	
)	
	
	7=<
 	 2 7=<  2 
 7=< 	
 
  	 '


	

.	
.7=<


2	
	.

)	
			
B%?	
)
) .  N
/

<2	)!#
.2

F	

	
1		
		
		
/		


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 14 of 68
(	

	
.
	 	
2!"24)<
	

24

?

2	

	! 	

	.
.2	!$24	
	
	,24
	..25
	6)
•
	
1
516111C, '#
•
=		
=	@5==@6111C, '-




<		
	

			

		

	
		1@		
2

	
 
	O  7=< 5	
 .	   	
6 
 	 2 7=<  2 
 7=< 	
 
  	 '


	

.	
.7=<


2	
	.

)
<  	
 
 . 	
	
 	
  
	

  

   	
 	
 . 2 
 


	
..			
.		
	


)
/
   	
? 
 .  	
 ..	
		
5>	@62
	
)
1
	
4..			2.	




		2
		2
	

	
	
)
	
   <0 0 	4 . 
.		
 	


			
?	
			F	

	
?	

	2				
			)
•
"541#
<  2 
 .   !  	 

  	 
 	


   
 2 	
 2 
  
. 


. 		 	
 	
 2  		 .  
  5

?
 	6)
	  	

2
	
7=<	



)
•
30)(-"56#
  	
 

	 	
 		 
	
 5 
.2 	 . 	6 2  . 	
  	
 2 
	
 	
2	
'  .	% 
5''	6)
•
&%<&()!)(-
>  . 	 >4 , 5@'6 >4 ', 5@,6 >4 ,& 5@!6 	

>4 !$ 5@&6 	
 2 
 
 

	 	
 		

	
5.2	.	6)7	
.	

 .	   	   
   	 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 15 of 68
.2
>4,	
>4' )
•
$4& !("5=#
>.	
	,24	.
	
5
.2	.	6)
•
))

	75		
.
		
				
				
6	.	

		
2
@'5@'6	
@,5@,6))	>4&$%	
' 	2
	
.	
.		

)
1

/	










(%%!
&)!
') *	.		
'%		
E
,) L..	.
&24

!) L . 	 5G
 K6 
 	
  	
	

	
.	
>			)
		.
 	.	
 .  	 	 . 	 E 
'"--
	

	

		


						

') *	
.		
2
'	
,) *	

		4.		
!) *
					4
&) 
G

#) 				
	5*<6	
2

$) 7
		.*<G
		4
-) 7
				G
		4
%) 

") L	
' ) 2
2
	G

	P	
'') 	2

P	
',) 		

.G
.
&) 	  7=<   	 2 7=<  2 
 7=<
	

	'

	

.	

.7=<

2	
	.

)
#) 	
	
			B%?)


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 16 of 68
$) :	/@4	

Q
<	4
.+	
./		
+	


 			 	 

 
 
	 	 2
 #
	
 '#R 5
6 	   	
 ,) 	
 2
	,

./@4
			S-R)
-) 2
	
	
	
	
	

	,24.	
	

+
/	
%%  &)!!(
'&
') 

	.	5	

		
T! ?
6
,) L	.	
!) 		.

.
	=<	

<B,.
	)
&) (	'
#) =.	

  2 	 
.	
 	


	
?

	2
.2	
	.
	
2
$) (	
 .  
 	
 . 	
	
 5

			4
	
6
#	
-) 	
2	
		
.	
4
%) 	
2
.				5))		
)6
") 	
 2 
 	 .	 2 U4 L	 	

5UL6/	1111@
' ) 	
2
	?

.


'') 	
2
					
',) /
	
	
	
.	
..2
		

	

.
		.
	

.			
	

	
			

		5.
6	.
		
	)
'!) L
	

.		
	
.


'&) 
 
	
	
  .	  	
 52 .
 
	.		6)
'#) G  
	  	4  .  K  .	
	
	

51(


6



	
	
  
	
 )) 
 	 	
	
		
	
?	





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 17 of 68
'$) 		
 
 	
 	 . 	
 
	
	   
2
 !  	   

   	
 2

	
	56
'-) >
.	

	5>:/06


		
2
2			
	2
'	
2

...

	
.&24	.
5.
		
2
	.		.	
'R	6	
•

5
	


	

6
	

	
		2

.	
5	

		
		
	6
•



	
	
		2


.	
5	
G		
	6
•

	
517(6
•

	

	
5176
•
			

•
		
5		
	
	
.			
	
			

			
.	6
•
		


1
		.	
	5

2


	
6	
.
	
	
.)<	
	>:/02
.K
	
	)
'%) 	?
	
'") 

	


	
5	
1(
6
, ) .		
	
,') 1
	
2



	V

.2
 

  
 
  	  	
 	K	
>@?>
)		

		
	
	
	2	..K	.>@?>	

•
4
..
4	
	.	
	
•
7		

	
	
	2
2
	K		
...
,,) 1
	
2


.






  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 18 of 68
		

		

	


	..	

5>	@6.	2
.	
)
 	  . -" 
 	  2 	 %#R 2   	
..

	
.')%?	>4!$	
	

	
		
!)-#?
	22	 ) #2

.	
)+
		.		'#R
	
.G	

	
	

	2"'	
	)

	+..	
	
<	..		
	2	

	56
	
	

.>	@5>@6	.!$24.
	
2.		
)

	 . 		
 5/:@6 2  !$ 24 >@ 	 	


		5=	:	
/	2	5=:/6	
?
	
.					2
		
		

6
	
  	 .	 	
 	 	
   	

>@	!$24			2	..	.
 2 	
 ) < 		 .
 
   		

.	
	 ) #2
.	
2.
 E  .
	  2 
 
 		 
.	

		)

<
	
	2	
.	
>4!$
>@
2.		)

< 	
 2
 >@ 	 >4 !$ 5	
 . 	
 
>4!$6	
.	2
	)
<..			
2.
	
	
)
<
	562		
		
.

.	 	
	)  
 	
	 
   56
	
2.)<
.	
2	
.   	
 2  
 . 	 . 	

  	
) <  . 	
  .  
	
2



		)


	+..	
	
	
	.


	..			/:@
2	
.	

		

			
	
		
	
	

2		
)


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 19 of 68

< =	 :	
 /	 2	 5=:/6  2   
	
		.	
	)

	.	
2		

	
.	

 K	  $ ? 	. ', ,& 	
 !$ 24 . 	
 	


	.	
	7		>4',>4,&
	
>4!$	.	
	7		>4,2
	
	

		
	
..
2
	

)(

		.

		
	5		'.	

	
S$? 
26) <	
  	
 	
 	 

	
 2 

	


		)

<  	 7 	  2  	
	 
 
	
		2	
	
	
7			)


	.	
	7		>4',>4,&
	
>4!$	.	
	7		>4,2
	
	)

 
 .  
 2  	   
	


)


	.
	
+		
.	.2..W	.	
X	
2
	 
 .K
 . 	 
 	. 	4 		
			
)
+
2
*(
		
2
	. . 	 	
   

  
 	


	.	
	
		
+
		

)
	. 2  	  	
 ..
 2
  2
	


•
1

.	+
)
•
+
?		
)
•
>	2		
+
)
•
	.	4)
•
=				
•
@	



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 20 of 68





 
 


 	 2  
   	 	) 		

.	
2	.
	2	
 ) #)

	
.			
			22G.
	
 
 
  		 
	 	
 56)  < 		

		
2.
		

..			4):
	
		

.
	1/L/
	2
.
	
G.
	
	.
)
			
	2.
.2	)



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 21 of 68
$"
%&'.!

	
		
		
	


	
	
	
















 
!










"!	

"#
"
"

"

"

"

"
"$
"%
"&
'
(!
$#
)#
)





)
)%
)$*
)$

	
	
	
	
 	!!"#		$	$
	%		$	"				&#	'%








  
Sponsor:Menarini International Operations Luxembourg S.A.
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 22 of 68
 	


	




	



	



	



	



	




	


	

	

  



!"
#
$	


%&	$		

%&	$		

%&	$		

'

!	()	

!	
*
  
+(,
	
	






		







		







	







			







	







  !	"#





 	$	"



%&'()*



 $+ , $,#- $ 
!		"	





../"	.




01,






2+"-3,22'
(3(2.%&




4		-/.5'α"
!	




4 	 	 +	
	-
,,+$5'#







5"+







*5




1 ,! 	 ,!
		





/6	7		







  
Sponsor:Menarini International Operations Luxembourg S.A.
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 23 of 68










	
			
	
			 !"	 !
	
	 !#	
$

%	&
		#	
	#	#$	"
"'		()*+*$$$		%	,	&"
"($*$	$	*$*
	
$'-.*



"/012	"3		$4			/	/012"
"!	5*	 !

		
#	6		4#			
$7+06/06089"!#		
				$	 !#	%$	

$


#	&	
$		 !
7+68696:6/*	$	$	"
"!1)%!1)&*#$	

$	$#	%		*	0;1	
&
"	<		
:"/
1
!


$		$.1	"
	4			"	







1"





0(!		/





"





	!






,++









  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 24 of 68



	
	

	
	
	
	





	
	



	



		
			
 !
	
 		!	


"	
#
"
	$	
	
%
%
!
&		


"		
'
	(
%

	%
'%
	'%		

'
'
	)	*	

"!
+	("&
			!




	
,%
,	
	%
-
-
	"!.
/
0
-!,
-.	
 
 
&	

  !
 &	
"
	
 		!	
,
,
	
.
,.		)&
			
"
!, /
!.
/
!, 0
!.
0
!1
!1
	
!12
!12	

	



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 25 of 68
-
	
"	

3
3

	

2-
"	
&/
 %&4
 	%"
+
"			
("

3
3	
("
1,!
1
"		
(
	
1%
2
1	
%



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 26 of 68


	


	



	


	




  
   
  
 
   



	

		




	
		


 
     
   
  

  

	
		



 	!




	



 

"













	#


 
$

   	
 
  $ 
  
   	
 
  

	 
 
   %   
   
 
& 



 

 '
()(* 
    	
 	  

	


 +




		


		



%

,$

		


 -.  	
 
  
  	
 
  
	
 / 
0 
 	 
  	
 ,$ 	 
  
  


	

-1

2-1







	   %		
	

 
 

 
 
  
 
  

 
 
	 

 ,





&
	
	

 3	,$





		
	4.


%(
5%(6%(67-8


	
	

 9

	
	


	


 %



',(*

 ,(



	


&




 %












   
 	
 
 
   	 
 	 
   
"	


	
	






	



 
   % 
  
 
 

   
 
	:


 







	
	







 	


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 27 of 68





	




	 

	



;<<	1)
7<
6=<	1)


	


 
%

	


	

 
    
    
 
"
  
	      
  
  )  	 
 	 
)
 



,(



	
 
	    
  $       
 


	



 

	

'>4*
/
0		

  % 
	
 >4   
 
    
 



	

	
         

 	  

 
	
 



 6==?   
   :   


>4
	
	:


 

"	





	
	
	 .
>4$
	







	 

,('



*	

	






 

	



	
	

 	  
:  
 	  
  7<6=< 	   
$

6<<5<<	
>4
'>4*;5

	 >4






	 


	

•
.->-
.->6==@;5
	A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 28 of 68
•
		
	'B>-α,$	
*6==@;5

	A
•

	C+
'+)$*+

'+>1*1&



'1()(*>

6='>1-6>1-=*D6==@;5

	A
•

6==@;5
	A
•
>

	




5	#
6==@;5
	 
•
	
,$

,$

E7 67 7
	#7 FF 5	#F G6< ;	#6< @66 <	#H66	#A
•
!BI)2>%
	6==@;5
	A
•
   	 
     	
  	# 

'	#*6==@;5
	A
•
>

,$46=4=@4;5
,$4=A
•

:

A
•
>4$'	


>4


	
*6==@;5
	
•


#
	'$+%$+4*6==@
;5
	'	



*
•
3


 
	
	
	!

	

$ 
	& 

 
  
  
 	 	

>% >
	&6E6




 




>
	

	&E67='F6		* 
>   
 
  
 
 ':
 * 
 	 
 
 



4 	 $
 >


,(

,(
,(	6	





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 29 of 68



,(



 >	
	H7	#



	
	

>	



E
6 +
	67
A
= "


@


; "
 
  ':
 * 
 
 
 	 
 
 



4 	 
"#$%$"#&'"()&&*+&#& '
,#-)#$$)#.#"++/.01+/*2#$&"#,E
6 +				

6
= +



; +


@ B

:

? 	
'+>*

5 ,+>:

G ,:

7 3



F "	
6< $		:

9
66 3




9
6= -
	

:


@ -
,(

,(
,(	6
	





,(




 
? >	H7	# 
5 1



J


2

3




3




  ?  6?K '* 
   


  =  > 
	=


LGK 
G 

		

 	=


	&



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 30 of 68


	
	


>  
   
       	 $-M 
  



E
6 3
'N;<	#	*
= "
; $  
 
   
 $(  $3 H=	 
	

	 
@ )	6
? ( 
	
 
    	

 #
 



	

	



5 )


	
	'
	*

?
G >
	




7 >		
'  E	
 *
F >
-M
"$

'-M"$*%%%
%
6< >#




66 >
6= 

	 	
 
 
 
  

E &
 	



	
	
&

	
		
&



	 &
	
 &	 
   '

$

*

	 
6; "





6@ $ 

 
 
 
 

 '  
  		 


* 
6? 3:   
   
  


 
  

	
 '-3$%) 
 
*  
 

 
 
   
      		 #
   
&	
65 >




;<




	

'*
6G 4
	 
  
  	
 
	 
   
	
6

	






   
  
 @    
	
 '  
	

6K*E


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 31 of 68
•

	'



*
	








'
	*
•




	








'
:	*
•
'%,)*
•

	
	'%,3*
•



•

	'




			

*
•

%
	
'

	
	
*



	 

41.>

	 
67 3
#



6F 3


	'$%)3*
=< $






=6 % 
    %
O 

 
 

  

  
 	 
  
 
  >4#>4$ 
  3

 
  	 
   
	  
   

>4#>4$		E
•
-



•
 	   
   
	  
 
	

== %


	

3
	
	
			!


 	






	 
!"#
$


$

	


•

 7< 	 	 
 A    
 G5?< 	 
 
 
	

  1  E  	
 
 		 



 
	
 
	  

  
 %% 

7?@=6=F
E


	
'26G6*	

;;?<



'26G=*A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 32 of 68
•

 6=< 	 	 
 A    
 66@G? 	 
 
 
	

  1  E  	
 
 		 



 
	
 
	  

  
 %% 

7?@=6=F
E


	
'26G6*	

;;?<



'26G=*A
•
$

6<<	A

	





 	&  
 
 
	  
 
	  


		A
•
$

;<<	A

	





 	&  
 
 
	  
 
	  


		A
•

< ?	 A    
 	
 
 
 
	

		A
•
-

	??<		
A
	




		
	
	

7<<<	
266<'*A
•
1	&
=<	A

	







	


		
	
 	  

	 	
 
 	

 '


* 
	  
 
 	 
    '

		
	

	


* 


	"		


•

'$P*7<	E	

#



/7<0
 
•

 '$P* 6=< 	E 	 
  
#
 

  
/6=<0
 
•
$

'$

2$*6<<	E


/@I60



 
•
$

'$

2$*;<<	E


/=I60




•

'
3
&*< ?	E
/< ?0	






  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 33 of 68
•
-

	'3??<*??<	E







Q3MQQ??<Q	

	

•
1	&
'1	&P*=<	E





	/1+2>B$R2-P=<0






 


	

%

	
$     	 
  $          

	

	


	


 
$       
   / 0 ' 
  
 
 @ *

'
	

	*	



	













 $
%




	
		 
$
/0 


	 
%
 
3%+>

 
%+>


	
	




		


%
 
$
$'
$*
%+>
 
(

	!

+>
%+>'!+>A$6;*


 
:




 
$



%+>
E
•
	




	

•
	

	
	
	



•
	

•
	

•


	

•
	


•



•

 	!
•




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 34 of 68
•


"##$%%%%	&
•
'



 

%


	%+>
 
2

%+>#
	
	
%
 
%+>	



B

	'B* 

	


$	
	

=?S


	


&


	

	
		


	6
@'
	* 
%
	:



 	

	
:

	

B 
:
	
	



	EK
	
T	
6<<#	

 

:
	
	

:
	

 
	
	



:	


: 
	
'*9
96'  6<A=6 * $:5<K
	

6=<K


	 

	


%




		

  
   
     $ 
   	   
 '

*




: $

 
$


)$

	
	

 

			
$
	


3

 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 35 of 68
$
	


)B
	

 
$

 
&
		

)

'
*





3


'
	

"
"	

	

+$%&&+%$2"'4&

7<	
 %	U5	#=

	

6=<	
	
	
 
+$%&&+%$2##*'+$#



6<<	


6<<	=
	

H5	# 
 			 
 
 

       
  
 


5<<	 
)
	





%


	



:


3	> 
+$%&&+%$22$)$&'&+%'#+*+-$5+2


	
5	


< ?6	V)



-
??<	.%)1	&

'=<@<	
*
 
!


-
??<	.%)



-3$%)
 
 -
 
   
  
	  !% 

  %  

-3$%)
#


  
  

 #
 
 '
 
 
:
*




(
		

3


#


;5
	
=

 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 36 of 68

	



		

	&




	
	
>% 

	&

/B$-,-%0
		

3$3

'3$3%-,3$* B
	&
6E6








	&

	 
   
 
 
	&
       
 
	
  
  
  
   	  
 
  

	& 
#

	

'
 *
	 
% 
           ' 

 
	
*




		 
   -
.-> .-> 	 
 		
  
 
#


  	 !B    	 
     	

	#

	

 


	





		

	 =

	&



 $

B 

	









		

	E
•
&

•
	

•



•
	
	
•
&

•
	
		
&

•


	
•
&
	

•
&	
•

'
$

*
•

•


•

	


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 37 of 68

	


!




-
'??<	.%)*




-3$%)  
    
 -
 
  1 
 #
 
 '
 

:
*


 >

7 6

 

	
3:


	

	
	
 
6

!
777	7

&

		
  
	& 

 
  
    $   

'46*:	

	&

	

7<6=<	

$

6<<5<<	 
!




':
*
	





4 	
 >

,(


,(
,(	6	






,(



 >	
	H7	# 

7"'4&+2


	&




7<	 %
	H5	#=
	

6=<	

		
 

##*'+$#+2


	&


 
6<<	
6<<	
 =     	  

  H5 	#    			  
 








5<<	 

7#+*+-$+2


	
5	


< ?6	V)

2,($B 
!




-
'??<	.%)*




-3$%)

-


	!%

 %

-3$%)
#





#

'


:
*


 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 38 of 68



'

= =*E

$&$18/&19:;18<&)+$%-$&$=>



6

 

	
        
	 
E 
#
  	



		
	

	

6= 2!	 


  '	, $   

 *
	



	
 
>	





	

	 
 
 
	  
   >4 		   


	
 >



=6 
)

,$



,$	


'*	




	


O

O


,$ 	

,$



,$

G



	&
 

$&$9/9>

3:
	&




 

	
E 

	 	
    	 '  
  
 .-> -
.-> 
  	 	 
 		
 


#

!B

I)2>%

	

	


	

	# 
*   
 :
  	
  

 
	

A	



	&
 
%	

#
:>4>4$	

	&



	


	


 

$&$8:;?@/&>







,$

 %
,$
	

	
	&

,$46='=*



,$



6=<	#





=<<	# >
6=<	#
,$
46='=* >



,$
 

 
  
  			
 5<< 	#A   
 


  
,$
46=
'=* 



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 39 of 68


	E

		
,$	




	
	









 

$&$?:;8?@/&>


	E

		
	

 	 '>  
     .-> -
.-> 
 
		
		


#
!B
I)2>% 
	  	 
 	  	# 
*  	 



'	,$

*
:
	

 

 
	
     	
 
 
 
 





 

$&$:;?@/&>


	E

		
	

 	 '>  
    .-> -
.-> 
 
		
		


#
!B
I)2>% 
	  	 
 	  	# 
*  	 



'	,$

*
:
	

 

 
	
     	
 
 
 
 





 

$&$:; @/&<'/$&$=>


	E

		
	

 	 '>  
    .-> -
.-> 1 
		
		


#
!B
I)2>% 
	  	 
 	  	# 
*  	 



'	,$

*
:

	



	

 

$&$/##,1'*$&$<))'+&6:;&++2$A$B/&+=>


	E	
	



	



 

$$#-$&$&>
>	

,$'

	

	



	

	
*	


'	H5	#*4='6*46='=*  E4@57
6<






			
	 $


		


 



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 40 of 68
+#/:$+,#$&$>
$	
'*	



	
 
2
3'23*


&
	
	 
!

W
>4

3:      

 
   6< 	   

   
	
	

	

'1	
G<?>%%* >

  
	


   3	

  
	  	 '$
 +
!
,I* 43	

	>4


 
	   
  	
  	   	
  

   	  
 
     
 
 
	         7<K 
   
  >4  $ 
	


	   	
 
  >4  
   
   
$	      
   
   
  
	 	 
    ) 
 
 >4 

 




	X>44
%
 

&
	


•
.->-
.->6==@;5
	A
•
		
	'B>-α,$	
*6==@;5

	A
•

	C+
'+)$*+

'+>1*1&



'1()(*>

6='>1-6>1-=*D6==@;5

	A
•

6==@;5
	A
•
>

	




5	#
6==@;5
	 
•
	
,$

,$

E7 67 7
	#7 FF 5	#F G6< ;	#6< @66 <	#H66	# 
•
!BI)2>%
	6==@;5
	A
•
   	 
     	
  	# 

'	#*6==@;5
	A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 41 of 68
•
>

,$46=4=@4;5
,$4=A
•

:

A
•
>4$'	


>4


	
*6==@;5
	A
•


#
	'$+%$+4*6==@
;5
	'	



*
)

>4$



	X>4$4

%
 




	
		

•
.->-
.->
•
+
		
EB>-8	

•
1	E+)$+>11()(>1-6>1-=
•
+


#
E$+%$+4
•
,$!3		


•
(

) 
   

       
  
(

+ 

&

3


	'6*
4='6E
$2
*6='=*=@';*;5'@*E
•


	
'$2* 
•
>	
'
		
	





		
	

*
•
'
#





	*
•
	E

	

	
	




	
	
		""B.


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 42 of 68
4.
$3$(Y!3"()">IB



'>#
%-B*X



*
•
>''
	





	
*

C
:	
D:7!
	
	
	7
D!

3



E

	
		





 	    
 
   	   	
	  	  



 
> 
 
 
	     
	   	
   


	
	


'3E237 6
>
 
3			




E
W
>
	
W
B

W
%
	




W


	



	


			
3


3





#
$2 


	
	B 
$

	


'
	:

	
*


	#
	3

 

89


(




( )*+,-+*+./ !
$
	

:		




	 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 43 of 68
$ $2  
   
    '  
	 


*	
	
	


	





	
 
( ,01	+23/45.-647

$2:




E
6 +$E$2
	

	







	 



  '* 
       	  
	

 
 
	

   
  
 
 
= !+""#E$2

	

	








	


 
 
 
  '*  B 
	
 '$2


*


 
; !&&$"#E$2

	

	








	 %
	


'*	
 
@ 1&&&&"#E

:

	





	
 
? #$;#/E$



– 
	


#

–  	
 
 
  	
 
   	   

	
 
5 #E$


E
– 

#

– 
	

)2#

– 
 
( )*+,-+,01	+38/45.- 	-!
$)B



	



	 
 
 	  
 
 
   
     
%
 + >
 '%+>*   	     '* 
 	 


 
$)B
$2


E
6 
= >

; >



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 44 of 68
@ ,
$2
$)B
:E
? ,
5 -

( +,450-.+--
$$2#$)B
+$'&E
•
A
•
A
E(
$2
	

A  
 
  
    
 	       	

 
•









A
•

#A
•


	#A
•
 
 	 	
 

  	 :
   
 	 






	
 $	



	






		



 
$$2#$)B
1&+$'&






3

$2#$)B 
( )*+,-+*+./ !9)*+,-+,01	+38/45. 	!
./+.-4/:
   
  3
 
  -

 $2 
 $)B   
 
  



E
•
$#E


A


	

	
•
+E    
 A   
 

     
	

	 
•
-+E		


	
A



	

	 

( )*+,-+*+./ !9)*+,-+,01	+38/45. 	!;7+8/+).+--
$ $2#$)B  
 '4*)     
 

	 
  $2#$)B  


   
	
 
   B 3 )
	 "		  
(
&)



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 45 of 68
( +,450-.+;7+8/+))*+,-+,01	+38/45. 	!
$ 
   :   %
 
  3

   ' 3

6< 6 ;*

$)B'3,3$B* 
3,3$B  : 
  
    3
 6< ; =    /B

>
0

%+> 

(

	
		
	
$$2

	


B 
$%

:

:$2 
$2
		
O




	

 %%


	
	

	

$2 
4$2
	-&$%+&##+)+,$$))+**++2/)&.
"&+$'&1&+$'&.,++'%"+'%1+#



'
#*:	


	 
$
	

	'

	
 *

#

B 
%



$2



'


*	

	
 
 %
   
 

   $2 
      





	
$2	 

(
3.31+<+./5=+,450-)*+,-+*+./-
( 	+75,/4.10/4+-5=/6+
.*+-/413/5,
 %
 	 
   
 
	
 
  3
 $2 '3$2  
 





*#	
$2
	
#+?'+&









E


B1>	
1E2I:
3&	
3:


EZ@76=5==@@5<

2	E[
	 
	

EZ@76=5==@@5=

+
EZ@75F6F<;?@@



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 46 of 68
 
    
  	 
 
 
  


	
 

%  
 
 
# 
 #
    %
 


		



	

,
	$5$5 


	
,
	%

B1


 

 
	
  %
  
  B1 
  


 

4  
  B  
 	 
 

	 	
 



B1
3


$ 
	
  
 
	
  
	 '

 







 *


=@

%

B1
	
%
	

	


'*


$)B



B
$
#2
		 

( 	+75,/4.10/4+-5=/6+75.-5,
 3

      
	
 
   
  

'3,3$B*



	$
'
2+


2	*
2
		'



*

B1


3,3$BE


•


GA
•
1


6? 
3


	


	


	





	




	
 

 :
		





E
•
3$2


•
>
	
	



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 47 of 68
•
$





	 
4
3


	



%
 
(
3.31+<+./5=.5.>-+,450-3)*+,-++*+./- -!
%


	


-3$2

$2
	
	
B1'
6< ; 6*6<

 

B1

3


	
$2
	





 
4
B
	


		




B1
3

 

$
	


	

	'





   *
%





B1



3

 

$3
















	


#
#


	
,
	.

( 3.31+<+./5=23?5,3/5,:3?.5,<324/4+-
)
	

'
%+>	


 
 
 
 
 
	*   
    
>
'


	





	%+>

*

$2 



		

'
7 ;*

B

 
"
/

0

B13



	
 

(
3.31+<+./5=,+1.3.8:;75-0,+3-+-
 %
   
 
    
 
	   
  


   	  
  O    	  

 


	
B1?	
 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 48 of 68
B1
	

	
3

=@
 
%







	 
%
	

	
B3$2	

 
88

E	



/0):580<+./3/45.93/3522+8/45.


3-+	+75,/5,<-
)


B'B*
 )


B



	 %
	

	

B 
1  B        	    3   
 	    	 
	
 
 
	
 
    	  
 
)


B	





 

%



B

B
 

2B		2 	

B



	%





	
 


		B
	
 

3/4+./	+85,)-950,8+3/3580<+./3/45.

%
	




	
B 



	



B 
'>



	6=(2!
#


B* 

3/3$0324/:5./,529/0):5.4/5,4.1
%

	


 	






%








	 B

	







	E
	



	


$2



 $	


		 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 49 of 68
%



	



 
%

	



		
	



 B1
		

 

)$
>	>)E
	

'*


	
'  
*

B
  



	





 )	


	


	




   $  
   
  
   
	 
  





	
	


3


 

$0324/:--0,3.8+
$#
		

 #
3

V$
'V$*$
%B.#2 


8?


	
	


 

	

!

	&




	
	
>% 

	&

/B$-,-%0
		

3$3

'3$3%-,3$*
	&
6E6








	&

	 

  
 
 
 
	&
       
 
	
  
  
  
   	  
 
  

	& 
#

	

'
 *
	 
%
'  E	


>4
 

 	
 *   
	  




	
 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 50 of 68
   -
.-> .-> 	 
 		
  
 
#


  	 !B   	 
    	

	#

	

 


	


@

  	  
 '> 4 
* 
    
 
 



 
$	&
GF
7?K

	
6 7	#
4;5	
		

; G?	#


< <?
 2



	6?K
	

:

	&

	&F6		 








E
•
 $ 3 '$3*E $ 
	  
     
 
 
 %+>
	 
  
	  
 	  	'>4*

	
 
•
>


 '>>*E $  
	 
  
  
 	 
  

	
	:





	 
•
3E$
	


	




%+> 
>>


	&
E
•

	:


	


	A
•
7<K
	

	


	&

A
•

	
	


 
•


	>>

	

 

.


:

	
 
	


	>


>





	 $



	:
	




	
 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 51 of 68


	

>	
	
:





>4

'>4*;5
	 	;5>4
 
3








E
•
.->-
.->6==@;5
	A
•
		
	'B>-α,$	
*6==@;5

	A
•

	C+
'+)$*+

'+>1*1&



'1()(*>

6='>1-6>1-=*D6==@;5

	A
•

6==@;5
	A
•
>

	




5	#6==@
;5
	 
•
	
,$

,$

E7 67 7
	#7 FF 5	#F G6< ;	#6< @66 <	#H66	#
•
!BI)2>%
	6==@;5
	A
•
   	 
     	
  	# 

'	#*6==@;5
	A
•
>

,$46=4=@4;5
,$4=A
•

:

A
•
>4$'	


>4


	
*6==@;5
	'
*A
•


#
	'$+%$+4*6==@
;5
	'	



*
•
3





$    
 
  	   3      

< <?< %< <<6
/N< <<6 0%
< FFF
/H< FFF 0



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 52 of 68
3
	3$33
 


 	      
   $ 3 '$3*A     

	&     	 
  > 4 
 '>4*  ;5  

	



 		(1


'(1*
A	

	

	
	

 

$

'$-1$*;5>4	




  >4;5



	

	
 




  < <? 
     	
 
	  	
A   	
  

   
  
 
 
 
    	 


$-1$	
	
	

 	  
 
  % 
      < 6 



	


 

      
	  
 4 ;5   
   

		
	 


>44;5'
	
4;5*




 



	
$3>>>

 $3'$3*
	

 $
>>


'>>*>


 
	    	 
   
	  >> 

   		& 
	 

	>>

	


 

3
2$

   
 

 
    $-1$ 	
   
	

	

	

		
	
 

(1

'(1*	
&
		
 
>

	




5	#6=
=@;5
	

,$46=4
=@4;5,$4=&


	
	

		 )


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 53 of 68


	'6

L5	#<
* 
	


 

	
,$ 


&	
	

,$
 

>

,$46=4=@4;5
,$4= 

-



	


 


3$

2


	
/

0


	

	 

3
	
	
E
W %
$2 
W 3
$2#
&
 
W 4
$2 
W 3	 
•
(



•
'
#




	* 


$2
+)B$

	

	
$2



	 




		
	


		& (


&

	



	


 3
	


 


  
##
  
	     
##
 

	 


>	
:	
 



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 54 of 68





	
	


		& 





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 55 of 68


	


	
#











	&



	&

	






)
B
		 





$ 
 
	    
    :  
	  
3 $ > '3$>*    3 $ >   &  
 
 


 1
%"3B


	:
	
 
 
 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 56 of 68
8
	
	5	
5
	!
	
5.4/5,4.1
2
	  '#
 *  
 
 
  
 









 
   '   B  
  * 
  : 
 
  2
	O 	

 
   
  
 
 
 
 
 

O 	

 '
 *  
 
   B   







A
	


A





 	




:O	




 B  %  	
   
  
  
    
	

	


 




	



	

	



 

0)4/-
%
%"!>2
	O#
O
3

O	

 %

'  	


*







	



%"!>
	 
 
  	      
 	   

 

 
  $  
  
 
   
 	    




!>
	A

 :  
A      
  
 
  %+>  



		 

	+1023/5,:
.-7+8/45.-
B

	
	


	
 $

    
  	    
   
	 %+> 





 %




	

 

#



	3

2
	#

)$2+$


%B.#%2 




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 57 of 68
8

D	!


     
  
	    


  
		
 


	  
 	 : 
  )
 
 " %
 
 

"	

X!

>'%"!>*!2,)=<<6#=<
$@=<<6

	

 
$




:
!> #

 3

 #
  
#
 " $
    	  $
%
	





"$
#
3

#
	
	






 


/648-5<<4//++-
.
         


   
	
 '>

	

	

	%
O.
*		

 
   %
 B .
#2 
		 '%B.#2*   
	
$
'$*

 
%


	







 
   
    $ 		 
  


 
 		
  
	
2



3




%
 
 $ %B.#2
   
   
	 
 



   
   
  	  	
  
   
	
 



.=5,<+)85.-+./
>

:O
	


	

%



:O
	

 
  
    
  
 
 
  

	

:O

B13

$
 
	 " $
   
 
 '  
 
  2

2

	$*
 
%
%


	






 

>

	


*	*	
(
	"*(&	








%B.#2 
%
	

	

	

	




	


%
+>



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 58 of 68
'%+>*  	
 
 	 
 	   	    
	
%+> 
>

	
	





 %


	
	 
$
	%


>%





 %

	


>%%
O



 
%


		
	
>%




	
%B.#2

 
%


	

		 


3/4+./A-
.-0,3.8+

3






	 
) 
   
	   	  

   	  

>%#


	

	 
$ 
 
      
 
  %
      
%
OO+'+* 

%
	

3

		


	
 

8
7	
		

!

	:!	
.    


  %
   %
 '  
 *


	
	


 >


3




'  

   
*E  

   	
   3

   

	

	






	






B1 




3

%
#


B1%
#

 .

  
  3  %
  
    > %
  


 
!

	
3


	'


%  *



	


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 59 of 68

%
%
'
*
	
3

 
 
  

 
 
   3  

     

	E'*

:
3
	

/
	



	


0A'*




:
3


A'*


:A'*




&
%  	
 
.


%
'#
*	
	


	
3

	
 
-

		





	

	3

 
%
 	   O 
	   	   %
   


O		
	 %

	



	

	



		

	3

 %
3

#
	
 $
	




3

 
 3

     
      
  
%
O	



%
 
1  > %
     
  3

    
  

	

	



B
$
 %
	








&

	3

 




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 60 of 68

8 


	

%


	%"#!>3
7/2
)
	


0
	

	'*%
\ 
 %
   	 
   
 	 
 
 

	 
2 
	 	      =     
 
  	

%"



		

 %" 
 
    =      
	 

 
 

	


 
 
	    
  
 
      

	
	3

 
%
%






	


    
 
 	   
  
 
   

 
3

	

	

 
%
	
3

#
B
$


	


%
		

	
 
$


	
3







Q 
83
!
	7	
	



	



	
	



	

 
  





		 3		  







 %		  

	







	





%B.#2
$


		
		
 

	
	









%B.#2





		 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 61 of 68
$  		 
  


        


  
>%
	
	


 




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 62 of 68
86
7
/5%	(663		
		$6 
(7-60889,0:;:<=>/?5@/9//&/90/
05 (	66	"""		
.
"	
.		.	"A		
	6"		"608/0%;B0>05@:0?&::9
:5$7%6		
		@

C
""6
7-088<;//9@9/B&90B6
D5 2"	 !6  6 	
 
  	 	 
 	$  	 	 	
 
	
"
	
@"!3-6+
	
60888;:B@/8?0&/8?9<5
<5%
(76		
		6" + 		(	&C/=?/&
/==0
B5 , !C  C 'E" 'C #
" -C ,C C #&
 6  	 	
	
"	$$	
	67 "60889;/=@0D8?F/:6
?5#	"

6'
"	$		
	
6"		"088B;<D@0B99&=6
95"	+#
"
'6


	(
	
	$
"	6		

088?;//B@9=D&=886
=5 #	"

   6 
(& 	 	 
( 	&( 
 	" (6 " 

  -
0889;/B9@//8D&/86
/85#	"

6
	
C.		
		@"	$	"		
(6"(
08/8;D=@/00=&:96
//5 	 G  6 ,.		) &
	 		
 &
		 	
 	
 	" 	 (@  
&	
("6	
"	088D;::=@//?F00
/05#%6			
"	
$
		

	""6&	

6"(08/8;D=@//9=&=B6
/:52"6		
			"		

		
	


	(
C
"
	
67+
	
08//;0D@::&:=6
/D576"			
		

	"	@"#

	&
		"6"	0:/>08/:5/D<&/</6
/<5 G"	$ 6  6 3	 	   , 	

 	
 (	
 		 	
  


"	67!"	!"	60889;0=<@//9:&=8
/B5'"66
		

		.			6 	 	 		0889;0?@=B?&=?9
/?5    6 3	 	 	  "   		
 
 .		  	 "

	
&
(	
	
67+
60889;0B@0B=&0?<
/95 -	
 17  6 	
 	
 -3&	
 .	 
  
""	  ( E
  "" 
 
    
	

 	
 $	
 
 "		 	


"	
	

	676"608/8;:?@/009&:<
/=5-'		%6
	
		"
	
	6		
088=;//=@//:<&
D<6
085((	663		
	
$6+76088B-;0?>/85@//?D&9/


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 63 of 68
0/5 	 G  6 ,.		) &
	 		
 &
		 	
 	
 	" 	 (@  
&	
("6	
"	088D;::=@//?F006
005 #"
 %  6 	
 
  	  	
 	
 $ 	6 	
"	0889;0B>D5@0D?&<06
0:5"
16.
"	
.		
"			
	"	


"	
	

	"
  	
 "		 	
 	" "
	 " 	@   0  
 	6
		
0880;/8<@0B/=&0D6
0D5#
-6
"			"	

C	
	

C

	
		
	
	"


	
6
3 "088?;:=@/00?&::6
0<5 %	(   6   	
 
    
 	" 
 	(
 
	
"
	
@
	)	67-0889;:88@=0D&D06
0B51	6	



	

	67	
!"
08//;?/>D5@B88&?6
0?5$-6%.	"	
	
	
	""		
(6 
(7-
088<;:<:@0D<8&B/6
095$-6"&	
(	
.	
"
""		
(@", %-	6"		"08/8;/0>05@B:608/8B6
0=5 -	$ 3G  6 %. 	
"			
  
"	&
 H,@ 			
  (	
(  ,
	
6%		-08//;</>/5@/?=&9D6
:85
C$7C2
C6.



		
@"(	
	
	
			
6+7088B;0?@0<99&B8<6
:/5 
 C 	 !C  C  6 	 	
 	 
 	


 	  & 

			
"
		
6+
	
088/;:?@/0:B&D/6
:05 	$"
$ #C 	 C 

 'C  6 	 & 	 
 	 	
"	  	 	

	
(	

@
	
(	
.
	
A		
0880;/8B@089<&=86
::5 " 7C '	
 !C !

	 C  6   	 	
 
 	 	
 
&( 
 	6
		
/===;==@0D:D&=6
:D5 
& #C  EE C  -C  6  	   	C  $  	
	
C		
	
&
	
	
(6		
088<;///@::9D&=86
:<51	&+

C
7C&!
C6!(
				
.
		
	
"(
	
6		
088B;//:@BBD&?86
:B5-&%3C

7C+
C6		

	$
"	

$@"6		
088B;//:@B<?&B:6
:?52"CH
	!C2	'C6		
			"		


		
	

	(
C
&"
	
67+
08//;0D@::&=6
:95 	1C +
( IIC 	
 C  6 3	 	 	 
 	


 	  	 	
 	
 "
	
	
6+2088=;0D@:?/&<6
:=5"	)$ C"	)$ICC6+	("					"	
 		
	

7
	
		6"	088?;/=0@/:/&?6


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 64 of 68
D85#%CI#+C%C6			
"	
$
		

	""@
&	
6"(>,.508/8;D=@//9=&=B
D/5"
HC	IC"
(C6		
			"		

	
"	

$	
(67+
08/8;0:@:9?&=0
D05 !	&%
( +C"&I
 "
(C1
&"
( IC  6 "    3	 	 
 	
"
	
		$		
08/:;0=@/D0/<8
D:52	))	%C!	C
	
	'C!	C%*	2CC2	C)
'!C-C	'C
!
	6		
((
(	
	"
	
6+
	
6088<;D<@==/FB6
DD52	))	%C
	
	'CC%*	2C!	C
	 C"	C	C	'C!
	6-	
"		
	
	
(	

	"
	
67+
6088?;08@/0?BF
906
D<5-
	'666C08/:+J'		
"
(
	"
	
67+
2
:/;?C08/:
DB5 1 C  6  !		
 		  " 			
  "  "		  	 (6 "		
"/=??;08@9=<&=886
D?5
'		

		
	
	
	
		 >	
08/05+7>08/05::C
/B:<&/?8/
D95G"
(163	

	
(6!@
(
6$
"3
	
(	

	
	
		
	
("	>56

"
	088B;B<@/:/0&0D
D=5#"

66'		
-
(
'6!0@"

		
!".	
'"		6	
("(08/0
<85#"
6!"$	
		
	

	
	
		
.
 67	

!"6088B;DB@9<<&9BB5
</5
	
-	6C	
	&%!12	

		
((	"

++
	
6088<;D<@000&00B
<05

&+!					
	
	
		

+
7
>08/85;:/@C0::9&0:<8
<:5#"
%6C	"	0B>088950D?F0<0,K$%CE	6
	
		

("
	@			

	
	
6,	
	
	
088<;08>D5@0?<&09/
<D5 "
 +C  6 		
  
 	    "	 
	
  	

62		
(
	)

	
6		
/==?;=<@/90?F/9:B6
<<5 1 C  6 	 	
C  	
C 
 " 	$  
  	6 		

088D;/8=@/9DF/9=6
<B51	$	

C6"	

"
(
	
	
.

		
"
6
7!"	0888;<0<>!/5@0B:F0?86
<?5 
&" IC  6 	   	 	 	 
 		
@ 
 	
		
		
 &
	  	 	
   /?CB:< E6 7 >08/:5 	@
/86/8/BJE6E608/:68=68B:



  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 65 of 68
<9567+
608/0;:8>:5@DD<&962
-C
C	!C"	
)$!C	$"
$7#C
$C%		$7C+"C-&%3C!(C"		'C(!C2"C1
;	;
	+
	
1$	
('
2
%
	
;

 $   
	
	 
	(	
  ( 	6 . 

 
 
 " 
 
		
	
			
(	&	

<=56  + 76 08/8 ,;:/>/=5@0::9&<8 	

    	 	
 ""  
 	
 "

		$@L	"	
(


L6

2		
L	
6

B85
	C-	6 			67	6/9088?;<8>0<5@0:<?&B96

B/5 -	 C  6   " @ 	
( 
		 	  	
 	
	 	6  7 + %	6 
0889;/8>=5@90D&:=




  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 67 of 68

.*+-/413/5,A-377,5*3231+

%-23%!$1BO3$>>B1$(>$!2
'

B1O*

%
	



'$P*
		
 	
 
   

    


  


	
   
	
 E >


 %
O .
  
 
	  



	

 

%


	





%
2
		
		


			&
 

%
	%





'	

   

*  
   !

  > '!>*  )
 

"



 

%
	%








 

%
	%	
	











 


!+$)$*#	-&$%+>]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]

3^)E]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]












  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 68 of 68
APPENDICES 
Appendix  1: Declaration of Helsinki 
Appendix  2: the  Joint Task Force of the European Society of Cardiology and other European Societies on 
cardiovascular disease prevention in clinical practice 
Appendix  5: “Preliminary criteria for the classification of the acute arthritis of primary gout - ACR 1977”  
  
Appendix  6a:  Hepatic Adverse Event additional information form  
Appendix  6b:  Cutaneous Adverse Event additional information form  
Appendix  3: SmPC Febuxostat: (ADENURIC®). 
Appendix  4: SmPC Allopurinol (Allopurinol TEVA) . 

SAP_000.pdf: 
	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	









 !"
#
$
% & 
%'&(
 )'*+,"%-)'.
#
&)'  
 &/(&
 0)'



0/1/2&  / +$&
*'.!34$3 -
& 
5
62
73.
8

/$

29























 -.
/
-01
.
-.
1.
2//
10

3
--

.4
/
/.
/
-
 *	
/
1.
/0-

3
0-

.4
0
/
/.
/
.0.

/
.
5.
2/0

2


.	
"
.

/
-01
1.4
3
-0-

-

.
.
41

.1-

.4
/
1

34
.4
/
1.	








	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	










 4
/8
2/
/
$
)


3
-,



%'&''$ 1&&*&'&0)''&

& 5& /)/*' &2/&'
'& +& &-=
/



7'' *& )=
/2/' '&/
&
/'
/*& 



7'' *& )=
/+
 /('*&
'$-2')() 
/'
/*& 2&  /*
//'/(/&









78
708
% &
:3;!:




+//****-





	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



6


 /.5


+.
0/
.

:''&
78
708
;.5
2/4
/
..1
$*"
 .-
 $*"
 .
 -

 /
 
 .
 3
 ..'
46-
 .
 .-
 )	
 
	,	
 
 
 /
 .'
.1
 /.-
..-4
3
1-


	
	
9
78
708
"<
.


	





	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



9


!
*
 *""

+01
.0/6.
																																																																																																																																	

 4
/8
2/
/
$
)


3
-,
																																																																			

 /.5

																																																																																																																																																
&
!
*
 *""
																																																																																																																															
=

0-4
1..
																																																																																																																																															
:

0-4
1.
																																																																																																																																									
:
2.1 Primary objective .......................................................................................................................................... 8
2.2 Secondary objective ...................................................................................................................................... 8
2.3 Study design.................................................................................................................................................. 9
2.4 Planned sample size .................................................................................................................................... 11

>.
1.
																																																																																																																																				

3.1 Background details ..................................................................................................................................... 12
3.2 Deviations from the trial protocol with regard to statistical analyses ......................................................... 12
3.3 Individual protocol deviations .................................................................................................................... 12
&
.4
$0.
																																																																																																																																			

4.1 Safety population ........................................................................................................................................ 13
4.2 Full analysis set population ......................................................................................................................... 13
4.3 Per-protocol population .............................................................................................................................. 13
4.4 Subgroup analyses ...................................................................................................................................... 13
=
..
.4
																																																																																																																																						
&
5.1 Conventions ................................................................................................................................................ 14
5.1.1
Baseline definition ........................................................................................................................... 14
5.1.2
Missing data ..................................................................................................................................... 14
5.1.3
Pooling of centers ............................................................................................................................. 15
5.2 Demographic and other background data ................................................................................................... 15
5.2.1
Basic description .............................................................................................................................. 15
5.3 IMP exposure, compliance ......................................................................................................................... 16
5.4 Medical history, physical examination ....................................................................................................... 16
5.5 Prior and concomitant medication .............................................................................................................. 16
5.6 Concomitant non-pharmacological measures, pre-medication ................................................................... 16
5.7 Efficacy ....................................................................................................................................................... 17
5.7.1
Primary endpoint .............................................................................................................................. 17
5.7.2
Secondary endpoints ........................................................................................................................ 18
5.8 Pharmacokinetics / Pharmacodynamics ...................................................................................................... 19
5.9 Safety .......................................................................................................................................................... 19
5.9.1
Adverse events ................................................................................................................................. 19
5.9.2
Vital signs ........................................................................................................................................ 20
5.9.3
Safety laboratory variables ............................................................................................................... 20
5.10Other variables ............................................................................................................................................ 20
5.11Interim analyses .......................................................................................................................................... 21

?0.4
 
																																																																																																																																												

@

																																																																																																																																																			

:
-
																																																																																																																																																		

8.1 Formulas for derived variables ................................................................................................................... 22
8.2 List of Tables, Listings, Figures ................................................................................................................. 22





	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






!
*
*"

33.
+
$:
$/(:(
$	7!$
$ *7(&
$	!$
$ *&
>
>/*/#
>	
>	
&/
7?:
7'&?/*:/ *&  
73.
73.
73!
7&3&'!1
73
7 & 
/*3
70&
7/&
 0&


&*+4@!7/%'

-

 

 / 
:7;
: &&/
:!%
:/% 
73.
: &&73.
;.3
:/; 
 . 3
.$
.
  $ *
'73
@'(*73

( /& /
&
3>
//3()>/
"!7.
"!(7/.)/
$
 / /'*/
!
* #/
/3$
/& &*3
 *$&(

	 & 
	%>	
	 />	


	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



A


33.
+
!#""
!#/1/")*"&'  
!	
#
!	
#

& 
4$

 4($ *
4

 4( &*
%
/%
B7
Quality Control
$:

$/(:(
$.
*$ *
$
& $ * 
$
& $ *)&0

//(
!7
*!7 
!
//!&/

sICAM
 
 &  
 7  
 $/' &
 
,$

,7&
7$
 
 &
 7  $/' &
 
%:$:
%:$/(:(
%".
% 2"2.

%.
% . 
%	.C
%

	&.&$ '
%
% &
%@
%'*/
 @
,"%
,")%'*
(4.
4  /.&
4@!
4 /@ '!1



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






 A+#
!
%'  ) )&//'$
+01

+.
& 2&  /
6
73.
8

2

2


 A+#
"**"
	 $1.4
3B
%' * <&(  ' &  ' &  
# /   
  

 4( &*+4-)0

	 -.4
3B
•
7'>	/	%>	( 
26/)0
•
7' 0+'732%	.C2,$2/ -
26/)0
•
7'#/(D / /'*/+$-2* #/
+!-!#/1/ )/* +!#""-226/)0

•
7' / 26/)0
•
&
)'

&& '=
 
5/ 26/)0
•
%&'(,$ ( /,$ (  
  )5/ 2885/ 28A5/ 265/ 2E5/ 
•
7';.3)'7?:
 26/)0
•
7'  
  
 #&  ( 
/ *   
  

5&+5-26/)0
•
&(',$ ( 402406/40
'(&'/',$ ( 40
•
%//)  <&



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



8


•

  4( $ * +& 
/ /&  42   2 & 
 /
/
/#-26/)0
•
7'  /'   &(5/' 0 +7$2 7$2 (4.2 
 &-26/)0+%')  ( 
/

  / &/& *-
•
*/  *

	 0-4
-5
%'
/*///1/2&(&  /2  2( 
 /2 
  
2
 &2
  2' )  /1/
&(
#  
 
%')  #9'  )&
;*2'	' /2 *2
 /223

/* /
  /(/
   )    8 )0 %' & 
/  )0 

5&/)'&'&#//#/*&2  )/*
)0/)0*  )
+*'&  -
%'
/*'*& /1//

 *'/ 
 //

/*/&/')  ( (/'&&*( 

&'/1/'
/*
7( *2'
/*'*&5 '&&*( 
+
 4(
 &*-)   /
/*//20*&&*( )  
/ *  // &  * )' ' &  / )     /  '
/
.  /  ( 2 	%>	2 >	2 0    / /'   &(
5/'2 #/( 2 ;.32 &'  
  
 #& 
( 
/* 
5&)   
/*&  
*
:  )  /1/)'  
 
#
+-,  
 
#'#
//
'
/**/)40/402 )&' )/ 
$  )
*)  /*'&  )0
/*





	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






%  )&'
*
40
*
40F
6/*
40F
6/*
406F
6/*
40
F6
/*
40
G/*






6
9
'
&  
&
3/1
!%

!%

!%

:/

/*
(
*
.  )


& 
5#& 
&
H


/&
H


3/1
H


/& '*
H


7&/&
H
H
H
H
H
H

'*& #
H
H
H
H

 +>2@3/*

-
H
H

H
H
H

@'2>/*4'2/
'*
H






"/:7;
H



 4($ *+4$-
42 2&
  /
2

/#

H

H
H
H

>	2	%>	
H
H
H
H



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






*
40
*
40F
6/*
40F
6/*
406F
6/*
40
F6
/*
40
G/*






6
9
'
&  
&
3/1
!%

!%

!%

:/

/*
(
*
.  )



,&$&/
H
H
H
H
H

!#/(
$2!2!#""2
!	/!	

H

H
H
H

0 
'732%	.C2 


H

H
H
H

0/'  &(
5/'7$2
7$2(4.2 &
+ &/-

H

H
H
H

. / ( 
H
H
H
H

;.3
H
H
H
H

,$ 
#&

/$ 
&


H

H
H
H

%//)  <
&


H

H
H
H

702 &' 
&

H
H
H
H
H
H
H
,&*
H

H

*"*%
H
H
H
H

/
H
H
H
H

&&
 *
H
H
H
H

$/((
H
H
H
H
H
H
H
NOTES: * screening period lasts up to 7 days but can be extended to max 30 days in case of re-testing of sUA. sUA can be 
re-tested if current sUA level is changed due to acute (transient) condition as it is not in line previous medical data as per 
investigator opinion and approval from the Sponsor.
	& $.-
.1
6
$ 1A8&'
)  '(9I)/&/&
5&40
''&///(A95&

)
)'9)//&& ( :#&/

# *9I2' 

<&/1//&'('
 / 1)  82 




	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






 >"!
"**"
	 .850-
-.
%'/)  /$'7 & */&
 & # /)   /$'/'
&  *
%'$)   1// &0/
 /

	 +.
1
/
.

2/
5.-

..
..4

*<&'&/*/J#
+!	-K/J#+!	-K)
/1*&&(*2

&)//&'&) /*'
& '*'(& 
//'//&/9A%'
2 *&/!	/!	 /'& 

	 --0.

-.
$*/(& )  /&
/&*&/ &0
 /
)'''/('//<+/' /#
& 
&
  *
 -
%'/(/
 & /()  /3()$
&  & /(/'<
/
<&/
)  // &0$  /( )''/&'

<&)  &///')  &'
/*
/$/&  <& ( )  & 
//' 
'73

7<& ( )   & 
/
•
$*
 ( #& 
&
•
,'/&&/&'*)''
&&*
•
3&)/
/*/&3/1
•
% 
<&'/( /
/*)'/) &
))'/)2
&)/2
&&/&  )/
•
	& & / 0  
/* /
2    ' I   '
I=
/
/*/
0& (+ &9-


	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






$*/('& +& /<-)  &&/ *
&&*/5))''

& "!#
$*$A!*"
%'/
<&)  / */&&/'  ) *
 
•
*+$.-
 2
•
.
  $ *+.$-2
•
& +-
 


&	 .4
0.
$  /1/*')
/'(0 
/

&	 0
..4

0.
%'
   *
 +.$-& 
/  /1/)''(0 
/// *&&*+4-
/1

&	 $'
0.
%'& +-
 
'.$
 
%)& 
 )  &//
& 
 +-& 
/  /1/'')

/'(& /'
/*)'
*<& ( 
 ///()
'(& /  ' /
/*(/
'(( 
/'*/'
/*' (
& 
 +-& 
/  /1/'')
 
 / '( & / ' 
/* )'
 < &  (  )'&'
''(&'( 
'*<&('
/*


&	& 0350
..4
	

 * /


	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



6


=  !
"!#
$  &  *)  /
$L4/)+8 -
&(&)   )*(*
. /&(
 2'*)   ('
 
, ')/ )   *)  /'.$
 

/')'  )///&(&)  /
&(&&

/
	

<&+	-2'&2///(+-2
2 )=

 2/2
=
 /#
)  /,
  */=
 )  
'(/& 2/& '' ( 
+()'2#-M
	'/& %'/&(&)  //
/( 
/
/& 
&(&&& /
$ 
=
&+	-/ (=
&+I-)  /)'/& 2
&( *.&' 2' */
 &
/')  & )  /)///*
 *αN9$  ( 
)  
//'/&  && 
&&)  /& /'
//( 
)   '9( 
 '
)  /OPQ( 
'888)  /
OE888Q
$  &/&( +7-)  /(/)///&/& *
αN89
"
$  /)   /*/*
/&( 
)  &
2
/$*/(// /)   
/ */)  & &
 /
 /&'$

=	  
=		 .
-
> //' ( 
/1//


=		 5
-..
%'*/)   *1/*)&'2)'
*0/

/)'
/.'*//)  



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



9


/
'"!(7/.)/+"!7.-&'.'
( 

'
)
'&')  /

/'(  /)'
(
)  &/
&/ 


  )  /
.'&/*/2( 
)   
/*
'"!7.
&'

=		 $5


$   )  / (  &&
/&%'/


&
*)  '/&'


=	
+15./
.-
/
3.850-
-..
=		 .
-
%'/
<&+&&6-)  
 /*/'

  & /()   /
&
/)  /&/*=
&*/
& 
/'/
/(/
  
'&/+/2+&& /&

-2)'2''2/*
/#+>-2&2'&
-)  
1/ //'$.2.$
/
 /*
!' &0
//2
/&&2)  &/&( '$./
 
'  )( 
•
0
&//1
•
$ &' &
&//1
•
 +* &// & /
2 
 //*
-
&//1
•
:7;( 
+ 5 -
•
'*& #+ 5 -
•
;
@*/730&

%'  )&0
//)   * /
•
/& '*


	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






•
/&&&/
/
+#&'/
/7&
'*-
•
7' / /
&*

=	 $
;0
1.
%& &)  /6+/
/*-
%'

/*/&0*'
<&)  /(/*&
'

 ///
/' )'&')  &//'73.
%'& &'
/*/& &
 //&/&

$)''0 I/'I'=
/
/*/

0&' ()  &//& 
$  / )   /

=	& -.
/4
/4.
;.1.
/& '*/'*& #)   //& '*)  &/
/&&/'/& &*3
 *$&(+/3$-7/)  
()/*/& :#/(/*'/ &0

=	= $
.-
1.
1-.
$* (/&//)''&/)  //J/&
K/)  
1/ *7&/&+/&/
'&/-//7&/&+/&//
'
&/
//'/  )  
1/  '
$  / /&&/&)   /& 
/2'
2/2
=
&*2////&
/&)  &//
'4@!'

'(&
'
/ &07/)  /*'73!//
)''
/ &0+&-.&&/& )  ')'=

&
<&*4@!//&)   * /

=	  1.
'/.1.5.
1.0
'1-.
	 & 



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



A


=	@ .4
%'&&*( 
'*/)  /'.$/

 %' .
  $ *  +.$-)    ' *  * 
   '
&* *$(* */'& +-
 
)  /

=	@	 $1.4
-
%'*&&*/
 4( &*+4-)0
)'
#  
 
$ )4
)  0(%'( 


)  /*)// * 
( /& 
// 
*)   &/*#&//& # & /'
/  &'454$')  
/'& 
 */&/'/&
/O454$&& &Q&
99$/#: ( 
  
&
//( /)  & &
 /(/)  
 ( 
(

$ *&(&+$	7!$-)'')04( 
//( 2

&/2  /
2 4&(2)  

/&'&&*')

%'
'
/ */ 
&' */
 /'*
(&)  (/
&& ( 
$  &(
/&  *&'9)//&& ( 2
)  (/'/ /' / )   *& 
/&  *&
&(
.&(
/&2'*&(&)  ( 

/
$	7!$/ )''2&(/*&(
&
&&  *&')//&& ( 2//  
*)  /# '&
$(* *)''&' 40( )  
/  *'* *
%' ')440+&' 40-/
#
)    
 /)  # /
& 
%' "!7. '/ )    
 1/   / 
  /&/  &
9



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






=	@	 -.4
-
$  &/*&&*( )   *1//'.$
 
. '  *  &

 &/* &&* ( 2 ' $	7!$ /  )'
&' &(( /&( 
( 
/
''/ )  
/&''
 / )%'"!7.'/)  
//

•
7'>	/	%>	( 
26/)0
•
7' 0+'732%	.C2,$2/ -
26/)0
•
7'#/(D / /'*/+$-2* #/
+!-!#/1/ )/* +!#""-2R26/)0

•
7' / 26/)0
•
7';.3)'7?:
 26/)0
•
7'  
  
 #&  ( 
/ *   
  

5&+5-26/)0
•

  4( $ * +& 
/ /&  42   2 & 
 /
/
/#-26/)0
•
%'*4(+)0-)   *1/

/
/ 
•
7'  /'   &(5/' 0 +7$2 7$2 (4.2 
 &-26/)0+%')  ( 
/

  / &/& *-
•
%//)  <&


"&)  
/ *1' )'/&)

&')''//( //*

&+
&&S5/ 2')-/
/
 
&&)  & 
////( 
•
&
)'

&& '=
 
5/ 26/)0
•
&(',$ ( 402406/40
'(&'/',$ ( 40



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	



8


 '1// )'
&()  
/(
•
%&'(,$ (   )' ,$// 
&(
•
%&'(,$ ( /,$ (    )
5/ 2885/ 28A5/ 265/ 2E5/ 
•
%&'(,$ (   //,$ ( 
   )E/P85/ 2E8/P5/ 2T5/ )  //
  */

&/( @1/
' 0)  
/
/

=	: $/.1.8

$/.1.-4.1
	 & 

=	C .4
$   *)  /'$.
 

=	C	 -

$/((+$:-)  &//*'73!*;
&&/'/3$
'

7/)  /
)''/ &0+&-
% /( ( +%:$:-)     *1/2     ) /)
#/((&&
/

 / 

/'&'&*$:)*'$:)  /*
'(M'&
&'&)   *1/ 0/''$:
$/&( *)  /;  &/& )''
(
/
)'(**& +!7-//
+%-)  & &
 /
•
$  %:$:&('&
 *
3 /%:$:+7 *2 *2 *3 //, -

•
%:$:*)(*
•

%:$:
•
%:$:)'




	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






%' *&'  )  *

•
;  &/&
•
&/&***& +!7-/&/&%)'
*!7/&&/'  *$/!/

  &
)'%!7+//& 
//&'/
&-)  &
/ *&'& &
 &/&
$ U& &U&
<&/&22#2$:/&2
//)  /'  )*%$:
•

/((+$:-
•
$/(()'&' //'
•
$/(()'&' //&

$  /((&//&'7.)   /'/'
! *%:$:)  
1/' 

=	C	 .
5
 +* &5/ & /
2
 2/*)'2#  */*

-)  /&2(22//' 
&( *( 
/'&' )  /

=	C	 .4
.3.4
..3
.=
( *2&' '/
/*
()  ' ( 
)  
1/"*/( 
)  &
1/ )2 2''/ ' 
/'
/*
'   ( 
)  &/&'( %'' 
&
 '=
&*)' ( 
 )5)'5(' 
(
 ( 
 )5)'5(' 

.=
&* '=
(
 *
 )  /*(

.=
&*  ( 
& /& &  *&*'(
)  (// & 

=	 */
..3

	 & 



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






=	 1
..4

	 & 

 ?A!#
 *"*!
%' <&)  ()'$(//'
()%'$)  / *)'( 'V
(&(/
"   $L// *)  &'&0/2)/

&
  * ' &   $   / )    '  / 
&/
%' (&')  / )'  
' &&&'(
$  )  ( //*'
'
%''

)''$2'&&*/ 
 *)  
&'&0/*'%(2'%)  ()'

/& 2
/ */&' *

@ " 
	&&&)
/



	

	



 
 
 !
"!#
$!"
$
"%
"&'$(
)*(+,
	






: $$"+ 
:	 10.

--
..3
 
&

))/
" / 
   /  
 2 #/  /*
+30
)  2'/'-

<&& &+I-

	
 &
  *0#5#&/

 )'&''
 /'(0
	
    &
  *
0
&)'
 '//

'/'


/ 
/
/& / *'
:#&/ 
   
(
	
/*/(#W/(#
%  #&/ 
 
 0
+

  /*/(#W/(#-
G
7 (
7 & T I /   ' I  ' 
=
/
/*/
0&' (

:	 !

.3
!5
50
$&   2 
+%".-)  (/&
)'&'
&
//)'

/'$%' )  (&''
2' &/'& /& 
/' *
& 

/
&/%'2' )  (/*'
&&'& 
$  

)  '//)''/&*'
/*/(
/
/* 
$  

)  ///'(
'VD#5*RV)'#/
'&
)'

/*' 
'


$  & 

)  /*'
/ * *
 //&'

5('
 +	-/'
5(&
  *
&
'&
 

+-$  & 

)  /

/ + & -
$   )  &//  *'/&' *
 
/'

