Clinical trial NCT02841267
Conditions: LGMD2I
Sponsor: Kathryn Wagner
Start date: 2016-07-01; Completion date: 2019-01-01
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigational product PF 06252616, a humanized anti myostatin monoclonal antibody that neutralizes myostatin (GDF8) is in development for the treatment of Limb Girdle Muscular Dystrophy 2I (LGMD2I) to preserve and/or improve muscle function.

This study will provide the clinical assessment of the safety, tolerability, Pharmacokinetics and Pharmacodynamics of PF 06252616 following repeat IV doses in ambulatory adults with LGMD2I.

Detailed description:
This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the safety, tolerability, efficacy, PK and PD of PF 06252616 in ambulatory adults with LGMD2I. The study design is intended to determine the optimal safe and pharmacologically active dose of PF 06252616 in LGMD2I while providing an opportunity for all subjects to receive active drug for a rare and disabling disorder. The study will be conducted in three periods: Lead-In, Treatment and Follow-up periods. The Lead-In and Follow-up periods will each be 16 weeks to allow an assessment of the change of various outcome measures of this period of time and comparison of change in function before, during and after treatment. The Treatment period will be 32 weeks. Three cohorts of participants will be enrolled and receive escalating doses of PF 06252616. The first cohort will have the option to crossover to the highest dose.

Arms: arm 1: 4 subjects will be enrolled in cohort 1 and will receive an initial dose of 5mg/kg PF 06252616 IV every 4 weeks. Following 32 weeks of treatment and a safety review, if no stopping rules have been met, subjects will be receive an additional 32 weeks of treatment with 40 mg/kg PF 06252616 IV every 4 weeks. arm 2: 8 subjects will be enrolled in cohort 2 and receive 20 mg/kg of PF 06252616 IV every 4 weeks for 32 weeks. arm 3: 8 subjects will be enrolled in cohort 3 and receive 40 mg/kg of PF06252616 IV every 4 weeks for 32 weeks.
Interventions: intervention 1: PF 06252616
Intervention descriptions: intervention 1: None

Protocol documents:
ICF_000.pdf: 

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Approved March 1, 2018
	

	
			

 !"#$%

.&
'()*&	(*'+,	-.,/0	/
!	
B,:*&,D,&),*

7,	*&:
&&
&,**	,*,	,* 6	*	&		
 B,	,**
	
:,A
**(&,	 6
*,&:
:)	&	(*
:
:) ":*
	&*	
*,	:)**,	
,*

&$	B,:)7*	*,*	**&	(*
&	()&	
)*:,*	
*,	 

0$9A	
B,:)7*),,		

*
(*
,	7		,74
	 

%	
?$6	A(&,	)* 
(
A(:)*
:,*
*, B,	:)(,	**,	*2 B,	:
:)(,	*	,* 

,7
B,	)*	,	(	,			*)		>?:)


7* 0:)*	*:
:	,	
,**	,
))&	*&	,	
,**	, 

8>
$
&
&"*:)7&	(,

7,	*
&&*	,,*A
*2 ),)&)*:)


*&	(,		( 

</$
E	:)

*

7,	7*&,
*&&*	,
,*A
*2 

=			&,	&(:
)&
*	,:
,		
,* B,:))	
,*&,	
	*&,)
(	*,	,*,**	,:)*
,* 

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,:)*	)7:	*:&	*&,	
((	,	* :	:*	
,* 

&,	(	&(	
,(,	,	
2	(*)	
	(*

*
		
	,,,* :	:,	(*&
	


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B,:):((>?(,7:)	**
, 6(:),*A
3*2*()
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&$	$	*0-$$	B,:)*(
7&	(,		(),K)&	)&&
&,**	,
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>
*	(
*(
?*&	)&&
&
,**	,,	((,(>((,
?*
*,*
*, 

;!
$$*$		4B-B,:)*(7
	,,,*(,	:(,
&,**	,,	)*		*&( 
),K&)*:)

*&	(,		(*,	
 



Approved March 1, 2018
	

	
			

 !"#$%

:&
'()*&	(*'+,	-.,/0	/
2
		$*	-6(,	
	

&,		*:
)	&	(*:,*
*, 

2		$>,*:&	?:)	&	(*:,*
*,
*	(&				)(((7,&&	,)4,* 

%)
$!	5	
*)5-,	,*,:)7*
D,	)		*(*
,		(	,	
,	& 

&		

	,(	(	,	,	&,:)	&		*(
	
	*	 

,CB,:)7*
(&:D,	:
,*
*,)&,	)(7	&&	:	D, 

 **,-*,	(,
,	D,&&D,	>J3?(,	:,	
*&&
,	*	, 
 4	8	(<4,	2%96D,	:)	,*	*,		
*	)(	*,	(,

* 

8$$B,:&:(
*,	)*
:,*
*,
 
!
(>!?&	
 !&7(,
6:
,*:)*!*

!

	(&)*,(*	*: 	
*,	(,

7'6
		**!A( 6!A(:7),%
(,>	?*),,	>(,
? 		A(,:)7*
(
*	*D,	 6,	&D,	,	,	)&
	!	 

4
!(
,	(:	
	(,(7	
,*&,
(7	(**&)			
		(*
	

	(
*
			( 

&,	&(,	*	,:*A2	A(&,	7,
	*	&*,&!A(&&	, 

6	,	!,:***) &***
:)
*	
:	
,	:)7 6):
,	:)(*
	&
!(:
77		:,) 5,,)(&

&*>
,	)
?(
 &)	,&!&& 

B,(*,		
,*()!&& !

,		7	*2*(
&*	,* 	(&	
!(
(7,*)*

7 B,:)7*:		,	
*&	,	
(&	*,	 &***
:)
*:	

,	:)7 




Approved March 1, 2018
	

	
			

 !"#$%

;&
'()*&	(*'+,	-.,/0	/
,	A(!&&)*	, B,:))	!&& 
6!&&:)7,	,,!A(*(,(	,

		**,	)	(
 B,:	)	D,*
	&
	,,A( 

6!&7(,
(7),,	&	
* "
,&
&(*
	,()
(A,),	
*,		()*&&
,
&	,7 B,(7,	,**
	&	(*
>	-(?:
(,
*,	!
 

	

6!I
*
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	*	(,		&		
,*:)
	:*)D,&*	C,:,*)&,:	(	
*,	*
	&,		,(*

	 6	):	:,	!I	


	*	(:()	(:**A
,* 6:

*G
*&* H:,7:&:,

*&* 

*&
*&*:(

,)(	) 
&
	,(	
((,	( D,&*	>,,(()	
&		
(?:7,&	
*&* B,*
*
&	(),
*&* 

&,:::&	(),
*&*,		(	*
		::
	&	,		*
	&	&,		, 


*&*(
,,&A, 4

*&*:)	&,	
(*
	
	*(&&
,	
,			&,,	&	,	

	 6	7:
	**&,	
* 

6
&	
	:)***		
*&*:,*)
*&	)		
,* 6
:,*),		) 

 ,2	I2	)	(	>I?6:(,	,	)**
(,	,	&*)*( 	*	

,	(,	(,
,*:,	)&	
 B,:)7*
)&	),%(, 
 I&:)*:))**,	3*20%#*
&,	
	**,	3*20%*&,	
'	*% 
 I&*:))**,	0%#*&,	
'	**,	0%*&,	'	*% 
 I:)	&	(*&,,*	 

<6	
$6&:&&,
:)	&	(*:
,*
*,

 3,&,
2::(,
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 ,
4	62:(,	:	(,
&,		(*
,*		 



Approved March 1, 2018
	

	
			

 !"#$%

&
'()*&	(*'+,	-.,/0	/
 6(*&,
:
,*&:
  6(*,*2(*(,	:&,*,&	(:7
&	,		,*:7)
7
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&E	3()>E3?L&((&,		(**

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&		:)	(*:=,*>-&	,*? 
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
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Approved March 1, 2018
	

	
			

 !"#$%

&
'()*&	(*'+,	-.,/0	/
,
	$&&"
829/99
		
(	7:
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,*
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&&
	*,**	,:
	
,* **,7	,*:):
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&&
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,**	,(
, 6,*((,(*
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 6&&
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	 

1&(,&,**	,)*,(*),():*
*(:			*)*&&
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*,*),():*( 6)
,,**	,
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	
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*): 

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
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
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,**(,()	&*,,	*,**	,(
>(7*	? 

*,,	,*(,)C
	
***(	,	
*
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*,* 8:	*,	
**=(* "*	,
&	(
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,*	:	*&&
(*)	*829/99 

(,*&:*&&
:	*

 3	*(
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	,?*
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*&829/99 3	*(:
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*&*(**	
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()	(&,*()))	*)&	)
(	(&,		
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	 
 )*	*(*&&
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	*	
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:)*7&		),*,,		 &)*			*
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 4(
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:	,**	,*:
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
	 (	
	*
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,	*	,,	7
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,*(	&	*&&
 



Approved March 1, 2018
	

	
			

 !"#$%

%&
'()*&	(*'+,	-.,/0	/
1	*&&

 1	>)*?*	,:(	829/99)
(&:(A	
**&&

,*)**7	 
 ,7::	829/99
&&
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6*	,
C
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	()*&		:7	( 

'
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*&&
(A	
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&*&&
	7: 6	()		*,7:*&&

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()&	 

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	
()		7	,7: *	,	7&	
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7 1		
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**,:)(*
&		
	
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(	,		((**&&
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

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
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
>
	(?,	7,()	)&	*
* 

"*

)**	:(
,&&((&)	,	
)*&,
,	 B,(	
((*
>
	(?,	7,()
	)&	*
* 6(,&)*:)7&	(,*,	
	,*:)),=9(3>),
,	%)?&,	'		),%
(>),
,	#)? 

E	*

B,(A	
*
(&	*,	

&,		 

5';B,(A	
*
(&	:
7		
	*		(		(* 
6	()&7				* 

5

	*	(B,(&	,	,	
&	(	*,
	 B,(A	

7		*	&	(,**,	,* 

I*I2	6		
,*
,*A,		*&	(A2		((	 6
	*A,	&			
,	*	&,	(*

	 I2	*((
	
*(
),:*)*,,)		
 



Approved March 1, 2018
	

	
			

 !"#$%

,&
'()*&	(*'+,	-.,/0	/
6	*A,	>I
*)7,A2	?,:		
,*
 /	(>	(,&)	)*	*? 6 %	(		
E*4
	&	(,	,	
7,,	
	&** 6
	7&	(	*A,			
,*	( 

6	*A,	*
	)*	:,:&	(		
,* *

,*A,	,(	
*	:	
&	(	(*
,*&
,*		&,	(*

	 &,D,),(,&	*,
:)	
,,*7,	*
	 

88
,*
,*--*
(
*
(&		& 

!6&&
&(
&*!
	)A,** 
&
	7)&,*&	(,&!
,())	*)!(

*)&&)
*>
,	)? B,:)7*:		,	
	:( B,:))7	,*&,&
&:)
,&	7&	(!	&
	
(7	(		
(
)C
,	)*>
,*,		? B,()
(A,&	(

:,( 6!
*A,A2		* 

3	-(>?	:*--&
	**
,
),		*
	),		
(

,	 4	,*&&
()
,7)
,&:*&		
*,	 6*&&

,*(+(*

>,
,
*	,&,
*?,		*
	*&&
,
7
,,,:7	,):7((		)(&&
>,

&				?	,))	>
*,	?

*(,
),	*(,
),(&(	*
(&	 
(*
(),*,		
*,	 B,(((()**(*
)	,	,*&		
*,	 6		7&&
	*(*((
&	(&	((,
) ((

&)*,*	7 &
((

,	**,		
,)*()
	 6	7&&

	*(*((&	(&	(*(,
)M>? 

8,
(B,(&((**
(&	*+	)
(	**),)*
(&	7*&, ,	,&,
,(A	
*--
	***,	*&	 B,
&(&		 

4
+J,	6
	D,	(
D,	,	 
B,(	&,:	D,(7,&,
(&	) &,

	&	

(D,	,,*

,	,**
	 B,(	*	)	*:
:	7,D,	,	
(D,	 B,*:	
D,,*::	 

!:&	*'	
(*B,(A	
*
(&	*&()		*
::	D,),,	((	,	*	(*&
	
 

6('(((6		
,*(,,* B,((((:	7
*:&( 	-	
,*&
(
(((@	&	
::*,	)
*,,	

 



Approved March 1, 2018
	

	
			

 !"#$%

8&
'()*&	(*'+,	-.,/0	/
'&*6		7&	(),,()
(7:,*
,* :	((-

&)	(	*&	&	(
)*(

* 4(:))*:
**7
*:)7
:	*2	
*
(,	.<7:)

)	

	*,*7	 6(:)	*&

)4	 

B,(&**	
*	D,	
&&	 **(
(),
(&	) 

6	()*&&
**
(&		7: 

8

	"
6&&
&829/99	(	
	,	
*	7: &,	

)
*	*	A,
,(,,)	
	
*

		
	,,	,* 

6		7:	7&	(!(:,
	*,		
 6	()	7&	(
	-( 6	()	7	
,		,7: 

6,**
	:*
,:,:*(*&)	
	*,			
,*
*:,
)	
			&	, 6,**
	:	,
,

*
		
,&,	
*)	
	(**	:
,	,&)	

	 


8((7**	)(		*,
	>)
7**(&&

	?*	>:7?&
	A* 
(,7::	829/99

,	(()	+&,:
	:( 829/99,*):(:

*	:	
,&&
(*&
	
 
,7::	829/99*,((7 6	&	829/99,*
):(:	,	)) 

	6

 /
"	
	(*:,*
*
		
		&
 &,)
(
		&	
*	:	D,	*)	
	*,	,*,,*
,**
	((* B,():*	:&	(,*&,*
,)	
	
)
(		&	
*

*
	::)7
	&,*,		
,7	
,* 6,**
	:7&,	,					
*
	:	*
,*		&	
*,
( 

6		
(,	()		&,::*
,		7: 

<
!&!"
6	(	()*	
)&,&	(),* <:		,	
,:)&: 

&	(&	(,*(	:3;&,,	 



Approved March 1, 2018
	

	
			

 !"#$%

<&
'()*&	(*'+,	-.,/0	/
=
& !"
&,*
*C,*		) B,*C,*
	( 1		((
,*
	&		*	(*),	

 

6,**
	:*
,:,	7*)&&		( 
B,*C,* &,*C,	
	*		*.<7
:)&&
* 

.


	!"
6	:)
	,&	,		
,* 6,**	,,*2	*
	
*,	*,*:)	**
	,	,	,	

( 
*
,		*7	&,*:)	**	*&	 

B,:*
,),
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(&	7	,* !)	A>
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* ***,	
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,*,	,**
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&	(	*	,*	&&
,(A	
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,* &,	7,	,	-,
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Approved March 1, 2018
	

	
			

 !"#$%

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'()*&	(*'+,	-.,/0	/

$ &
"
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 4,*:,*)	(&, 
 B,*	(:*,* 
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 
 B,)
(	 
 6,*
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* 
 6	()		7,,&,*:*7:( 

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*&&	(**&	,*	&:2,


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(	 

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
*&	(,
)*	*)(7:		D,
,**
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*&	(,	(:)7(
,&,* 


#  

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&	(),, 8*	*:*&*	(*
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	,	(
	(? 

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,	,	*
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),	*
	&	,	& 

,*&.<7(*		
,	&	(&	,* 5A(

,*	(
>,
8**	,*(	?&(		
,**
(	,* 

&,	

	,*	
&*	&,*'
	,>'?:
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*,*:,,	,	-,*,,	&	( B,*
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:,**
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	)*&	(*,	
&	

	
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,	&	(()
	*)
	(	)&*		
!, 	(7,		:*,	
&	(7
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,	,	&	(:)	2*
* 



Approved March 1, 2018
	

	
			

 !"#$%

.&
'()*&	(*'+,	-.,/0	/
6,**
,	&,	&	((( B,(	7>

?,		(
,**
,	&	(()&	
	&,*)
	:	 &,

	
	),(,&:2,:
:		D,
,*,*,()	*,	

&	( 6	
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	F(**	*&A&	(	&
&	( 

&,*
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,	,	-,**
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*&,		&	(),,:)

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>
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	
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,	,	- 

%


D&
	

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	&,*		
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		*	 B,:)7*,&	
		*	,, 

5A51)52#1)92)3(6)(((*
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
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NNNNNNNNB:,**
	&	((	(	
	
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&(
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NNNNNNNN*:,**
	&	((	(	
	
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NNNNNNNN*	(	
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,
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!&'"
.<7*		(,&,	,			)*	,&	()
,* <:	(*
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&		(	
	,	
	,&,*2	*C,		

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"&	(,:,	,7
(&	C,	 

%

 !	"
 
5 >*5>- 	"
6.<7*
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 
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 5
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6!"	:,(		
,* 	
	*:&	&7	
,* B,(

!"&,D,),,			
	
&,7,)	*&	 6!"&&
,()	=2#//2% B,(

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		
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Approved March 1, 2018
	

	
			

 !"#$%

:&
'()*&	(*'+,	-.,/0	/
.<74
&*
,!:"	*>!"?	:,*
	>,?	)&	&
*,
&,**&	
&:	
	*).<7!" 

&,		
*		,,(

	'A0
	*
*!	
*(		==%2#%2#% 

! &D!"
'	
		 		==%2#%2#// &,:,(

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SAP_002.pdf: 
DMB02-GSOP-RF03 1.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR WRD STATISTICS 02-APR-2012
Page 1 of 31
This Document is Company Confidential.  The official version of this template is located in the electronic document repository 
accessible via the global SOP Portal DMB02 home page.
Protocol WI203720
A Phase 1b/2, Open-Label, Multiple Ascending Dose 
Study to Evaluate the Safety, Tolerability, Efficacy, 
Pharmacokinetics and Pharmacodynamics of PF-
06252616 in Ambulatory Participants with LGMD2I
Statistical Analysis Plan 
(SAP)
Version: 1.0
Author: Nazila Shahri
Date:
7-February-2019


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................7 
2. INTRODUCTION .......................................................................................................................7 
2.1. Study Design ...................................................................................................................7 
2.2. Safety Monitoring and Dose Escalation..........................................................................8 
2.2.1. Dose Escalation and Stopping Rules ..................................................................9 
2.2.2. Safety Monitoring Committee (SMC)................................................................9 
3. BLINDING ................................................................................................................................10 
4. STUDY OBJECTIVES..............................................................................................................10 
4.1. Objectives......................................................................................................................10 
4.1.1. Primary .............................................................................................................10 
4.1.2. Secondary .........................................................................................................10 
4.1.3. Exploratory .......................................................................................................11 
4.2. Endpoints.......................................................................................................................11 
4.2.1. Primary Safety ..................................................................................................11 
4.2.2. Secondary Endpoints ........................................................................................11 
4.2.2.1. Pharmacokinetic..............................................................................11 
4.2.2.2. Pharmacodynamic ...........................................................................11 
4.2.2.3. Strength and Function .....................................................................11 
4.2.2.4. Patient Reported Outcomes.............................................................12 
4.2.2.5. Immunogenicity ..............................................................................12 
4.2.3. Exploratory Endpoint........................................................................................12 
4.2.3.1. Pharmacologic.................................................................................12 
4.2.3.2. Function...........................................................................................12 
5. ANALYSIS SETS .....................................................................................................................12 
5.1. Full Analysis Set ...........................................................................................................12 
5.2. Safety Analysis Set........................................................................................................12 
5.3. Other Analysis Sets .......................................................................................................12 
5.3.1. PK Concentration Analysis Set ........................................................................12 
5.3.2. GDF-8 Concentration Analysis Set ..................................................................13 
6. ENDPOINTS AND COVARIATES .........................................................................................13 
6.1. Safety Endpoints ...........................................................................................................13 
6.1.1. Vitals,ECGs and Cardiac Echocardiogram.......................................................13 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
6.1.2. Laboratory Data................................................................................................13 
6.1.3. Adverse Events .................................................................................................14 
6.1.4. Physical Examination/Nose and Throat Exam .................................................14 
6.2. Secondary Endpoints.....................................................................................................14 
6.2.1. Patient Reported Outcomes ..............................................................................15 
6.2.2. PK Endpoints....................................................................................................16 
6.2.3. PD Endpoints....................................................................................................16 
6.2.4. Columbia-Suicide Severity Rating Scale (C-SSRS).........................................16 
6.3. Covariates......................................................................................................................17 
7. HANDLING OF MISSING VALUES ......................................................................................17 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................17 
8.1. Statistical Methods ........................................................................................................19 
8.2. Statistical Analyses .......................................................................................................19 
8.2.1. Safety Analysis .................................................................................................19 
8.2.1.1. Adverse Events................................................................................19 
8.2.1.2. Vital Signs.......................................................................................19 
8.2.1.3. Electrocardiogram ...........................................................................20 
8.2.1.4. Cardiac MRI/Echocardiogram ........................................................20 
8.2.1.5. Liver MRI........................................................................................20 
8.2.1.6. Other Safety Data............................................................................20 
8.2.1.7. Immunogenicity ..............................................................................20 
8.2.2. Secondary Analyses..........................................................................................21 
8.2.3. PK Analyses......................................................................................................22 
8.2.3.1. Concentrations below the limit of quantification............................22 
8.2.3.2. Deviations, missing concentrations and anomalous values ............22 
8.2.3.3. Pharmacokinetic parameters ...........................................................22 
8.2.3.4. PK Concentrations...........................................................................23 
8.2.4. GDF-8 Analysis................................................................................................23 
8.2.4.1. Deviations, missing concentrations and anomalous values ............23 
8.2.4.2. GDF-8 Concentration......................................................................24 
8.2.5. Other Analyses..................................................................................................24 
8.2.5.1. Exploratory Analyses ......................................................................24 
9. REFERENCES ..........................................................................................................................25 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
APPENDIX 1.................................................................................................................................26 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
LIST OF ABBREVIATIONS
This is a list of abbreviations that may be used in the SAP.
Abbreviation
Term
2MWT
two minute walk test
4SC
four stair climb
10MR
ten meter run
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
CL
clearance
C-SSRS
Columbia Suicide Severity Rating Scale
DXA
dual energy x-ray absorptiometry
ECG
Electrocardiogram
FAS
full analysis set
FEV1
Forced expiratory volume in 1 second
FSH
follicle stimulating hormone
FVC
forced vital capacity
GDF-8
growth differentiation factor 8
GGT
gamma-glutamyl transferase
GLDH
glutamate dehydrogenase
InQoL
Individualized Neuromuscular Disease Quality of Life
IRB
institutional review board
IV
intravenous
LH
luteinizing hormone
LGMD2I
limb girdle muscular dystrophy 2I
LVEF
left ventricular ejection fraction
LVESV
left ventricular end systolic volume
MEP
mean expiratory pressure
MIP
mean inspiratory pressure
MMT
manual muscle testing
MRC
Medical Research Council
MRI
magnetic resonance imaging
Nab
neutralizing antibodies
PK/PD
pharmacokinetic/pharmacodynamics
PT
prothrombin time
PUL
Performance of Upper Limb
RNA
ribonucleic acid
SAP
statistical analysis plan
SF-36
Short Form 36 Health Survey
SMC
Safety Monitoring Committee
SOP
standard operating procedure
TEAEs
treatment emergent AEs


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 6
TIBC
total iron binding capacity
TUG
timed up and go


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 7
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This is the initial version of the statistical analysis plan.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Design
This is a Phase 1b/2, open-label multiple ascending dose study to evaluate the safety, 
tolerability, efficacy, PK and PD of PF-06252616 administered to in ambulatory participants 
diagnosed with LGM2I.  Three IV infused dose levels administered every 28 days will be 
investigated in a dose escalating fashion.
PF-06252616 dose levels:

5 mg/kg.

20 mg/kg.

40 mg/kg.
Approximately 20 eligible subjects will be consecutively assigned to 1 of 3 cohorts for 
approximately 96 weeks (cohort 1) or 64 weeks (cohorts 2 and 3).
Cohort 1 (n=4):

Lead-in period (16 weeks)

Treatment A: PF-06252616 5 mg/kg (32 weeks)

Treatment B: PF-06252616 40 mg/kg (32 weeks)

Follow-up period (16 weeks)
Cohort 2 (n=8):

Lead-in period (16 weeks)

Treatment: PF-06252616 20 mg/kg (32 weeks)

Follow-up period (16 weeks)
Cohort 3 (n=8):

Lead-in period (16 weeks)


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8

Treatment: PF-06252616 40 mg/kg (32 weeks)

Follow-up period (16 weeks)
At each dose level, subjects will be followed for an initial 16-week lead-in period to establish 
individual change in disease progression.  
The study will begin with 4 subjects being enrolled into Cohort 1.  Following the lead-in 
period, subjects in Cohort 1 will be dosed with 5 mg/kg for a total of 32 weeks (8 doses).  
Cohort 2 will begin dosing at the mid dose level (20 mg/kg) once safety has been confirmed 
with subjects in Cohort 1 who have been treated for 16 weeks.  Cohort 1 and 3 will begin 
dosing at the highest dose level (40 mg/kg) once safety has been confirmed with subjects in 
Cohort 2 who have been treated for 16 weeks. 
Each dose level will be evaluated for 32 weeks (8 doses each). Cohort 1 is the only cohort 
who will receive 2 dose levels (5 mg/kg and 40 mg/kg) and their total treatment time will be 
64 weeks.  
At the conclusion of the treatment period, subjects will be followed for an additional 16 
weeks to monitor for safety, PK and duration of response. 
2.2. Safety Monitoring and Dose Escalation
Safety monitoring will be conducted by the Investigator, Pfizer Medical Monitor and an 
External Medical Monitor.  This group will be refered to as the Safety Monitoring Committee 
(SMC).  Safety monitoring by these individuals will include the following reviews:  

Dose escalation


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9

Quarterly safety and

Ad hoc safety
At each review, a consideration will be made of the number of subjects who have severe AEs 
or serious AEs in the same organ system which are determined to be related to 
investigational product.   The first dose escalation decision, whether or not to increase from 
5 mg/kg in Cohort 1 to 20 mg/kg in Cohort 2 will occur after review of all safety data after 
the 4th subject of Cohort 1has completed the planned 16 weeks (day 85) or 4 doses.  The 
second dose escalation decision, whether or not to increase from 20 mg/kg in Cohort 2 to 40 
mg/kg in Cohorts 1 and 3 will occur after the 4th subject in Cohort 2 had completed the 
planned 16 weeks (day 85) or 4 doses.  The SMC may determine it is necessary to close or 
adjust a dose level within the study.
2.2.1. Dose Escalation and Stopping Rules
Table 1.
Criteria to Determine Dose Escalation or Stopping
DECISION
CRITERIA
Dose Escalation
SMC review of aggregate safety data from either:

Cohort 1 (n=4) 16 weeks (day 85) or

Cohort 2 (n=4) 16 weeks (day 85) 
and agree that safety is met and
The estimate as determined by R2* value is within the normal range (R2*139 
Hz at 3.0 T ) 1,2,,3
No Escalation, Stop 
Dosing
SMC review of aggregate safety data from either:

Cohort 1 (n=4) 16 weeks (day 85) or

Cohort 2 (n=4) 16 weeks (day 85) 
And agree that the current dose is not safe or
The liver iron content estimate as determined by R2* value is above the “mild 
overload” range for any subject within the cohort (R2* >369 Hz at 3.0 T) 1,2,3
If dosing is terminated at any dose level, subjects will continue to be followed for resolution 
of the safety finding or until a new baseline is established.  Depending on the nature of the
reason for stopping dosing, the SMC will consider if the enrolled subjects can be continued 
at a lower dose level. 
2.2.2. Safety Monitoring Committee (SMC)
The SMC will be composed of three members:  The Investigator, Pfizer Medical Monitor and 
an External Medical Monitor.  The External Medical Monitor will be a clinical trialist and 
an expert in the neuromuscular field.  The External Medical Monitor will not be a member of 
the Investigator’s institutions (Johns Hopkins School of Medicine [JHSOM] and Kennedy 
Krieger Institute [KKI]) nor an employee of Pfizer.  The SMC will be responsible for ongoing 
safety monitoring from the initiation of the study through the final study visit.  Reviews will 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 10
include aggregate safety, targeted medical events of special interest including liver toxicity, 
and serious AE data.  The SMC may also complete ad hoc safety reviews.  Ad hoc PK data 
may be provided to the SMC as requested. 
Following the data review, the SMC will determine if the study should be continued with no 
changes, modified, or stopped (eg, due to safety). Decision to continue the study must be 
unanimous.  Decision to stop the study can be made by any of the three memebers. In all 
other decisions, the External Medical Monitor will cast the deciding vote.  The 
recommendations made by the SMC to modify the study will be forwarded to JHSOM IRB for 
final decision.  At any time the SMC may indicate that the limit of safety and/or tolerability 
has been reached and that any of the dose levels will be removed from the study.
The SMC will consider the following safety criteria during their safety review:

The number of subjects who have severe AEs or serious AEs in the same organ 
system which are determined to be related to study medication.

Other findings that indicate that dose escalation should be halted.
3. BLINDING 
This study is open label.  Subjects, investigators and pharmacists will be aware of the active 
treatment and dose level.  
4. STUDY OBJECTIVES
4.1. Objectives
4.1.1. Primary

To determine the safety and tolerability of multiple ascending repeat IV doses of 
PF-06252616 in ambulatory participants with LGMD2I.  
4.1.2. Secondary

To assess the PK exposures of PF-06252616 in LGMD2I.

To evaluate the PD activity of PF-06252616 based on the percent change of muscle 
volume as measured on MRI compared to baseline.

To evaluate the PD activity of PF-06252616 based on GDF-8 (myostatin) modulation 
in blood and in tibialis muscle.

To characterize the functional effects of PF-06252616 on muscle strength and 
functional assessments compared to baseline.

To characterize the effects of PF-06252616 on respiratory function compared to 
baseline.


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 11

To characterize the effects of PF-06252616 on Patient reported outcome measures. 

To evaluate the immunogenicity of PF-06252616.
4.1.3. Exploratory

To evaluate functional outcome measures in LGMD2I.
4.2. Endpoints
4.2.1. Primary Safety

Incidence of dose limiting or intolerability treatment related AEs by day 337 or 561.

Incidence, severity and causal relationship of treatment emergent AEs (TEAEs) and 
withdrawals due to TEAEs by day 337 or 561.

Incidence and magnitude of abnormal laboratory findings (clinical laboratory tests 
[hematology, chemistry], GGT, GLDH, PT,  aPTT, creatine kinase, amylase, serum 
ferritin, serum iron, % transferrin saturation, Total Iron Binding Capacity (TIBC), 
LH, FSH, estrogen, cardiac troponin I, fecal occult blood and urinalysis) by day 337 
or 561.

Abnormal and clinically relevant changes in liver MRI and physical examinations, 
weight, vital signs, ECG, echocardiogram measured LVEF, DXA (bone mineral 
density), menstruation cycle as monitored by diary and C-SSRS (See Appendix 1 And
Appendix 2 of the protocol) parameters by day 337 or 561.  
4.2.2. Secondary Endpoints
4.2.2.1. Pharmacokinetic

All subjects receiving active drug: serum PF-06252616 Cmax and Ctrough for all 
visits with PK collections and at steady-state.
4.2.2.2. Pharmacodynamic

Mean percent change from baseline in muscle volume as measured on MRI.

Total serum GDF-8 concentrations for all visits with GDF-8 collections
4.2.2.3. Strength and Function

Mean change from baseline on function tests including PUL, Timed up-and-go
(TUG), 10-meter walk/run (10MR), 2-meter walk test (2MWT), and 4 stair climb 
(4SC).

Mean change from baseline on pulmonary function tests including forced vital 
capacity (FVC), FEV1(forced expiratory volume in 1 second), maximal 
inspiratory pressure (MIP) and maximal expiratory pressure (MEP). 


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Mean change from baseline on muscle strength by manual muscle test (MMT) and 
Hand-Held dynamometry.
4.2.2.4. Patient Reported Outcomes

Mean change from baseline on Patient reported outcomes (InQoL, SF-36)(See 
Appendix 3 and Appendix 4 of the protocol).
4.2.2.5. Immunogenicity

Incidence of ADA and NAb development.
4.2.3. Exploratory Endpoint
4.2.3.1. Pharmacologic

Mean percent change from baseline in lean body mass by DXA.

Mean percent change from baseline in muscle quality (fat infiltration) as 
measured by quantitative Dixon. 

Mean change from baseline in muscle quality as measured by T1/STIR. 
4.2.3.2. Function

Evaluate the utility and changes from baseline of Functional Workspace as an 
outcome measure for LGMD2I. 
5. ANALYSIS SETS
5.1. Full Analysis Set
All analyses will be based on the full analysis set (FAS) which includes all enrolled subjects 
who have received at least one dose of study drug.  
5.2. Safety Analysis Set
Safety analyses will be based on the full analysis set. 
5.3. Other Analysis Sets
5.3.1. PK Concentration Analysis Set
The PK concentration population is defined as all enrolled subjects who received at least 
1 dose of PF-06252616 and in whom at least 1 concentration value is reported.  


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5.3.2. GDF-8 Concentration Analysis Set
The GDF-8 concentration population is defined as all enrolled subjects in whom at least 
1 concentration value is reported.  
6. ENDPOINTS AND COVARIATES
6.1. Safety Endpoints
Safety data will be summarized according to current Pfizer data standards including 
incidence of anti-drug antibodies and neutralizing antibodies by days 1 (to capture low dose 
safety) and 561 (last visit) for cohort 1 and day 337 (last visit) for cohorts 2 and 3.
At the screening visit, the “ Baseline/Screening” assessment from the Columbia Suicide 
Severity Rating Scale will be performed.  At all other visits the “ Since Last Visit” 
assessment will be performed.  The score at the screening visit will be the baseline. All 
adverse events will be reported under the treatment last received prior to the onset of the 
adverse event.
6.1.1. Vitals,ECGs and Cardiac Echocardiogram
Baseline values for vital signs , ECG and Cardiac Echocardiogram will be the last acceptable 
pre-dose measurement taken either on the day of dosing or at the baseline or screening visit.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula: QTcF 
= QT / (RR)^(1/3), where RR = 60/HR (if RR is not provided).
Echocardiograms should be collected at times specified in the Schedule of Activities (please
see protocol). To ensure safety of the subjects, a qualified individual at the investigator site 
will evaluate the echocardiogram for ejection fraction (EF) and left ventricular end systolic 
volume (LVESV).
6.1.2. Laboratory Data
Using the current Pfizer data standards, the last pre-dose value before the first day of dosing 
is used as the baseline for all laboratory parameters.
Clinical laboratory tests include hematology with complete blood count and differential, 
comprehensive metabolic panel (sodium, potassium, chloride, carbon dioxide, blood urea 
nitrogen, creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase), cardiac troponin I, gamma-glutamyl transferase (GGT), prothrombin 
time (PT), activated partial thromboplastin time (aPTT), creatine kinase, amylase and 
urinalysis.  If total bilirubin is abnormal, direct bilirubin will be tested reflexively.   The 
samples for serum ferritin, serum iron, transferrin saturation and TIBC should be collected 
in the morning following an 8 hour fast. Hormone testing will include LH,FSH and estrogen 
in female subjects only. Laboratory monitoring will also be performed to detect ADA and 
NAb.


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6.1.3. Adverse Events
Severity is the key baseline information for adverse events. To judge an increase in adverse 
event severity after dosing, the post-dosing adverse event severity  will be compared to the 
adverse event severity reported prior to the first day of study drug administration will be 
used.
6.1.4. Physical Examination/Nose and Throat Exam
The physical examination will include head,ears,eyes,nose,mouth,skin,heart and lung 
examinations, lymph nodes, gastrointestinal musculoskeletal, and neurological systems. A 
targeted and throat muscosal exam will be performed according to the Protocol’s Schedule 
of Activities to monitor for any signs of mucosal telangiectasias.
6.2. Secondary Endpoints

Mean change from baseline on function tests including PUL, Timed up-and-go
(TUG), 10-meter walk/run (10MR), 2-meter walk test (2MWT), and 4 stair climb 
(4SC).

Mean change from baseline on pulmonary function tests including forced vital 
capacity (FVC), FEV1(forced expiratory volume in 1 second), maximal 
inspiratory pressure (MIP) and maximal expiratory pressure (MEP). 

Mean change from baseline on muscle strength by manual muscle test (MMT) and 
Hand-Held dynamometry.
Functional Assessment :
Functional assessments will be obtained according to the Protocol Schedule of Activities.  In 
order to provide optimal testing conditions and consistency in endpoint measurements, the 
functional assessments will be performed after the MRI and before needle muscle biopsy 
whenever possible. All functional assessments will be conducted by a trained physiotherapist.  
Pulmonary Function 
Pulmonary function testing will be completed to evaluate the maximal lung function 
recording FVC, FEV1, MIP and MEP. 
4 Stair Climb (4 SC)
The 4 SC quantifies in seconds the time required for a subject to ascend 4 standard steps.  
The method the subject uses (eg, using the hand rails) to climb the stairs is recorded to 
understand any change in technique that occurs over time. 
Two Minute Walk Test (2MWT)
The 2-minute walk test (2MWT) is a shorter measure of walking performance than the 6-
minute walk test (6MWT).  In this test, subjects start from a clearly marked line of tape on the 


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floor and walk up and down a 21 meter hallway for 2 minutes at a fast but comfortable speed 
wearing their regular footwear.
10-meter walk/run
The 10-meter walk/run is a frequently used timed function test in muscular dystrophy trials 
demonstrating good test-retest reliability in several different populations and has been used 
in studies of LGMD2I 19,27. Individuals are instructed to walk at a fast but comfortable speed 
in a long cooridor with an even surface.  Measurement of time begins at a still-standing start 
and stops when the individual passes the 10-meter mark while continuing to walk 2.5 meters 
beyond the mark.   
Timed Up & Go (TUG) 
The Timed Up & Go is a measure of hip strength as well as dynamic balance.  This timed 
function test has good test-retest reliability and has been used in studies of LGMD2I 19,27.
The individual is asked to rise from a seated position in a standardized armchair (44-45 cm),
walk at a comfortable and safe pace to a tape mark on the floor 3 meters away, turn around 
the mark, go back to the chair, turn and sit down. 
Strength Assessment
Muscle strength will be quantified by means of manual muscle testing (MMT) quantified by 
the modified Medical Research Council (MRC) scale and by handheld dynamometer 
quantified in pounds (lbs).  The following muscle groups will be evaluated: shoulder 
abduction, elbow flexion, elbow extension, hip extension, hip flexion, knee extension, knee 
flexion.
Performance of Upper Limb (PUL)
The PUL scale has been devised to assess motor performance of the upper limb.  Motor 
performance will be impacted by muscle strength and contractures and the scale aims to 
incorporate performance of shoulder, elbow, wrist and hand function. 
For all the above endpoints except forced vital capacity, more than one assessment may be 
performed at the site.  If more than one assessment is performed, the site is to record the best 
(maximum) score in the case report forms.  For the forced vital capacity, 3 attempts will be 
made and the percent predicted will be calculated based on the maximum forced vital 
capacity.  
6.2.1. Patient Reported Outcomes

Mean change from baseline on Patient reported outcomes (InQoL, SF-36)(See
Protocol Appendix 3 and Appendix 4).
InQoL
InQoL survey consists of 45 questions within 10 sections. Four sections focus on the impact 
of key muscle disease symptoms (weakness, locking, pain, and fatigue), five look at the 


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impact (degree and importance of impact) muscle disease has on particular areas of life, and 
one section asks about the positive and negative effects of treatment4.
SF36
SF-36 questionnaire is a multi-purpose, short form patient-reported health survey with only 
36 questions. It is a generic measure, providing an 8-scale profile of functional health as 
well as measuring physical and mental health. Each scale is transformed into a 0-100 scale, 
with a score of 0 being equivalent to maximum disability and a score of 100 being indicative 
of no disability5. It provides a measure of relative disease burden and allows differentiating 
the health benefits produced by various different treatments. 
6.2.2. PK Endpoints 
Blood samples for PK analysis of PF-0625616 will be taken according to the Schedule of 
Activities in the protocol. Serum PF-06252616 concentration data for the following subjects 
and visits will be derived.

All subjects receiving active drug: Cmax, and Ctrough for all visits with PF-06252616
dosing.
6.2.3. PD Endpoints 
The baseline for all pharmacodynamics endpoints is the last pre-dose value before the first 
day of dosing.
Graphical analysis of total GDF-8 levels as absolute and percentage of baseline will be 
performed.  Analyses will be employed to determine the effects of dose and concentration on 
the GDF-8 levels over time. The GDF-8 concentrations will be summarized descriptively by 
treatment and time points.
6.2.4. Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be evaluated at times specified in the Schedule of Activities of the protocol.
The Baseline/Screening (Version 1/14/09) (Appendix 1 of the protocol) of the C-SSRS should 
be completed at the Screening Visit (Visit 1).  At all study visits following the Screening Visit, 
the Since Last Visit (Version 1/14/09) (Appendix 2 of the protocol) of the C-SSRS should be 
utilized.  The Since Last Visit version refers to the subject’s experience since their last visit.
At Screening or Baseline, if the subject endorses a 4 or 5 on the C-SSRS ideation section or 
reports any suicidality behavior, then the subject is not eligible for study participation and 
an evaluation of suicide risk (risk assessment) must be completed. 
At every visit after Screening, if the subject endorses a 4 or 5 on the C-SSRS ideation section 
or reports any suicidality behavior, then the subject must be discontinued as outlined in 
Section 6 of the protocol, Subject Withdrawal and evaluation of suicide risk (risk assessment) 
must be completed. 


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6.3. Covariates 
Covariates will be summarized for the FAS and by treatment. Continuous baseline covariates 
will be summarized by: n, mean, median, standard deviation, min and max. Binary and factor 
covariates will be summarized by percent and counts.
Additional covariates including the qualitative assessment for the 4SC will be summarized 
over time and may be explored in the modeling of the 4SC statistical analysis.
7. HANDLING OF MISSING VALUES
Missing data for the secondary endpoints will be imputed using maximum likelihood 
techniques for a mixed effects model.  This analysis is unbiased under the assumption of 
missing at random when the model assumptions hold.  Subjects who lose motor functions 
(e.g. TUG, 2MWT) will be regarded as missing not at random.  Additional imputation 
methods to assess the sensitivity of the analysis to missing not at random data may also be 
performed.  A completer analysis will also be conducted as a sensitivity analysis.
Missing data for the patient reported outcome will be handled according to the guidance of 
the developers.
Laboratory values below the limit of quantification will be analyzed at the limit of 
quantification for that parameter except for PK data.  For laboratory listings, the <BLQ will 
be used with the actual limit of quantification used in place of BLQ.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
Continuous variables will be summarized by the number (N), mean, median, standard 
deviation, minimum and maximum.  Categorical variables will be summarized by percent 
and counts.  All summaries will be displayed by treatment. Efficacy data will be listed, 
tabulated and graphically represented, as appropriate.  
All analyses will be based on the full analysis set (FAS) which includes all enrolled subjects 
who have received at least one dose of study drug.  
Below is outlining the definition of baseline for secondary endpoints :
As per Figure 1 below shows each treatment period has been divided into 16 week intervals.
Endpoint is the change from the baseline to the subsequent 16th week.
A placebo group is constructed by combining the 3 cohort’s running periods. Each cohort has 
an initial 16 week running period , they are combined together to form a placebo group 
which will be used as a comparison group, testing against active treatments. There will be a 
total of 20 subjects in the placebo group. 
For cohort 1 the first comparison would be : placebo ( 3 cohort’s running periods) vs. active 
treatment (1st interval ) which starts from the end of the running period to the end of the first 
16 weeks of active treatment i.e. week 17 to week 32. The next comparison would be placebo 


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vs. active treatment (second interval) which starts from the end of the second 16 week active 
treatment i.e. week 33 to week 48. Then the next comparison would be placebo vs. active 
treatment (third interval) i.e. week 49 to week 64. Finally comparing placebo vs. active 
treatment (fourth interval) i.e. week 65 to week 80, as shown in the table 1 below.
The above rational is to be used for cohorts 2 and 3.
To conclude there will be 8 statistical tests. 
Table 1. Active Treatment Intervals
Active treatment Intervals
Cohort 1
Cohort 2
Cohort 3
17-32
17-32
17-32
33-48
33-48
33-48
49-64
65-80
Figure 1. LGMD2i Active vs. “Placebo”
Baseline 
of 
Placebo 
Baseline of 
Active 
Baseline of 
Active 
Baseline of 
Active 
Baseline of 
Active 
Baseline of 
Active 
Baseline of 
Active 
Baseline of 
Active 


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8.1. Statistical Methods
The planned statistical methods and analyses for the primary and all secondary endpoints are 
described in detail in Section 8.2.1and Section 8.2.2 below.
To explore the data further and to assess the goodness-of-fit of all statistical models, separate 
SAS datasets will be provided by the clinical programmer to the statistician. Covariates for 
data exploration may include baseline and/or demographic covariates such as gender, age, 
weight (continuous and/or Pfizer standard categorical cut-offs), site, country, etc.
8.2. Statistical Analyses
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for safety (adverse events and laboratory data), pharmacokinetics 
(PK) and all secondary efficacy measures (FAS).  Frequency counts will be supplied for 
subject discontinuation(s) by treatment.  Data will be reported in accordance with the sponsor 
reporting standards.
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by treatment cohort in accordance with the sponsor 
reporting standards.
The following data will also be summarized by treatment and in accordance with the current 
sponsor reporting standards:
Discontinuations, adverse events, laboratory data, vital signs, ECG and concomitant 
medication data will be summarized by treatment and in accordance with current Pfizer data 
standards.
8.2.1. Safety Analysis
For all safety variables and vital signs, the baseline will be predose measurement taken either 
on the day of dosing or at the baseline or screening visit.
8.2.1.1. Adverse Events
All adverse event summaries will be presented for the complete study.  Additionally, 
summary tables of the most frequent adverse events will be presented by cohorts.  Based on 
the review of the frequency and timing of adverse events, additional summaries may be 
requested.
8.2.1.2. Vital Signs
Systolic blood pressure, diastolic blood pressure and pulse rate will be listed and tabulated 
by dose group and week with descriptive statistics.  Change from baseline will also be 
summarized using the same descriptive statistics by dose group and visit.


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8.2.1.3. Electrocardiogram
The following ECG data will be listed: QT, QTc (Fridericia’s), heart rate, QRS duration, PR 
and RR interval.
Baseline and change from baseline for QT, QTcF, heart rate, QRS, PR and RR will be 
summarized using descriptive statistics by treatment and study week. Any triplicate 
measurements will be averaged prior to the calculation of summary statistics.  For QTcF a 
classification of absolute values and increase from baseline will be used.
The number of subjects with average of the triplicate QTcF <450 ms, 450 ms QTcF 
<480 ms, 480 ms  QTcF <500 ms and QTcF values 500 ms will be tabulated by treatment 
and visit. The number of subjects with maximum increase from baseline QTcF <30 ms, 
30 ms  QTcF <60 ms and QTcF 60 ms will be tabulated by treatment and study week.  In 
addition, the number of subjects with uncorrected QT values 500 ms will be summarized.
Triplicate measures will be averaged prior to categorizing subjects.  However, the number of 
subjects with any single uncorrected QT value 500 ms (not the average) will be 
summarized.
8.2.1.4. Cardiac MRI/Echocardiogram
The mean absolute and percent change from baseline in LVEF and LVESV will be evaluated.
LVEF shift tables will be prepared for cohorts and the total.  
8.2.1.5. Liver MRI
The mean absolute and percent change from baseline in the R2* value will be tabulated for 
each subject. Summaries of the categorical assessment of iron overload (normal, above 
normal, etc.) will be presented.
8.2.1.6. Other Safety Data
C-SSRs, DXA (spine and hip), prior medication(s), medical history and physical examination 
will be listed in accordance with the sponsor reporting standards but not subjected to formal 
statistical analysis.
Any other screening data that is captured on the study database will be listed.
8.2.1.7. Immunogenicity
Immunogenicity analysis will be based on the immunogenicity analysis population which 
will be the same as the safety analysis population.  This will include anti-drug antibody and 
neutralizing antibody development by all visits with ADA samples until the end of follow-up.
Both continuous endpoints (titer) and categorical endpoints (i.e. positive, negative and 
inconclusive) will be reported for the anti-drug antibody and neutralizing antibody assays by 
dose and sampling time points.  Data permitting, the incidence of anti-drug antibody and 
neutralizing antibody will be summarized by time points within each dose cohort and may be 


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also summarized by dose.  The impact of anti-drug antibody and neutralizing antibody on PK 
and PD parameters and profiles, efficacy and safety may be also evaluated but no formal 
statistical inference will be drawn.
8.2.2. Secondary Analyses
The secondary endpoints, change from baseline in FVC, muscle strength, timed function tests 
and patient reported outcome measures, will be analyzed based on the FAS using a mixed 
effects model with REML estimation. The change over the lead-in period, treatment, time 
and treatment by time interaction and will be included as fixed effects in the model.  The 
following covariance structures and random effects will be considered: Marginal 
Unstructured, Marginal Variance Components, Marginal Compound Symmetry, Variance 
Components with Random Intercept, Unstructured with Random Intercept and Slope, 
Compound Symmetry with Random Intercept and Slope, Spatial Linear with Random 
Intercept and Slope. Choice of final model will be based on minimum AIC. 
.
The dependent variable:  change from Visit 3 at each post-baseline interval, i.e.:
Change over post-baseline interval 1: (visit 7 –visit 3)
Change over post-baseline interval 2: (visit 11-visit 3)
Change over post-baseline interval 3: (Visit 15-Visit 3), for Cohort 1 only
Change post-baseline interval 4: (Visit 19-Visit 3), for Cohort 1 only 
Covariates are :

Fixed effects:
o
Baseline interval change (Visit 3 – Visit 2)
o
Treatment category (Dose= “5mg/kg”, “5 + 40 mg/kg”, “20mg/kg” or 
“40mg/kg”) 
o
Time coded as Interval Indicator
o
Treatment category by time interaction

Random effects:
o
Choice among Marginal Model, Random Intercept Model, and 
Random Intercept and Slope are selected based on the minimum AIC
Model-estimated change over each post-baseline interval with, 95% two-sided confidence 
intervals, will be displayed in tabular format.
For each dose level graphical displays will show model-based estimates of change in the 
mean functional measure from visit 3 at each visit and corresponding confidence intervals
derived from the model.
Additionally a completer analysis will also be conducted as a sensitivity analysis for the 
missing data handling under the mixed effects modeling.  The completer analysis will only 


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include subjects that completed all assessments at the last scheduled visit using the same 
longitudinal mixed effects model as the primary analysis.  
Transformation of the data will be considered if model assumptions are not met.
8.2.3. PK Analyses
8.2.3.1. Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
8.2.3.2. Deviations, missing concentrations and anomalous values
In summary tables and plots of the median values at each time point, statistics will be 
calculated having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (i.e. not done) or NS (i.e. no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
8.2.3.3. Pharmacokinetic parameters 
Nominal PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (i.e. not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (i.e. analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as incomplete administration of the IV infusion dose), this will be 
footnoted in summary tables and will not be included in the calculation of summary statistics.
The PK parameters will be listed and summarized for subjects in the PK parameter analysis 
set. Parameters will be summarized by cohort and dose.  Each PK parameter will include the 
set of summary statistics as specified in the table below:


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Table 3.
PK Parameters
Parameter
Summary Statistics
Cmax, Ctrough, 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean, geometric CV%
8.2.3.4. PK Concentrations
To assess the PK profile of PF-06252616, PK concentrations will be listed, summarized and 
plotted for subjects in the PK analysis set, where missing and BLQ values will be handled as 
detailed in Section 8.2.4.2.
Presentations for PF-06252616 will include:

A listing of all concentrations sorted by dose, subject ID, cohort and nominal time 
postdose.  The listing of concentrations will include the actual sample collection times, 
and the time of dosing.  Deviations from the nominal time will be given in a separate 
listing.

A summary of concentrations by cohort, dose and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median trough (predose) concentrations against nominal dosing week by cohort and dose.
Individual subject trough concentrations will also be plotted.  Linear scale. 

Median concentrations at the end of infusion (nominally at 2 hour post start of infusion) 
against nominal dosing week by cohort and dose, as described above for trough 
concentrations.  Individual subject end of infusion concentrations will also be plotted.   
Linear scale.
The range for the x-axes of these plots will be decided on review of the data, and will depend 
on how long PF-06252616 concentration is quantifiable in the matrix.
For summary statistics and median plots by sampling time, the nominal PK sampling time 
will be used.  For individual subject plots by time, the actual PK sampling time will be used.
8.2.4. GDF-8 Analysis
8.2.4.1. Deviations, missing concentrations and anomalous values
In summary tables and plots of the median values at each time point, statistics will be 
calculated having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (i.e. not done) or NS (i.e. no sample),


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2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
8.2.4.2. GDF-8 Concentration
To assess the PD profile of PF-06252616, GDF-8 concentrations will be listed, summarized 
and plotted for subjects in the PD analysis set, where missing the data will be handles as 
outlined in Section 8.2.5.1.

A listing of all concentrations sorted by dose, subject ID, cohort and nominal time 
postdose.  The listing of concentrations will include the actual sample collection times, 
and the time of dosing.  Deviations from the nominal time will be given in a separate 
listing.

A summary of concentrations by dose, cohort and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median total GDF-8 concentrations and Change from Baseline against nominal time 
postdose by cohort and Dose.  Linear scale.

Mean total GDF-8 concentrations and Change from Baseline against nominal time 
postdose by cohort and Dose.  Linear scale.

Individual total GDF-8 concentrations and Change from Baseline against actual time 
postdose by cohort and Dose (including all subjects). Linear scale.
The range for the x-axes of these plots will be decided on review of the data, and will depend 
on how long GDF-8 concentration is quantifiable in the matrix.
For summary statistics and median plots by sampling time, the nominal GDF-8 sampling 
time will be used.  For individual subject plots by time, the actual GDF-8 sampling time will 
be used.
8.2.5. Other Analyses
8.2.5.1. Exploratory Analyses
All exploratory endpoints, including the pharmacologic and health outcome endpoints will be 
summarized by treatment group.  Additional analyses may be performed to understand the 
relationship between these endpoints and treatment.  
Any population PK/PD analysis conducted will be reported separately.


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Additionally, data permitting, relationships between PF-06252616 PK, GDF-8, imaging data 
(DXA, MRI), functional assessment, immunogenicity and any safety signals may be explored.
9. REFERENCES
1
Hankins, J. S. et al. R2* magnetic resonance imaging of the liver in patients with iron 
overload. Vol. 113 (2009).
2
Wood, J. C. et al. MRI R2 and R2* mapping accurately estimates hepatic iron 
concentration in transfusion-dependent thalassemia and sickle cell disease patients.
Vol. 106 (2005).
3
Storey, P. et al. R2* imaging of transfusional iron burden at 3T and comparison with 
1.5T. Journal of Magnetic Resonance Imaging 25, 540-547, doi:10.1002/jmri.20816 
(2007).
4
Marshall, W. A. & Tanner, J. M. Variations in the Pattern of Pubertal Changes in 
Boys. Arch Dis Child 45, 13-23 (1970).
5
Ware, J. E. SF-36 Health Survey Update. Spine 25, 3130-3139 (2000).


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APPENDIX 1.
Planned Data Display
Item
Number
Title
Population
ENROLLMENT AND DISPOSITION
Table 
Table 14.1.1.1
Subject Evaluation Groups by Cohort
All Enrolled Subjects
Listing
Table 14.1.1.2
Subject Evaluation Groups 
All Enrolled Subjects
Listing
Table 14.1.1.3
Subject Discontinuation
All Enrolled Subjects 
DEMOGRAPHICS
Table 
Table 14.1.1.4
Subject Demographics and Baseline Characteristics
FAS
Listing
Table 14.1.1.5
Subject Demographics and Baseline Characteristics
FAS
Listing
Table 14.1.1.6
Clinical Significance of Physical Examination
FAS
Study Drug
Table 
Table 14.1.1.7
Summary of Number of Subjects by Cohort and Dose Level    
FAS 
Listing
Table 14.1.1.8
Administration Schedule                                                               FAS 
Listing
Table 14.1.1.9
Infusion Site Assessment
FAS
Listing
Table 14.1.1.10
Dose Administration by Dose Level and Visit
FAS 
Listing
Table 14.1.1.11
Dose Administration by Dose Level, Cohort and Visit
FAS 
Listing
Table 14.1.1.12
Dose Administration by Cohort, Total and Visit 
FAS 
Safety
Table 
Table 14.1.1.13
Treatment-Emergent Adverse Events (All Causalities) by 
Dose Level and Cohort
FAS 
Table 
Table 14.1.1.14
Treatment-Emergent Adverse Events (All Causalities) by 
Cohort and Total
FAS 
Table 
Table 14.1.1.15
Incidence and Severity of Treatment-Emergent Adverse 
Events by Dose Level and Cohort (All Causalities)
FAS 
Table 
Table 14.1.1.16
Incidence and Severity of Treatment-Emergent Adverse 
Events by Cohort and Total (All Causalities)
FAS 
Table 
Table 14.1.1.17
Treatment-Emergent Adverse Events (Treatment Related) by 
Dose Level and Cohort
FAS 
Table 
Table 14.1.1.18
Treatment-Emergent Adverse Events (Treatment Related) by 
Cohort and Total
FAS 
Table 
Table 14.1.1.19
Incidence and Severity of Treatment-Emergent Adverse 
Events by Dose Level and Cohort (Treatment Related)
FAS 
Table 
Table 14.1.1.20
Incidence and Severity of Treatment-Emergent Adverse 
Events by Cohort and Total (Treatment Related)
FAS 
Table 
Table 14.1.1.21
Serious Adverse Events by System Organ Class by Dose 
Level and Cohort (All Causalities)
FAS 
Table 
Table 14.1.1.22
Serious Adverse Events by System Organ Class by Cohort 
and Total (All Causalities)
FAS 
Table 
Table 14.1.1.23
Serious Adverse Events by System Organ Class by Dose 
Level and Cohort (Treatment Related)
FAS 
Listing
Table 14.1.1.24
Discontinuations Due to Adverse Events
FAS 
Listing 
Table 14.1.1.25
Adverse Events
FAS 
Listing 
Table 14.1.1.26
Individual Listing of Deaths
FAS 
Listing 
Table 14.1.1.27
Serious Adverse Events 
FAS 
Listing 
Table 14.1.1.28
Treatment Related Serious Adverse Events
FAS 
 
Clinical Laboratory 
 
Table 
Table 14.1.1.29
Incidence of Laboratory Test Abnormalities (without Regard 
to Baseline Abnormality) by Dose Level and Cohort
FAS 
Table 
Table 14.1.1.30
Serum Iron Indices (Total Iron Binding Capacity, Serum Iron, 
FAS 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 27
Serum Ferritin, % Transferrin Saturation) - Observed values, 
Change and Percent Change from Baseline
Table 
Table 14.1.1.31
Categorical Summary of Serum Ferritin, Serum Iron and % 
Transferrin Saturation
FAS 
Table 
Table 14.1.1.32
Serum Iron Indices (Total Iron Binding Capacity, Serum Iron, 
Serum Ferritin, % Transferrin Saturation)
FAS 
Table 
Table 14.1.1.33
Serum Ferritin, Serum Total Iron, and % Transferrin 
Saturation Values Meeting Categorical Summarization 
Criteria
FAS 
Table 
Table 14.1.1.34
Serum PF-06252616 Concentration (ng/mL) versus Time 
Summary                                                                                       
FAS 
Listing 
Table 14.1.1.35
Laboratory Abnormalities, by Cohort and Subject                       FAS 
Listing 
Table 14.1.1.36
Laboratory Abnormalities, by Dose Level and Subject                FAS 
Listing 
Table 14.1.1.37
Laboratory Abnormalities, by Cohort, Dose Level and Test        FAS 
Vital Signs
 
Figure  
Figure 14.1.1.1
Vital Signs Absolute Values by Dose level
FAS 
Figure 
Figure 14.1.1.2
Vital Signs Change from baseline by Dose Level
FAS 
Electrocardiogram
 
Table 
Table 14.1.1.38
Mean Baseline and Mean Changes from Baseline
FAS 
Table 
Table 14.1.1.39
Categorical Summary of Post-Baseline ECG Data - Absolute 
Values
FAS 
Table 
Table 14.1.1.40
Categorical Summary of Post-Baseline ECG Data - Increases 
from Baseline
FAS 
Table 
Table 14.1.1.41
Number (%) of Subjects with Single Uncorrected QT Values 
Greater than or Equal to 500 msec
FAS 
Table 
Table 14.1.1.42
ECG Change from Baseline
FAS 
Table 
Table 14.1.1.43
ECG Qualitative Results   
FAS 
Table 
Table 14.1.1.44
ECG Post-Baseline Values Meeting Categorical 
Summarization Criteria                                                                 
FAS 
Figure  
Figure 14.1.1.3
QTcF Interval (Fridericia's Correction) values over Time by 
Dose Level - Box Plots
FAS 
Figure 
Figure 14.1.1.4
QTcF Interval (Fridericia's Correction) values change from 
baseline over Time by Dose Level - Box Plots
FAS 
Figure  
Figure 14.1.1.5
QT versus Heart Rate by Dose Level
FAS 
Cardiac MRI/Echocardiogram
 
Table 
Table 14.1.1.45
Shift Table of Left Ventricular Ejection Fraction over time by 
and Echocardiogram
FAS 
Table 
Table 14.1.1.46
Mean absolute and percent change from baseline in Left 
Ventricular Ejection Fraction( LVEF)
FAS 
Table 
Table 14.1.1.47
Mean absolute and percent change from baseline in Left 
Ventricular End Systolic Volume (LVESV)
FAS 
Listing
Table 14.1.1.48
Echoardiagram
FAS 
Liver MRI
 
Table 
Table 14.1.1.49
Summary of Average R2* Values and Percent Change from 
Baseline by Visit and Magnet Field Strength
FAS 
Table 
Table 14.1.1.50
Summary of Iron Accumulation
FAS 
Table 
Table 14.1.1.51
Number (%) of Liver Enzyme Abnormalities by dose level
FAS 
Listing 
Table 14.1.1.52
Liver Enzyme Abnormalities
FAS 
Listing 
Table 14.1.1.53
Liver MRI
FAS 
Listing 
Table 14.1.1.54
Liver MRI Abnormalities: R2* Elevations
FAS 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 28
DXA
FAS 
Table 
Table 14.1.1.55
Bone Mineral Density over Time by Treatment (Whole Body)
FAS 
Table 
Table 14.1.1.56
Bone Mineral Density over Time by Treatment (Hip)
FAS 
Table 
Table 14.1.1.57
Bone Mineral Density over Time by Treatment (Lumbar 
Spine)
FAS 
Listing
Table 14.1.1.58
DXA
FAS 
Concomitant Medication
 
Listing
Table 14.1.1.59
Concomitant Medications
FAS
CSSR
Listing 
Table 14.1.1.60
C-SSRS by Time (Baseline/screen Version and Since last 
Visit) 
FAS
Listing 
Table 14.1.1.61
C-SSRS by Time (Baseline/screen Version and Since last 
Visit) – Cont.
FAS 
ADA
 
Table
Table 14.1.1.62
Anti-drug Antibodies (ADA) Status by Dose Level 
FAS 
Secondary Endpoints:
 
Table 
Table 14.1.1.63
Summary of absolute value for Forced Vital Capcity (FVC)
FAS 
Table 
Table 14.1.1.64
Mean Change from Baseline for Forced Vital Capcity (FVC)
FAS 
Table 
Table 14.1.1.65
Mean Forced Vital Capcity (FVC)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.66
Mean Forced Vital Capcity (FVC)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.6
Plot of Mean Absolute Value on Frorced Vital Capcity
FAS 
Figure 
Figure 14.1.1.7
Plot of Mean Change from Baseline on Frorced Vital Capcity
FAS 
Table 
Table 14.1.1.67
Summary of absolute value for Performance of Upper 
Limb(PUL)
FAS 
Table 
Table 14.1.1.68
Mean Change from Baseline for Performance of Upper 
Limb(PUL)
FAS 
Table 
Table 14.1.1.69
Mean Performance of Upper Limb(PUL)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.70
Mean Performance of Upper Limb(PUL)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Table 
Table 14.1.1.71
Listing of Performance of Upper Limb
FAS
Listing
Table 14.1.1.72
Listing of items, Description and Scores Performance of 
Upper Limb
Figure 
Figure 14.1.1.8
Plot of Mean Absolute Value on Performance of Upper 
Limb(PUL)
FAS 
Figure 
Figure 14.1.1.9
Plot of Mean Change from Baseline on Performance of Upper 
Limb(PUL)
FAS 
Table 
Table 14.1.1.73
Summary of absolute value for Timed Up & Go (TUG)   
FAS 
Table 
Table 14.1.1.74
Mean Change from Baseline for Timed Up & Go (TUG)   
FAS 
Table 
Table 14.1.1.75
Mean Timed Up & Go (TUG)   
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.76
Mean Timed Up & Go (TUG)   
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 29
Figure 
Figure 14.1.1.10
Plot of Mean Absolute Value on Timed Up & Go (TUG) 
FAS 
Figure 
Figure 14.1.1.11
Plot of Mean Change from Baseline on Timed Up & Go 
(TUG) 
FAS 
Table 
Table 14.1.1.77
Summary of absolute value for for10-meter walk/run (10MR)    FAS 
Table 
Table 14.1.1.78
Mean Change from Baseline for10-meter walk/run (10MR)    
FAS 
Table 
Table 14.1.1.79
Mean 10-meter walk/run (10MR)    
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table
Table 14.1.1.80
Mean 10-meter walk/run (10MR)    
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.12
Plot of Mean Absolute Value on 10-meter walk/run (10MR)  
FAS 
Figure 
Figure 14.1.1.13
Plot of Mean Change from Baseline on  10-meter walk/run 
(10MR)
FAS 
Table 
Table 14.1.1.81
Summary of absolute value for Two Minute Walk Test 
(2MWT)     
FAS
Table 
Table 14.1.1.82
Mean Change from Baseline for Two Minute Walk Test 
(2MWT)     
FAS 
Table 
Table 14.1.1.83
Mean Two Minute Walk Test (2MWT)     
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.84
Mean Two Minute Walk Test (2MWT)     
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.14
Plot of Mean Absolute Value on Two Minute Walk Test 
(2MWT) )  
FAS 
Figure 
Figure 14.1.1.15
Plot of Mean Change from Baseline on  Two Minute Walk 
Test (2MWT) 
FAS 
Table 
Table 14.1.1.85
Summary of absolute value for 4 Stair Climb (4SC)    
FAS 
Table 
Table 14.1.1.86
Mean Change from Baseline for 4 Stair Climb (4SC)     
FAS 
Table 
Table 14.1.1.87
Mean 4 Stair Climb (4SC)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.88
Mean 4 Stair Climb (4SC)
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.16
Plot of Mean Absolute Value on 4 Stair Climb (4SC)
FAS 
Figure 
Figure 14.1.1.17
Plot of Mean Change from Baseline on  4 Stair Climb (4SC)
FAS 
Table 
Table 14.1.1.89
Summary of absolute value for Forced Expiratory Volume in 
1 second (FEV1)     
FAS 
Table 
Table 14.1.1.90
Mean Change from Baseline for Forced Expiratory Volume in 
1 second (FEV1)      
FAS 
Table 
Table 14.1.1.91
Mean Forced Expiratory Volume in 1 second (FEV1) 
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.92
Mean Forced Expiratory Volume in 1 second (FEV1) 
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.18
Plot of Mean Absolute Value on Forced Expiratory Volume 
in 1 second (FEV1) 
FAS 
Figure 
Figure 14.1.1.19
Plot of Mean Change from Baseline on  Forced Expiratory 
Volume in 1 second (FEV1) 
FAS 
Table 
Table 14.1.1.93
Summary of absolute value for Maximal Inspiratory Pressure 
(MIP)      
FAS 
Table 
Table 14.1.1.94
Mean Change from Baseline for Maximal Inspiratory 
FAS 


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 30
Pressure (MIP)       
Table 
Table 14.1.1.95
Mean Maximal Inspiratory Pressure (MIP)  
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.96
Mean Maximal Inspiratory Pressure (MIP)  
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS
Figure 
Figure 14.1.1.20
Plot of Mean Absolute Value on Maximal Inspiratory 
Pressure (MIP)  
FAS 
Figure 
Figure 14.1.1.21
Plot of Mean Change from Baseline on  Maximal Inspiratory 
Pressure (MIP)  
FAS 
Table 
Table 14.1.1.97
Summary of absolute value for Maximal Expiratory Pressure 
(MEP)        
FAS 
Table 
Table 14.1.1.98
Mean Change from Baseline for Maximal Expiratory Pressure 
(MEP)         
FAS 
Table 
Table 14.1.1.99
Mean Maximal Expiratory Pressure (MEP)    
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.100
Mean Maximal Expiratory Pressure (MEP)    
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population
Figure 
Figure 14.1.1.22
Plot of Mean Absolute Value on Expiratory Pressure (MEP)    
FAS 
Figure 
Figure 14.1.1.23
Plot of Mean Change from Baseline on  Maximal Expiratory 
Pressure (MEP)    
FAS 
Table 
Table 14.1.1.101
Summary of absolute value for Muscle Strength BY Manual 
Muscle Test (MMT)  and Hand-Hels dynamometry         
FAS 
Table 
Table 14.1.1.102
Mean Change from Baseline for Muscle Strength BY Manual 
Muscle Test (MMT)  and Hand-Hels dynamometry          
FAS 
Table 
Table 14.1.1.103
Mean Muscle Strength BY Manual Muscle Test (MMT)  and 
Hand-Hels dynamometry     
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
FAS 
Table 
Table 14.1.1.104
Mean Muscle Strength BY Manual Muscle Test (MMT)  and 
Hand-Hels dynamometry     
Mixed Model Repeated Measures (MMRM) of Change from 
Baseline
Completer Population 
Listing 
Table 14.1.1.105
Listing of Manual Muscle Test (MMT)  and Hand-Helded 
dynamometry (Manual Muscle Test)
FAS 
Listing 
Table 14.1.1.106
Listing of Manual Muscle Test (MMT)  and Hand-Helded 
dynamometry (Hand Held Myometry)
FAS 
Figure 
Figure 14.1.1.24
Plot of Mean Absolute Value on Muscle Strength BY Manual 
Muscle Test (MMT) and Hand-Hels dynamometry     
FAS 
Figure 
Figure 14.1.1.25
Plot of Mean Change from Baseline on Muscle Strength BY 
Manual Muscle Test (MMT) and Hand-Hels dynamometry    
FAS 
Table 
Table 14.1.1.107
Total Score for InQol
FAS 
Table 
Table 14.1.1.108
InQol: Summary Statistics for Weakness Symptom  
FAS 
Table 
Table 14.1.1.109
InQol: Summary Statistics for Locking Symptom  
FAS 
Table 
Table 14.1.1.110
InQol: Summary Statistics for Pain Symptom  
FAS 
Table 
Table 14.1.1.111
InQol: Summary Statistics for Fatigue Symptom  
FAS 
Table 
Table 14.1.1.112
SF-36 Questionnaire : Listing of Physical and Mental 
Components
FAS 
GDF-8 Concentration
Table
Table 14.1.1.113
Serum Total GDF-8 Concentration (NG/ML) versus Time 
Listing


Protocol WI203720
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 31
Figure 
Figure 14.1.1.25
Individual Serum Total GDF-8 Concentration (NG/ML) -
Time Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.26
Individual Change from Baseline of Serum Total GDF-8
Concentration (NG/ML) - Time Plot by Cohort (Linear Scale)
Table 
Table 14.1.1.114
Serum Total GDF-8 (NG/ML) versus Time Summary
Table 
Table 14.1.1.115
Changes from Baseline for Serum Total GDF-8 (NG/ML)
Figure 
Figure 14.1.1.27
Median Serum Total GDF-8 Concentration (NG/ML) - Time 
Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.28
Median Change from Baseline of Serum Total GDF-8
Concentration (NG/ML) - Time Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.29
Mean Serum Total GDF-8 Concentration (NG/ML) - Time 
Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.30
Mean Change from Baseline of Serum Total GDF-8
Concentration (NG/ML) - Time Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.31
Median Serum Total GDF-8 Concentration (NG/ML) - Time 
Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.32
Median Change from Baseline of Serum Total GDF-8
Concentration (NG/ML) - Time Plot by Cohort (Linear Scale)
Figure 
Table 14.1.1.116
Descriptive Summary of Serum Total GDF-8 Parameters
PK Summary
Table 
Table 14.1.1.117
Serum PF-06252616 Concentration [NG/MG] versus Time 
Summary for All Subjects
Table 
Table 14.1.1.118
Serum PF-06252616 Concentration [NG/MG] versus Time 
Summary for Subjects with Additional Sampling
Figure 
Figure 14.1.1.33
Median Serum PF-06252616 Concentration - Time Plot by 
Cohort (Linear Scale) for All Subjects
Figure 
Figure 14.1.1.34
Median Serum PF-06252616 Concentration - Time Plot by 
Cohort (Linear Scale) for Subjects with Additional Sampling
Figure 
Figure 14.1.1.35
Mean Serum PF-06252616 Concentration - Time Plot by 
Cohort (Linear Scale) for All Subjects
Figure 
Figure 14.1.1.36
Mean Serum PF-06252616 Concentration - Time Plot by 
Cohort  (Linear Scale) for Subjects with Additional Sampling
Figure 
Figure 14.1.1.37
Median Serum PF-06252616 Concentration - Time Plot by 
Cohort (Linear Scale) for All Subjects
Figure 
Figure 14.1.1.38
Median Trough Serum PF-06252616 Concentration - Time 
Plot by Cohort (Linear Scale)
Figure 
Figure 14.1.1.39
Median End of Infusion Serum PF-06252616 Concentration -
Time Plot by Cohort (Linear Scale)
Table 
Table 14.1.1.119
Descriptive Summary of Serum PF-06252616 PK Parameters 
for All Subjects
Table 
Table 14.1.1.120
Descriptive Summary of Serum PF-06252616 PK Parameters 
for Subjects with Additional PK Sampling
Table 
Table 14.1.1.121
Descriptive Summary of Serum PF-06252616 PK Parameters 
for All Subjects – Process 1 vs Process 2





Prot_001.pdf: 
PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 1 
   
 
A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in 
Ambulatory Participants with LGMD2I 
Study Sponsor: 
 
Compound: 
Hugo W. Moser Research Institute at 
Kennedy Krieger, Inc.  
PF-06252616 
Compound Name: 
Anti-Myostatin 
 
 
Protocol Number: 
WI203720 
Phase: 
1b/2 
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 2 
1.1. Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Final protocol 
7 December,  
2015 
N/A 
Revisions requested 
by JHSOM IRB II 
18 March, 2016 
 
Version 3 
01 Nov 2016 
For test-retest reliability of timed function tests 
in LGMD2l,  a second day of testing will be 
performed on Visit 3 (Day 1) prior to the first 
dose.  
Premedication prior to MRI of whole body and 
thigh for study participants who may be anxious 
because of the procedure and the length of time 
in the scanner. 
Version 4 
20 January 2017 
The nontreatment, Lead in period of Cohort 2 
may be extended depending on the timing of 
enrollment and evaluation of safety in the 5 
mg/kg dose (Cohort 1), 
Dose escalation of Cohort 1 from 5 mg/kg to 
40mg/kg may be delayed depending on the time 
of enrollment and evaluation of safety in the 
Cohort 2 (20 mg/kg). 
As a clarification in Schedule of Events for 
Cohort 1, MRI of liver is only obtained on Visit 
11 and not Visit 3. 
As an exploratory endpoint, PD activity of PF-
06252616  will be evaluated based on the 
percent change of muscle volume as measured 
on MRI compared to baseline as indicated by 
the whole body MRI evaluation and/or lean 
body mass DXA results. 
Uric acid and serum phosphorus are removed 
from the table of Laboratory Tests, page 67. 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 3 
Version 5 
04 May 2017 
Collection of pharmacodynamic (PD) blood 
samples at the same time point as 
pharmacokinetic(PK) sampling  to provide 
more information regarding  GDF-8 activity . 
During dosing visits, vital signs will be 
obtained before the dose and after completion 
of the infusion.  
The Table of Contents was organized to move 
Pharmacodynamics under Exploratory 
Endpoints (page 35). 
Version 6 
14 February 2018 
Added Extension Period and Telephone 
Follow-up to the study. 
Update on ongoing clinical studies (B5161002, 
B5161004) with PF-06252616 in Section 1.8 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 4 
TABLE OF CONTENTS 
1. INTRODUCTION ...............................................................................................................29 
1.2. Mechanism of Action/Indication .............................................................................29 
1.3. Background and Rationale ......................................................................................29 
1.3.1. Myostatin Role in Muscle 
Regulation ........................................................................................................29 
1.4. Limb Girdle Muscular Dystrophy 2I .......................................................................29 
1.4.1. PF-06252616...............................................................................................30 
1.5. Nonclinical Pharmacodynamics ..............................................................................30 
1.6. Nonclinical Pharmacokinetics .................................................................................31 
1.7. Toxicology ..............................................................................................................32 
1.8. Clinical Experience with PF-06252616 ..................................................................34 
1.9. Immunogenicity Risk Assessments .........................................................................35 
1.9.1. Nonclinical Immunogenicity ......................................................................35 
1.9.2. Immunogenicity Results 
B5161001 .........................................................................................................35 
1.10. Rationale for Dosage Selection and 
Method of Administration .........................................................................................36 
1.11. Study Design Rationale .........................................................................................36 
1.12. Anticipated Risks and Safety 
Monitoring .................................................................................................................38 
1.12.1. Hepatic Injury ...........................................................................................38 
1.12.2. Gastric Erosion and 
Haemorrhage ....................................................................................................38 
1.12.3. Bone Metabolism ......................................................................................38 
1.12.4. Cardiac ......................................................................................................39 
1.12.5. Special considerations in 
females .............................................................................................................39 
1.12.6. Radiation ...................................................................................................39 
1.12.7. Needle Muscle Biopsy ..............................................................................40 
1.12.8. Other possible risks...................................................................................40 
1.12.9. Other Safety Monitoring ...........................................................................40 
1.13. Summary of Risk Benefit ......................................................................................40 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................40 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 5 
2.1. Objectives ................................................................................................................40 
2.1.1. Primary .......................................................................................................40 
2.1.2. Secondary ...................................................................................................40 
2.1.3. Exploratory .................................................................................................41 
2.2. Endpoints .................................................................................................................41 
2.2.1. Primary Safety ............................................................................................41 
2.2.2. Seconday Endpoints....................................................................................41 
2.2.2.1. Pharmacokinetic ........................................................................41 
2.2.2.2. Strength and Function ...............................................................42 
2.2.2.3. Patient Reported 
Outcomes ...........................................................................................42 
2.2.2.4. Immunogenicity ........................................................................42 
2.2.3. Exploratory Endpoint..................................................................................42 
2.2.3.1. Pharmacologic ...........................................................................42 
2.2.3.2. Function .....................................................................................42 
                                 2.2.3.3  Pharmacodynamic…………………………………………..    42 
3. STUDY DESIGN.................................................................................................................42 
3.1. Study Overview .......................................................................................................42 
3.2. Duration of Subject Participation ............................................................................44 
3.3. Approximate Duration of Study ..............................................................................45 
3.4. Planned Number of Subjects ...................................................................................45 
3.5. Safety Monitoring and Dose Escalation ..................................................................45 
3.5.1. Dose Escalation and Stopping 
Rules 46 
3.5.2. Safety Monitoring Committee 
(SMC) 46 
4. SUBJECT SELECTION ......................................................................................................47 
4.1. Inclusion Criteria .....................................................................................................47 
4.2. Exclusion Criteria ....................................................................................................48 
4.3. Enrollment Criteria ..................................................................................................48 
4.4. Lifestyle Guidelines ................................................................................................48 
4.4.1. Meals and Dietary Restrictions ...................................................................49 
4.4.2. Activity .......................................................................................................49 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 6 
4.4.3. Contraception ..............................................................................................49 
4.5. Rater Qualifications .................................................................................................50 
4.5.1. Columbia-Suicide Severity 
Rating Scale (C-SSRS) ....................................................................................50 
4.5.2. Physiotherapists ..........................................................................................50 
5. STUDY TREATMENTS .....................................................................................................50 
5.1. Allocation to Treatment ..........................................................................................52 
5.2. Blinding ...................................................................................................................52 
5.3. Subject Compliance .................................................................................................52 
5.4. Drug Supplies ..........................................................................................................52 
5.4.1. Dosage Form(s) and Packaging ..................................................................52 
5.4.2. Preparation and Dispensing ........................................................................53 
5.5. Investigational Product Administration ..................................................................53 
5.6. Investigational Product Storage ..............................................................................54 
5.7. Investigational Product Accountability ...................................................................54 
5.8. Destruction of Investigational Product 
Supplies .....................................................................................................................55 
5.9. Concomitant Treatment(s) .......................................................................................55 
5.9.1. Permitted Therapies ....................................................................................55 
5.9.2. Prohibited Therapies ...................................................................................55 
5.9.3. Rescue Medication ......................................................................................56 
6. STUDY PROCEDURES .....................................................................................................56 
6.1. Screening: Visit 1 (Screening Day -125 to 
-112) ..........................................................................................................................56 
6.2. Lead-in Period: Visit 2 (Baseline Day 
-111 to -110 prior to dosing on Day 1) ......................................................................58 
6.3. Active Treament Period:  Visit 3 (Day 1) 
and for Cohort 1, Visit 11 (Day 225±3) ....................................................................59 
6.4. Active Treatment:  Visit 4 (Day 29±3), 8 
(Day 141±3), 10 (Day 197±3) and for 
Cohort 1, Visit 12 (Day 253±3), 16 (Day 
365±3), 18 (Day 421±3) ............................................................................................61 
6.5. Active Treatment:  Visit 5 (Day 57±3), 9 
(Day 169±3) and for Cohort 1, Visit 13 
(Day 281±3), 17 (Day 393±3) ...................................................................................62 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 7 
6.6. Active Treatment: Visit 6 (Day 85±3) and 
for Cohort 1, Visit 14 (Day 309±3) ...........................................................................63 
6.7. Active Treatment:  Visit 7 (Day 113±3) 
and for Cohort 1, Visit 15 (Day 337±3) ....................................................................64 
6.8. Follow up: For Cohort 1, Visit 19 (Day 
449±3) and for Cohort 2 and 3, Visit 11 
(Day 225±3) ...............................................................................................................65 
6.9. Follow-up:  For Cohort 1, Visit 20 (Day 
561±3) and for Cohort 2 and 3 Visit 12 
(Day 337±3) ...............................................................................................................67 
         6.10 to 6.12. Extension Period…………………………………………………………68 
         6.13 Telephone Follow-up Period……………………………………………………...71 
6.14. Unscheduled Visits ................................................................................................71 
6.15. Subject Withdrawal ...............................................................................................72 
6.16. Subject Lost to Follow-Up ....................................................................................75 
7. ASSESSMENTS ..................................................................................................................75 
7.1. Safety .......................................................................................................................76 
7.1.1. Clinical Laboratory .....................................................................................76 
7.1.2. Physical Examinations/Nose and 
Throat Exam.....................................................................................................78 
7.1.3. Vitals ...........................................................................................................78 
7.1.4. Electrocardiogram (ECG) ...........................................................................79 
7.1.5. Echocardiogram ..........................................................................................79 
7.1.6. Assessment of Suicidal Ideation 
and Behavior –Columbia Suicide 
Severity Rating Scale (C-SSRS) ......................................................................80 
7.2. Banked Biospecimens .............................................................................................80 
7.2.1. Markers of Drug Response .........................................................................80 
7.2.2. Additional Research ....................................................................................82 
7.3. Pharmacokinetics (Serum for Analysis of 
PF-06252616) ............................................................................................................82 
7.4. Anti-Drug Antibody (ADA) 
anti-PF-06252616 and Neutralizing 
Antibody          (NAb) ................................................................................................83 
7.5. Pharmacodynamics/Serum for Total 
GDF-8 ........................................................................................................................83 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 8 
7.6. Imaging Assessments ..............................................................................................84 
7.6.1. Liver MRI ...................................................................................................84 
7.6.2. MRI of Skeletal Muscle. .............................................................................84 
7.6.3. Duel-energy X-ray 
Absorptiometry (DXA) and X-ray ...................................................................84 
7.6.3.1. DXA ..........................................................................................84 
7.6.3.2. Radiation Exposure ...................................................................85 
7.7. Functional Assessments ..........................................................................................85 
7.7.1. Pulmonary Function....................................................................................85 
7.7.2. 4 Stair Climb (4 SC) ...................................................................................85 
7.7.3. 10-meter walk/run .......................................................................................85 
7.7.4. Timed Up & Go (TUG) ..............................................................................85 
7.7.5. Strength Assessment ...................................................................................85 
7.7.6. Performance of Upper Limb 
(PUL) 86 
7.7.7. Two Minute Walk Test (2MWT) ...............................................................86 
7.8. Quality of Life Assessments ...................................................................................86 
7.8.1. InQoL ..........................................................................................................86 
7.8.2. SF-36...........................................................................................................86 
7.9. Needle Muscle Biopsy ............................................................................................86 
7.10. Triggered Requirements ........................................................................................87 
7.11. Infusion Site Monitoring .......................................................................................87 
8. ADVERSE EVENT REPORTING......................................................................................87 
8.1. Adverse Events ........................................................................................................87 
8.2. Reporting Period .....................................................................................................87 
8.3. Definition of an Adverse Event ...............................................................................88 
8.4. Medication Errors ....................................................................................................88 
8.5. Abnormal Test Findings ..........................................................................................89 
8.6. Serious Adverse Events ...........................................................................................89 
8.6.1. Protocol-Specified Serious 
Adverse Events ................................................................................................90 
8.6.2. Potential Cases of Drug-Induced 
Liver Injury ......................................................................................................90 
8.7. Hospitalization ........................................................................................................91 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 9 
8.8. Severity Assessment ................................................................................................92 
8.9. Causality Assessment ..............................................................................................93 
8.10. Exposure During Pregnancy ..................................................................................93 
8.11. Occupational Exposure .........................................................................................94 
8.12. Withdrawal Due to Adverse Events (See 
Also Section on Subject Withdrawal) .......................................................................95 
8.13. Eliciting Adverse Event Information ....................................................................95 
8.14. Reporting Requirements ........................................................................................95 
8.14.1. Serious Adverse Event 
Reporting Requirements ..................................................................................95 
8.14.2. Nonserious Adverse Event 
Reporting Requirements ..................................................................................96 
8.14.3. Sponsor Reporting 
Requirements to Regulatory 
Authorities........................................................................................................96 
9. DATA ANALYSIS/STATISTICAL METHODS ...............................................................96 
9.1. Sample Size Determination .....................................................................................96 
9.2. Efficacy Analysis ....................................................................................................96 
9.2.1. Analysis of Primary Endpoint ....................................................................96 
9.2.2. Analysis of Secondary Endpoints ...............................................................97 
9.2.3. Analysis of Exploratory 
Endpoints .........................................................................................................97 
9.2.4. Analysis of Pharmacokinetics .....................................................................97 
9.2.5. Analysis of Pharmacodynamics ..................................................................97 
9.3. Safety Analysis ........................................................................................................98 
9.3.1. Vital Signs ..................................................................................................98 
9.3.2. Electrocardiogram .......................................................................................98 
9.3.3. Cardiac Echocardiogram ............................................................................98 
9.3.4. Liver MRI ...................................................................................................98 
9.3.5. Other Safety ................................................................................................98 
10. QUALITY CONTROL AND QUALITY ASSURANCE .................................................98 
11. DATA HANDLING AND RECORD KEEPING .............................................................99 
11.1. Case Report Forms/Electronic Data 
Record ........................................................................................................................99 
11.2. Record Retention ...................................................................................................99 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 10 
12. ETHICS............................................................................................................................100 
12.1. Institutional Review Board (IRB)/Ethics 
Committee (EC) .......................................................................................................100 
12.2. Ethical Conduct of the Study ..............................................................................100 
12.3. Subject Information and Consent ........................................................................100 
12.4. Subject Recruitment ............................................................................................101 
12.5. Reporting of Safety Issues and Serious 
Breaches of the Protocol or ICH GCP .....................................................................101 
13. DEFINITION OF END OF TRIAL .................................................................................101 
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................101 
15. PUBLICATION OF STUDY RESULTS ........................................................................101 
15.1. Communication of Results ..................................................................................101 
15.2. Publications by Investigators ..............................................................................102 
16. REFERENCES ................................................................................................................103 
 
LIST OF TABLES 
Table 1. 
Predicted Exposures and Margins 
Relative to Toxicokinetics Limits at 
Planned PF-06252616 Doses ................................................................................36 
Table 2. 
Criteria to Determine Dose Escalation 
or Stopping............................................................................................................46 
 
LIST OF APPENDICES 
Appendix 1. Columbia-Suicide Severity Rating 
Scale:  Baseline ...................................................................................................105 
Appendix 2. Columbia-Suicide Severity Rating 
Scale (C-SSRS): Since Last Visit .......................................................................109 
Appendix 3. InQoL ................................................................................................................113 
Appendix 4. SF-36 .................................................................................................................130 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 11 
List of Abbreviations 
 
This is a list of abbreviations that may be used in the protocol. 
Abbreviation 
Term 
2MWT 
two minute walk test 
6MWT 
six minute walk test 
4SC 
four stair climb 
4SD 
four stair descend 
10MR 
ten meter run 
ACE 
angiotensin-converting-enzyme 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin II receptor blocker 
AST 
aspartate transaminase 
BMD 
bone mineral density 
BMP/TGF 
bone morphogenetic protein/ transforming growth factor- 
CDC 
Center for Disease Control 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
clearance 
CNS 
central nervous system 
CRF 
case report form 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DAI 
dosing and administration instructions 
DILI 
drug-induced liver injury 
DMD 
Duchenne muscular dystrophy 
DNA 
deoxyribonucleic acid 
DXA 
dual energy x-ray absorptiometry 
EC 
ethics committee 
ECG 
electrocardiogram 
EDP 
exposure during pregnancy 
EDTA 
ethylene diamine triacetic acid 
EF 
ejection fraction 
ELISA 
enzyme-linked immunosorbent assay 
FAS 
full analysis set 
FEV1 
Forced expiratory voume in 1 second 
FKRP 
Fukutin-related protein 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GDF-8 
growth differentiation factor 8 
GDF-11 
growth differentiation factor 11 
GGT 
gamma-glutamyl transferase 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 12 
GLDH 
glutamate dehydrogenase 
HPLC-MS/MS 
high performance liquid chromatography-mass spectrometry 
IB 
investigator brochure 
ICD 
informed consent document 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IgG1 
immunoglobulin G1 
IND 
investigational new drug application 
InQoL 
Individualized Neuromuscular Disease Quality of Life 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
institutional review board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IV 
intravenous 
LBM 
lean body mass 
LFT 
liver function test 
LH 
luteinizing hormone 
LGMD2I 
limb girdle muscular dystrophy 2I 
LLN 
lower limit of normal 
LSLV 
last subject last visit  
LVEF 
left ventricular ejection fraction 
LVESV 
left ventricular end systolic volume 
MEP 
mean expiratory pressure 
MHP 
mental health provider 
MIP 
mean inspiratory pressure 
MMT 
manual muscle testing 
MRC 
Medical Research Council 
MRI 
magnetic resonance imaging 
N 
number 
N/A 
not applicable 
Nab 
neutralizing antibodies 
NHP 
non-human primate 
NOAEL 
no observed adverse effect levels 
PFT 
pulmonary function test 
PK/PD 
pharmacokinetic/pharmacodynamics 
POM 
proof of mechanism 
PPV-23 
pneumococcal polysaccharide vaccine 
PT 
prothrombin time 
PUL 
Performance of Upper Limb 
PWRD 
Pfizer Worldwide Research and Development 
QMT 
quantitative muscle test 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 13 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36 
Short Form 36 Health Survey 
SMC 
Safety Monitoring Committee 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SSID 
single subject’s identification 
SWFI 
sterile water for injection 
TEAEs 
treatment emergent AEs 
TFT 
timed function test 
TIBC 
total iron binding capacity 
TK 
toxicokinetic 
TMDD 
Target mediated drug disposition 
TUG 
timed up and go 
ULN 
upper limit of normal 
US 
United States 
ULN 
upper limit of normal 
Vss 
steady state volume distribution 
WB-MRI 
Whole-Body MRI  
WOCBP 
women of child bearing potential 
 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 14 
 
SCHEDULE OF ACTIVITIES  
Table 1 Cohort 1  
  
Screen 
Lead-
In 
Treatment  
Follow-up 
Early 
With-
drawal 
Visit Number  
(Study Day Visit 
Window)a 
1  (-125 
to -112) 
 2       
(-111 
to -
110) 
A (5 mg/kg) 
19 
(449 
±3) 
20 
(561 
±3) 
  
  
3 
 (1) 
4 
(29 
± 3) 
5 
(57 
±3) 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
 
 
 
B (40 mg/kg) 
 
 
 
11 
(225 
±3) 
12 
(25
3 
±3) 
13 
(28
1 ± 
3) 
14 
(30
9 
±3) 
15 
(337 
±3) 
16 
(365 
±3) 
17 
(393 
±3) 
18 
(421 
±3) 
 
 
 
Entry/Safety Assessments 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical Historyb 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medication History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion  
X 
 
  
  
  
  
  
  
  
  
  
  
  
Enrollmentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Pregnancy Testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary Cardsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weighte 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 15 
  
Screen 
Lead-
In 
Treatment  
Follow-up 
Early 
With-
drawal 
Visit Number  
(Study Day Visit 
Window)a 
1  (-125 
to -112) 
 2       
(-111 
to -
110) 
A (5 mg/kg) 
19 
(449 
±3) 
20 
(561 
±3) 
  
  
3 
 (1) 
4 
(29 
± 3) 
5 
(57 
±3) 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
 
 
 
B (40 mg/kg) 
 
 
 
11 
(225 
±3) 
12 
(25
3 
±3) 
13 
(28
1 ± 
3) 
14 
(30
9 
±3) 
15 
(337 
±3) 
16 
(365 
±3) 
17 
(393 
±3) 
18 
(421 
±3) 
 
 
 
12- lead ECG 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Laboratory 
Testsg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Ferritin, 
Serum Iron, 
Transferrin 
Saturation, TIBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hormone Testing 
(LH, FSH, estrogen)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GLDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal Occult Bloodi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging Assessments 
MRI-Liver 
X 
  
 Xo  
  
  
 X 
 
  
  
  
X 
X 
X 
MRI-Musclej 
  
X 
X 
  
  
  
  
  
  
  
X 
X 
X 
DXA Whole Body 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
DXA Spine and Hip 
 
 
X 
  
  
  
  
  
  
  
X 
X 
X 
Functional Assessments 
Muscle Strength 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 16 
  
Screen 
Lead-
In 
Treatment  
Follow-up 
Early 
With-
drawal 
Visit Number  
(Study Day Visit 
Window)a 
1  (-125 
to -112) 
 2       
(-111 
to -
110) 
A (5 mg/kg) 
19 
(449 
±3) 
20 
(561 
±3) 
  
  
3 
 (1) 
4 
(29 
± 3) 
5 
(57 
±3) 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
 
 
 
B (40 mg/kg) 
 
 
 
11 
(225 
±3) 
12 
(25
3 
±3) 
13 
(28
1 ± 
3) 
14 
(30
9 
±3) 
15 
(337 
±3) 
16 
(365 
±3) 
17 
(393 
±3) 
18 
(421 
±3) 
 
 
 
(MMT, 
dynamometry) 
4SC 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
10-meter walk/run 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
2MWT 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
Timed up-and-go 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
PUL 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
InQol, SF-36 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Respiratory Function 
(FVC, FEV1, 
MIP/MEP) 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Study Treatment Administration  
Study Treatment 
Administrationk 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
 
  
  
PK/PD/Immunogenicity 
Needle muscle biopsy 
  
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Immunogenicity 
  
 
X 
 
 
 
 
 
 
 
X 
X 
X 
PD samplel 
  
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
PK samplesl 
  
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Biomarkers 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 17 
  
Screen 
Lead-
In 
Treatment  
Follow-up 
Early 
With-
drawal 
Visit Number  
(Study Day Visit 
Window)a 
1  (-125 
to -112) 
 2       
(-111 
to -
110) 
A (5 mg/kg) 
19 
(449 
±3) 
20 
(561 
±3) 
  
  
3 
 (1) 
4 
(29 
± 3) 
5 
(57 
±3) 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
 
 
 
B (40 mg/kg) 
 
 
 
11 
(225 
±3) 
12 
(25
3 
±3) 
13 
(28
1 ± 
3) 
14 
(30
9 
±3) 
15 
(337 
±3) 
16 
(365 
±3) 
17 
(393 
±3) 
18 
(421 
±3) 
 
 
 
collectionm 
Adverse event 
monitoring 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion site reaction 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
medications 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 2MWT=Two minute walk test; 4 SC= Four stair climb, C-SSRS=Columbia Suicide Severity Rating Scale, DXA=Dual-energy x-ray 
absorptiometry; ECG = electrocardiogram; FSH= Follicle stimulating hormone; FVC=Forced vital capacity; FEV1 = Forced expiratory voume in 1 second; 
GLDH=glutamate dehydrogenase,  LH-Lutenizing hormone, MIP= Mean inspiratory pressure; MEP= Mean expiratory pressure; MMT= manual muscle testing, 
MRI=magnetic resonance image; PD=Pharmcodynamics, PK=Pharmocokinetics, PUL=Performance of Upper Limb, TIBC=Total iron binding capacity, INQoL 
= Individualized Neuromuscular Disease Quality of Life, SF-36 = Short Form 36 Health Survey 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 18 
SCHEDULE OF ACTIVITIES  
Table 2 Cohort 2 and 3   
 
  
Screen 
Lead-
in 
Treatment 
Follow-up 
 Early 
Withdrawal 
Visit Number  (Study Day Visit 
Window)a 
1  (-125 
to -112) 
2 (-111 
to -110) 
3  
(1) 
4 
(29 
± 
3) 
5 
(57 
±3) 
 
 
 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
11 
(225 
±3) 
12 
(337 
±3) 
 
Entry/Safety Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollmentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Pregnancy Testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary Cardsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weighte 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12- lead ECG 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory Testsg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Ferritin, Serum Iron, Transferrin 
Saturation,TIBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hormone Testing (LH, FSH, estrogen)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 19 
  
Screen 
Lead-
in 
Treatment 
Follow-up 
 Early 
Withdrawal 
Visit Number  (Study Day Visit 
Window)a 
1  (-125 
to -112) 
2 (-111 
to -110) 
3  
(1) 
4 
(29 
± 
3) 
5 
(57 
±3) 
 
 
 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
11 
(225 
±3) 
12 
(337 
±3) 
 
GLDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal Occult Bloodi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging Assessments 
MRI-Liver 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
MRI-Musclej 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
DXA Whole Body 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
DXA Spine and Hip 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Functional Assessments 
Muscle Strength (MMT, dynamometry) 
  
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
4SC 
 
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
10-meter walk/run 
  
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
2MWT 
  
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
Timed up-and-go  
  
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
PUL 
  
X 
Xn 
 
 
 
X 
 
 
 
X 
X 
X 
InQol, SF-36 
  
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Respiratory Function (FVC, FEV1, 
MIP/MEP) 
  
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Study Treatment Administration 
Study Treatment Administrationk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
PK/PD/Immunogenicity 
Needle muscle biopsy 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Immunogenicity 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
PD sample 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
PK samplesl 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 20 
  
Screen 
Lead-
in 
Treatment 
Follow-up 
 Early 
Withdrawal 
Visit Number  (Study Day Visit 
Window)a 
1  (-125 
to -112) 
2 (-111 
to -110) 
3  
(1) 
4 
(29 
± 
3) 
5 
(57 
±3) 
 
 
 
6 
(85 
±3) 
7 
(113 
±3) 
8 
(141 
±3) 
9 
(169 
±3) 
10 
(197 
±3) 
11 
(225 
±3) 
12 
(337 
±3) 
 
Biomarkers collectionm 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion site reaction 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 2MWT=Two minute walk test; 4 SC= Four stair climb, C-SSRS=Columbia Suicide Severity Rating Scale, DXA=Dual-energy x-ray 
absorptiometry; ECG = electrocardiogram; FSH= Follicle stimulating hormone; FVC=Forced vital capacity; FEV1 = Forced expiratory voume in 1 second; 
GLDH=glutamate dehydrogenase, LH-Lutenizing hormone, MIP= Mean inspiratory pressure; MEP= Mean expiratory pressure; MMT= manual muscle testing, 
MRI=magnetic resonance image; PD=Pharmcodynamics, PK=Pharmocokinetics, PUL=Performance of Upper Limb, TIBC=Total iron binding capacity, INQoL 
= Individualized Neuromuscular Disease Quality of Life, SF-36 = Short Form 36 Health Survey 
a. 
Assessments should be conducted on the Study Day within the visit window.  Visits with MRI, DXA and functional assessments may be conducted over 
2 days. The following order of testing is preferred.  On the first day of assessments: an am fasting blood collection followed by fasting DXA and MRI. 
On the second day of assessments:  the functional assessments and muscle biopsy. Whenever possible, functional testing and MRI should occur prior to 
biopsy.  Depending on the timing of enrollment and evaluation of safety in the 20 mg/kg dose (Cohort 2), the dose escalation of Cohort 1 to 40 mg/kg 
may be delayed.  Subjects in Cohort 1 will only receive 8 doses of the 5 mg/kg dose and not proceed to the 40 mg/kg dose until review by the SMC.    In 
addition, depending on the timing of enrollment and evaluation of safety in the 5 mg/kg dose (Cohort 1), the Lead-In period for Cohort 2 may be 
extended prior to initiation of treatment phase.  
b. 
Medical history will include confirmation by genetic testing of the diagnosis of Limb Girdle Muscular Dystrophy (LDMG2I) as obtained from an 
approved laboratory.  Results must confirm the presence of a biallelic alteration in the FKRP gene known or likely to be pathogenic. 
c. 
Enrollment can be performed once all screening results are available and eligibility is confirmed.  
d. 
Pregnancy tests (highly sensitive urine or serum) and hormone testing will only be conducted for women of child bearing potential (WOCBP).  In 
addition, diary cards will be used to collect the first day of menstrual cycle for WOCBP.  
e. 
Weight collected within a month of the visit can be used to calculate the appropriate dose by body weight. 
f. 
Vital sign evaluations will include supine blood pressure, pulse rate, respiratory rate and oral temperature. 
g. 
Clinical laboratory tests include hematology with complete blood count and differential, comprehensive metabolic panel (sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen, creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, alkaline phosphatase), cardiac 
troponin I, gamma-glutamyl transferase (GGT), prothrombin time (PT), activated partial thromboplastin time (aPTT), creatine kinase, amylase and 
urinalysis.  If total bilirubin is abnormal, direct bilirubin will be tested reflexively.   The samples for serum ferritin, serum iron, transferrin saturation and 
TIBC should be collected in the morning following an 8 hour fast.   


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 21 
h. 
Hormone testing will include LH, FSH and estrogen in female subjects only. 
i. 
Fecal Occult Blood testing will be performed at home within 1 week of the scheduled visit. 
j. 
MRI of skeletal muscle will include a Whole Body MRI and a dedicated thigh MRI. 
k. 
Investigational product should be delivered in a 2 hour window 15 minutes not including the flush time.  Subjects are required to be observed for 
1 hour after the infusion of the investigational product is completed.  If a dosing visit cannot be conducted within the visit window, attempts should be 
made to bring the subject back for dosing as soon as possible; however the dosing must not occur within 2 weeks prior to the next scheduled dose.  If 
the subject cannot return in this timeframe, the dose should be missed and the next visit 
l. 
PK/PD assessments will occur predose and 2 hours post dose.  The window for the PK /PDassessments post dosing at 2 hours is + 30 minutes  If the 
infusion rate is slowed (following an infusion site reaction) the PK/PD assessments should be collected at the time of infusion completion 
(+30 minutes). 
m. 
Prep B1.5 (K2 EDTA plasma collection optimized for biomarker/proteomic/metabonomic analysis) will be collected at: Cohort 1 at Visits 2 (baseline), 7 
(Day 113), 10 (Day 197), 15 (Day 337) and 18 (Day 421) and Cohort 2 and 3 at Visit 2 (baseline), 7 (Day 113) and 10 (Day 197)    
Prep B2.5 (serum collection optimized for biomarker/ proteomics/metabonomic analysis) will be collected  at:  Cohort 1 at Visits 2 (baseline), 7 (Day 
113), 10 (Day 197), 15 (Day 337) and 18 (Day 421) and Cohort 2 and 3 at Visit 2 (baseline), 7 (Day 113) and 10 (Day 197)    
Prep R1 (PAXGene whole blood collection optimized for RNA analysis) will be collected at:  Cohort 1 at Visits 2 (baseline), 10 (Day 197) and 18 (Day 
421) and Cohort 2 and 3 at Visit 2 (baseline) ) and 10 (Day 197)    
Prep 4 (Cell-free RNA) will be collected at: Cohort 1 at Visits 2 (baseline), 10 (Day 197) and 18 (Day 421) and Cohort 2 and 3 at Visit 2 (baseline) ) 
and 10 (Day 197)    
Prep D1.5 (K2 edetic acid (ethylenediaminetetraacetic acid) (EDTA) whole blood collection optimized for DNA analysis) will be collected at the 
Screening visit. 
             n      Timed Function tests and PUL will be repeated on Day 2 of Visit 3 prior to the first dose. 
             o      MRI of the liver is performed on Visit 11 only (and not on Visit 3) for Cohort 1. 
 
 
 
 
 
 
 
 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 22 
 
SCHEDULE OF ACTIVITIES  
Table 3 Extension Study 
Table 3.1 Cohort 1 Extension 
Cohort 1 Extension Period (40mg/kg) 
Treatment 
Follow-up 
 
Early 
Withdrawal 
Visit Number  (Study Day Visit Window) 
21 
(+3) 
22 
(+3) 
23 
(+3) 
24 
(+3) 
25 
(+3) 
26 
(+3) 
27 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
Physical Examination 
 
 
 
X 
 
 
X 
 
X 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary Cards 
X 
X 
X 
X 
X 
X 
X 
 
X 
Contraception Review 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
 
 
 
 
 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
 
 
 
X 
 
 
X 
 
X 
12- lead ECG 
 
 
 
 
 
 
X 
 
X 
Echocardiogram 
 
 
 
 
 
 
X 
 
X 
Clinical Laboratory Tests 
 
 
 
X 
 
 
X 
 
X 
Serum Ferritin, Serum Iron, Transferrin 
Saturation,TIBC 
 
 
 
X 
 
 
X 
 
X 
Hormone Testing (LH, FSH, estrogen) 
 
 
 
 
 
 
X 
 
X 
GLDH 
 
 
 
X 
 
 
X 
 
X 
PK, PD, Immunogenicity, Biomarkers 
 
 
 
 
 
 
X 
 
X 
Fecal Occult Blood 
 
 
 
X 
 
 
X 
 
X 
C-SSRS 
 
 
 
X 
 
 
X 
 
X 
Questionnaires (InQol, SF-36) 
 
 
 
 
 
 
X 
 
X 
MRI-Liver 
 
 
 
 
 
 
X 
 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 23 
Cohort 1 Extension Period (40mg/kg) 
Treatment 
Follow-up 
 
Early 
Withdrawal 
Visit Number  (Study Day Visit Window) 
21 
(+3) 
22 
(+3) 
23 
(+3) 
24 
(+3) 
25 
(+3) 
26 
(+3) 
27 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
DXA Spine and Hip 
 
 
 
 
 
 
X 
 
X 
Muscle Strength (MMT, dynamometry) 
 
 
 
X 
 
 
X 
 
X 
4SC; 10-meter walk/run; 2MWT ; Timed up-and-go 
 
 
 
X 
 
 
X 
 
X 
PUL 
 
 
 
X 
 
 
X 
 
X 
Respiratory Function (FVC, FEV1, MIP/MEP) 
 
 
 
X 
 
 
X 
 
X 
Study Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion site reaction monitoring 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 2MWT=Two minute walk test; 4 SC= Four stair climb, C-SSRS=Columbia Suicide Severity Rating Scale, DXA=Dual-energy x-ray 
absorptiometry; ECG = electrocardiogram; FSH= Follicle stimulating hormone; FVC=Forced vital capacity; FEV1 = Forced expiratory voume in 1 second; 
GLDH=glutamate dehydrogenase, LH-Lutenizing hormone, MIP= Mean inspiratory pressure; MEP= Mean expiratory pressure; MMT= manual muscle testing, 
MRI=magnetic resonance image; PD=Pharmcodynamics, PK=Pharmocokinetics, PUL=Performance of Upper Limb, TIBC=Total iron binding capacity, INQoL 
= Individualized Neuromuscular Disease Quality of Life, SF-36 = Short Form 36 Health Survey 
 
 
 
 
 
 
 
 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 24 
Table 3.2 Cohort 2 Extension 
 
 Cohort 2 Extension (40mg/kg) 
Treatment 
Follow-up 
 
Early 
Termination 
Visit Number  (Study Day Visit 
Window) 
13 
(+3) 
14 
(+3) 
15 
(+3) 
16 
(+3) 
17 
(+3) 
18 
(+3) 
19 
(+3) 
20 
(+3) 
21 
(+3) 
22 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
Physical Examination 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary Cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Contraception Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
 
 
 
 
 
 
 
 
 
X 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
12- lead ECG 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Echocardiogram 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical Laboratory Tests 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Serum Ferritin, Iron, Transferrin  
Saturation,TIBC 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Hormone Testing (LH, FSH, estrogen) 
 
 
 
 
 
 
 
 
 
X 
 
X 
GLDH 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
PK/ PD/Immunogenicity/Biomarkers 
 
 
 
 
 
 
 
 
 
X 
 
X 
Fecal Occult Blood 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
C-SSRS 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Questionnaires: InQol, SF-36 
 
 
 
 
 
 
 
 
 
X 
 
X 
MRI-Liver 
 
 
 
 
 
 
 
 
 
X 
 
X 
DXA Spine and Hip 
 
 
 
 
 
 
 
 
 
X 
 
X 
Muscle Strength (MMT, dynamometry) 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
4SC; 10-meter walk/run; 2MWT; 
Timed up-and-go 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
PUL 
 
 
 
X 
 
 
X 
 
 
X 
 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 25 
 Cohort 2 Extension (40mg/kg) 
Treatment 
Follow-up 
 
Early 
Termination 
Visit Number  (Study Day Visit 
Window) 
13 
(+3) 
14 
(+3) 
15 
(+3) 
16 
(+3) 
17 
(+3) 
18 
(+3) 
19 
(+3) 
20 
(+3) 
21 
(+3) 
22 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
Respiratory Function (FVC, FEV1, 
MIP/MEP) 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Study Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion site reaction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 2MWT=Two minute walk test; 4 SC= Four stair climb, C-SSRS=Columbia Suicide Severity Rating Scale, DXA=Dual-energy x-ray 
absorptiometry; ECG = electrocardiogram; FSH= Follicle stimulating hormone; FVC=Forced vital capacity; FEV1 = Forced expiratory voume in 1 second; 
GLDH=glutamate dehydrogenase, LH-Lutenizing hormone, MIP= Mean inspiratory pressure; MEP= Mean expiratory pressure; MMT= manual muscle testing, 
MRI=magnetic resonance image; PD=Pharmcodynamics, PK=Pharmocokinetics, PUL=Performance of Upper Limb, TIBC=Total iron binding capacity, INQoL 
= Individualized Neuromuscular Disease Quality of Life, SF-36 = Short Form 36 Health Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 26 
Table 3.3 Cohort 3 Extension 
 
 Cohort 3 Extension (40mg/kg) 
Treatment 
 
Follow-up 
Early 
Withdrawal 
Visit Number  (Study Day Visit Window) 
13 
(+3) 
14 
(+3) 
15 
(+3) 
16 
(+3) 
17 
(+3) 
18 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
Physical Examination 
 
 
X 
 
 
X 
 
X 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
 
X 
Diary Cards 
X 
X 
X 
X 
X 
X 
 
X 
Contraception Review 
X 
X 
X 
X 
X 
X 
 
X 
Height 
 
 
 
 
 
X 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
 
 
X 
 
 
X 
 
X 
12- lead ECG 
 
 
 
 
 
X 
 
X 
Echocardiogram 
 
 
X 
 
 
X 
 
X 
Clinical Laboratory Tests 
 
 
X 
 
 
X 
 
X 
Serum Ferritin, Serum Iron, Transferrin 
Saturation,TIBC 
 
 
X 
 
 
X 
 
X 
Hormone Testing (LH, FSH, estrogen) 
 
 
 
 
 
X 
 
X 
GLDH 
 
 
X 
 
 
X 
 
X 
PK/PD/Immunogenicity/Biomarkers 
 
 
 
 
 
X 
 
X 
Fecal Occult Blood 
 
 
X 
 
 
X 
 
X 
C-SSRS 
 
 
X 
 
 
X 
 
X 
Questionnaires: InQol, SF-36 
 
 
 
 
 
X 
 
X 
MRI-Liver 
 
 
 
 
 
X 
 
X 
DXA Spine and Hip 
 
 
 
 
 
X 
 
X 
Muscle Strength (MMT, dynamometry) 
 
 
X 
 
 
X 
 
X 
4SC; 10-meter walk/run; 2MWT; Timed up-and-go 
 
 
X 
 
X 
X 
 
X 
PUL 
 
 
X 
 
X 
X 
 
X 
Respiratory Function (FVC, FEV1, MIP/MEP) 
 
 
X 
 
 
X 
 
X 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 27 
 Cohort 3 Extension (40mg/kg) 
Treatment 
 
Follow-up 
Early 
Withdrawal 
Visit Number  (Study Day Visit Window) 
13 
(+3) 
14 
(+3) 
15 
(+3) 
16 
(+3) 
17 
(+3) 
18 
(+3) 
Telephone Follow-up 
30+ 3 days after final 
dosing visit 
 
Study Treatment Administration 
X 
X 
X 
X 
X 
X 
 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion site reaction 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 2MWT=Two minute walk test; 4 SC= Four stair climb, C-SSRS=Columbia Suicide Severity Rating Scale, DXA=Dual-energy x-ray 
absorptiometry; ECG = electrocardiogram; FSH= Follicle stimulating hormone; FVC=Forced vital capacity; FEV1 = Forced expiratory voume in 1 second; 
GLDH=glutamate dehydrogenase, LH-Lutenizing hormone, MIP= Mean inspiratory pressure; MEP= Mean expiratory pressure; MMT= manual muscle testing, 
MRI=magnetic resonance image; PD=Pharmcodynamics, PK=Pharmocokinetics, PUL=Performance of Upper Limb, TIBC=Total iron binding capacity, INQoL 
= Individualized Neuromuscular Disease Quality of Life, SF-36 = Short Form 36 Health Survey 
 
a. 
Assessments should be conducted on the Study Day within the visit window.  Visits with MRI, DXA and functional assessments may be conducted over 
2 days. The following order of testing is preferred.  On the first day of assessments: an am fasting blood collection followed by fasting DXA and MRI. 
On the second day of assessments:  the functional assessments and muscle biopsy. Whenever possible, functional testing and MRI should occur prior to 
biopsy.   
b. 
Pregnancy tests (highly sensitive urine or serum) and hormone testing will only be conducted for women of child bearing potential (WOCBP).  In 
addition, diary cards will be used to collect the first day of menstrual cycle for WOCBP.  
c. 
Weight collected within a month of the visit can be used to calculate the appropriate dose by body weight. 
d. 
Vital sign evaluations will include supine blood pressure, pulse rate, respiratory rate and oral temperature. 
e. 
Clinical laboratory tests include hematology with complete blood count and differential, comprehensive metabolic panel (sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen, creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, alkaline phosphatase), cardiac 
troponin I, gamma-glutamyl transferase (GGT), prothrombin time (PT), activated partial thromboplastin time (aPTT), creatine kinase, amylase and 
urinalysis.  If total bilirubin is abnormal, direct bilirubin will be tested reflexively.   The samples for serum ferritin, serum iron, transferrin saturation and 
TIBC should be collected in the morning following an 8 hour fast.   
f. 
Hormone testing will include LH, FSH and estrogen in female subjects only. 
g. 
Fecal Occult Blood testing will be performed at home within 1 week of the scheduled visit. 
h. 
Investigational product should be delivered in a 2 hour window 15 minutes not including the flush time.  Subjects are required to be observed for 
1 hour after the infusion of the investigational product is completed.  If a dosing visit cannot be conducted within the visit window, attempts should be 
made to bring the subject back for dosing as soon as possible; however the dosing must not occur within 2 weeks prior to the next scheduled dose.  If 
the subject cannot return in this timeframe, the dose should be missed. 
i. 
PK/PD assessments will occur predose. 


PF-06252616 
Final Protocolv6,   14 February 2018 
 
Page 28 
j. 
Prep B1.5 (K2 EDTA plasma collection optimized for biomarker/proteomic/metabonomic analysis), Prep B2.5 (serum collection optimized for 
biomarker/ proteomics/metabonomic analysis), Prep R1 (PAXGene whole blood collection optimized for RNA analysis),  and Prep 4 (Cell-free RNA) will be 
collected at: Cohort 1 at Visit 27, Cohort 2 at Visit 22, and Cohort 3 at Visit 18, or at Early Termination. 
k. 
MRI of the liver is performed on Visit 27 for Cohort 1, Visit 22 for Cohort 2, and Visit 18 for Cohort 3, or at Early Termination.  


PF-06252616 
Final Protocol v  5,  04 May 2017 
 
 
CONFIDENTIAL 
Page 29 
 
1. INTRODUCTION 
1.2. Mechanism of Action/Indication 
The investigational product PF-06252616, a humanized anti-myostatin monoclonal antibody 
that neutralizes myostatin (GDF8) is in development for the treatment of Limb Girdle 
Muscular Dystrophy 2I (LGMD2I) and Duchenne Muscular Dystrophy (DMD) to preserve 
and/or improve muscle function.  Other potential indications for PF-06252616 include other 
muscular dystrophies, muscle frailty conditions such as cancer cachexia and sarcopenia and 
rehabilitation of muscle strength. 
The safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of 
PF-06252616 have been demonstrated in healthy adults following administration of either 
single ascending intravenous (IV) or a subcutaneous (SC) dose(s) and, subsequently, repeat 
IV doses in adult healthy subjects. 
This study will provide the clinical assessment of the safety, tolerability, PK and PD of 
PF-06252616 following repeat IV doses in ambulatory adults with LGMD2I. 
Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure.  
1.3. Background and Rationale 
1.3.1. Myostatin Role in Muscle Regulation 
Myostatin or growth and differentiation factor 8 (GDF-8) is a member of the bone 
morphogenetic protein, transforming growth factor- (BMP/TGF) superfamily of secreted 
differentiation factors 1.  The muscle-specific, negative regulatory role of GDF-8 is well 
conserved between zebrafish, dogs, cattle, mice and humans.  GDF-8 has been best studied in 
skeletal muscle where GDF-8 null mice possess muscles that are 100% to 200% larger than 
wild-type controls due to a combination of muscle fiber hyperplasia and hypertrophy 2.  
Despite having increased skeletal muscle and decreased fat, the GDF-8 null mice appear to be 
normal and healthy.  Consistent with its role in mice, genetic loss of myostatin is associated 
with increased muscle mass in many different species 1.  One case of a human has been 
reported with a homozygous mutation of the GDF-8 gene, associated with an absence of 
GDF-8 protein, increased muscle strength and, by age 4, no apparent untoward health effects 
3. Pharmacologic inhibition of GDF-8 activity in rodents results in increased muscle mass and 
improved muscle function in both normal and dystrophic animals 4.  Given its effect on 
skeletal muscle and the absence of abnormality in knockout mice, GDF-8 represents an 
attractive target for diseases associated with muscle loss. 
1.4. Limb Girdle Muscular Dystrophy 2I 
LGMD2I is a genetic, autosomal recessive, disorder. It is one of the most common forms of 
LGMD accounting for at lease 10% of all known LGMDs 5. LGMD2I is caused by mutations 
in the gene for Fukutin-related protein (FKRP), which codes for an enzyme that glycosylates 
-dystroglycan on the muscle membrane 6,7.  In the absence of FKRP, -dystroglycan is 


PF-06252616 
Final Protocol v  5,  04 May 2017 
 
 
CONFIDENTIAL 
Page 30 
improperly glycosylated and does not make crucial linkages of the muscle membrane to 
laminin in the basal lamina.  This loss of linkage results in muscle cell death.  Reduction in 
dystroglycan glocyoslyation by FKRP as well as other enzymes causes several different 
LGMDs and congenital muscular dystrophies which are referred to collectively as 
dystroglycanopathies 5.   
 
There is a wide variability in the clinical severity of LGMD2I with childhood onset and fast 
progression to mid-adult onset and slow progression 8.   The majority of people with LGMD2I 
have initial symptoms of weakness and wasting in the hip, with difficulty walking and 
climbing stairs during teenage or early adult years. As the condition progresses, shoulder 
girdle muscles may also become weak although scapular winging is absent.  Mobility 
becomes increasingly difficult and may result in loss of ambulation.  Cardiomyopathy 
develops in approximately half of LGMD2I patients 8,9. Repiratory involvement requiring 
noninvasive nighttime ventilation has been described 8. 
 
Treatment of LGMD2I is supportive only. This includes, for example, bracing, mobility 
equipment and ventilatory support, generic to most muscular dystrophies.  Cardiomyopathy is 
frequently treated with angiotensin converting enzyme (ACE) inhibitors  10.  There are no 
pharmacological therapies known to improve the progressive skeletal muscle weakness 
associated with the disorder. Anecdotal reports describe positive responses to corticosteroids 
but there have been no randomized controlled trials of corticosteroids in LGMD2I and such 
treatment is not currently widely practiced or considered standard of care 11.   
 
This study will provide the initial clinical assessment of the safety, tolerability, efficacy, PK 
and PD of PF-06252616 following repeat IV doses in adult ambulatory participants with 
LGMD2I. 
1.4.1. PF-06252616 
PF-06252616, also referred to as Anti-Myostatin, is a humanized recombinant antibody 
immunoglobulin G1 (IgG1) that neutralizes GDF-8 (myostatin).  PF-06252616 was developed 
by humanization of a mouse monoclonal antibody, designated mRK35, generated by 
immunizing GDF-8 knockout mice with recombinant GDF-8 and isolating monoclonal 
antibodies by splenic fusion using standard hybridoma methodology.  The substitution of 
specific amino acid residues in the Fc region of PF-06252616 has reduced the effector 
functions of the molecule.  The humanized recombinant antibody has a human kappa constant 
domain and a human IgG1 constant domain with 3 mutations to reduce potential effector 
function.  PF-06252616 investigational drug product is supplied as a lyophilized sterile 
powder for solution for injection in a single use vial.  The vials will be reconstituted with 
sterile water for injection (SWFI).  The reconstituted PF-06252616 drug product is clear and 
colorless to slightly yellow. 
1.5. Nonclinical Pharmacodynamics 
Initial studies in mouse demonstrated that mRK35 was superior to a previous anti-myostatin 
monoclonal antibody, MYO-029, which prompted humanization of the antibody 
(PF-06252616).  Administration of PF-06252616 to naïve and dystrophic mdx mice resulted 
in increased muscle mass and function.  Subsequent studies demonstrated that PF-06252616 


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could significantly increase lean mass and muscle volume in nonhuman primates (NHP) in a 
dose-dependent manner.  In one NHP study, the animals were monitored during a washout 
period following the last dose, which showed the muscle that accrued during the study was 
maintained for several weeks after the last dose.  Collectively the pharmacology data show 
that muscle anabolic activity of PF-06252616 has been observed in all studies, in both mice 
and NHP. 
The epitope to which PF-06252616 binds in myostatin is also highly conserved with growth 
differentiation factor 11 (GDF-11), another member of the TGF- superfamily, and PF-
06252616 binds both proteins with comparable affinity.  PF-06252616 binds with 360x lower 
affinity to BMP-6 than myostatin.  PF-06252616 demonstrates no significant binding against 
other BMPs, activins, inhibins, and TGF-.   
1.6. Nonclinical Pharmacokinetics 
PK of PF-06252616 after a single IV dose of 10 mg/kg in mice, rats and monkeys, was 
characterized by low clearance, low apparent volume of distribution (at steady state) and long 
terminal elimination half-lives.  The calculated bioavailability following a single 
subcutaneous (SC [10 mg/kg]) or intraperitoneal (IP [1, 3, and 10 mg/kg]) dose in mice 
ranged from 47 to 118%, while bioavailability following a single SC (10 mg/kg) dose in 
monkeys was 80%. 
Following weekly IV or SC administration up to 1 month in rats (15, 50, 150, 282.5 and 
565 mg/kg) and monkeys (10, 30, 100 and 282.5 mg/kg), systemic PF-06252616 exposure, as 
assessed by Cmax and AUC168, increased with increasing dose and was generally similar for 
males and females.  All rats (up to 150 mg/kg) and monkeys (up to 100 mg/kg) were negative 
for the induction of anti-drug antibodies (ADA).  ADA was not assessed at the other doses in 
these studies. 
Serum and cerebrospinal fluid (CSF) concentrations of PF-06252616 were determined after 
weekly IV administration for 26 weeks to male and female juvenile rats (50, 150 and 
471.5 mg/kg) and monkeys (10, 50 and 284 mg/kg).  In general, serum toxicokinetic (TK) 
parameters were similar for males and females for all dose groups.  Systemic exposure 
increased with dose in a less than dose proportional manner in rats and a dose proportional 
manner for monkeys.  Mean CSF/serum ratios were low, indicating limited central nervous 
system (CNS) penetration of PF-06252616 in these species.  No induction of ADA was 
detected in juvenile rats during treatment phase.  However, 2 rats from the recovery phase 
tested positive for ADA.  All juvenile monkeys were negative for the induction of ADA in 
both the dosing and recovery phases. 
The PK and tissue distribution of [125I]PF-06252616 in female C57BL/6 mice (n=4/time 
point) were determined after a single IV dose of 8 mg/kg.  Following administration, 
[125I]PF-06252616 was eliminated from circulation with a serum clearance (CL) of 
12.7 mL/day/kg, and a terminal elimination half-life (t½) of 123 hours (5.1 days).  The 
relatively low steady state volume distribution (Vss) of 89.0 mL/kg suggested that the test 
article was mainly confined to the vascular space. 


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The concentrations of [125I]PF-06252616 in all tissues of interest were significantly lower for 
all the time points tested compared to corresponding serum concentrations.  The tissue to 
serum ratio (T/S) AUCinf ratios were less than 0.1 for all tissues of interest except lung and 
skin, with values of 0.154 and 0.159, respectively.  The Tmax for skeletal muscle was 24 hours 
with a Cmax of 2.5 0.5 (g eq./gram) and a T/S AUCinf ratio of 0.036.  Radioactive equivalent 
concentrations in tissues of interest, such as skeletal muscle, declined with time in parallel to 
that for serum. 
1.7. Toxicology 
PF-06252616 was administered to rats (n=10/sex) and cynomolgus monkeys (n=3/sex) once 
weekly via IV and SC routes in initial pivotal 1-month toxicity studies that also included 
assessments of neurofunctional activity in rats and respiratory rate and cardiovascular function 
in cynomolgus monkey.  Subsequent 1-month studies in rats and monkeys with IV dosing 
once weekly were conducted at the maximum feasible dose.  The no observed adverse effect 
levels (NOAELs) in these studies were the highest doses tested, which were 565 and 
282.5 mg/kg/week in the rat and cynomolgus monkey, respectively. 
Test-article related increases in body weight and skeletal muscle in rats and/or monkeys and 
increases in lean muscle mass and quadriceps, gastrocnemius, and/or sternocephalicus 
muscles in monkeys were observed in the 1-month toxicology studies in rats and/or 8-week 
pharmacokinetic/pharmacodynamics (PK/PD) study in monkeys. 
PF-06252616 produced no effects on the CNS function in rats or on respiration rate in 
cynomolgus monkeys.  Although there were no changes in cardiac function as assessed by 
electrocardiogram (ECG) and ultrasound analysis, reductions in heart rate were noted in the 
initial 1-month IV/SC study in male cynomolgus monkeys and appeared to show a dose 
dependency although rates remained within the normal range observed for cynomolgus 
monkeys.  This effect was not observed in the subsequent studies conducted up to 26 weeks at 
the higher doses up to 284 mg/kg/week, and when present was not considered adverse.  
Additional nonadverse test article-related effects related to administration of PF-06252616 
were considered attributable to its pharmacological effect on muscle; specifically, effects on 
red blood cell (RBC) mass parameters, creatinine, and phosphorus. 
Subsequently, PF-06252616 was administered by IV (bolus) injection to juvenile Wistar Han 
rats and cynomolgus monkeys (age 5.5 weeks and 18 months, respectively) at doses up to 
471.5 mg/kg/week in rats and 284 mg/kg/week in cynomolgus monkeys for 26 weeks 
followed by a 13-week recovery phase to assess reversibility.   
In the 26-week study in juvenile rats (n=15/sex), hepatic iron accumulation was present at all 
doses (50 mg/kg/week) in males and females, and associated with liver lesions in females 
only.  Microscopic findings in the liver of females given 50 mg/kg/week consisted of 
minimal hepatocellular foci of alteration (basophilic), minimal to moderate predominantly 
periportal hepatocellular hypertrophy, and minimal to mild hepatocellular cytomegaly; these 
findings persisted through the recovery period.  Hepatocellular hypertrophy was frequently 
associated with disruption of the hepatic cords in the portal regions, and additionally some 
females had distinct cytomegalic hepatocytes, often bi- or multinucleated or contained an 


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increased number of mitotic figures, that were notably larger than the adjacent hypertrophied 
hepatocytes.  Based on the abnormality of the cytomegalic hepatocytes, this finding and the 
more pronounced hypertrophy with hepatic cord disruption finding were considered adverse at 
all doses in females.  Following recovery (n=5/sex), microscopic findings in liver were similar 
to those observed at the end of the dosing period.  In males, there was an increased incidence 
and severity of hemorrhage and erosion in the glandular stomach with associated 
inflammation at 471.5 mg/kg/week, which was considered adverse, based on the severity of 
the findings.  The findings in the glandular stomach were reversible during the recovery 
period. 
Weekly IV administration of PF-06252616, to juvenile cynomolgus monkeys (n=4/sex) for up 
to 26 weeks at doses of 0, 10, 50, or 284 mg/kg/week also resulted in hepatic iron 
accumulation at all doses, and adverse findings at 284 mg/kg/week affecting liver in both 
sexes and reproductive organs in females.  The findings in the liver consisted of moderate to 
severe iron deposits in hepatocytes associated with portal macrophage accumulation and/or 
fibrosis, single cell necrosis and hepatocellular cytoplasmic rarefaction with correlating 
increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities.  
Pigment deposit was also observed in the kidney, pancreas and duodenum of 1 female.  
Adverse findings in the female reproductive tract consisted of arrested development of ovarian 
follicles and atrophy of the endometrium, cervical mucosa, and vaginal epithelium.  Following 
a 13-week recovery period (n=2/sex), adverse PF-06252616-related microscopic findings 
were still noted in the liver of male and female monkeys.  In the liver, single cell necrosis and 
macrophage accumulation were present, and there was no reversal of the pigment deposit 
(iron/hemosiderin) and its associated changes.  Pigment deposition was also present in the 
pancreas (including pancreatic lymph nodes) and kidney.  Hepatic cytoplasmic rarefaction 
was not observed at the end of the recovery period suggesting a complete reversal of this 
change.  In the female reproductive tract, some of the changes were still evident for 1 female 
while a complete recovery was noted for the other female. 
Although differences are apparent in the nature of the hepatic findings noted in toxicity 
studies in rats and cynomolgus monkeys, excessive iron accumulation resulting in hepatic 
overload is considered to be the basis of the findings in both species.  Experimental models of 
oral and parenteral iron overload in rats have shown that iron has a mitogenic effect on the 
liver characterized by a proliferative hepatocellular response that develops in the absence of 
accompanying hepatocellular necrosis/degeneration, fibrosis, or inflammation 12.  
Morphologically periportal hepatocellular hypertrophy 13, and/or oval cell proliferation 14 
were observed.    The increased sensitivity of female rats administered PF-06252616 is 
consistent with reports that the severity of pigmentation of parenchymal and nonhepatocytic 
cells in the livers of iron overloaded rats was greater in females compared with males 15.  
However, test article-related increases in hepatic iron and associated hepatic findings in 
female cynomolgus monkeys were comparable in severity with male cynomolgus monkeys.  
This is consistent with the absence of female sensitivity, and sometimes relative insensitivity 
compared with males, to hepatic injury in human genetic iron disorders, as female primates 
are afforded some protection through menses that does not occur in female rodents 16,17. 
Additional investigative efforts have provided in vivo and in vitro evidence that direct anti-
BMP-6 activity of PF-06252616, resulting in suppression of BMP-6 induced hepcidin 


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expression, is the mechanism leading to hepatic iron overload in the 26-week studies in rats 
and cynomolgus monkeys.   
In the 26-week IV studies, the NOAELs were 150 (males only) and 50 mg/kg/week for rats 
and cynomolgus monkeys, respectively.  The margins at these NOAELs were 7x and 3x the 
predicted exposure (Cav) at the highest projected dose in humans for rats and cynomolgus 
monkeys, respectively. 
1.8. Clinical Experience with PF-06252616 
As of June 2015, there are one completed clinical study (B5161001) and one ongoing clinical 
study (B5161002) with PF-06252616.   
The initial clinical program for PF-06252616 was a Phase 1 first in human, randomized, 
double-blind (sponsor and pharmacist unblinded), placebo-controlled study (B5161001) 
evaluating the safety, tolerability, PK, PD, and pharmacologic (anabolic) effects of escalating 
single doses of PF 06252616 in healthy adult subjects.  This study fully enrolled 73 subjects at 
a single site and completed in July 2014.  Doses of 1, 3, 10, 20, and 40 mg/kg administered by 
the intravenous (IV) route and 3 mg/kg administered by the subcutaneous route, or placebo 
have been studied.  In addition, a repeat IV administration of PF 06252616 10 mg/kg at 2 
week intervals over a 28-day treatment period has been investigated.  Safety was 
demonstrated at all dose levels and there were no dose-related trends in frequency of reported 
treatment emergent adverse events (TEAEs). 
PF-06252616 serum concentrations in Study B5161001 were measured using a validated 
enzyme-linked immunosorbent assay (ELISA) method.  Target mediated drug disposition 
(TMDD) was evident at the lower concentration levels mainly below 1 g/mL.  The 
individual and mean PK serum profiles following the single dose administrations and the 
PF-06252616 serum concentrations following the repeat dose were analyzed.  PF-06252616 
demonstrated a bi-phasic PK profile with a mean terminal half-life in days (~12 to 19 days), 
slow CL (2.38 to 3.54 mL/day/kg) and small volume of distribution (56 to 78 mL /kg), all 
attributes of a typical IgG1molecule.  Following SC administration, PF-06252616 was 
absorbed slowly with a median time to maximum concentration of 7 days, a half-life of 
approximately 13 days, and apparent bioavailability of ~61%. 
The PD activity of PF-06252616 was evaluated in Study B5161001, by measuring total serum 
GDF-8 (myostatin) levels using a validated liquid chromatography/mass spectrometry 
(HPLC-MS/MS) method.  Following PF-06252616 administration, total serum GDF-8 levels 
were modulated at all dose levels.  The mean time to maximum GDF-8 levels was generally 
between 11 and 30 days.  The extent of modulation increased between 1 and 10 mg/kg IV 
doses and seemed to plateau at higher doses. In the repeat-dose cohort, the median GDF-8 
baseline level was 3.1 ng/mL on Day 1 and following 10 mg/kg IV dosing, the median GDF-8 
concentration increased to 18.6 ng/mL after the third dose.   
One of the secondary objectives of Study B5161001 was to demonstrate proof of mechanism 
(POM) for evidence of a pharmacologic effect based on a percentage change in lean body 
mass (LBM) as measured in dual-energy x-ray absorptiometry (DXA) in the repeat dose 
cohort (10 mg/kg IV every 2 weeks for 1 month). Per the analysis criteria, the percent change 


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in LBM in the repeat dose cohort did not reach significance at any time point evaluated.  The 
criteria were then applied in an exploratory analysis to the magnetic resonance imaging (MRI) 
T1 measurements of muscle volume and the T2 measurements of muscle fat content at each 
time point.  On the T1 measurement of quadriceps muscle volume an increase in muscle 
volume at Day 113, where a mean 4.48% difference from baseline, relative to placebo, was 
observed.  On the T2-mapping, an increase of 6.11% (change from baseline as compared to 
placebo at Day 113) in the proportion of tissue exhibiting T2 signals associated with muscle 
rather than fat.  
Study B5161002 is a first-in-patient Phase 2, randomized, 2-period, double-blind, placebo-
controlled, multiple ascending dose study to evaluate the safety, efficacy, PK, and PD of PF-
06252616 administered to ambulatory boys with DMD.  Three (3) IV-infused dose levels (5, 
20, and 40 mg/kg) will be investigated in a “within subject” dose-escalating fashion.  
Approximately 120 subjects will be enrolled.    The first subject first visit was November 
2014. As of 26 January 2018, 120 subjects were enrolled in the study and 38 of whom had 
completed the study. Subjects who completed Study B5161002 have the option to enroll in the 
Open-label extension study (Study B5161004). Thirty one subjects are currently enrolled in 
this extension study. 
1.9. Immunogenicity Risk Assessments 
1.9.1. Nonclinical Immunogenicity 
Antigenicity studies with PF-06252616 have not been conducted.  However, in general, 
anti-PF-06252616 antibodies were not detected post dose up to 26 weeks in rats and 
cynomolgus monkey.  It should be noted that circulating levels of PF-06252616 may have 
interfered with the detection of any anti-PF-06252616 antibodies.  In addition, toxicokinetics 
up to 26 weeks in rats and cynomolgus monkeys indicate drug levels increase with time 
following repeated dosing suggesting no production of ADA. 
The potential for immunotoxicity was evaluated in rats and cynomolgus monkeys up to 
26 weeks.  No adverse effects were observed in hematology parameters or on microscopic 
examination of lymphoid organs.  Since no adverse findings or indications of immunotoxicity 
were observed no further evaluations have been performed. 
1.9.2. Immunogenicity Results B5161001 
Following PF-06252616 administration in Study B5161001, 5 adult healthy subjects in the 
single dose groups (1 in the 1 mg/kg IV group, 2 in the 20 mg/kg IV group, and 2 in the 
3 mg/kg SC group) and 1 subject in the 10 mg/kg IV repeat dose group were found to have 
treatment-induced ADA responses.  Among the 6 subjects with ADAs, 4 subjects (1 in each of 
the 1 mg/kg IV, 3 mg/kg SC, 20 mg/kg IV, and 10 mg/kg repeat dose IV cohorts) have shown 
neutralizing antibodies (NAb).  However, none of these subjects with NAb showed any 
discernibly lower GDF-8 levels than others in the same cohort.  In summary, for Study 
B5161001, there was a confirmed ADA incidence rate of 11.3% but without any obvious 
impact on the PF-06252616 PK or GDF-8 modulation. None of these subjects experienced 
clinical signs or symptoms consistent with an immune response. 


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1.10. Rationale for Dosage Selection and Method of Administration 
PF-06252616 has been administered to healthy adult subjects in Study B5161001 and found to 
be safe and well tolerated as a 2-hour intravenous infusion at single doses of 1, 3, 10, 20, and 
40 mg/kg, as a subcutaneous injection in a single dose of 3 mg/kg, and in repeat intravenous 
doses of 10 mg/kg at 2 week intervals over a 28-day treatment period.   
A target mediated drug disposition PK/PD model was developed based on healthy volunteer 
data from study B5161001 and used to predict PF-06252616 exposures and corresponding 
GDF-8 coverage of the proposed dosing regimens for the current study.  Based on available 
data from the investigator’s database, the range of body weights, BMI and lean body weights 
for LGDM2I subjects is expected to be similar to healthy adult volunteers.  As such, it is 
assumed that the weight normalized population PK parameters and the GDF-8 binding 
parameters will be similar between healthy adult volunteers and LGMD2I subjects, especially 
since PF-06252616 is to be administered as a body weight based (mg/kg) dosing.  These 
parameters are then used to simulate both the expected PK profile (to compare to toxicology 
exposure margins) (see Table 1) and the expected PD profile (considering target coverage in 
serum).  
 
For this study, 5 mg/kg administered every 4 weeks is being proposed as the starting dose in 
Cohort 1, as it is expected to show median GDF-8 serum coverage over 80% and therefore 
may demonstrate pharmacologic activity while providing sufficient safety multiple of 17.2 
and 28.7 for Cmax and Cav, respectively, at steady state.  A mid dose of 20 mg/kg administered 
every 4 weeks is expected to provide target coverage similar to the 10 mg/kg every 2 weeks 
dose in Study B5161001, which produced positive MRI signal changes in healthy volunteers.  
The highest dose of 40 mg/kg administered every 4 weeks is expected to maximize the 
potential for efficacy while still maintaining a 2-fold safety margin to the toxicology limits.   
Table 1. 
Predicted Exposures and Margins Relative to Toxicokinetics Limits at 
Planned PF-06252616 Doses 
IV Dose 
(mg/kg) 
Predicted 
Cmax 
(µg/mL) 
Fold Difference 
with Cmax 
Cynomologus 
Monkey NOAEL 
Predicted Cav 
(µg/mL) 
Fold Difference with Cav 
Cynomolgus Monkey 
NOAEL  
5 
156 
17.2 
65 
28.7 
20 
598 
4.5 
265 
7.1 
40 
1200 
2.2 
550 
3.4 
Toxicology limit set by the NOAEL of 50 mg/kg in 26 week non-human primate juvenile study (Cmax = 2690 
µg/mL, Cav = 1870 µg/mL). 
The predicted human AUC672 was converted to Cav as follows: AUC672/672 = Cav. 
Cmax = maximum concentration at steady-state; Cav= average concentration at steady state. 
1.11. Study Design Rationale 
This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the 
safety, tolerability, efficacy, PK and PD of PF-06252616 in ambulatory adults with LGMD2I.  
The study design is intended to determine the optimal safe and pharmacologically active dose 
of PF-06252616 in LGMD2I while providing an opportunity for all subjects to receive active 


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drug for a rare and disabling disorder.  The study will be conducted in four periods:  Lead-In, 
Treatment, Follow-up, and Extension periods.  The Lead-In and Follow-up periods will each 
be approximately 16 weeks to allow an assessment of the change of various outcome 
measures of this period of time and comparison of change in function before, during and after 
treatment.  The Treatment period will be 32 weeks. This time of active treatment was chosen 
to maximize the possibility of observing trends in efficacy. After the Follow-up period, the 
subject will be given the option to continue treatment in the Extension period. 
This study is primarily a safety and tolerability study of PF-06252616 in LGMD2I adults.  
The rationale for dose selection and escalation has been described above.  A limited number 
of patients (4) will be enrolled in cohort 1 and will receive an initial dose of 5mg/kg 
PF-06252616 IV every 4 weeks.  Following 16 weeks of treatment and a safety review, if no 
stopping rules have been met, 8 subjects will be enrolled in cohort 2 and receive 20mg/kg of 
PF-06252616.  Subjects in cohort 2 will received 16 weeks of treatment and then a safety 
review will be performed.  If no stopping rules have been met, cohort 1 will escalate to 
receive 40 mg/kg.  This will occur after they have already received 5 mg/kg of PF-06252616 
for 32 weeks.  At the same time, cohort 3 will be enrolled and begin dosing at 40 mg/kg. For 
cohort 1, subject will receive 32 weeks of treatment with 5 mg/kg followed by an additionl 32 
weeks of treatment with 40 mg/kg PF-06252616.  The rationale for this design is that it 
provides a dose escalation to determine safety of each dose and allows each cohort to 
potentially receive a meaningful dose.  Thirty-two weeks of treatment maximizes the 
opportunity to determine if there is a treatment effect at any given dose level.  Finally, the 
design will provide long-term, 64 week dosing data on a limited number of subjects (4). All 
subjects, who completed the Follow-up period, will have the option to continue treatment in 
the extension period at 40mg/kg for up to 28 weeks in Cohort 1, up to 40 weeks in Cohort 2, 
and up to 24 weeks in Cohort 3 
Exploratory outcome measures of efficacy will also be obtained. There has been only one 
published drug intervention trial to date which has included LGMD2I subjects 18.  This was a 
trial of myostatin neutralizing antibody MYO-029 which was trialed in subjects with various 
different adult muscular dystrophies.  Various assessments of efficacy were obtained in this 
trial including manual muscle testing (MMT), quantitative muscle testing (QMT), timed 
function tests (TFTs), pulmonary function tests (PFTs), MRI, DXA and subject-reported 
outcomes.  These assessments of efficacy were found to be feasible in the LGMD2I 
population.  However, no efficacy was found in the combined LGMD group to provide 
information on optimal outcome measures for LGMD.  There is one published natural history 
study on adult LGMD2I 19.  In this study various functional outcome measures were studied in 
32 individuals over 12 months.  QMT, timed up and go (TUG), 4 stair-climb (4SC), 4 stair-
descend (4SD), 10 meter run (10MR),  6 minute walk test (6MWT) and forced vital capacity 
(FVC) were assessed.  Of these functional measures, only FVC had a statistically significant 
decline in 12 months.  The study also evaluated fat fraction by quantitative Dixon MRI and 
found increased fatty infiltration in 9 of 14 muscles within 12 months. Qualitative assessment 
of T1 weighted MRI was insensitive to change within this time frame.  FVC and quantitative 
Dixon MRI therefore are high priorty outcome measures of this trial.  However, considering 
the possibility that PF-06252616 will improve function rather than stabilize function, other 
outcome measures will be included as described above. 
 


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1.12. Anticipated Risks and Safety Monitoring 
Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure. 
Anticipated risks are based on clinical and toxicology data. 
A total of 53 healthy adult subjects have received PF-06252616 in a phase 1 study.  Forty-two 
received single IV or SC doses and 11 received a repeat dose (3 doses of 10 mg/kg 
PF-06252616 IV over a 4 week period).  There are no safety findings of concern from this 
study.  In 1 month toxicology studies performed with PF-06252616 in rat and monkey, no 
adverse findings were reported.  Consistent with the pharmacological response anticipated 
from this anti-myostatin monoclonal antibody, effects on skeletal muscle were noted.  In the 
26-week repeat dose toxicity studies in juvenile rats and monkeys, adverse and/or clinically 
relevant findings were noted and provide the basis of the warnings and precautions below. 
1.12.1. Hepatic Injury 
Accumulation of iron in the liver resulting in fibrosis and single cell necrosis of the liver is 
considered a potential side-effect of treatment with PF-06252616.  In the intended indication 
of LGMD2I, transaminase elevation related to muscle pathology is common. Alternative 
biomarkers of liver injury that are not affected by muscle pathology include GGT and GLDH 
which will be monitored in this trial.  The prevention of hepatic iron accumulation is the best 
strategy for avoidance of liver injury in this disease.  Approaches developed in the treatment 
and prevention of hepatic damage in haemochromatosis and iron overload syndromes provide 
a basis for monitoring using % Transferrin saturation (serum iron/total iron binding capacity x 
100) 20 and MRI measurement of hepatic iron 21. 
Abnormal values for serum ALT or AST concurrent with abnormal elevations in total 
bilirubin that meet the criteria for Hy’s law and in the absence of other causes of liver injury 
are considered potential cases of drug-induced liver injury (potential Hy’s law cases) and 
should always be considered important medical events.  Subjects meeting these criteria will 
follow the steps for confirmation required in Section 8.6.2.  The utility and necessity of 
continued monitoring of liver iron by MRI will be formally reviewed prior to dose escalation.   
1.12.2. Gastric Erosion and Haemorrhage 
An increase in gastric erosion and haemorrhage was seen at necropsy observed in male rats 
administered 471.5 mg/kg/week for 26 weeks.  Study subjects will be asked specifically to 
report symptoms that may be associated with such pathology.  Monitoring of haemoglobin, 
haematocrit and fecal occult bloods will be performed. 
1.12.3. Bone Metabolism 
In the 26 week rat study, bone biomarker changes were identified suggestive of a decrease in 
bone turnover.  Bone mineral density (BMD) as measured by peripheral quantitative 
computed tomography however was generally increased at the end of the study.  The 
biomarker changes were reversible.  In the monkey studies BMD and bone strength was 
increased.  A positive effect on BMD would clearly be considered a positive PD effect.  Spine 
and hip DXA will be used to monitor for changes in bone mineral density. 


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1.12.4. Cardiac 
Based on recent literature on the biology of GDF-8 and GDF-11 in modulation of 
cardiomyocyte and cardiac function and the potential for cardiac dysfunction in the target 
population of LGMD2I subjects, it is appropriate to focus on the potential for an interaction.  
In monkey toxicity studies up to 26 weeks, no abnormality of cardiac function or histology 
was observed.  In rats dosed with 150 mg/kg/week for 26 weeks, a reduction in heart weight 
was noted, but there were no microscopic findings.  In light of the hypothetical risk of an 
effect of PF-06252616 on cardiac muscle development or function, monitoring with 12-lead 
ECG for rhythm or morphological change by echocardiography to evaluate left ventricular 
ejection fraction (LVEF) and left ventricular end systolic volume (LVESV) and cardiac 
Troponin I for cardiac muscle tissue injury will be performed.  Additional cardiac parameters 
(eg, cardiac strain) may be collected by echocardiogram for exploratory analyses.  Abnormal 
values for each of these measures have been reported in LGMD2I 22,23.  In light of the 
variability of findings in disease, no pre-specified stopping rules have been defined. 
1.12.5. Special considerations in females 
In the 26-week female juvenile rat toxicity study, adverse hepatic changes were seen at all 
doses, and a NOAEL was not identified.  Female cynomolgus monkeys were not different 
from males in their sensitivity to iron accumulation or hepatocellular injury.  It is possible 
therefore that in human studies, females may have a higher sensitivity to liver injury and 
appropriate care is taken to monitor using GLDH and iron parameters. 
Reproductive and developmental toxicity studies with PF-06252616 have not been conducted.  
In the absence of evidence to the contrary, it must be assumed that administration of PF-
06252616 would pose a risk to the fetus in early pregnancy. Adult female patients who are of 
child bearing potential may be enrolled into clinical studies with PF-06252616 if they are 
using at least one highly effective means of contraception as outlined in the Section on 
Contraception. These methods must be in place at the start of screening continued until the 
final study visit.  
In a 26-week juvenile cynomolgus monkey study, there was no evidence of menses and 
marked arrested development of sexual organs was noted in female cynomolgus monkeys 
dosed at 284 mg/kg/week.  These changes were partially to fully reversible. Despite >3x 
margin from the NOAEL exposure at the dose of 40 mg/kg/4 weeks, it is appropriate to 
monitor adult female patients reproductive health.   
1.12.6. Radiation  
Possible risks related to subject’s undergoing evaluation with DXA include the risk of 
radiation exposure.  The average effective dose of radiation received for a single DXA scan 
may vary due to the instrument and the subject’s body.  Subject may require a skull X-ray 
prior to MRI if there is a question of intraocular metal.  This skull X-ray also carries the risks 
associated with radiation exposure. The maximum amount of radiation that a subject could 
receive is from 5 whole body DXA scans (in cohort 1), 3 DXA scans of the hips, 3 DXA 
scans of the spine and 1 skull X-ray. The expected total radiation dose for this maximum 
exposure is not expected to exceed 30 mrem.  This is less than 1 year of natural background 
radiation which is approximately 300 mrem per year 24.  


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1.12.7. Needle Muscle Biopsy 
Needle muscle biopsy is used to obtain small amounts of tissue (milligrams) for molecular 
studies in a clinic setting without the requirement of recovery time.  Needle muscle biopsies 
have been used previously in clinical trials of muscular dystrophy for this purpose where 
histology is not needed 25. There is a risk of reaction to local anesthesia (1% lidocaine with 
1:100,000 epinephrine).  There is also a risk of bleeding, bruising, hematoma formation, 
infection and peripheral nerve damage.  The combined risk of any of these adverse events 
occurring from needle muscle biopsy is estimated to be less than 1%.   
1.12.8. Other possible risks 
Possible risks related to the administration of the study drug and/or as a consequence to 
phlebotomy may include hematoma or bruising. 
1.12.9. Other Safety Monitoring 
Additional safety monitoring will include the parameters of adverse events (AEs), physical 
examination, vital signs, and clinical laboratory parameters (comprehensive metabolic panel 
[sodium, postassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, calcium, 
glucose, total protein, albumin, total bilirubin, AST, ALT, alkaline phosphatase], 
gamma-glutamyl transferase [GGT], glutamate dehydrogenase [GLD], prothrombin time 
[PT], activated partial thromboplastin time [aPTT], creatine kinase, amylase, cardiac troponin 
I and urinalysis) and Columbia Suicide Severity Rating Scale (C-SSRS).  Laboratory 
monitoring will also be performed to detect ADA and NAb. 
1.13. Summary of Risk Benefit 
This is a therapeutic study being conducted in adult subjects with LGMD2I.  There is no 
accepted pharmacological treatment for this disorder. There has been only one other 
therapeutic trial to date in this rare disease which did not demonstrate efficacy. PF-06252616 
may demonstrate pharmadynamic activity in subjects. 
In view of the initial clinical evidence of safety and the monitorable nature of key nonclinical 
toxicological findings, data support an acceptable risk profile for PF-06252616 in the current 
study and support a favorable benefit risk profile in the indication of LGMD2I.  Authorities 
will be kept informed of any additional data (eg, results from clinical studies) which may 
affect the assessment of the risk/benefit ratio for PF-06252616. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
2.1.1. Primary  
 To determine the safety and tolerability of multiple ascending repeat IV doses of 
PF-06252616 in ambulatory participants with LGMD2I.   
2.1.2. Secondary 
 To assess the PK exposures of PF-06252616 in LGMD2I. 


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 To evaluate the PD activity of PF-06252616 based on GDF-8 (myostatin) modulation 
in blood and in tibialis muscle. 
 To characterize the functional effects of PF-06252616 on muscle strength and 
functional assessments compared to baseline. 
 To characterize the effects of PF-06252616 on respiratory function compared to 
baseline. 
 To characterize the effects of PF-06252616 on patient reported outcome measures.  
 To evaluate the immunogenicity of PF-06252616. 
2.1.3. Exploratory 
 To evaluate functional outcome measures in LGMD2I. 
 To evaluate the PD activity of PF-06252616 based on the percent change of muscle 
volume as measured on MRI compared to baseline as indicated by the whole body MRI 
evaluation and/or lean body mass DXA results.  
 
2.2. Endpoints 
2.2.1. Primary Safety 
 Incidence of dose limiting or intolerability treatment related AEs by day 337 or 561. 
 Incidence, severity and causal relationship of treatment emergent AEs (TEAEs) and 
withdrawals due to TEAEs by day 337 or 561. 
 Incidence and magnitude of abnormal laboratory findings (clinical laboratory tests 
[hematology, chemistry], GGT, GLDH, PT,  aPTT, creatine kinase, amylase, serum 
ferritin, serum iron, % transferrin saturation, Total Iron Binding Capacity (TIBC), LH, 
FSH, estrogen, cardiac troponin I, fecal occult blood and urinalysis) by day 337 or 561. 
 Abnormal and clinically relevant changes in liver MRI and physical examinations, 
weight, vital signs, ECG, echocardiogram measured LVEF, DXA (bone mineral 
density), menstruation cycle (as monitored by diary), and C-SSRS (See Appendix 1 and 
Appendix 2) parameters by day 337 or 561.   
2.2.2. Seconday Endpoints 
2.2.2.1. Pharmacokinetic 
 All subjects receiving active drug: serum PF-06252616 Cmax and Ctrough for all visits 
with PK collections and at steady-state. 
 Total serum GDF-8 concentrations for all visits with GDF-8 collections 


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2.2.2.2. Strength and Function 
 Mean change from baseline on function tests including PUL, Timed up-and-go (TUG), 
10-meter walk/run (10MR), 2-meter walk test (2MWT), and 4 stair climb (4SC) 
 Mean change from baseline on pulmonary function tests incuding forced vital capacity 
(FVC), FEV1(forced expiratory volume in 1 second), maximal inspiratory pressure 
(MIP) and maximal expiratory pressure (MEP)  
 Mean change from baseline on muscle strength by manual muscle test (MMT) and 
Hand-Held dynamometry 
2.2.2.3. Patient Reported Outcomes 
 Mean change from baseline on Patient reported outcomes (InQoL, SF-36)(See 
Appendix 3 and Appendix 4) 
2.2.2.4. Immunogenicity 
Incidence of ADA and NAb development. 
2.2.3. Exploratory Endpoint 
2.2.3.1. Pharmacologic 
 Mean percent change from baseline in lean body mass by DXA 
 Mean percent change from baseline in muscle quality (fat infiltration) as measured by 
quantitative Dixon  
 Mean change from baseline in muscle quality as measured by T1/STIR  
2.2.3.2. Function 
 Evaluate the utility and changes from baseline of Functional Workspace as an outcome 
measure for LGMD2I  
2.2.3.3. Pharmacodynamic 
 Mean percent change from baseline in muscle volume as measured on MRI as indicated 
by the whole body MRI evaluation and/or lean body mass DXA results. 
 
3. STUDY DESIGN 
3.1. Study Overview 
This is a Phase 1b/2, open-label multiple ascending dose study to evaluate the safety, 
tolerability PK and PD of PF-06252616 administered to ambulatory participants diagnosed 
with LGM2I.  Three IV infused dose levels administered every 28 days will be investigated in 
a dose escalating fashion.  


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PF-06252616 dose levels: 
 5 mg/kg. 
 20 mg/kg. 
 40 mg/kg. 
Approximately 20 eligible subjects will be consecutively assigned to 1 of 3 cohorts for 
approximately 96 weeks (cohort 1) or 64 weeks (cohorts 2 and 3). 
Cohort 1 (n=4): 
 Lead-in period (16 weeks) 
 Treatment A: PF-06252616 5 mg/kg (32 weeks) 
 Treatment B: PF-06252616 40 mg/kg (32 weeks) 
  Follow-up period (16 weeks) 
 Extension period: PF-06252616 40 mg/kg (28 weeks) 
Cohort 2 (n=8): 
 Lead-in period (16 weeks) 
 Treatment: PF-06252616 20 mg/kg (32 weeks) 
 Follow-up period (16 weeks) 
 Extension period: PF-06252616 40 mg/kg (40 weeks) 
 
Cohort 3 (n=8): 
 Lead-in period (16 weeks) 
 Treatment: PF-06252616 40 mg/kg (32 weeks) 
 Follow-up period (16 weeks) 
 Extension period: PF-06252616 40 mg/kg (24 weeks) 
 


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At each dose level, subjects will be followed for an initial approximate 16-week lead-in period 
to establish individual change in disease progression.   
 
The study will begin with 4 subjects being enrolled into Cohort 1.  Following the lead-in 
period, subjects in Cohort 1 will be dosed with 5 mg/kg for a total of 32 weeks (8 doses).  
Cohort 2 will begin dosing at the mid dose level (20 mg/kg) once safety has been confirmed 
with subjects in Cohort 1 who have been treated for 16 weeks.  Cohort 1 and 3 will begin 
dosing at the highest dose level (40 mg/kg) once safety has been confirmed with subjects in 
Cohort 2 who have been treated for 16 weeks.  
Each dose level will be evaluated for 32 weeks (8 doses each). Cohort 1 is the only cohort 
who will receive 2 dose levels (5 mg/kg and 40 mg/kg) and their total treatment time will be a 
minimum of 64 weeks.  Subjects in Cohort 1 will only receive 8 doses of the 5 mg/kg dose 
and not proceed to the 40 mg/kg dose until safety review and approval by the SMC.   
At the conclusion of the treatment period, subjects will be followed for an additional 16 weeks 
to monitor for safety, PK and duration of response.  
All subjects completing the follow-up period will have the option to continue treatment with 
40mg/kg dose in the Extension Period. 
 
 
3.2. Duration of Subject Participation 
Subject’s participation will begin during screening (up to 2 weeks) followed by a lead-in 
period (16 weeks), treatment period (64 weeks for Cohort 1, 32 weeks for Cohorts 2 and 3) , 
follow-up period (ending 16 weeks after the last study dose in the treatment period), and the 
extension period (up to 28 weeks for Cohort 1, up to 40 weeks for Cohort 2, and  up to 24 


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weeks in Cohort 3). Periods of participation are estimates and are dependent on enrollment 
and safety review of concurrent dosing cohorts.  Subjects will return to the site monthly for 
study drug administration as well as completion of safety and efficacy assessments. 
 
In order to ensure consistency in assessment collection, visits that include functional 
assessments and imaging assessments (DXA and WB-MRI) will be collected over 2 
consecutive days, within the study visit window.  In the case where subjects are traveling from 
a distance, the site will offer nearby overnight accommodations. 
3.3. Approximate Duration of Study 
The study is estimated to complete in approximately 151 weeks allowing for 27 weeks of 
enrollment and up to124 weeks on the study. 
 
The end of the study will be the last visit of the last subject for purposes informing the 
institutional review board/ethics committee (IRB/EC), and ceasing to send Council for 
International Organizations of Medical Sciences (CIOMS) reports. 
3.4. Planned Number of Subjects 
A minimum of 20 subjects will participate.  In order to ensure adequate enrollment, a 
sufficient number of subjects may be screened. 
3.5. Safety Monitoring and Dose Escalation 
Safety monitoring will be conducted by the Investigator, Pfizer Medical Monitor and an 
External Medical Monitor.  This group will be refered to as the Safety Monitoring Committee 
(SMC).  Safety monitoring by these individuals will include the following reviews:   
 Dose escalation 
 Quarterly safety and 
 Ad hoc safety 
At each review, a consideration will be made of the number of subjects who have severe AEs 
or serious AEs in the same organ system which are determined to be related to investigational 
product.   The SMC may determine it is necessary to close or adjust a dose level within the 
study. The first dose escalation decision, whether or not to increase from 5 mg/kg in Cohort 1 
to 20 mg/kg in Cohort 2 will occur after review of all safety data after the 4th subject of Cohort 
1has completed the planned 16 weeks (day 85) or 4 doses.  The second dose escalation 
decision, whether or not to increase from 20 mg/kg in Cohort 2 to 40 mg/kg in Cohorts 1 and 
3 will occur after the 4th subject in Cohort 2 had completed the planned 16 weeks (day 85) or 
4 doses.  A break in dosing of subjects in Cohort 1 between 5 mg/kg and 40 mg/kg may occur 
to ensure all safety data from Cohort 2 at 20 mg/kg has been evaluated by the SMC.  Should  a 
break be required in Cohort 1 between Day 197 and 225 (±3 days) which is longer than the 
planned 28 days between dosing visits and outside the visit schedule, the window will not be 
applied.  When the dosing resumes in Cohort 1 at the highest dose, the first day of dosing will 
be Visit 11 and the remaining dosing schedule will follow the  Schedule of Activities, 
whereby dosing will occur every 28 days (± 3 days).     


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3.5.1. Dose Escalation and Stopping Rules 
Table 2. 
Criteria to Determine Dose Escalation or Stopping 
DECISION 
CRITERIA 
Dose Escalation 
 
SMC review of aggregate safety data from either: 
 
Cohort 1 (n=4) 16 weeks (day 85) or 
 
Cohort 2 (n=4) 16 weeks (day 85)  
and agree that safety is met and 
The estimate as determined by R2* value is within the normal range (R2*139 
Hz at 3.0 T ) 17,21,26 
No Esclation, Stop Dosing 
 
 
SMC review of aggregate safety data from either: 
 
Cohort 1 (n=4) 16 weeks (day 85) or 
 
Cohort 2 (n=4) 16 weeks (day 85)  
And agree that the current dose is not safe  or 
 
The liver iron content estimate as determined by R2* value is above the “mild 
overload” range for any subject within the cohort (R2* >369 Hz at 3.0 T) 
17,21,26 
If dosing is terminated at any dose level, subjects will continue to be followed for resolution 
of the safety finding or until a new baseline is established.  Depending on the nature of the 
reason for stopping dosing, the SMC will consider if the enrolled subjects can be continued at 
a lower dose level.  
3.5.2. Safety Monitoring Committee (SMC) 
The SMC will be composed of three members:  The Investigator, Pfizer Medical Monitor and 
an External Medical Monitor.  The External Medical Monitor will be a clinical trialist and an 
expert in the neuromuscular field.  The External Medical Monitor will not be a member of the 
the Investigator’s institutions (Johns Hopkins School of Medicine [JHSOM] and Kennedy 
Krieger Institute [KKI]) nor an employee of Pfizer.  The SMC will be responsible for ongoing 
safety monitoring from the initiation of the study through the final study visit.  Reviews will 
include aggregate safety, targeted medical events of special interest including liver toxicity, 
and serious AE data.  The SMC may also complete ad hoc safety reviews.  Ad hoc PK data 
may be provided to the SMC as requested.  
Following the data review, the SMC will determine if the study should be continued with no 
changes, modified, or stopped (eg, due to safety). Decision to continue the study must be 
unanimous.  Decision to stop the study can be made by any of the three memebers. In all other 
decisions, the External Medical Monitor will cast the deciding vote.  The recommendations 
made by the SMC to modify the the study will be forwarded to JHSOM IRB for final 
decision.  At any time the SMC may indicate that the limit of safety and/or tolerability has 
been reached and that any of the dose levels will be removed from the study. 


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The SMC will consider the following safety criteria during their safety review: 
 The number of subjects who have severe AEs or serious AEs in the same organ system 
which are determined to be related to study medication. 
 Other findings that indicate that dose escalation should be halted. 
4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  
4.1. Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Male and female patients age ≥ 18 
2. Diagnosis of LGMD2I as defined by clinical presentation consistent with LGMD2I 
and FKRP gene testing showing biallelic alterations known or likely to be pathogenic. 
Diagnosis must be confirmed in subject’s medical history and by genetic testing 
obtained during routine clinical care for diagnostic purposes as reported from an 
appropriate regulated laboratory using a clinically validated genetic test (genetic 
testing is not provided by the sponsor). 
3. Ability to walk/run 10m  
4. Abilit to rise from chair 
5. Adequate hepatic and renal function on screening laboratory assessments  
 GGT  upper limit of normal (ULN). 
 Alkaline phosphatase  ULN. 
 Total Bilirubin  ULN. 
 Serum Albumin  LLN. 
 Serum creatinine  ULN. 
6. Iron content estimate on the screening liver MRI within the normal range as 
determined by R2* value (R2* ≤ 139 Hz at 3.0T).  
7. Participant must provide written informed consent for participating in study. 
8. Participant must possess the ability, per the Principal Investigator (PI), to understand 
and comply with protocol instruction for the entire duration of the study.  
 


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4.2. Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. Known cognitive impairment or behavioral issues that would impede the ability to 
provide informed consent or to follow study instructions. 
2. History of major surgical procedure within 6 weeks of signing the informed consent or 
planned surgery during the study.  
3. Any injury which may impact functional testing.  Previous injuries must be fully healed 
prior to consent. Prior lower limb fractures must be fully healed and at least 3 months 
from injury dates.  
4. Previous treatment with another investigational product within 30 days or 5 half-lives, 
(whichever is longer) prior to consenting. 
5. Corticosteroid treatment within 3 months prior to consenting. 
6. Compromised cardiac function (left ventricular ejection fraction <50%). 
7. Unwilling or unable (e.g. metal implants, requires sedation) to undergo examination with 
closed MRI without sedation. 
8. History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein.  
9. Female subjects who are pregnant or nursing. 
10. Subjects who, are biologically capable of having children who are unwilling or unable to 
use highly effective methods of contraception (as outlined in this protocol) during sexual 
activity for the duration of the study and through completion of final study visit.  
11. Predisposition to iron accumulation.  (Serum iron >1.2 X ULN, serum ferritin >1.2 
ULNN). 
12. Underlying disposition for bleeding disorder on screening laboratory assessment 
(PT/INR>1.25 X ULN, aPTT > 1.25 ULN, fecal occult blood is positive)  
13. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, neurologic, or allergic disease. 
14. Unwillingness or inability to comply with the requirements of this protocol (in the 
opinion of the PI) including, but not limited to, the presence of any condition (physical, 
mental, or social) that is likely to affect the participant’s ability to return for study visits 
or adhere to the visit schedule.  
Note: Screening laboratory tests with results considered by the investigator to be transient and 
inconsistent with the subject’s clinical condition may be repeated once during the screening 
period for confirmation of eligibility. 
4.3. Enrollment Criteria 
Subjects will be enrolled into the study and begin the Lead-in period, provided they have 
satisfied all selection criteria.  Women of child bearing potential (WOCBP), must have a 
negative highly sensitive pregnancy test recorded within one month of intiating dosing.     
4.4. Lifestyle Guidelines  
The following guidelines are provided: 


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4.4.1. Meals and Dietary Restrictions 
Subjects should maintain their normal dietary intake throughout the study with the following 
exceptions: 
 Subjects should abstain from large amounts of caffeine within 24 hours of study visits. 
Negligible amounts are not of concern.  
 Subjects will be asked to fast for at least 8 hours prior to collection of blood to evaluate 
serum ferritin, serum iron, trasferrin saturation, and TIBC.   
 For at least 4 hours prior to the DXA scan, subjects should fast, or at a minimum avoid 
large meals.  No calcium supplements should be taken within 24 hours of a DXA scan. 
 Two days prior to collection of stool sample for fecal occult blood testing, whenever 
possible, subjects should refrain form eating red meat, turnips, horseradish or 
medications containing aspirin or vitamin C. It is recommened that subjects consume 
small amounts of chicken, canned tuna fish, peanuts, popcorn, bran cereal, vegetables 
and fruit.  
4.4.2. Activity 
Subjects should be instructed to continue with routine physical therapy including stretching or 
use of orthoses to prevent or minimize contractures or muscle deformities. 
Subjects will be instructed to maintain normal activity levels and avoid activities that are not 
part of their normal daily routine within 24 hours of study visits where imaging or functional 
assessments will be performed.  
4.4.3. Contraception 
All male and female subjects who, in the opinion of the investigator are biologically capable 
of having children and are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly from screening until the final study visit.  The 
investigator, in consultation with the subject will confirm the subject has selected the most 
appropriate method of contraception for the individual subject and his/her partner from the 
permitted list of contraception methods (see below) and instruct the subject in its consistent 
and correct use.  The investigator or his/her designee will discuss the need to use highly 
effective contraception consistently and correctly according to the Schedule of Activities and 
document such conversation in the subject’s chart.  At each study visit, the investigator will 
confirm and document consistent and correct use.  In addition, the investigator or his/her 
designee will instruct the subject to call immediately if the selected birth control method is 
discontinued or if partner pregnancy is known or suspected. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include: 


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 combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 oral 
 intravaginal 
 transdermal 
 progestogen-only hormonal contraception associated with inhibition of ovulation: 
 oral 
 injectable 
 implantable 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomized partner 
 sexual abstinence  
In addition, all sexually active male subjects must agree to prevent potential transfer of and 
exposure to drug through semen to their partners by using a condom consistently and 
correctly, beginning with the first dose of investigational product and continuing through the 
final study visit. 
4.5. Rater Qualifications  
4.5.1. Columbia-Suicide Severity Rating Scale (C-SSRS) 
Clinical staff must be trained to complete the C-SSRS.  Training is web-based and available 
on Columbia’s Training Campus.   Upon completion a certification will be provided to the 
trained individual.  
Should a risk of suicide ideation or behavior be identified during completion of the C-SSRs, 
the risk assessment for the C-SSRS must be then performed by a clinically qualified mental 
health provider (MHP).  In the United States, clinically qualified MHPs include the following: 
(1) general psychiatrists, (2) Psy.D or Ph.D. level Clinical Psychologists, (3) licensed Master’s 
level Clinical Social Workers, or (4) licensed psychiatric Nurse Practitioners who have 
training and experience in the diagnosis and treatment of individuals with psychiatric 
disorders.  
4.5.2. Physiotherapists 
Functional assessments including the respiratory function (FVC, FEV1, MIP and MEP) 4SC, 
strength (MMT, QMT), PUL, 10-meter walk/run (10 MR), 2MWT and TUG will be 
conducted by a trained physiotherapist.   
5. STUDY TREATMENTS 
Subjects will be treated with IV infused PF-06252616 in this open-label, multiple ascending 
dose study.  Please refer to the Dosing and Administration Instruction (DAI) for complete 
information on storage, stability, preparation and administration of drug product 
(PF-06252616). 


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Table 3. 
Dosing Schedule for Cohort 1 
Study Visit 
Day 
1 
29 
57 
85 
113 
141 
169 
197 
Cohort 1 
5mg/kg once every 4 weeks 
Study Visit 
Day 
225 
253 
281 
309 
337 
365 
393 
421 
Cohort 1 
40 mg/kg once every 4 weeks 
Study Visit 
Day 
589 
617 
645 
673 
701 
729 
757 
Cohort 1 
EXTENSION PERIOD:  40 mg/kg once every 4 weeks 
 
Table 4. 
Dosing Schedule for Cohort 2 and 3 
Study Visit 
Day 
1 
29 
57 
85 
113 
141 
169 
197 
Cohort 2 
20 mg/kg once every 4 weeks 
Study Visit 
Day 
365 
393 
421 
449 
477 
505 
533 
561 
589 
617 
Cohort 2  
EXTENSION PERIOD: 40 mg/kg once every 4 weeks 
Study Visit 
Day 
1 
29 
57 
85 
113 
141 
169 
197 
Cohort 3 
                                              40 mg/kg once every 4 weeks 
Study Visit 
Day 
365 
393 
421 
449 
477 
505 
Cohort 3 
EXTENSION PERIOD: 40 mg/kg once every 4 weeks 
 
This study is a 3 cohort clinical trial.  In a dose escalating fashion, subjects will be enrolled in 
one of 3 cohorts and will receive treatment on a 28 day schedule, per the Schedule of 
Activities.  The dose will be dependent on the cohort and calculated based on the subject 
weight at each visit prior to each infusion.   
Subjects in Cohort 1 will receive treatment with 5 mg/kg of PF-06252616 for 32 weeks and 
after safety and tolerability review of Cohort 1 subjects receiving 5 mg/kg and Cohort 2 
subjects receiving 20 mg/kg will be escalated to 40 mg/kg of PF-06252616 for an additional 
32 weeks.  Subjects in Cohort 2 will receive treatment with 20 mg/kg of PF-06252616 for 32 


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weeks.   Subjects in Cohort 3 will receive treatment with 40 mg/kg of PF-06252616 for 32 
weeks. Subjects who completed the Follow-up period and opt to continue in the Extension 
period will receive treatment with 40mg/kg of PF-06252616 for up to 28 weeks in Cohort 1 
and up to 40 weeks in Cohort 2, and 24 weeks in Cohort 3. 
Subjects should be administered the investigational product within the visit window according 
to the Schedule of Activities. If a dosing visit cannot be conducted within the visit window, 
attemps should be made to bring the subject back for dosing as soon as possible; however the 
dosing must not occur within 2 weeks prior to the next scheduld dose. If the subject cannot 
return for dosing in this timeframe, the dose should be missed and the next visit should be 
conducted per the Schedule of Activities. 
5.1. Allocation to Treatment 
Subjects will be consecutively enrolled into cohorts.  The first 4 subjects to successfully 
complete screening will be enrolled in Cohort 1. Following demonstration of safety in 
subjects enrolled in cohort 1 as described in the Section Safety Monitoring and Dose 
Escalation, the subsequent 8 subjects will be enrolled in Cohort 2.  The final 8 subjects will be 
enrolled in Cohort 3.    
5.2. Blinding  
This study is open label.  Subjects, investigators and pharmacists will be aware of the active 
treatment and dose level.  As this study is planned to be conducted at the same time as a 
double-blind, placebo-controlled Duchenne muscular dystrophy (DMD) study is being 
conducted, by the same investigator, the following steps will occur to assure the blind is 
maintained in the DMD study: 
 Subjects in the LGMD2I will be dosed in separate rooms from the pediatric subjects 
who are dosed in the DMD study.   
 Separate research nurses will be used to infuse subjects from the LGMD2I study and 
the DMD study.  They will not work on both studies. 
 IV infusion bag, will covered with an amber sleeve 
 IV drip chamber, will be covered transparent colored tape 
5.3. Subject Compliance 
Study treatment will be administered under the supervision of investigator site personnel. 
5.4. Drug Supplies 
5.4.1. Dosage Form(s) and Packaging 
PF-06252616 will be provided by Pfizer Worldwide Research and Development (PWRD) as a 
lyophilized powder for injection as single use, sterile vials.  The drug product is supplied in a 
glass vial sealed with a coated lyophylized stopper and an aluminum overseal and labeled 
according to local regulatory requirements.  The drug product is designed to be reconstituted 


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with SWFI for IV infusion.  The reconstituted solution of PF-06252616 is clear and colorless 
to slightly yellow in appearance. 
Details of the drug product and preparation are provided in the DAI. 
PF-06252616 will be packaged as open-label supplies.  The external packaging (carton) will 
describe its contents indicating it as active drug product.  Each carton will contain ten vials of 
study medication.  Each carton will be packaged with a tamper-resistant seal.  Pfizer must be 
notified of any study medication in which the tamper-resistant seal has been broken and this 
medication should not be used.   
5.4.2. Preparation and Dispensing 
See the DAI for instructions in how to prepare the investigational product for administration. 
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced unblinded member of the study staff (eg, pharmacist, pharmacist technician) 
designated to participate in the study as allowed by local, state, and institutional guidance.  
Site pharmacists will receive study specific training on the obligations of the role and will sign 
an agreement that will be maintained in the Master File.   
Subject’s body weight will be measured at each visit.  Weights obtained within one month 
may be used to calculate the dose of study drug to be administered.  
Under aseptic conditions, PF-06252616 should then be prepared according to the DAI 
document provided by the sponsor. 
5.5. Investigational Product Administration 
Following preparation of the study treatment investigational product (PF-06252616) by the 
site pharmacist, the prepared product will be provided to the nurse administrator.  Topical 
anesthetics (eg, topical lidocaine at the site of infusion) may be administered to subjects, 
consistent with institutional guidelines. 
The IV infusion should be administered by qualified healthcare professionals trained to detect 
any infusion related issues.  Infusion times, rates, any infusion interruptions or infusion rate 
reduction, will be recorded.  The study drug should be infused over a 2-hour period where 
time 0 is the beginning of the infusion.  The infusion time will be recorded, but the flush time 
will not be reported. 
Should subjects experience any infusion site reaction during the IV infusion period, the 
treatment administration should be interrupted and supportive care should be provided 
according to the investigator’s standard practice (eg, treatment with an antihistamine).  
Treatment administration may resume if the reaction resolves.  Following the interruption at 
the discretion of the investigator, the infusion rate may be decreased to half the required rate 
(eg, decreased from 50mL /hr to 25mL/hr or duration may be increased from 2 to 4 hours).   If 
the infusion rate should be decreased, the window for delivery (± 15 minutes) will not be 
applied.  Should the infusion be decreased, the PK will be collected per the Schedule of 
Activities.  The duration of the treatment interruption should not exceed the limits of stability 


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of the drug product solution per the DAI.  Consult the DAI for detailed instructions regarding 
study drug preparation, stability and administration.  No more than 1 treatment interruption 
should occur during any single infusion. 
Subjects should be obsereved for 1 hour following completion of the investigational product 
administration. 
5.6. Investigational Product Storage 
The pharmacy personnel, (eg, pharmacist, pharmacy technician) will ensure that all 
investigational products are stored in a secured area with controlled access under 
recommended storage conditions and in accordance with applicable regulatory requirements. 
Upon receipt at the study site, the investigational products (PF-06252616) must be stored in a 
2 to 8C temperature-monitored refrigerator and in the original carton, according to labeled 
storage conditions.  The investigational product cannot be used after the expiration date.  
Please refer to the DAI for complete information on storage, handling and stability of the 
investigational products both prior to and following reconstitution. 
Storage conditions stated in the single reference safety document (SRSD) (ie, Investigator’s 
Brochure [IB]) will be superseded by the storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage conditions, 
as soon as possible.  Deviations from the storage requirements, including any actions taken, 
must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides documentation of permission to use the investigational product.  Specific 
details regarding information the site should report for each excursion will be provided to the 
site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions. 
5.7. Investigational Product Accountability  
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product. 


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5.8. Destruction of Investigational Product Supplies 
Pfizer or designee will provide guidance on the destruction of unused investigational product 
(eg, at the site).  If destruction is authorized to take place at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer and all 
destruction must be adequately documented. 
5.9. Concomitant Treatment(s) 
 Subjects will abstain from all prohibited concomitant medications, except if required 
for treatment of AEs. 
 All concomitant medications taken during the study will be recorded with the indication 
and start and stop dates of administration.  All subjects will be questioned about 
concomitant medications at each visit. 
 Medications taken within 28 days prior to Day 1 will be documented as prior 
medication.  Medications taken from the time of Day 1 will be documented as 
concomitant medications. 
5.9.1. Permitted Therapies 
 Subjects will be permitted to receive ACE inhibitors, ARB (angiotensin II receptor 
blocker), aldosterone blocker and/or  blockers; however, subjects must have initiated 
treatment more than 3 months prior to screening and plan to remain on a stable dose 
during the study. 
 Supplements such as vitamin D, coenzyme Q10, carnitine, aminoacids (glutamine, 
arginine), anti-inflammatory/anti-oxidants (eg, fish oil, vitamin E, green-tea extract) are 
permitted but must be be initated more than 3 months prior to screening and remain 
stable during the study.  Calcium is permitted but should not be taken with 24 hours of 
a DXA scan.  Multi-vitamin without iron is permitted. 
5.9.2. Prohibited Therapies 
The following are prohibited from the time of signing the informed consent through the final 
study visit. 
 Immunosuppressant therapy (including glucocorticosteroids). 
 Other investigational therapies. 
 Androgens or human growth hormones current and in the past 3 months.  Testosterone 
replacement in hypogonadal males will be permitted as long as the subject has been on 
a stable dose for the past 3 months prior to enrollment and is anticipated to remain on a 
stable dose for the length of the study. 
 Multi-vitamin with iron or iron supplements. 


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5.9.3. Rescue Medication 
Should subjects experience an infusion site reaction during the IV infusion period, the 
treatment administration should be paused for the subject and supportive care should be 
provided according to the investigator’s standard practice (eg, treatment with an 
antihistamine). 
6. STUDY PROCEDURES  
Every attempt should be made to schedule the visits on the day specified in the Schedule of 
Activities.  In order to provide optimal testing conditions and consistency in endpoint 
measurements, at visits when the functional assessments, imaging and clinical laboratory 
assessments are scheduled to be completed at the same visit, the visit should be completed on 
two days within the visit window and at approximately the same time of day in the order 
described below.  
There is no window for Day 1(first dosing day).  The visit window for the additional treatment 
visits is 3 Day.  For the final follow up visit, the window is 3 days.  The window for the PK 
assessments post dosing at 2 hours is +30 minutes.   If the infusion rate is decreased 
(following an infusion site reaction) the PK/PD assessment should be collected at the time of 
infusion completion and flush (within a +30 minute window). Subjects are required to be 
observed for 1 hour after administration of PF-06252616.  
6.1. Screening: Visit 1 (Screening Day -125 to -112) 
During screening, subjects will be assessed for study eligibility.  All screening must be 
completed and reviewed for subject eligibility before the subject is enrolled into the study.  
Screening laboratory tests with results considered by the investigator to be transient and 
inconsistent with the subject’s clinical condition may be repeated once during the screening 
period for confirmation of eligibility.  Imaging based examinations for screening must be 
reviewed before the subject is enrolled to assure an adequate baseline image has been 
acquired.  If the image is determined to be of poor quality, it will be repeated.  The visit 
window (Day -125 to -112) for screening is to allow for the analysis of laboratory testing, 
assurance of imaging quality and to provide multiple days to perform the assessments in the 
order described below.  As soon as this is completed and subject’s eligibility has been 
confirmed, they may be randomized into the study.  
 Informed Consent:  The subject must sign the informed consent document (ICD) prior 
to initiation of any screening assessments.   
 Demographics: Information such as date of birth, race, and gender will be collected. 
 Medical History: Medical history will include confirmation by genetic testing of the 
diagnosis of LGMD2I as obtained as reported from an appropriate regulated laboratory 
using a clinically validated genetic test (genetic testing is not provided by the sponsor).  
Results must confirm the biallelic alteration in the FKRP gene known to be or likely to 
be pathogenic and associated with LGMD2I.  The mutation type will be reported.  
Medical history will also be reviewed for any significant medical/surgical histories and 
concurrent illnesses that required or are requiring specialist consultation or treatment. 


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 Medication History: Complete history will include all prescription or nonprescription 
drugs, and dietary and herbal supplements taken within 28 days prior to the planned 
first dose.   
 Physical Examination, including Nose and Throat Mucosal Exam 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
women of childbearing potential (WOCBP). 
 Diary Cards: Will be provided with instructions to all WOCBP to record the first day 
of each menstruation cycle.  
 Contraception Review: Confirmation of use of acceptable forms of contraception. 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate. 
 Echocardiogram  
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, %  transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood:  Fecal sample is to be collected at home within 1 week of 
scheduled visit and mailed to site for testing.   
 C-SSRS 
 MRI-liver:  Liver MRI will be obtained for iron accumulation  
 Inclusion/Exclusion Criteria: Subjects will be assessed against inclusion and 
exclusion criteria. 


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 Enrollment: Enrollment can be performed once all screening results are available and 
eligibility is confirmed 
6.2. Lead-in Period: Visit 2 (Baseline Day -111 to -110 prior to dosing on Day 1) 
The following procedures and studies should be performed in the morning (before noon) of 
Visit 2 whenever possible 
 Physical Examination, including Nose and Throat Mucosal Exam 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects and must be confirmed as negative within 1 month of receiving first 
dose. 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review: Confirmation of use of acceptable forms of contraception 
 Height: Height should be measured in the morning.   
 Weight 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 C-SSRS 
 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
The following procedures should be performed in the afternoon of Visit 2 whenever 
possible: 
 DXA:  Whole body DXA will be performed for lean body mass. 
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Needle muscle biopsy:  Following WB-MRI and functional assessments a needle 
muscle biopsy of the tibialis muscle will be performed.  
 PD sample collection 


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 Biomarker collection:  Blood will be collected for proteomic, metabolomic, and 
genomic biomarker analysis 
 Adverse event monitoring 
 Concommitant medications 
6.3. Active Treament Period:  Visit 3 (Day 1) and for Cohort 1, Visit 11 (Day 225±3) 
Visit 3 will be divided into a 2 day visit 
Prior to dosing, the following procedures will be completed: 
 Physical Examination, including Nose and Throat Mucosal Exam 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate 
 Clinical laboratory tests:   
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal occult blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 


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 Immunogenicity: Baseline  
 PD sample collection: Predose 
 PK sample collection:  Predose 
 MRI-liver:  Liver MRI will be obtained for iron accumulation (visit 11 only) 
 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
 DXA Whole Body:  Whole body DXA will be performed for lean body mass.  
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Quality of Life assessments 
 InQol 
 SF-36 
On Day 2 of Visit 3 (Day 1)- prior to dosing,  
 Functional assessments: Must be conducted in the following order:  4SC, 2MWT, 10-
meter walk/run, TUG, and PUL. 
 Needle muscle biopsy:  Following the Functional assessments, a needle muscle biopsy 
of the tibialis muscle will be performed.  
Dosing 
 Study treatment administration. 
After dosing, the following procedures will be completed: 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature  
after completion  of infusion.PK sample collection: Collected at end of infusion 
(hour 2) 
 PD sample collection: Collected at end of infusion (hour 2) 
 Infusion site reaction monitoring. 
 Adverse event (AE) monitoring. 


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 Concomitant medication monitoring.  
6.4. Active Treatment:  Visit 4 (Day 29±3), 8 (Day 141±3), 10 (Day 197±3) and for 
Cohort 1, Visit 12 (Day 253±3), 16 (Day 365±3), 18 (Day 421±3) 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
Dosing 
 Study treatment administration. 
After dosing, the following procedures will be completed: 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature 
after completion  of infusion.Infusion site reaction monitoring. 
 AE monitoring. 


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 Concomitant medication monitoring.  
6.5. Active Treatment:  Visit 5 (Day 57±3), 9 (Day 169±3) and for Cohort 1, Visit 13 (Day 
281±3), 17 (Day 393±3) 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 PK/PD sample:  predose 
Dosing 
 Study treatment administration. 
After dosing, the following procedures will be completed: 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature at - 
after completion of infusion.  


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 PK/PD sample collection: Collected at end of infusion (hour 2) 
 Infusion site reaction monitoring. 
 AE monitoring. 
 Concomitant medication monitoring.  
6.6. Active Treatment: Visit 6 (Day 85±3) and for Cohort 1, Visit 14 (Day 309±3)  
 Physical Examination, including Nose and Throat Mucosal Exam. 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12 lead ECG: ECGs will be performed in triplicate 
 Clinical laboratory sample collection:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 MRI of liver: Liver MRI will be obtained for iron accumulation 


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Dosing 
 Study treatment administration. 
After dosing, the following procedures will be completed: 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature 
after completion  of infusion.Infusion site reaction monitoring. 
 AE monitoring. 
 Concomitant medication monitoring.  
6.7. Active Treatment:  Visit 7 (Day 113±3) and for Cohort 1, Visit 15 (Day 337±3) 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 PK/PD sample:  predose 


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 Biomarker collection:  Blood will be collected for proteomic, metabolomic, and 
genomic biomarker analysis 
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
Dosing 
 Study treatment administration. 
After dosing, the following procedures will be completed: 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature 
after completion  of infusion.PK/PD sample collection: Collected at end of infusion 
(hour 2) 
 Infusion site reaction monitoring. 
 AE monitoring. 
 Concomitant medication monitoring.  
6.8. Follow up: For Cohort 1, Visit 19 (Day 449±3) and for Cohort 2 and 3, Visit 11 (Day 
225±3) 
This visit will occur over 2 days. 
 Physical Examination, including Nose and Throat Mucosal Exam. 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate 
 Echocardiogram  
 Clinical laboratory testing:  


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 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 MRI-liver:  Liver MRI will be obtained for iron accumulation 
 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
 DXA Whole Body:  Whole body DXA will be performed for lean body mass 
assessment.  
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Needle muscle biopsy:  Following WB-MRI and functional assessments, a needle 
muscle biopsy of the tibialis muscle will be performed.  
 Quality of Life assessments 
 InQol 
 SF-36 
 Immunogenicity sample collection. 
 PD sample collection  
 PK sample collection 


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 Adverse Event monitoring 
 Infusion site reaction monitoring 
 Concomitant medication  
6.9. Follow-up:  For Cohort 1, Visit 20 (Day 561±3) and for Cohort 2 and 3 Visit 12 (Day 
337±3) 
 Physical Examination, including Nose and Throat Mucosal Exam. 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate 
 Echocardiogram  
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 MRI-liver:  Liver MRI will be obtained for iron accumulation 


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 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
 DXA Whole Body:  Whole body DXA will be performed for lean body mass 
assessment.  
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Needle muscle biopsy:  Following WB-MRI and functional assessments, a needle 
muscle biopsy of the tibialis muscle will be performed.  
 Quality of Life assessments 
 InQol 
 SF-36 
 Immunogenicity sample collection. 
 PK sample collection 
 PD sample collection  
 Adverse Event monitoring 
 Concomitant medication  
6.10. Extension Period:  For Cohort 1 (Visits 21,22,23,25, and 26), for Cohort 2 (Visits 
13,14,15,17,18,20,21), for Cohort 3 (Visits 13,14, 16, 17) 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Dosing: study treatment administration 
 Infusion site reaction monitoring. 
 AE monitoring. 


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 Concomitant medication monitoring.  
6.11. Extension Period:  For Cohort 1 (Visit 24), for Cohort 2 (Visits 16 and 19), and for 
Cohort 3 (Visit 15) 
 Physical Examination, including Nose and Throat Mucosal Exam 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate (only in Cohort 2- Visit 19) 
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Dosing: study treatment administration 
 Infusion site reaction monitoring. 
 AE monitoring. 


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 Concomitant medication monitoring.  
6.12. Extension Period:  For Cohort 1 (Visit 27), for Cohort 2 (Visit 22), and for Cohort 
3 (Visit 18) 
 Physical Examination, including Nose and Throat Mucosal Exam 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Cards: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Weight 
 Height 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate 
 Echocardiogram  
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 MRI-liver:  Liver MRI will be obtained for iron accumulation 
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  


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 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry) and PUL. 
 Quality of Life assessments 
 InQol 
 SF-36 
 Dosing: study treatment administration 
 Immunogenicity sample collection. 
 PK sample collection 
 PD sample collection  
 Biomarker collection:  Blood will be collected for proteomic, metabolomic, and 
genomic biomarker analysis 
 Infusion site reaction monitoring. 
 AE monitoring. 
 Concomitant medication monitoring.  
6.13. Telephone Follow-up: 30 +/-3days after final dosing visit 
 AE monitoring. 
 Concomitant medication 
6.14. Unscheduled Visits 
Subjects may return for unscheduled visits as determined by the investigator or the sponsor to 
complete unscheduled safety assessments.  These assessments may include: 
 Fecal occult blood.  
 C-SSRS 
 Weight. 
 Physical Examination, including Nose and Throat Mucosal Exam. 
 Vital Signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12 lead ECG. 


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 Echocardiogram  
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 Preganancy test: A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 PK sample collection.  
 PD sample collection. 
 MRI-liver:  Liver MRI will be obtained for iron accumulation 
 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
 DXA Whole Body:  Whole body DXA will be performed for lean body mass 
assessment.  
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  
 Infusion site reaction monitoring. 
 Adverse event (AE) monitoring. 
 Concomitant medication monitoring.  
6.15. Subject Withdrawal 
Subjects who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures.  The only exception to 
this is when a subject specifically withdraws consent for any further contact with him/her.  
The subject should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is from further 
treatment with study drug only or also from study procedures and/or post treatment study 
follow-up, and entered on the appropriate CRF page.  In the event that vital status (whether 
the subject is alive or dead) is being measured, publicly available information should be used 
to determine vital status only as appropriately directed in accordance with local law. 


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If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort should 
be made to document subject outcome, if possible.  The investigator should inquire about the 
reason for withdrawal, request that the subject return for a final visit, if applicable, and 
follow-up with the subject regarding any unresolved AEs.  
It may be appropriate for the subject to return to the clinic for final safety assessments and to 
be questioned regarding their reason for withdrawal.  The following assessments may be 
performed according to the Schedule of Activities:  
Assessments in the Early Withdrawal visit may include: 
 Physical Examination, including Nose and Throat Mucosal Exam. 
 Pregnancy Test:  A highly sensitive urine pregnancy test will be performed on all 
female subjects 
 Diary Card: For collection of first day of each menstrual cycle for WOCBP. 
 Contraception Review:   Confirmation of use of acceptable forms of contraception 
 Vital signs: Supine blood pressure, pulse rate, respiratory rate, and oral temperature. 
 12-lead ECG:  ECGs will be performed in triplicate 
 Echocardiogram  
 Clinical laboratory testing:  
 Hematology with complete blood count and differential, comprehensive metabolic 
panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, calcium, glucose, total protein, albumin, total bilirubin, AST, ALT, 
alkaline phosphatase) gamma-glutamyl transferase (GGT), prothrombin time (PT), 
activated partial thromboplastin time (aPTT), creatine kinase, amylase, cardiac 
troponin I. Urinalysis. 


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 Serum ferritin, serum iron, % transferrin saturation, TIBC:  fasting blood 
collection 
 Horomone Testing: LH, FSH, estrogen in WOCBP 
 GLDH 
 Fecal Occult Blood: Fecal sample is to be collected at home within 1 week prior to 
scheduled visit.   
 C-SSRS 
 MRI-liver:  Liver MRI will be obtained for iron accumulation 
 MRI-muscle:  WB-MRI and dedicated thigh MRI will be performed for muscle 
quantity and quality  
 DXA Whole Body:  Whole body DXA will be performed for lean body mass 
assessment.  
 DXA Spine and Hip: Spine and hip DXA will be performed for BMD.  
 Functional assessments: Must be conducted in the following order:  Respiratory 
function (FVC, FEV1, MIP, MEP), 4SC, 2MWT, 10-meter walk/run, TUG, strength 
assessment (MMT, hand-held dynamometry), and PUL. 
 Needle muscle biopsy:  Following WB-MRI and functional assessments, a needle 
muscle biopsy of the tibialis muscle will be performed.  
 Quality of Life assessments 
 InQol 
 SF-36 
 Immunogenicity sample collection. 
 PD sample collection  
 PK sample collection 
 Adverse Event monitoring 
 Infusion site reaction 
 Concomitant medication  


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In the extension period, all the tests and procedures listed in the early withdrawal visit 
will be completed except for MRI- muscle, DXA of the whole body, and needle 
muscle biopsy. 
In the event of clinically important treatment-emergent suicidal ideation or suicidal behavior, 
the subject will be withdrawn from the study and will receive the appropriate medical care.  
The Investigator will follow up until the subject’s condition has stabilized.  Additionally, a 
risk assessment or evaluation of suicide risk will be completed by a mental health provider as 
part of the psychiatric evaluation and assessment of subject safety.  Refer to Section7, 
Assessments.  Clinically important suicidality includes but is not limited to: 
 Suicidal behavior (with or without intent of suicide or serious self-harm). 
 Determination of “yes” on question 4 (Active Suicidal Ideation with Some Intent or Act, 
Without Specific Plan) for the Suicidal Ideation section of the C-SSRS.  
 Determination of “yes” on question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) for the Suicidal Ideation section of the C-SSRS. 
 Determination of “yes” on the question of Actual Attempt, Interrupted Attempt, Aborted 
Attempt, or Preparatory Acts or Behavior for Suicidal Behavior section of C-SSRS. 
 Acute suicidality to such a degree that precaution against suicide must be exercised. 
6.16. Subject Lost to Follow-Up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by subject to one 
registered mail letter.  All attempts should be documented in the subject’s medical records.  If 
it is determined that the subject has died, the site will use permissible local methods to obtain 
the date and cause of death.  The site staff and representative will consult publicly available 
sources, such as public health registries and databases, in order to obtain updated contact 
information.  If after all attempts, the subject remains lost to follow-up, then the last known 
alive date as determined by the investigator should be reported and documented in the 
subject’s medical records. 
7. ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. 


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7.1. Safety 
7.1.1. Clinical Laboratory  
The following safety laboratory tests will be performed at times defined in the Schedule of 
Activities section of this protocol.  Unscheduled clinical labs may be obtained at any time 
during the study to assess any perceived safety concerns.  


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Laboratory Tests 
 
HEMATOLOGY CHEMISTRY URINALYSIS 
OTHER 
 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN and 
Creatinine 
Glucose  
Calcium 
Sodium 
Potassium 
Chloride 
Total 
CO2 (Bicarbonate) 
AST, ALT 
Total Bilirubin 
Alkaline 
phosphatase 
Albumin 
Total protein 
 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte 
esterase 
Microscopya 
HCGb 
GLDH 
GGT 
PT/INR 
aPTT 
Creatine 
kinase 
Amylase 
 
Cardiac 
Troponin I 
 
Serum 
Ferritinc 
Serum Ironc 
Total Iron 
Bindingc 
Capacity 
(TIBC)c 
% 
Transferrin 
Saturationc 
Horomone 
Testing: 
LH, FSH, 
estrogen 
 
 
 
Fecal 
Occult 
 
Urine 
Pregnancy 
Test 
 
Additional Testsd 
 
 
 


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AST, ALT 
(repeat) 
Total bilirubin 
(repeat) 
Albumin (repeat) 
Alkaline 
phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
Creatine kinase 
GGT 
GLDH 
PT/aPTT 
 
 
 
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
b.  A urine HCG pregnancy test will be performed in female subjects as per the 
Schedule of Activities.  A positive urine HCG pregnancy test will trigger a blood 
HCG test.   
c. Following an 8 hour overnight fast. 
 dAdditional testing for potential Hy's Law cases only. 
 
7.1.2. Physical Examinations/Nose and Throat Exam 
Physical examinations may be conducted by a physician, trained physician's assistant, or nurse 
practitioner as acceptable according to local regulation.  The physical examination will 
include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, and neurological systems.  A targeted nose and throat 
mucosal exam will be performed according to the Schedule of Activities to monitor for any 
signs of mucosal telangiectasias.  
7.1.3. Vitals 
Supine blood pressure, pulse rate, respiratory rate and oral temperature will be measured at 
times specified in Schedule of Activities section of this protocol.  Unscheduled collection 
times will be permitted, as necessary, to ensure appropriate collection of safety data. 
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mm Hg after at least 5 minutes of rest.  Whenever possible, 
the same arm (preferably the dominant arm) should be used throughout the study.  
The use of automated devices for measuring BP and pulse rate are acceptable, although, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds.  


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7.1.4. Electrocardiogram (ECG) 
ECGs should be collected at times specified in the Schedule of Activities section of this 
protocol. 
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained approximately 2-4 minutes apart; the average of the 
triplicate ECG measurements collected at Day 1(Visit 3), will serve as each subject’s 
time-controlled baseline QTc value.  
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTc interval is increased by 45 msec from the 
baseline, or an absolute QTc value is 500 msec for any scheduled ECG, then 2 additional 
ECGs will be collected, approximately 2-4 minutes apart, to confirm the original 
measurement.  If either of the QTc values from these repeated ECGs remains above the 
threshold value (45 msec from the baseline; or is 500 msec), then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.  
If the average of QTc values from the triplicate measurements remains above the threshold 
value (45 msec from the baseline; or is 500 msec), then a single ECG must be repeated at 
least hourly until QTc values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement. 
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner at the discretion of the investigator); or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a qualified 
physician’s interpretation determines that the QTc values are in the acceptable range. 
7.1.5. Echocardiogram 
Echocardiograms should be collected at times specified in the Schedule of Activities section 
of this protocol.  To ensure safety of the subjects, a qualified individual at the investigator site 
will evaluate the echocardiogram for ejection fraction (EF) and left ventricular end systolic 
volume (LVESV). 


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7.1.6. Assessment of Suicidal Ideation and Behavior –Columbia Suicide Severity Rating 
Scale (C-SSRS) 
C-SSRS: The C-SSRS will be evaluated at times specified in the Schedule of Activities.  The 
Baseline/Screening (Version 1/14/09) (Appendix 1) of the C-SSRS should be completed at the 
Screening Visit (Visit 1).  At all study visits following the Screening Visit, the Since Last 
Visit (Version 1/14/09) (Appendix 2) of the C-SSRS should be utilized.  The Since Last Visit 
version refers to the subject’s experience since their last visit. 
At Screening or Baseline, if the subject endorses a 4 or 5 on the C-SSRS ideation section or 
reports any suicidality behavior, then the subject is not eligible for study participation and an 
evaluation of suicide risk (risk assessment) must be completed.  
At every visit after Screening, if the subject endorses a 4 or 5 on the C-SSRS ideation section 
or reports any suicidality behavior, then the subject must be discontinued as outlined in 
Section 6, Subject Withdrawal and evaluation of suicide risk (risk assessment) must be 
completed.  
Risk Assessment: In the event that a subject endorses a 4 or 5 on the C-SSRS ideation section 
or reports any suicidality behavior, an evaluation of suicide risk (risk assessment) will be 
completed as part of the psychiatric evaluation and assessment of subject safety to participate 
will be performed by the following mental health provider:  Psychiatrists (board certified or 
board eligible), Psy. D. or Ph.D. level Clinical Psychologists, licensed Master’s level Clinical 
Social Workers (MSW) or licensed psychiatric Nurse Practitioners (PNP) who have training 
and experience in the diagnosis and treatment of psychiatric disorders. 
Written documentation of the risk assessment should be included in the subject’s source 
documentation and the risk assessment CRF will be completed.  The risk assessment CRF 
serves as further verification that the psychiatric evaluation and assessment of subject safety 
have been completed for all subjects endorsing items 4 or 5 on the C-SSRS ideation section or 
reporting suicidal behavior.  
7.2. Banked Biospecimens  
7.2.1. Markers of Drug Response 
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment.  Collecting biospecimens for 
exploratory pharmacogenomic/biomarker analyses and retaining them in a bioBank makes it 
possible to better understand the drug’s mechanism of action and to seek explanations for 
differences in, for example, exposure, efficacy, tolerability, or safety not anticipated prior to 
the beginning of the study.  Providing these biospecimens is a required study activity for study 
sites and subjects, unless prohibited as such by local regulations or ethics committee decision.  


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To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the SSID number.  Samples will be kept in a locked freezer.  Data will be 
stored on password-protected computer systems.  The key between the code and the subject’s 
personal identifiers will be held at the study site; the researchers using the biospecimens and 
data generated from them will not have access to the key nor any personally identifying 
information.  Biospecimens will only be used for the purposes described here and in the 
informed consent document/patient information sheet; any other uses require additional 
ethical approval.  Unless a time limitation is required by local regulations or ethical 
requirements, biospecimens will be stored indefinitely to allow for future research on the 
topics described here, including research conducted during the lengthy drug development 
process and also postmarketing research.  Subjects can withdraw their consent for the use of 
their biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses.  It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants.  Subjects are notified in the informed 
consent document/patient information sheet that their results will not be given to them, unless 
required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians, nor will 
they be recorded in the subject’s medical record.  There is no intention to contact subjects 
after completion of the clinical study. 
A 2-mL blood biospecimen Prep D1.5 (K2 edetic acid (ethylenediaminetetraacetic acid) 
(EDTA) whole blood collection optimized for DNA analysis) will be collected at the 
Screening visit to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport protein 
genes, or genes thought to be related to the mechanism of drug action may be examined.  
Additional biospecimens will be collected in the morning following an 8 hour fast to be 
retained for exploratory analyses in this study include the following:   
 Prep B1.5 (K2 EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): A 2-mL blood biospecimen will be 
collected at Visits 2 (Screening), and Visits 7, 10, 15 and 18 for Cohort 1 and Visits 7 
and 10 for Cohorts 2 and 3.  
 Prep B2.5 (serum collection optimized for biomarker/ proteomics/metabonomic 
analysis): A 2-mL blood biospecimen will be collected at Visits 2 (Screening), and 
Visits 7, 10, 15 and 18 for Cohort 1 and Visits 7 and 10 for Cohorts 2 and 3.  
 Prep R1 (PAXGene whole blood collection optimized for RNA analysis): A 2.5-mL 
blood biospecimen will be collected at Visits 2 (Screening), and Visits 10 and 18 for 
Cohort 1 and Visits 10 for Cohorts 2 and 3 .  
 Prep P4 Cell-free RNA: A 10-mL blood biospecimen will be collected at Visits 2 
(Screening), and Visits 10 and 18 for Cohort 1 and Visits 10 for Cohorts 2 and 3.The 


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banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.   
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event. 
7.2.2. Additional Research 
Subjects will be asked to indicate on the consent form whether they will allow the banked 
biospecimens to also be used for the following research: 
 Investigations of the disease under study in the clinical study, and related conditions. 
 Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer or the investigator is researching drug therapies; use in 
characterizing the natural variation among people in genes, RNA, proteins, and 
metabolites; and use in developing new technologies related to 
pharmacogenomics/biomarkers.  
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Markers of Drug Response section will be used.  Subjects may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section. 
7.3. Pharmacokinetics (Serum for Analysis of PF-06252616) 
During all study periods, blood samples (2 mL) to provide serum for pharmacokinetic analysis 
will be collected into the appropriate tubes (containing no anticoagulant or gel separator) at 
times specified in the Schedule of Activities section of the protocol.  
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time 
relative to dosing as described in the Schedule of Activities.  
Samples will be analyzed using validated analytical methods in compliance with Pfizer 
standard operating procedures.  
As part of understanding the pharmacokinetics and immunogenicity of the study drugs, 
samples may be used for evaluation of the bioanalytical method. This additional 
characterization will be used for internal exploratory purposes and will not be included in the 
clinical report. Samples collected for this purpose will be retained in accordance to local 
regulations and if not used within this timeframe, will be destroyed. 
 


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7.4. Anti-Drug Antibody (ADA) anti-PF-06252616 and Neutralizing Antibody          
(NAb) 
During all study periods, blood samples (2 mL) to provide serum for analysis of 
anti-PF-06252616 will be collected into the appropriate tubes (containing no anticoagulant or 
gel separator) at times specified in the Schedule of Activities section of the protocol.  
All efforts will be made to obtain the samples at the exact nominal time relative as described 
in the Schedule of Activities. 
Samples will be analyzed using validated analytical methods in compliance with Pfizer 
standard operating procedures.  All samples that are positive in a screening assay will be 
confirmed for antibody specificity and further characterized for titer.  Samples that are 
determined to be positive for ADA may be further tested for the presence of neutralizing 
antibodies. 
The PK and immunogenicity samples must be processed and shipped as indicated to maintain 
sample integrity.  Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the sponsor.  On a case-by-case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any sample 
deemed outside of established stability, or of questionable integrity, will be considered a 
protocol deviation. 
As part of understanding the pharmacokinetics or immunogenicity of the study drug, samples 
may be used for further characterization and/or evaluation of the bioanalytical method.  These 
data will be used for internal exploratory purposes and will not be included in the clinical 
report.  Samples collected for this purpose will be retained in accordance to local regulations 
and if not used within this timeframe, will be destroyed. 
7.5. Pharmacodynamics/Serum for Total GDF-8 
All efforts will be made to obtain the samples at the exact nominal time relative as described 
in the Schedule of Activities.  
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
The PD samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PD processing steps, including any actions taken, must be 
documented and reported to the sponsor.  On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation. 
As part of understanding the pharmacodynamics of the study drug, samples may be used for 
evaluation of the bioanalytical method.  These data will be used for internal (ie, Pfizer) 
exploratory purposes and will not be included in the clinical report. 


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Blood samples (2 mL) to provide serum will be collected into appropriately labeled tubes 
(containing no anticoagulant or gel separator) to provide a minimum of 1 mL serum for GDF-
8 analysis at times specified in the Schedule of Activities section of the protocol. Allow to clot 
in upright position at room temperature for at least 30 minutes. Place clotted samples into an 
ice bath for approximately 10 minutes prior to centrifugation. Centrifuge samples at 
approximately 1200 x g for about 15 minutes at 4°C. Withdraw serum (approximately 1 mL) 
and equally divide into 2 aliquots (approximately 0.5 mL each) and transfer into appropriately 
labeled screw-capped polypropylene tubes. Place into a -70°C (or lower) non-frost-free 
freezer within approximately 70 minutes of collection and ship frozen samples on dry ice. 
Blood samples will be collected for the analysis of total GDF-8 at times specified in the 
Schedule of Activities. 
 
 
7.6. Imaging Assessments 
7.6.1. Liver MRI 
Liver MRI will be obtained according to the Schedule of Activities to monitor for safety by 
quantifying iron accumulation.  All images will be acquired using a standardized imaging 
protocol with consistent analysis.  
7.6.2. MRI of Skeletal Muscle  
Magnetic resonance imaging will be used for qualitiative, semi-quantitative and quantitative 
assessment of muscle quantity and quality.  The imaging procedures will include a whole-
body MRI exam as well as thigh imaging protocols.  Both whole-body and thigh imaging will 
use quantitative and qualitative methods to evaluate muscle quantity and quality.   
Quantitative measures will focus on thigh muscle volume and fat fraction.  Qualitatitive and 
semi-quantitative assessments will be used to evaluate signal changes corresponding to 
inflammation, edema, and/or fat content.   
The MRI of the skeletal muscle takes approximately 2 hours for scanning and positioning. 
Because of the length of time inside the scanner, some participants may become anxious about 
the procedure.  They may be premedicated, as needed, with Ativan (Lorazepam)  1 mg orally 
30 minutes  before the procedure. If needed, another dose of  Ativan 1 mg may be given after 
30 minutes. 
 
7.6.3. Duel-energy X-ray Absorptiometry (DXA) and X-ray 
7.6.3.1. DXA 
DXA scans will be obtained according to the Schedule of Activities to measure the percent 
change in lean body mass (LBM) over time and to evaluate bone mineral density (BMD) on 
the spine and hip.  Ideally, whole body scans will be taken at approximately the same time of 
day (morning) and subjects will have fasted for at least 4 hours prior to the scan, but should be 
in a state of euhydration.  


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7.6.3.2. Radiation Exposure 
Possible risks related to subject’s undergoing evaluation with DXA include the risk of 
radiation exposure.  The average effective dose of radiation received for a single DXA scan 
may vary due to the instrument and the subject’s body.  Subject may require a skull X-ray 
prior to MRI if there is a question of intraocular metal.  This skull X-ray also carries the risks 
associated with radiation exposure. The maximum amount of radiation that a subject could 
receive is from 5 whole body DXA scans (in cohort 1), 3 DXA scans of the hip, 3 DXA scans 
of the spine and 1 skull X-ray. The expected total radiation dose for this maximum exposure is 
not expected to exceed 30 mrem.  This is less than 1 year of natural background radiation 
which is approximately 300 mrem per year (Blake, Naeem et al., 2006).   
7.7. Functional Assessments 
Functional assessments will be obtained according to the Schedule of Activities.  In order to 
provide optimal testing conditions and consistency in endpoint measurements, the functional 
assessments will be performed after the MRI and before needle muscle biopsy whenever 
possible. All functional assessments will be conducted by a trained physiotherapist.   
7.7.1. Pulmonary Function  
Pulmonary function testing will be completed to evaluate the maximal lung function recording 
FVC, FEV1, MIP and MEP.  
7.7.2. 4 Stair Climb (4 SC) 
The 4 SC quantifies in seconds the time required for a subject to ascend 4 standard steps.  The 
method the subject uses (eg, using the hand rails) to climb the stairs is recorded to understand 
any change in technique that occurs over time.  
7.7.3. 10-meter walk/run 
The 10-meter walk/run is a frequently used timed function test in muscular dystrophy trials 
demonstrating good test-retest reliability in several different populations and has been used in 
studies of LGMD2I 19,27.  Individuals are instructed to walk at a fast but comfortable speed in 
a long cooridor with an even surface.  Measurement of time begins at a still-standing start and 
stops when the individual passes the 10-meter mark while continuing to walk 2.5 meters 
beyond the mark.    
7.7.4. Timed Up & Go (TUG)  
The Timed Up & Go is a measure of hip strength as well as dynamic balance.  This timed 
function test has good test-retest reliability and has been used in studies of LGMD2I 19,27.  The 
individual is asked to rise from a seated position in a standardized armchair (44-45 cm), walk 
at a comfortable and safe pace to a tape mark on the floor 3 meters away, turn around the 
mark, go back to the chair, turn and sit down.  
7.7.5. Strength Assessment 
Muscle strength will be quantified by means of manual muscle testing (MMT) quantified by 
the modified Medical Research Council (MRC) scale and by handheld dynamometer 


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quantified in pounds (lbs).  The following muscle groups will be evaluated: shoulder 
abduction, elbow flexion, elbow extension, hip extension, hip flexion, knee extension, knee 
flexion.   
7.7.6. Performance of Upper Limb (PUL) 
The PUL scale has been devised to assess motor performance of the upper limb.  Motor 
performance will be impacted by muscle strength and contactures and the scale aims to 
incorporate performance of shoulder, elbow, wrist and hand function.  
7.7.7. Two Minute Walk Test (2MWT) 
The 2-minute walk test (2MWT) is a shorter measure of walking performance than the 6-
minute walk test (6MWT).  In this test, subjects start from a clearly marked line of tape on the 
floor and walk up and down a 21 meter hallway for 2 minutes at a fast but comfortable speed 
wearing their regular footware.  The 6MWT has been used extensively in pediatric DMD 
trials 28. The 2MWT may be more feasible in populations such as LGMD2I where the 6MWT 
is too fatiguing.  Studies of the 2MWT in adult patient populations have reported good test-
retest and interrater reliability 29.   
7.8. Quality of Life Assessments 
7.8.1. InQoL 
This survey consists of 45 questions within 10 sections. Four sections focus on the impact of 
key muscle disease symptoms (weakness, locking, pain, and fatigue), five look at the impact 
(degree and importance of impact) muscle disease has on particular areas of life, and one 
section asks about the positive and negative effects of treatment 30. 
7.8.2. SF-36 
This questionnaire is a multi-purpose, short form patient-reported health survey with only 36 
questions. It is a generic measure, providing an 8-scale profile of functional health as well as 
measuring physical and mental health. Each scale is transformed into a 0-100 scale, with a 
score of 0 being equivalent to maximum disability and a score of 100 being indicative of no 
disability 31. It provides a measure of relative disease burden and allows differentiating the 
health benefits produced by various different treatments.  
7.9. Needle Muscle Biopsy 
Needle muscle biopsy is used to obtain small amounts of tissue (milligrams) for molecular 
studies in a clinic setting without the requiment of recovery time.  Needle muscle biopsies 
have been used previously in clinical trials of muscular dystrophy for this purpose where 
histology is not needed 25.  In this procedure, the skin overlying the tibialis muscle is sterilely 
prepped and local anesthesia (1% lidocaine with 1:100,000 epinephrine) is infused 
subcutaneously and into the soft tissue to be biopsied.  A nick is made in the skin with the tip 
of a scalpel.  Through the skin incision, measuring less than 0.5 cm, a 14 gauge biopsy needle 
is inserted.  Several small samples of skeletal muscle can be withdrawn through the same skin 
incision with the biopsy needle, each measuring less than 0.5cm by 0.02 cm.  A sterile 
bandage is applied following the procedure.  


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7.10. Triggered Requirements  
Condition/ Criteria  
Action 
Moderate Iron overload/ If the liver iron content 
estimate as determined by R2* value is above the “mild 
overload” range (R2* >369 Hz at 3.0 T 
The subject should be referred to a hepatologist for 
further assessment 
Cardiomyopathy/ If the LVEF falls 10% of baseline on 
the cardiac echocardiogram at any follow-up visit 
The subject should be referred to a cardiologist for 
further assessment. 
 
7.11. Infusion Site Monitoring 
From the initiation of the IV infusion subjects will be monitored for signs of any infusion site 
reactions including but not limited to erythema, swelling, bruising, pain or prutitis. 
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an 
serious adverse event (SAE) requiring immediate notification to Pfizer.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.  
8.2. Reporting Period 
For SAEs, the active reporting period to Pfizer begins from the time that the subject provides 
informed consent, which is obtained prior to the subject’s participation in the study, ie, prior 
to undergoing any study-related procedure and/or receiving investigational product, through 
and including 112 calendar days after the last administration of the investigational product.  
SAEs occurring to a subject after the active reporting period has ended should be reported to 
Pfizer if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported 
to Pfizer. 


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 AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from 
the time the subject has taken at least 1 dose of study treatment through the last subject 
visit.  
8.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
 Abnormal test findings; 
 Clinically significant symptoms and signs; 
 Changes in physical examination findings; 
 Hypersensitivity; 
 Progression/worsening of underlying disease  
 Drug abuse; 
 Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
 Drug overdose; 
 Drug withdrawal; 
 Drug misuse;  
 Drug interactions; 
 Extravasation; 
 Exposure during pregnancy (EDP); 
 Exposure via breastfeeding; 
 Medication error; 
 Occupational exposure. 
8.4. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the medication error 


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case report form (CRF) which is a specific version of the adverse event (AE) page, and on the 
SAE form when appropriate.  In the event of medication dosing error, Pfizer should be 
notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
 Medication errors involving subject exposure to the investigational product; 
 Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF 
page.  
8.5. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
 Test result is associated with accompanying symptoms; and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
 Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy; and/or 
 Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.6. Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
 Results in death; 
 Is life-threatening (immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 


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 Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
8.6.1. Protocol-Specified Serious Adverse Events  
Unless the investigator believes that there is a causal relationship between study drug and an 
event specified below, these events should not be reported by the investigator as SAEs as 
described in the Serious Adverse Event Reporting Requirements section on this protocol.  
These events are anticipated to occur commonly in a population with LGMD2I.  However, 
these events should still be captured as AEs in the CRF. 
Protocol-specified events that will not normally be reported in an expedited manner:  
 Loss of mobility or ambulation. 
 Muscle weakness. 
 Cardiomyopathy. 
 Fracture. 
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epi data, literature, or other data,  then this will be 
submitted and reported in accordance with Pfizer’s safety reporting requirements.  Aggregate 
analysis of safety data will be performed on a quarterly basis by the SMC.  
8.6.2. Potential Cases of Drug-Induced Liver Injury  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
 Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 X ULN or not available; 


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 For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
 For subjects with preexisting AST or ALT baseline values above the normal range: 
AST or ALT values 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller). 
Concurrent with 
 For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or 
if the value reaches 3 X ULN (whichever is smaller). 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase and GLDH.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted.  All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for liver function test (LFT) 
abnormalities identified at the time, should be considered potential Hy’s law cases irrespective 
of availability of all the results of the investigations performed to determine etiology of the 
abnormal LFTs.  Such potential Hy’s law cases should be reported as SAEs. 
8.7. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
Hospitalization does not include the following: 
 Rehabilitation facilities; 
 Hospice facilities; 
 Respite care (eg, caregiver relief); 


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 Skilled nursing facilities; 
 Nursing homes; 
 Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE 
is not in itself an SAE.  Examples include:  
 Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pre-treatment laboratory abnormality); 
 Social admission (eg, subject has no place to sleep); 
 Administrative admission (eg, for yearly physical examination); 
 Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
 Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
 Hospitalization for observation without a medical AE; 
 Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject; 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.8. Severity Assessment 
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, these 
intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with the 


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subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above. 
8.9. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
8.10. Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy occurs 
if: 
 A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;  
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
 A male subject has been exposed (eg, because of treatment or environmental exposure) 
to the investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.  
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form and 
Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE has 
occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and within 


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24 hours of awareness of the exposure.  The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
 Spontaneous abortion includes miscarriage and missed abortion; 
 Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product.  
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis (eg, 
follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner. 
8.11. Occupational Exposure 
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event. 
An occupational exposure is reported to safety within 24 hours of Investigator’s awareness, 
using the SAE Report form, regardless of whether there is an associated AE/SAE.  Since the 
information does not pertain to a subject enrolled in the study, the information is not reported 
on a Case Report Form (CRF), however a copy of the completed SAE Report form is 
maintained in the study master file. 


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8.12. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal) 
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 
8.13. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject’s parent/legally acceptable representative.  In addition, each study subject’s 
parent/legally acceptable representative will be questioned about AEs. 
8.14. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
8.14.1. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  
As noted in the Protocol-Specified Serious Adverse Event section, should an investigator 
judge one of the identified protocol-specified SAE to have a causal relationship with the 
investigational product the investigator must report the event to Pfizer within 24 hours of 
investigator awareness. 
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an expedited 
fashion.  This information collected for SAEs is more detailed than that captured on the AE 
CRF.  In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality.  
Information on other possible causes of the event, such as concomitant medications, vaccines, 
and/or illnesses, must be provided.  In the case of a subject death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer or its designated 
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8.14.2. Nonserious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities 
AE reporting, including reporting suspected unexpected serious adverse reactions will be 
carried out in accordance with applicable local regulations. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
9.1. Sample Size Determination 
No formal sample size calculation was performed. The sample size is based on feasibility and 
appropriateness for a safety trial.     
9.2. Efficacy Analysis 
Continuous variables will be summarized by the number (N), mean, median, standard 
deviation, minimum and maximum.  Categorical variables will be summarized by percent and 
counts.  All summaries will be displayed by treatment.  Efficacy data will be listed, tabulated 
and graphically represented, as appropriate.   
All analyses will be based on the full analysis set (FAS) which includes all randomized 
subjects who have received at least one dose of study drug.   
9.2.1. Analysis of Primary Endpoint  
Change from baseline in FVC will be analyzed using a longitudinal mixed effects model.  The 
baseline result, treatment, time and treatment by time interaction will be included as fixed 
effects in the model.  Subject will be included as a random effect and the model will be fit 
with an unstructured covariance for the repeated measures.  Additionally, non-Gaussian 
models may be explored in the case of non-normal data for the FVC. 
Missing data will be imputed using maximum likelihood techniques for a mixed effects 
model.  This analysis is unbiased under the assumption of missing at random when the model 
assumptions hold.  Subjects who lose motor functions (e.g. TUG, 2MWT) will be regarded as 
missing not at random.  Additional imputation methods to assess the sensitivity of the analysis 
to missing not at random data may also be performed.  A completer analysis will also be 
conducted as a sensitivity analysis. 


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9.2.2. Analysis of Secondary Endpoints 
Secondary endpoints of change from baseline in functaional assessments, quality of life 
questionnaires and imaging endpoints will be analyzed using the same longitudinal mixed 
model as described for the primary analysis.  Transformation of the data will be considered if 
model assumptions are not met. 
9.2.3. Analysis of Exploratory Endpoints 
All exploratory endpoints, including the pharmacologic and health outcome endpoints, will be 
summarized by treatment group.  Additional analyses may be performed to understand the 
relationship between these endpoints and treatment.   
9.2.4. Analysis of Pharmacokinetics 
The PK concentration population is defined as all enrolled subjects who received at least 
1 dose of PF-06252616 and in whom at least 1 concentration value is reported.  The following 
PK concentrations for PF-06252616 following administration of PF-06252616 will be 
characterized.  
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum serum concentration 
Observed directly from data as the end 
of infusion concentration 
Ctrough 
Trough (predose) serum concentration 
Observed directly from data 
No formal inferential statistics will be applied to PK data. 
 
The serum PF-06252616 concentrations will be summarized through appropriate data 
tabulations, descriptive statistics, and graphical presentations which will be detailed in the 
statistical analysis plan.  Briefly, serum concentrations for PF-06252616 will be listed and 
summarized descriptively by nominal PK sampling time and dose.   
Any population PK analysis if conducted will be reported separately.  
9.2.5. Analysis of Pharmacodynamics 
The GDF-8 concentration population is defined as all enrolled subjects in whom at least 
1 concentration value is reported.   
Graphical analysis of total GDF-8 levels as absolute and percentage of baseline will be 
performed.  Analyses may be employed to determine the effects of dose and concentration on 
the GDF-8 levels over time.  From the GDF-8 data the following parameters will be reported.  
The GDF-8 concentrations will be summarized descriptively by treatment and time points. 
Any population PK/PD analysis conducted will be reported separately. 
Additionally, data permitting relationships between PF-06252616 PK GDF-8, imaging data 
(DXA, MRI), functional assessment, immunogenicity and any safety signals may be explored. 


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9.3. Safety Analysis 
Safety analyses will be based on the full analysis set.  
9.3.1. Vital Signs 
Systolic blood pressure, diastolic blood pressure and pulse rate will be listed and tabulated by 
dose group and week with descriptive statistics.  Change from baseline will also be 
summarized using the same descriptive statistics by dose group and month. 
9.3.2. Electrocardiogram 
The following ECG data will be listed: QT, QTc (Fridericia’s), heart rate, QRS duration, PR 
and RR interval.  QTc based on Fridericia’s correction will be derived. 
Baseline and change from baseline for QT, QTcF, heart rate, QRS, PR and RR will be 
summarized using descriptive statistics by treatment and study week.  The baseline for ECG 
parameters will be the average of the triplicate pre-dose measurements at Week 0.  Any 
triplicate measurements will be averaged prior to the calculation of summary statistics.  For 
QTcF a classification of absolute values and increase from baseline will be used. 
The number of subjects with maximum absolute QTcF <450 ms, 450 ms QTcF <480 ms, 
480 ms  QTcF <500 ms and QTcF values 500 ms will be tabulated by treatment and study 
week.  The number of subjects with maximum increase from baseline QTcF <30 ms, 30 ms 
 QTcF <60 ms and QTcF 60 ms will be tabulated by treatment and study week.  In 
addition, the number of subjects with uncorrected QT values 500 ms will be summarized. 
Triplicate measures will be averaged prior to categorizing subjects.  However, the number of 
subjects with any single uncorrected QT value 500 ms (not the average) will be summarized. 
9.3.3. Cardiac Echocardiogram 
The mean absolute and percent change from baseline in LVEF and LVESV will be evaluated.   
9.3.4. Liver MRI 
The mean absolute and percent change from baseline in the R2* value will be tabulated.  
Other exploratory analyses may be performed. 
9.3.5. Other Safety 
Adverse event data, laboratory data and concomitant medications will be tabulated and listed 
but not subjected to formal statistical analysis. 
Other safety data will be listed. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
During the study, periodic monitoring will be conducted to ensure that the protocol and Good 
Clinical Practices (GCPs) are being followed.  Review of source documents will be completed 
to confirm that the data recorded on CRFs are accurate.   


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The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits and/or to inspection by appropriate 
regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
possible audits or inspections and that sufficient time is devoted to the process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document. 
11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to International Conference on Harmonisation 
(ICH), according to local regulations. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or an independent third party arranged by Pfizer.  Investigator records 
must be kept for a minimum of 15 years after completion or discontinuation of the study or for 
longer if required by applicable local regulations.   


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The investigator must obtain Pfizer's written permission before disposing of any records, even 
if retention requirements have been met. 
12. ETHICS 
12.1. Institutional Review Board (IRB)/Ethics Committee (EC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and Pfizer in writing immediately after the 
implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
12.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.  
When study data is compiled for transfer to Pfizer and other authorized parties, subject names, 
addresses, and other identifiable data will be replaced by a numerical code consisting of a 
numbering system provided by Pfizer in order to de-identify study subjects.  The use of 
initials should be avoided.  The study site will maintain a confidential list of subjects who 
participated in the study linking their numerical code to the subject’s actual identity.  In case 
of data transfer, Pfizer will maintain high standards of confidentiality and protection of 
subject personal data consistent with applicable privacy laws. 
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws. 
The informed consent/assent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.   


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The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed, unless a waiver of 
informed consent has been granted by an IRB/EC.  The investigator will retain the original of 
each subject's signed consent/assent document. 
12.4. Subject Recruitment 
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.  In addition, the ongoing study may be publicized through DMD 
advocacy groups.  
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF TRIAL 
End of trial is defined as last subject last visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-06252616 at any time. 
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 1 week.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible. 
15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results  
During the study, periodic monitoring will be conducted to ensure that the protocol and Good 
Clinical Practices (GCPs) are being followed.  Review of source documents will be completed 
to confirm that the data recorded on CRFs are accurate.   
 
The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits and/or to inspection by appropriate 
regulatory authorities. 


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It is important that the investigator(s) and their relevant personnel are available during the 
possible audits or inspections and that sufficient time is devoted to the process. 
15.2. Publications by Investigators 
Pfizer has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug.  However, to ensure against inadvertent disclosure of confidential information or 
unprotected inventions, the investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 
action is required to protect intellectual property rights, the investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential information 
(other than the study results themselves) before disclosure. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 


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16. REFERENCES 
 
 
1 
McNally, E. M. Powerful Genes — Myostatin Regulation of Human Muscle Mass. 
New England Journal of Medicine 350, 2642-2644, doi:doi:10.1056/NEJMp048124 
(2004). 
2 
McPherron, A. C., Lawler, A. M. & Lee, S.-J. Regulation of skeletal muscle mass in 
mice by a new TGF- beta superfamily member. Nature 387, 83-90 (1997). 
3 
Schuelke, M. et al. Myostatin mutation associated with gross muscle hypertrophy in a 
child. New England Journal of Medicine 350, 2682-2688 (2004). 
4 
Bradley, L., Yaworsky, P. J. & Walsh, F. S. Myostatin as a therapeutic target for 
musculoskeletal disease. Cellular and Molecular Life Sciences 65, 2119-2124, 
doi:10.1007/s00018-008-8077-3 (2008). 
5 
Nigro, V. & Savarese, M. Genetic basis of limb-girdle muscular dystrophies:  the 2014 
update. Acta Myologica 33, 1-12 (2014). 
6 
Esapa, C. T., Benson, M. A., Schroder, J. E. & al., e. Functional requirements for 
fukutin-related protein in the Golgi apparatus. Hum Mol Genet 11, 3319-3331 (2002). 
7 
Brockington, M., Yuva, Y. & Prandini, P. Mutations in the fukutin-related protein 
gene (FKRP) identify Limb Girdle Muscular Dystrophy wI as a milder allelic variant 
of congenital muscular dystrophy MDC1C. Hum Mol Genet 10, 2851-2859 (2001). 
8 
Pope, M. et al. The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 
60, 1246-1251 (2003). 
9 
Willis, T. A. et al. Quantitative Magnetic Resonance Imaging in Limb-Girdle 
Muscular Dystrophy 2I:  A Multinational Cross-Sectional Study. PLOS One 9, e90377 
(2014). 
10 
Petri, H. et al. Progression of cardiac involvement in patients with limb-girdle type 2 
and Becker muscular dystrophies:  a 9-year follow-up study. International J 
Cardiology 182, 403-411 (2015). 
11 
Darin, N. et al. Inflammation and response to steroid treatment in limb-girdle muscular 
dystrophy 2I. Eur J Paediatr Neurol 11, 353-357 (2007). 
12 
An, S., Soe, K., Akamatsu, M., Hishikawa, Y. & Koji, T. Accelerated proliferation of 
hepatocytes in rats with iron overload after partial hepatectomy. Histochem Cell Biol 
773-786 (2012). 
13 
Whittaker, P., Hines, F. A., Robl, M. G. & Dunkel, V. C. Histopathological evaluation 
of liver, pancreas, spleen, and heart from iron-overloaded Sprague-Dawley rats. 
Toxicol Pathol (1996). 
14 
Smith, P. G. J. & Yeoh, G. C. T. Chronic iron overload in rats induces oval cells in the 
liver. Am J Pathol 149 (1996). 
15 
Masson, R. & Roome, N. O. Spontaneous iron overload in Sprague-Dawley rats. 
Toxicol Pathol 25, 308-316 (1997). 
16 
Alexander, J. & Kowdley, K. V. HFE-associated hereditary hemochromatosis Genet 
Med 11, 307-313 (2009). 
17 
Hankins, J. S. et al. R2* magnetic resonance imaging of the liver in patients with iron 
overload. Vol. 113 (2009). 


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18 
Wagner, K. R. et al. A phase I/IItrial of MYO-029 in adult subjects with muscular 
dystrophy. Annals of Neurology 63, 561-571, doi:10.1002/ana.21338 (2008). 
19 
Willis, T. A. et al. Quantitative Muscle MRI as an Assessment Tool for Monitoring 
Disease Progression in LGMD2I:  A Multicenter Longitudinal Study. PLOS One 8, 
e70993 (2013). 
20 
Danjou, F. et al. A decisional algorithm to start iron chelation in patients with beta 
thalassemia. Vol. 99 (2014). 
21 
Wood, J. C. et al. MRI R2 and R2* mapping accurately estimates hepatic iron 
concentration in transfusion-dependent thalassemia and sickle cell disease patients. 
Vol. 106 (2005). 
22 
Gaul, C. et al. Cardiac involvement in limb-girdle muscular dystrophy 2I. J Neurol 
253, 1317-1322 (2006). 
23 
Hollingsworth, K. G. et al. Subepicardial dysfunction leads to global left ventricular 
systolic impairment in patients with limb girdle muscular dystrophy 2I. Eur J Heart 
Failure 15, 986-994 (2013). 
24 
Blake, G. M., Naeem, M. & Boutros, M. Comparison of effective dose to children and 
adults from dual X-ray absorptiometry examinations. Bone 38, 935-942, 
doi:http://dx.doi.org/10.1016/j.bone.2005.11.007 (2006). 
25 
Wagner, K. R. et al. Gentamicin treatment of Duchenne and Becker muscular 
dystrophy due to nonsense mutations. Ann Neurol 49, 706-711 (2001). 
26 
Storey, P. et al. R2* imaging of transfusional iron burden at 3T and comparison with 
1.5T. Journal of Magnetic Resonance Imaging 25, 540-547, doi:10.1002/jmri.20816 
(2007). 
27 
Hammeraren, E., Ohlsson, J. A., Lindberg, C. & al., e. Reliability of static and 
dynamic balance tests in subjects with myotonic dystrophy type 1. Adv Physiother 14, 
48-54 (2012). 
28 
McDonald, C. M. et al. The 6-minute walk test as a new outcome measure in 
Duchenne muscular dystrophy. Muscle & Nerve 41, 500-510, doi:10.1002/mus.21544 
(2010). 
29 
Connelly, D. M., Thomas, B. K. & Smith, R. E. Clinical utility of the 2-minute walk 
test for older adults living in long-term care. Physiotherapy Canada 61, 78-87 (2009). 
30 
Marshall, W. A. & Tanner, J. M. Variations in the Pattern of Pubertal Changes in 
Boys. Arch Dis Child 45, 13-23 (1970). 
31 
Ware, J. E. SF-36 Health Survey Update. Spine 25, 3130-3139 (2000). 
 


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Appendix 1. Columbia-Suicide Severity Rating Scale:  Baseline 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions 
contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of 
the presence of suicidal ideation or behavior depends on the judgment of the individual administering the 
scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide 
History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience 
of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 
10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations 
of research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 
2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” 
section. If the answer to question 2 is “yes”, ask questions 3, 4 and 5.  If the 
answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section 
below. 
 
Lifetime: 
Time He/She 
Felt Most 
Suicidal 
Past __ Months 
1.  Wish to be Dead  
 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not 
wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
□    □ 
 
Yes     No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about 
killing myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the 
assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes       No 
   □    □ 
 
Yes     No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment 
period. This is different than a specific plan with time, place or method details worked out (e.g.  
thought of method to kill self but not a specific plan).  Includes person who would say, “I thought 
about taking an overdose but I never made a specific plan as to when, where or how I would actually 
do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
    Yes      No 
 □    □ 
 
Yes     No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such 
thoughts, as opposed to “I have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
   Yes      No 
□    □ 
 
Yes     No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some 
intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to 
carry out this plan? 
   
If yes, describe: 
 
   Yes       No 
 □    □ 
 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 
1-5 from above, with 1 being the least severe and 5 being the most severe).  Ask about time 
he/she was feeling the most suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  
________________________________________ 
                                                                       Type # (1-5)                                             Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   
________________________________________ 
                                                                      Type # (1-5)                                              Description of  Ideation 
Most Severe 
Most Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    
(5) Many times each day 
 
 
____ 
 
 
____ 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all 
types) 
 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was 
in part thought of as method to kill oneself. Intent does not have to be 100%.  If there is any 
intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There 
does not have to be any injury or harm, just the potential for injury or harm. If person pulls 
trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the 
behavior or circumstances. For example, a highly lethal act that is clearly not an accident so no other 
intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself 
(like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal 
intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious 
act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this 
becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, 
gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the 
trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is 
stopped from doing so. 
Has there been a time when you started to do something to end your life but someone 
or something stopped you before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Yes     No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they 
actually have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, 
except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Yes     No 
□   □ 
 
Total # of 
aborted 
 
______ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 
hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
 
____ 
____ 


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Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or 
preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill 
yourself (such as collecting pills, getting a gun, giving valuables away or writing a 
suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most 
Recent 
Attempt 
Date: 
Most Lethal   
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required 
(e.g., comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood 
loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose 
without reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital 
signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter 
Code 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no 
actual medical damage, had potential for very serious lethality: put gun in mouth and pulled the 
trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but 
pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter 
Code 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
  


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Appendix 2. Columbia-Suicide Severity Rating Scale (C-SSRS): Since Last Visit 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions 
contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of 
the presence of suicidal ideation or behavior depends on the judgment of the individual administering the 
scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide 
History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience 
of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 
10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations 
of research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 
2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
UMBIA 
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different 
than a specific plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  
Includes person who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or 
how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, 
with 1 being the least severe and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      
_________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each 
day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun 
is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling 
trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down 
from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before 
you actually did anything? 
If yes, describe: 
 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                            (0)  Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end 
the pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or 
how you were feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go 
on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you 
couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 


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Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Suicide: 
Answer for Actual Attempts Only 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of 
major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-
degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 
20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for 
very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with 
oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
 
 
 
 


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Appendix 3. InQoL 
 
 
HOW YOUR MUSCLE CONDITION AFFECTS 
YOU 
 
 
 
 
 
 
 
 
This questionnaire is designed to see how your muscle condition affects 
you.    
 
The first section will ask about your symptoms and how much they affect 
your life.  NOT all the symptoms mentioned may apply to you in which 
case please indicate this where asked and move on to the next question.   
 
The second section will be questions asking how you feel about your 
physical ability, independence, relationships, how you feel emotionally 
and the way you look.  
 
The third and last section will ask about any treatment you might receive.  
You will be asked about the effects this treatment has had and the effects 
you expect it to have. 
 
The information you provide will help doctors to understand your 
problems.  This will mean they can work towards better care and 
treatment for you. 
 
Please read the questions carefully and answer all the questions that 
apply to you.  
 
Thank you. 


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Appendix 4. SF-36 
 


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