A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 6 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated

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VERTEX PHARMACEUTICALS INCORPORATED
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The following efficacy endpoints will be analyzed using baseline values in the 
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SCHEDULE OF ASSESSMENTS 
6FKHGXOHV RI $VVHVVPHQWV DUH VKRZQ LQ 7DEOH  7UHDWPHQW &RKRUW DQG 7DEOH 
2EVHUYDWLRQDO &RKRUW $OO YLVLWV DUH WR EH VFKHGXOHG UHODWLYH WR WKH 'D\  9LVLW ILUVW GRVH RI
VWXG\ GUXJ )RU H[DPSOH WKH :HHN    GD\V 9LVLW ZRXOG RFFXU DIWHU  ZHHNV RI VWXG\
GUXJ DGPLQLVWUDWLRQ KDV EHHQ FRPSOHWHG LH 'D\  ILUVW GD\ RI :HHN 

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
4
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Protocol Synopsis ............................................................................................................. 4 
3 
Schedule of Assessments ................................................................................................ 11 
4 
Table of Contents ........................................................................................................... 18 
/LVW RI 7DEOHV   
/LVW RI )LJXUHV   
/LVW RI $EEUHYLDWLRQV   
5 
Introduction .................................................................................................................... 25 
 
%DFNJURXQG  
 
5DWLRQDOH IRU 3UHVHQW 6WXG\  
6 
Study Objectives ............................................................................................................ 27 
 
3ULPDU\ 2EMHFWLYH  
 
6HFRQGDU\ 2EMHFWLYHV   
7 
Study Endpoints ............................................................................................................. 27 
 
3ULPDU\ (QGSRLQW  
 
6HFRQGDU\ (QGSRLQWV  
 
2WKHU 6HFRQGDU\ (QGSRLQWV  
 
 
8 
Study Design ................................................................................................................... 30 
 
2YHUYLHZ RI 6WXG\ 'HVLJQ   
 
7UHDWPHQW &RKRUW  
 
7UHDWPHQW 3HULRG  
 
)ROORZXS  
 
(DUO\ 7UHDWPHQW 7HUPLQDWLRQ  
 
2EVHUYDWLRQDO &RKRUW  
 
'D\   
 
/RQJWHUP )ROORZXS  
 
/RVW WR )ROORZXS   
 
,QGHSHQGHQW 'DWD 0RQLWRULQJ &RPPLWWHH  
 
5DWLRQDOH IRU 6WXG\ 'HVLJQ DQG 6WXG\ 'UXJ 5HJLPHQV   
 
6WXG\ 'HVLJQ  
 
6WXG\ 'UXJ 'RVH DQG 'XUDWLRQ   
 
5DWLRQDOH IRU 6WXG\ $VVHVVPHQWV   
9 
Study Population ............................................................................................................ 40 
 
,QFOXVLRQ &ULWHULD  
 
([FOXVLRQ &ULWHULD 7UHDWPHQW &RKRUW 2QO\  
 
6WXG\ 5HVWULFWLRQV  
 
3ULRU DQG &RQFRPLWDQW 0HGLFDWLRQV DQG 2WKHU 6WXG\ 5HVWULFWLRQV  
 
3URKLELWHG 0HGLFDWLRQV  
 
3ULRU DQG &RQFRPLWDQW 0HGLFDWLRQV  
 
5HPRYDO RI 6XEMHFWV )URP 6WXG\ 'UXJ 7UHDWPHQW   

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
 
5HPRYDO RI 6XEMHFWV  
 
5HSODFHPHQW RI 6XEMHFWV   
10 Study Drug Administration and Management ........................................................... 45 
 3UHSDUDWLRQ DQG 'LVSHQVLQJ  
 $GPLQLVWUDWLRQ  
 0HWKRG RI $VVLJQLQJ 6XEMHFWV WR 7UHDWPHQW *URXSV   
 6WXG\ 'UXJ ,QWHUUXSWLRQ   
 'RVH 0RGLILFDWLRQ IRU 7R[LFLW\  
 3DFNDJLQJ DQG /DEHOLQJ   
 6WXG\ 'UXJ 6XSSO\ 6WRUDJH DQG +DQGOLQJ   
 'UXJ $FFRXQWDELOLW\   
 'LVSRVDO 5HWXUQ RU 5HWHQWLRQ RI 8QXVHG 'UXJ  
 &RPSOLDQFH  
 %OLQGLQJ DQG 8QEOLQGLQJ   
11 Assessments .................................................................................................................... 48 
 7LPLQJ RI $VVHVVPHQWV  
 ,QIRUPHG &RQVHQW$VVHQW  
 6XEMHFW DQG 'LVHDVH &KDUDFWHULVWLFV   
 3KDUPDFRNLQHWLFV  
 ([SORUDWRU\ $VVHVVPHQWV  
 (IILFDF\  
 
/XQJ &OHDUDQFH ,QGH[  
 
6ZHDW &KORULGH   
 
6SLURPHWU\   
 
:HLJKW +HLJKW DQG %0,   
 
&\VWLF )LEURVLV 4XHVWLRQQDLUH5HYLVHG   
 
7UHDWPHQW 6DWLVIDFWLRQ 4XHVWLRQQDLUH IRU 0HGLFDWLRQ  
 
2WKHU (YHQWV 5HODWHG WR 2XWFRPH   
 $QWLELRWLF 7KHUDS\ IRU 6LQRSXOPRQDU\ 6LJQ6\PSWRPV   
 +RVSLWDOL]DWLRQ IRU &)  
 6DIHW\  
 
$GYHUVH (YHQWV  
 
&OLQLFDO /DERUDWRU\ $VVHVVPHQWV   
 
(OHYDWLRQ RI /LYHU )XQFWLRQ 7HVW 3DUDPHWHUV  
 
3K\VLFDO ([DPLQDWLRQV 9LWDO 6LJQV DQG 3XOVH 2[LPHWU\  
 
(OHFWURFDUGLRJUDPV  
 
2SKWKDOPRORJLF ([DPLQDWLRQ  
 
6SLURPHWU\   

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
 
&RQWUDFHSWLRQ DQG 3UHJQDQF\  
 &RQWUDFHSWLRQ  
 3UHJQDQF\  
12 Statistical and Analytical Plans .................................................................................... 63 
 6DPSOH 6L]H DQG 3RZHU   
 $QDO\VLV 6HWV   
 $QDO\VLV 3HULRGV  
 6WDWLVWLFDO $QDO\VLV   
 
*HQHUDO &RQVLGHUDWLRQV  
 
%DFNJURXQG &KDUDFWHULVWLFV  
 6XEMHFW 'LVSRVLWLRQ   
 'HPRJUDSKLFV DQG %DVHOLQH &KDUDFWHULVWLFV  
 3ULRU DQG &RQFRPLWDQW 0HGLFDWLRQV   
 6WXG\ 'UXJ ([SRVXUH  
 6WXG\ 'UXJ &RPSOLDQFH  
 
(IILFDF\ $QDO\VLV  
 
6DIHW\ $QDO\VLV  
 $GYHUVH (YHQWV   
 &OLQLFDO /DERUDWRU\ $VVHVVPHQWV  
 (OHFWURFDUGLRJUDP  
 9LWDO 6LJQV  
 3XOVH 2[LPHWU\  
 2SKWKDOPRORJLFDO H[DPLQDWLRQV  
 6SLURPHWU\  
 3K\VLFDO ([DPLQDWLRQ  
 2WKHU 6DIHW\ $QDO\VLV   
 
,QWHULP DQG ,'0& $QDO\VHV  
 ,QWHULP $QDO\VLV  
 ,'0& $QDO\VLV   
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 77 
 $GYHUVH (YHQW DQG 6HULRXV $GYHUVH (YHQW 'RFXPHQWDWLRQ 6HYHULW\ *UDGLQJ DQG
5HSRUWLQJ   
 
$GYHUVH (YHQWV  
 'HILQLWLRQ RI DQ $GYHUVH (YHQW  
 &OLQLFDOO\ 6LJQLILFDQW $VVHVVPHQWV  
 'RFXPHQWDWLRQ RI $GYHUVH (YHQWV  
 $GYHUVH (YHQW 6HYHULW\  
 $GYHUVH (YHQW &DXVDOLW\  
 6WXG\ 'UXJ $FWLRQ 7DNHQ   
 $GYHUVH (YHQW 2XWFRPH   
 7UHDWPHQW *LYHQ  
 
6HULRXV $GYHUVH (YHQWV  
 'HILQLWLRQ RI D 6HULRXV $GYHUVH (YHQW  
 'RFXPHQWDWLRQ RI 6HULRXV $GYHUVH (YHQWV  
 5HSRUWLQJ 6HULRXV $GYHUVH (YHQWV   

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
 ([SHGLWHG 5HSRUWLQJ DQG ,QYHVWLJDWRU 6DIHW\ /HWWHUV   
 $GPLQLVWUDWLYH 5HTXLUHPHQWV  
 
(WKLFDO &RQVLGHUDWLRQV  
 
6XEMHFW ,QIRUPDWLRQ DQG ,QIRUPHG &RQVHQW   
 
,QYHVWLJDWRU &RPSOLDQFH  
 
$FFHVV WR 5HFRUGV  
 
6XEMHFW 3ULYDF\  
 
5HFRUG 5HWHQWLRQ  
 
6WXG\ 7HUPLQDWLRQ  
 'DWD 4XDOLW\ $VVXUDQFH  
 0RQLWRULQJ  
 (OHFWURQLF 'DWD &DSWXUH   
 3XEOLFDWLRQV DQG &OLQLFDO 6WXG\ 5HSRUW  
 
 
 
&OLQLFDO 6WXG\ 5HSRUW   
14 References ....................................................................................................................... 86 
15 Protocol Signature Pages .............................................................................................. 91 
 6SRQVRU 6LJQDWXUH 3DJH  
 ,QYHVWLJDWRU 6LJQDWXUH 3DJH  

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
List of Tables 
7DEOH  
6WXG\ 9; 7UHDWPHQW &RKRUW  
7DEOH  
6WXG\ 9; 2EVHUYDWLRQDO &RKRUW  
7DEOH  
6WXG\ 5HVWULFWLRQV  
7DEOH  
6WXG\ 'UXJ $GPLQLVWUDWLRQ  
7DEOH  
6WXG\ 'UXJ  
7DEOH  
6DIHW\ /DERUDWRU\ 7HVW 3DQHOV   
7DEOH  
 &RQILGHQFH ,QWHUYDOV $VVXPLQJ 'LIIHUHQW 2EVHUYHG ,QFLGHQFHV RI &)
OXQJ Q     
7DEOH  
)$6 7UHDWPHQW *URXS $VVLJQPHQW   
7DEOH  
$QDO\VLV RI (IILFDF\ DQG 6DIHW\ LQ 'LIIHUHQW 'RVLQJ 3HULRGV   
7DEOH  
*UDGLQJ RI $( 6HYHULW\   
7DEOH  
&ODVVLILFDWLRQV IRU $( &DXVDOLW\  
7DEOH  
&ODVVLILFDWLRQV IRU 6WXG\ 'UXJ $FWLRQ 7DNHQ :LWK 5HJDUG WR DQ $(   
7DEOH  
&ODVVLILFDWLRQV IRU 2XWFRPH RI DQ $(   
List of Figures 
)LJXUH  
6FKHPDWLF RI 6WXG\ 'HVLJQ  

3URWRFRO 9; 9HUVLRQ 
3DJH  RI 
9HUWH[ 3KDUPDFHXWLFDOV ,QFRUSRUDWHG
List of Abbreviations 
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'HILQLWLRQ
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DGYHUVH HYHQW
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STUDY OBJECTIVES 
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STUDY ENDPOINTS 
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9.1
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9.2
Exclusion Criteria (Treatment Cohort Only) 
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Study Restrictions  
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Study Restrictions 
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Prior and Concomitant Medications and Other Study Restrictions  
9.4.1
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10
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
10.1
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10.2
Administration 
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Table 10-1 
Study Drug Administration 
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10.3
Method of Assigning Subjects to Treatment Groups 
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10.4
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10.7
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Study Drug  
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10.8
Drug Accountability 
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10.9
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10.10
Compliance 
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Blinding and Unblinding 
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11
ASSESSMENTS  
11.1
Timing of Assessments 
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11.2
Informed Consent/Assent 
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Subject and Disease Characteristics 
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11.4
Pharmacokinetics 
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11.6
Efficacy 
11.6.1
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11.6.2
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11.6.4
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11.6.5
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11.6.6
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11.6.7
Other Events Related to Outcome 
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11.7
Safety 
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12.4.4.7
Spirometry 
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12.4.4.8
Physical Examination 
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12.4.4.9
Other Safety Analysis 
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12.4.5
Interim and IDMC Analyses 
12.4.5.1
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12.4.5.2
IDMC Analysis 
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13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1
Adverse Event and Serious Adverse Event Documentation, 
Severity Grading, and Reporting 
13.1.1
Adverse Events 
13.1.1.1
Definition of an Adverse Event 
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13.1.1.2
Clinically Significant Assessments 
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13.1.1.3
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13.1.1.4
Adverse Event Severity 
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13.1.1.5
Adverse Event Causality 
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13.1.1.6
Study Drug Action Taken 
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13.1.1.7
Adverse Event Outcome 
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13.1.1.8
Treatment Given 
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13.1.2
Serious Adverse Events 
13.1.2.1
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13.1.2.4
Expedited Reporting and Investigator Safety Letters 
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13.2
Administrative Requirements 
13.2.1
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13.2.2
Subject Information and Informed Consent 
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