A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children, Ages 6 to 17 Years, A Multicenter, Randomized, Double-blind, Placebo-controlled Safety and Efficacy Study of a Range of Linaclotide Doses Administered Orally to Children Ages 7-17 Years, With Irritable Bowel Syndrome With Constipation (IBS-C) (ie, Fulfill Rome III Criteria for Child/Adolescent IBS and Fulfill Modified Rome III Criteria for Child/Adolescent Functional Constipation
Phase: PHASE2
Conditions: Irritable Bowel Syndrome With Constipation
Sponsor: Forest Laboratories



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3. 0
O V E R A L L T A B L E O F C O N T E N T S
1. 0
TI T L E P A G E ....................................................................................................................................1
2. 0
S Y N O P SI S A N D S C H E D U L E O F E V A L U A TI O N S .....................................................................2
3. 0
O V E R A L L T A B L E O F C O N T E N T S ..............................................................................................7
3. 1
LI S T O F I N -T E X T T A B L E S .............................................................................................9
3. 2
LI S T O F I N -T E X T FI G U R E S ...........................................................................................9
4. 0
LI S T O F A B B R E VI A TI O N S .........................................................................................................1 0
5. 0
E T HI C A L C O N SI D E R A TI O N S ....................................................................................................1 2
5. 1
I nstit uti o nal Re vie w B oar d a n d I n de pe n de nt Et hics C o m mittee ......................................1 2
5. 2
Et hical C o n d uct of t he St u d y ............................................................................................1 2
5. 3
Patie nt I nf or mati o n a n d I nf or me d C o nse nt .......................................................................1 3
5. 3. 1
Patie nt Asse nt F or m ...........................................................................................1 3
5. 3. 2
Pare nt, Le gal G uar dia n, a n d Le gall y A ut h orize d Re prese ntati ve / C are giver
I nf or me d C o nse nt ...............................................................................................1 3
6. 0
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E ......................................1 5
7. 0
I N T R O D U C TI O N ..........................................................................................................................1 6
7. 1
S u m mar y of Li nacl oti de Pr o perties ..................................................................................1 7
7. 2
Cli nical E x perie nce ...........................................................................................................1 7
7. 2. 1
Ot her I nf or mati o n ...............................................................................................2 0
8. 0
S T U D Y O BJ E C TI V E S ...................................................................................................................2 1
9. 0
I N V E S TI G A TI O N A L P L A N .........................................................................................................2 2
9. 1
O verall St u d y Desi g n a n d Pla n: Descri pti o n ....................................................................2 2
9. 1. 1
Scree ni n g Peri o d .................................................................................................2 2
9. 1. 2
Pretreat me nt Peri o d ............................................................................................2 3
9. 1. 3
D o u ble -bli n d Treat me nt Peri o d ..........................................................................2 3
9. 1. 4
P ost -treat me nt Peri o d .........................................................................................2 4
9. 2
Disc ussi o n of St u d y Desi g n, I ncl u di n g t he C h oice of C o ntr ol Gr o u ps .............................2 5
9. 3
Selecti o n of St u d y P o p ulati o n ...........................................................................................2 5
9. 3. 1
I ncl usi o n Criteria ................................................................................................2 5
9. 3. 2
E xcl usi o n Criteria ...............................................................................................2 7
9. 3. 3
Re m o val of Patie nts fr o m T hera p y or Assess me nt .............................................3 0
9. 3. 4
Patie nt Re place me nt Pr oce d ures ........................................................................3 1
9. 4
Treat me nts ........................................................................................................................3 1
9. 4. 1
Treat me nts A d mi nistere d ...................................................................................3 2
9. 4. 1. 1
Resc ue Me dicati o n ...........................................................................3 2
9. 4. 2
I de ntit y of I n vesti gati o nal Pr o d ucts....................................................................3 2
9. 4. 3
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps
..........................................3 5
9. 4. 4
Selecti o n of D osa ges i n t he St u d y ......................................................................3 5
9. 4. 5
Selecti o n a n d Ti mi n g of D ose f or Eac h Patie nt ..................................................3 6
9. 4. 6
Bli n di n g ..............................................................................................................3 7
9. 4. 7
U n bli n di n g ..........................................................................................................3 7
9. 4. 8
Pri or a n d C o nc o mita nt T hera p y .........................................................................3 7

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4. 0 
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A N C O V A
a nal ysis of c o varia nce
β- h C G
beta h u ma n c h ori o nic g o na d otr o pi n
B M
b o w el mo v e m e nt
B P
bl o o d press ure
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
CI C
c hr o nic i di o pat hic c o nsti pati o n
C M H
C oc hra n -Ma ntel -Hae nszel 
C S B M
c o m plete s p o nta ne o us b o wel m o ve me nt
D S M B
Data a n d Safet y M o nit ori n g B oar d
E C G
electr ocar di o gra m, electr ocar di o gra p hic
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
e Diar y
electr o nic diar y
F C
f u ncti o nal c o nsti pati o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F GI D
fu ncti o nal gastr oi ntesti nal dis or ders 
F R
Fe deral Re gister
G C P
g o o d cli nical practice
GI
gastr oi ntesti nal
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
H R Q L
healt h -relate d q ualit y of life 
I B S
irrita ble b o wel s y n dr o me

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I B S- C
irrita ble b o wel s y n dr o me wit h c o nsti pati o n
I C F
i nf or me d c o nse nt f or m
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C
I n de pe n de nt Et hics C o m mittee
I N D
I n vesti gati o nal Ne w Dr u g (a p plicati o n)
I R B
I nstit uti o nal Re vie w B oar d
I T T
i nte nt t o treat (I nte nt-t o-Treat P o p ulati o n)
I W R S
i nteracti ve We b res p o nse syste m
L A R
le gall y a ut h orize d re prese ntati ve
L S M
least s q uares mea ns
N D A
N e w  Dr u g A pplicati o n
p- B S F S
Pe diatric Brist ol St o ol F or m Scale
P C S
p ote ntiall y cli nicall y si g nifica nt
Pe ds Q L ™
Pe diatric Q ualit y of Life I n ve nt or y 
PI D
patie nt i de ntificati o n
P K
p har mac o ki netic
P R O
patie nt re p orte d o utc o me
Q Tc B
Q T i nter val c orrecte d f or heart rate usi n g t he Bazett f or m ula 
( Q Tc B = Q T /( R R)½ ) 
Q Tc F
Q T i nter val c orrecte d f or heart rate usi n g t he Fri dericia f or m ula 
( Q Tc F = Q T /( R R)⅓)
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B M
s p o nta ne o us b o wel mo v e m e nt
S O C
s yste m or ga n class
T E A E
treat me nt-e mer ge nt a d verse e ve nt
U L N
u p per li mit of n or mal

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5. 0 
E T HI C A L C O N SI D E R A TI O N S
5. 1
I N S TI T U TI O N A L R E VI E W B O A R D A N D I N D E P E N D E N T
E T HI C S C O M MI T T E E
U nite d St ates
A p pr o val b y t he I nstit uti o nal Re vie w B oar d (I R B) bef ore t he start of t he st u d y  will be t he 
res p o nsi bilit y of t he I n vesti gat or. A c o p y of t he a p pr o val letter will be s u p plie d t o 
F orest Researc h I nstit ute, I nc. (t he S p o ns or), al o n g wit h a r oster of I R B me m bers or t he 
U S De part me nt of Healt h a n d H u ma n Ser vices ge neral ass ura nce n u m ber. D uri n g t he 
co urse of t he st u d y, t he I n vesti gat or will pr o vi de ti mel y a n d acc urate re p orts t o t he IR B 
o n t he pr o gress of t he st u d y , at i nter vals n ot e xcee di n g 1 year ( or as a p pr o priate), a n d will 
n otif y  t he I R B of seri o us a d verse e ve nts ( S A Es) or ot her si g nifica nt safet y fi n di n gs. T he 
st u d y pr ot oc ol, i nf or me d c o nse nt f or m (IC F), i nf or mati o n s heet a d vertise me nts, a n d 
a me n d me nts (if a n y)  will be a p pr o ve d b y t he I R Bs at t he st u d y sites i n c o nf or ma nce wit h 
t he U S C F R, Title 2 1, Part 5 6.
O utsi de t he U nite d St ates
If perf or me d o utsi de t he U nite d States, t his st u d y  will be carrie d o ut i n f ull c o m plia nce 
wit h t he g ui deli nes of t he i n de pe n de nt et hics c o m mittee (I E C) a n d g o ver n me nt a ge ncies 
of eac h res pecti ve c o u ntr y as well as t he E ur o pea n U ni o n Cli nical Trial Directi ve 
( Directive 2 0 0 1/ 2 0/ E C), w here a p plica ble. Bef ore t he st u d y  be gi ns, t he st u d y site will 
re q uire a p pr o val fr o m a n I E C a n d g o ver n me nt a ge nc y. D uri n g t he c o urse of t he st u d y, t he 
S p o ns or or a ut h orize d re prese ntati ve will pr o vi de ti mel y  a n d acc urate re p orts t o t he IE C 
o n t he pr o gress of t he st u d y , at i nter vals n ot e xcee di n g 1 ye ar ( or as a p pr o priate) a n d will 
n otif y  t he I E C of S A Es or ot her si g nifica nt safety fi n di n gs. T he st u dy pr ot oc ol, I C F, 
i nf or mati o n s heet a d vertise me nts, a n d a me n d me nts (if a ny) will be a p pr o ve d b y t he I E C 
at t he st u d y site i n c o nf or ma nce wit h C F R, Title 2 1, Part 5 6, t he E ur o pea n U ni o n Cli nical 
Trial Directi ve ( Directi ve 2 0 0 1/ 2 0/ E C), a n d l ocal re g ulati o ns.
5. 2
E T HI C A L C O N D U C T O F T H E S T U D Y
T his cli nical st u d y  will be c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve 
t heir ori gi ns i n t he Declarati o n of Helsi n ki.
T his cli nical st u d y  will c o m pl y wit h t he I C H G ui da nce o n Ge neral C o nsi derati o ns f or 
Cli nical Trials (I C H -E 8; 6 2 F R 6 6 1 1 3, 1 7 Dec 1 9 9 7) a n d G C P (I C H-E 6; 6 2 F R 2 5 6 9 2, 
0 9 Ma y  1 9 9 7), as well as Part 3 1 2 of t he U S C F R.

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5. 3 
P A TI E N T I N F O R M A TI O N A N D I N F O R M E D C O N S E N T
After bei n g gi ve n a n e x pla nati o n of t he st u d y a n d bef ore partici pati n g i n a n y st u d y 
pr oce d ures, eac h patie nt m ust pr o vi de asse nt, a n d his or her pare nt(s), le gal g uar dia n(s), 
or le gall y  a ut h orize d re prese ntati ve ( L A R) ( hereafter referre d t o as pare nt/ g uar dia n/ L A R) 
m ust pr o vi de v ol u ntar y  a n d writte n i nf or me d c o nse nt i n c o m plia nce wit h 2 1 C F R, Parts 
5 0 a n d 3 1 2 a n d gi ve HI P A A a ut h orizati o n ( or a n e q ui vale nt of HI P A A a ut h orizati o n i n 
n o n- U S c o u ntries).
T he si g ne d d oc u me nts will be place d i n t he I n vesti gat or’s st u d y  files. T he i nf or me d 
c o nse nt state me nt c o ntai ns all t he ele me nts of i nf or me d c o nse nt liste d i n A p pe n di x I of 
t his pr ot oc ol. 
 
5. 3. 1
P atie n t Asse nt F or m
T o partici pate i n t he st u d y , patie nts will rea d, asse nt t o a n u n dersta n di n g of, sig n t he 
asse nt f or m, a n d be ma de a ware t he y  ca n wit h dra w fr o m t he st u d y at a ny t i me. Patie nts 
w h o are u na ble t o rea d t he asse nt f or m will ha ve t he state me nts rea d t o t he m. I f t he 
patie nt ca n n ot si g n t he f or m, a wit ness will be all o we d t o pr o vi de writte n ver ificati o n of 
oral asse nt. A c o p y of t he si g ne d asse nt will be gi ve n t o t he patie nt’s 
pare nt/ g uar dia n/ L A R.
5. 3. 2
P are nt, Le g al G u ar di a n, a n d Le g all y A ut h orize d 
Re prese nt ati ve / C are gi ver I nf or me d C o nse nt
Writte n i nf or me d c o nse nt will be o btai ne d fr o m t he patie nt’s pare nt/ g uar dia n/ L A R bef ore 
t he patie nt partici pates i n a n y st u d y-relate d pr oce d ure. T o pr o vi de c o nse nt f or t he 
patie nt’s partici pati o n i n t he st u d y , t he patie nt’s pare nt/ g uar dia n/ L A R will rea d, asse nt t o 
a n u n dersta n di n g of, a n d si g n a n i nstr u me nt of i nf or me d c o nse nt or ot her l ocall y  
a p plica ble re g ulati o ns a n d a ut h orizati o n f or m after ha vi n g ha d a n o p p ort u nit y  t o disc uss 
t he f or ms wit h t he I n vesti gat or bef ore si g ni n g. T he pare nt/ g uar dia n/ L A R will be ma de 
a ware t hat t he patie nt ma y wit h dra w fr o m t he st u d y at a n y ti me a n d will recei ve a c o p y of 
t he si g ne d I CF. Patie nts w h o reac h t he a ge of maj orit y  (ie, 1 8 ye ars of a ge i n m ost 
j uris dicti o ns) d uri n g t he c o urse of t he st u dy are re q uire d t o re-c o nse nt.
A care gi ver is a pers o n i de ntifie d as a ble a n d willi n g t o pr o vi de safet y a n d efficac y 
i nf or mati o n a b o ut t he patie nt a n d o versee t he a d mi nistrati o n of i n vesti gati o nal pr o d uct 
a n d c o m pleti o n of t he dail y  electr o nic diar y (e Diar y), a n d ma y be a differe nt i n divi d ual 
t ha n t he pare nt/ g uar dia n/ L A R. T he care gi ver m ust c o m mit t o acc o m pa n y t he patie nt t o 
eac h st u d y visit. T o be eli gi ble f or t he st u d y, t he care gi ver, w het her or n ot he or s he is t he 
pare nt/ g uar dia n/ L A R, m ust rea d a n d si g n t he care gi ver c o nse nt or a c o mbi ne d 
p are nt/le gal g uar dia n/care gi ver per missi o n I C F d oc u me nt. If t he pare nt/ g uar dia n/ L A R is 
t he care gi ver, he or s he will be as ke d t o rea d a n d si g n b ot h t he pare nt/le gal g uar dia n 

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per missi o n (I C F) a n d t he c are gi ver c o nse nt or a c o m bi ne d p are nt/le gal g uar dia n/care gi ver 
per missi o n (I C F). T he pare nt/ g uar dia n/ L A R or care gi ver w h o s u per vises t he patie nt i n 
t he c o m pleti o n of t he e Diar y or a d mi nisters t he i nter vie wer-a d mi nistere d versi o n s h o ul d 
be t he sa me i n di vi d ual t hr o u g h o ut t he c o urse of t he st u d y . If a care giver is re place d 
d uri n g t he st u d y, eac h care gi ver m ust pr o vi de se parate I CF/care gi ver c o nse nts a n d be 
gi ve n a si g ne d c o p y of his or her care gi ver c o nse nt.

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6. 0 
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E 
S T R U C T U R E
T his st u d y  will be perf or me d at a p pr o xi matel y 5 0 – 1 0 0 st u d y sites.
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat a n i n vesti gati o n is c o n d ucte d acc or di n g 
t o t he si g ne d I n vesti gat or state me nt, t he i n vesti gati o nal pla n, G C P g ui deli nes, a n d 
a p plica ble re g ulati o ns; f or pr otecti n g t he ri g hts, safet y, a n d w elfare of patie nts u n der t he 
I n vesti gat or’s care; a n d f or t he c o ntr ol of i n vesti gati o nal pr o d ucts u n der i n vesti gati o n. A n 
I n vesti gat or s hall o btai n t he i nf or me d c o nse nt of eac h h u ma n patie nt pri or t o t he patie nt 
e nr olli n g i n t he st u d y a n d/ or pri or t o parti ci pati n g i n a n y st u d y-relate d acti vit y. 
T he In vesti gat or at eac h site m ust meet his or her o bli gati o ns t o t he patie nts, et hics 
c o m mittee, S p o ns or, a n d re g ulat or y  a ut h orities by mai ntai ni n g o versi g ht a n d c o ntr ol of 
t he st u d y’s c o n d uct a n d t he st u d y staff. It is t he res p o nsi bilit y of t he In vesti gat or t o 
e ns ure t hat a n y a n d all dele gate d d uties be assi g ne d t o q ualifie d staff b y e d ucati o n, 
e x perie nce, a n d lice ns ure (i n acc or da nce wit h l ocal re g ulati o ns) a n d t hat t he In vesti gat or 
o versi g ht is d oc u me nte d a n d ass ess me nt of t heir ca pa bilities a n d perf or ma nce c o nsiste nt 
wit h t he st u d y  i n vesti gati o nal pla n. T he In vesti gat or at eac h site will be res p o nsi ble f or 
t he ma na ge me nt of t he st u d y, i ncl u di n g mai ntai ni n g t he st u dy file a n d t he patie nt rec or ds, 
c orres p o n di n g wit h t he I R B /IE C , a n d c o m pleti n g t he electr o nic case re p ort f or ms 
(e C R Fs).

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7. 0
I N T R O D U C TI O N
F u ncti o nal gastr oi ntesti nal dis or ders ( F GI Ds) are c o m m o n c o n diti o ns of t he di gesti ve 
s yste m i n w hic h sy m pt o ms ca n n ot be e x plai ne d b y  t he prese nce of str uct ural or tiss ue 
a b n or malities (H y a ms, 1 9 9 9 ). T he R o me criteria were de vel o pe d t o classif y  t he F GI D S i n 
a d ults a n d c hil dre n base d o n cli nical s y m pt o ms. 
T he m ost c o m m o n a n d best researc he d F GI D is irrita ble b o wel sy n dr o me (I B S) 
(Sa n d u a n d Pa ul, 2 0 1 4 ). I B S is c haracterize d by a b d o mi nal pai n a n d altere d b o wel 
s ym pt o ms (altere d b o wel fre q ue nc y a n d c o nsiste nc y) (L o n gstret h et al, 2 0 0 6 ). It is a 
pre vale nt c o n diti o n t hat is ass ociate d wit h a si g nifica ntl y i m paire d healt h-relate d q ualit y 
of life a n d re d uce d w or k pr o d ucti vit y . Pre vale nce esti mates ra n ge fr o m 1 % t o m ore t ha n 
2 0 %, a n d it is o ne of t he m ost c o m m o n dis or ders ma na ge d b y gastr oe nter ol o gists a n d 
pri mar y  care p h y sicia ns (Bra n dt et al, 2 0 0 9 ). I n t he pe diatric p o p ulati o n, a literat ure 
re vie w esti mate d t hat 1 0 % t o 1 5 % of c hil dre n a n d a d olesce nts s uffer fr o m I B S
(Sa n d h u a n d Pa ul, 2 0 1 4 ). 
I n a d ults, R o me III criteria has classifie d I B S wit h c o nsti pati o n (I B S - C), I BS wit h 
diarr hea, mi xe d I B S , a n d u ns u bt ype d I B S, de pe n di n g o n t he st o ol c o nsiste nc y  
(L o n gstret h et al, 2 0 0 6 ). In c hil dre n, alt h o u g h I B S s u bt ype s are e nc o u ntere d i n cli nical 
practice, a classificati o n base d o n st o ol c o nsiste nc y  has n ot bee n s pecifie d
(Sa n d h u a n d Pa ul, 2 0 1 4 ). S uc h c lassificati o n is i m p orta nt as t he ma na ge me nt will , i n 
part, de pe n d o n t he prese nt i n g st o ol patter n.  
F u ncti o nal c o nsti pati o n ( F C) is a n ot her c o m m o n F GI D i n c hil d h o o d, wit h a n esti mate d 
pre vale nce of 3 % w orl d wi de. I t is ofte n ass ociate d wit h i nfre q ue nt a n d/ or pai nf ul 
defecati o n, fecal i nc o nti ne nce, a n d a b d o mi nal pai n. R o me III criteria (f or c hil dre n a n d 
a d olesce nts) disti n g uis h F C a n d I B S b y re q uiri n g t hat c hil dre n wit h F C ha ve i ns ufficie nt 
criteria f or a dia g n osis of I B S .
Gi ve n t he o verla p of cli nical prese ntati o n bet wee n I B S -C a n d F C, t he S p o ns or i nte grate d 
t he dia g n ostic criteria f or I B S wit h dia g n ostic criteria f or F C t o create a pe diatric I B S-C 
s u bt ype classificati o n. T heref ore, we defi ne d c hil d h o o d I B S -C as f ulfilli n g R o me III 
criteria f or chil d/ ad olesce nt I B S a n d m o difie d R o me III c riteria f or chil d/ ad olesce nt F C.
I B S n o l o n ger remai ns a c o n diti o n t h o u g ht t o affect o nl y  a d ults a n d a d olesce nts a n d is 
bei n g i ncreasi n gl y rec o g nize d as a c o m m o n c o n diti o n i n y o u n g c hil dre n. As t here is n o 
F D A -a p pr o ve d dr u g f or pe diatric I B S, well -pla n ne d, ra n d o mize d , place b o -c o ntr olle d 
e val uati o ns of p har mac ol o gical t hera pies i n c hil dre n are nee de d (Sa n d h u a n d Pa ul, 2 0 1 4 ).

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
1 7
7. 1 
S U M M A R Y O F LI N A C L O TI D E P R O P E R TI E S
Li nacl oti de, a 1 4 - a mi n o aci d pe pti de t hat acts o n t he a pical s urface of e pit helial cells i n 
t he i ntesti nal l u men t o sti m ulate g ua n yl ate c yclase s u bt ype C, is a p pr o ve d i n t he U nite d 
States f or t he treat me nt of a d ults wit h I B S -C a n d wit h c hr o nic i di o pat hic c o nsti pati o n 
( CIC) ( Li nzess, 2 0 1 5 ) a n d i n t he E ur o pea n U ni o n f or m o derate to se vere I B S - C. B y 
acti vati n g g ua n yl ate c yclase s u bt yp e C , orally a d mi nistere d li nacl oti de has bee n f o u n d t o 
i ncrease b ot h i ntesti nal fl ui d secreti o n a n d i ntesti nal tra nsit a n d t o als o decrease visceral 
pai n i n a ni mal m o dels. Li nacl oti de has mi ni mal oral b i oa vaila bilit y ( ≤0. 2 %) i n se veral 
a ni mal s pecies ( Br ya nt et al, 2 0 1 0; E uta me ne et al, 2 0 1 0 ). Refer t o t he I n vesti gat or’s 
Br oc h ure f or a m ore detaile d descri pti o n of t he c he mistr y , p har mac ol o g y, efficac y, a n d 
safety of li nacl oti de, base d o n st u dies c o n d ucte d i n a ni mals, healt h y v ol u nteers, a n d i n 
a d ult patie nts wit h I B S -C a n d CI C ( I n vesti gat or’s Br oc h ure, 2 0 1 6 ).
7. 2
C LI NI C A L E X P E RI E N C E
Li nacl oti de has bee n de vel o pe d b y t he S p o ns or a n d Ir on w o o d P har mace uticals, I nc. f or 
t he treat me nt of CI C a n d I B S-C i n a d ults. T he cli nical de vel o p me nt pr o gra m f or 
li nacl oti de t hat c ul mi nate d i n F D A a n d E ur o pea n Me dici nes A ge nc y a p pr o vals i ncl u de d 
t he f oll o wi n g N ort h A merica n st u dies i n a d ult patie nts:

4 lar ge d o u ble-bli n d, place b o -c o ntr olle d P hase 3 re gistrati o n st u dies ( 2 I B S -C st u dies 
[LI N -M D - 3 1 a n d M C P - 1 0 3- 3 0 2] a n d 2 CI C st u dies [LI N -M D - 0 1 a n d M C P - 1 0 3- 3 0 3]) 

2 l o n g -ter m safet y st u dies (LI N -M D - 0 2 a n d M C P - 1 0 3- 3 0 5), eac h wit h 7 8-wee k 
treat me nt peri o ds
I n a d diti o n, 2 ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, parallel -gr o u p , N ort h 
A merica n st u dies: P hase 3 b st u d y  (LI N -M D - 0 4) a n d P hase 3 st u d y ( M C P-1 0 3- 3 0 9) ha ve
bee n c o m plete d.
T he 2 I B S -C st u dies ( LI N -M D - 3 1 a n d M C P - 1 0 3- 3 0 2) e val uate d t he safet y a n d efficac y 
of li nacl oti de 2 9 0 u g (t he a d ult d ose s u bse q ue ntl y  a p pr o ve d by F D A) a d mi nistere d as a
s oli d oral ca ps ule f or 1 2 or 2 6 wee ks, res pecti vel y. I n t hese st u dies, li nacl oti de 
de m o n strate d statisticall y si g nifica nt a n d cli nicall y mea ni n gf ul i m pr o ve me nts i n patie nts’ 
c o nsti pati o n s ym pt o ms a n d a b d o mi nal pai n, a n d met all t he pre- s pecifie d pri mar y a n d 
sec o n dar y e n d p oi nts. St u d y  M C P -1 0 3- 3 0 2 de m o nstrat e d i m pr o ve me nt i n a b d o mi nal a n d 
b o wel s y m pt o ms at 1 2 wee ks t hat was mai ntai ne d t hr o u g h o ut 2 6 wee ks of treat me nt. 
St u d y LI N -M D -3 1 i ncl u de d a 4- wee k do u ble -bli n d, ra n d o mize d w it h dra wal p eri o d 
i m me diatel y f oll o wi n g t he 1 2- wee k treat me nt p eri o d t o assess t he p ote ntial f or re b o u n d 
w orse ni n g b o wel or a b d o mi nal s y m pt o ms. T he res ults fr o m t he ra n d o mize d w it h dra wal 
p eri o d s h o we d t hat t here was n o e vi de nce of de vel o p me nt of t olera nce, n or was t here 
e vi de nce of re b o u n d w orse ni n g of b o wel or a b d o mi nal s y m pt o ms relati ve t o baseli ne 
o nce t he li nacl oti de was disc o nti n ue d. T he m ost c o m m o n a d verse e ve nt ( A E) was 
diarr hea occ urri n g i n i n a p pr o xi matel y 2 0% of I BS -C patie nts i n b ot h st u dies. O verall, 

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
1 9
M C P - 1 0 3- 3 0 5 a n d St u d y LI N -M D -0 2 , t he m ost c o m m o nl y re p orte d A E was diarr hea, 
w hic h occ urre d i n a p pr o xi matel y  3 0 % of CIC patie nts a n d I B S -C patie nts i n b ot h st u dies. 
Neit her st u d y re p orte d S A Es of diarr hea.
T he c o m plete d P hase 3 b st u d y  (LI N -M D - 0 4) was a ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d, parallel- gr o u p, st u d y . Li nacl oti de at d oses of 1 4 5 ug/ da y  a n d 2 9 0 u g/ da y  was 
a d mi nistere d orall y f or 1 2 wee ks t o 4 8 7 ra n d o mize d a d ult patie nts wit h CI C a n d 
pr o mi ne nt a b d o mi nal bl oati n g at baseli ne (ie , bl oati n g ≥ 5. 0 o n a n 1 1 -p oi nt n u merical 
rati n g scale. No ne w safet y  tre n ds or c o ncer ns were i de ntifie d. T here were n o deat hs 
d uri n g t he st u d y a n d n o S A Es of diarr hea.
T he c o m plete d P hase 3 st u d y  ( M C P- 1 0 3-3 0 9) was a ra n d o mize d, d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p st u d y  i n patie nts wit h CIC at basel i ne. Li nacl oti de at 
d oses of 7 2 u g/ da y  a n d 1 4 5 u g/ da y was a d mi nistere d orally f or 1 2 wee ks t o 1 2 2 3 
ra n d o mize d a d ult patie nts. N o ne w safety tre n ds or c o ncer ns were i de ntifie d. T here were 
n o deat hs d uri n g t he st u d y a n d n o S A Es of diarr hea. O ne patie nt i n t h e li nacl oti de 1 4 5 -u g 
gr o u p e x perie nce d a n S A E of c olitis t hat was c o nsi dere d b y  t he i n vesti gat or t o be 
p ossi bl y  relate d t o st u d y dr u g.
Safet y  data fr o m t hese st u dies i n a d ults s h o we d t hat, e xce pt f or diarr hea, t he pr o p orti o n 
of patie nts re p orti n g a T E A E wa s si milar bet wee n place b o a n d, i n t he CI C st u dies, eac h 
li nacl oti de d ose gr o u p, a n d t he i nci de nce of T E A Es was n ot d ose-relate d. Wit h t he 
e xce pti o n of t he gastr oi ntesti nal ( GI ) s yste m or ga n class ( S O C), t he occ urre nce of 
T E A Es i n t he CI C a n d I B S-C patie nts was bala nce d acr oss treat me nt gr o u ps i n eac h S O C 
f or t he a d ult P hase 3 place b o-c o ntr olle d st u dies. Diarr hea was t he m ost c o m m o n T E A E 
i n li nacl oti de-treate d CI C a n d I B S-C patie nts, c o nsiste nt wit h its p har mac ol o g y ; h o we ver 
diarr hea was rarel y ass ociate d wit h seri o us se q uelae s uc h as de h y drati o n, fecal 
i nc o nti ne nce, or defecati o n ur ge nc y. 
S A Es were i nfre q ue nt a n d bala nce d acr oss treat me nt ar ms wit hi n eac h i n dicati o n. A n 
a nal ys is of t he S A Es acr oss t he e ntire cli nical de vel o p me nt pr o gra m re veale d n o patter n 
t o s u g gest t hat li nacl oti de ca uses a n y s pecific seri o us c o n diti o n.
Mi n or a b n or malities i n la b orat or y , vital si g n, or E C G para meters were o bser ve d rarely;  
o verall, t here were n o cli nicall y  mea ni n gf ul differe nces bet wee n li nacl oti de a n d place b o 
treat me nt gr ou ps f or a n y  of t hese para meters i n t he P hase 3 place b o-c o ntr olle d st u dies i n 
a d ults.
T he f oll o wi n g re gistrati o n st u dies were c o n d ucte d o utsi de of N ort h A merica:
•
I C P- 1 0 3-3 0 7: A P hase 3 i nter nati o nal, m ultice nter, ra n d o mize d, d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p efficac y  a n d safet y trial of li nacl oti de orall y 
a d mi nistere d o nce dail y f or 1 2 wee ks t o patie nts wit h I B S-C i n C hi na, A ustralia, Ne w 
Zeala n d, t he U S, a n d Ca na da. A t otal of 8 3 9 patie nts were ra n d o mize d i nt o 1 of 2 
treat me nt gr o u ps: li nacl oti de 2 9 0 u g ( 4 1 7 patie nts) or place b o ( 4 2 2 patie nts)

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
2 1
8. 0
S T U D Y O B J E C TI V E S
T he o bjecti ve of t his st u d y  is to e val uate t he d ose res p o nse, safet y , a n d efficac y of 
4 wee ks of treat me nt wit h 1 of 3 li nacl oti de d oses ( A, B, or C ) or 2 9 0 u g (as a n 
e x pl orat or y o bjecti ve i n t he a d olesce nt patie nts 1 2 - 1 7 y ears of a ge usi n g t he a p pr o ve d 
a d ult d ose) c o m pare d wit h place b o i n pe diatric patie nts 7 t o 1 7 y ears of a ge w h o f ulfill 
t he R o me III criteria f or chil d/a d olesce nt I B S a n d m o difie d R o me III criteria f or 
chil d/ ad olesce nt F C.

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
2 5
9. 2
DI S C U S SI O N O F S T U D Y D E SI G N, I N C L U DI N G T H E C H OI C E 
O F C O N T R O L G R O U P S
A m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p, safet y a n d 
efficac y d ose-ra n gi n g st u d y desi g n was c h ose n base d o n pri or st u dies t hat esta blis he d 
li nacl oti de efficac y a n d safety i n a d ult patie nts wit h I B S - C. A d diti o nall y , t his st u d y was 
desi g ne d wit h refere nce t o t he F D A G ui da nce f or I n d ustr y  E 1 1 Cli nical I n vesti gati o n of 
Me dici nal Pr o d ucts i n t he Pe diatric P o p ulati o n. I n t his pe diatric st u d y , I n vesti gat ors will 
e nr oll patie nts 7 t o 1 7 y ears of a ge wit h a dia g n osis of I B S-C base d o n R o me III criteria 
f or chil d/ ad olesce nt I B S a n d m o difie d R o me III criteria f or c hil d/a d olesce nt F C .
T he li nacl oti de d oses selecte d f or use i n t his st u d y  were base d o n pri or st u dies i n a d ult 
patie nts wit h I B S -C, c urre nt pr o d uct la beli n g f or t he treat me nt of I B S-C a n d/ or CI C i n 
N ort h A merica (ie, U S, Ca na da, a n d Me xic o f or b ot h i n dicati o ns i n a d ult patie nts) a n d 
t he E ur o pea n U ni o n (I B S-C o nl y  i n a d ult patie nts), a n d c o m m u nicati o ns wit h t he F D A. 
9. 3
S E L E C TI O N O F S T U D Y P O P U L A TI O N
9. 3. 1 
I ncl usi o n Criteri a
T o be eli gi b le t o partici pate i n t he st u d y, patie nts m ust meet t he f oll o wi n g criteria:
1.
P atie nt m ust p r o vi de writte n or ver bal i nf or me d asse nt a n d t he pare nt/ g uar dia n/ LA R 
a n d care gi ver m ust pr o vi de writte n i nf or me d c o nse nt bef ore t he i nitiati o n of a n y  
st u d y-s pecific proce d ures ( Secti o n 5. 3 )
2.
Patie nt is a male or fe male o ut patie nt, wei g hi n g ≥1 8 k g, 7 t o 1 7 y ears of a ge 
(i ncl usi ve) at t he ti me t he patie nt pr o vi des asse nt f or t he st u d y a n d 
pare nt/ g uar dia n/ L A R has pr o vi de d si g ne d c o nse nt

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
2 6
6.
Patie nt m eets R o me III criteria f or c h il d/a d olesce nt I B S: at least o nce per wee k f or at 
least 2 m o nt hs bef ore t he Scree ni n g Visit, t he patie nt e x perie nce d a b d o mi nal 
disc o mf ort (a n u nc o mf orta ble se nsati o n n ot descri be d as pai n) o r pai n ass ociate d wit h 
2 or m ore of t he f oll o wi n g at least 2 5 % of t he ti me:
a.
I m pr o ve me nt wit h defecati o n
b.
O nset ass ociate d wit h a c ha n ge i n fre q ue nc y  of st o ol
c.
O nset ass ociate d wit h a c ha n ge i n f or m (a p peara nce) of st o ol
7.
Patie nt m eets m o difie d R o me III criteria f or chil d/ ad olesce nt F C : F or at least 
2 m o nt hs bef ore t he Scree ni n g Visit, t he patie nt has ha d 2 or fe wer defecati o ns ( wit h 
eac h defecati o n occ urri n g i n t he a bse nce of a n y la xati ve, s u p p osit or y , or e ne ma use 
d uri n g t he prece di n g 2 4 h o urs) i n t he t oilet per wee k
I n a d diti o n, at least o nce per wee k, patie nt meets 1 or m ore of t he f oll o wi n g: 
a.
Hist or y  of rete nti ve p ost uri n g or e xcessi ve v oliti o nal st o ol rete nti o n
b.
Hist or y  of pai nf ul or har d b o wel m o ve me nts ( B Ms)
c.
Prese nce of a lar ge fecal mass i n t he rect u m
d.
Hist or y  of lar ge dia meter st o ols t hat ma y o bstr uct t he t oilet
e.
At le ast o ne e pis o de of fec al i nc o nti ne nce per wee k 
8.
Patie nt is willi n g t o disc o nti n ue a n y  la xati ves use d bef ore t he Pretreat me nt Visit i n 
fa v or of t he pr ot oc ol-per mitt e d resc ue me dici ne (A p pe n di x III )

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
2 8

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
2 9
6.
Patie nt has re q uire d ma n ual disi m pacti o n a n y ti me pri or t o ra n d o mizati o n or 
disi m pacti o n d uri n g i n -patie nt h os pitalizati o n wit hi n 1 y ear pri or t o ra n d o mizati o n

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
3 0
1 6. Patie nt is u na ble t o t olerate t he place b o pri or t o ra n d o mizati o n
9. 3. 3  
Re m o v al of P atie nts fr o m T her a p y or Assess me nt
A pre mat ure disc o nti n uati o n will occ ur w he n a patie nt w h o ga ve v ol u ntar y  asse nt a n d 
w h ose pare nt/ g uar dia n/ L A R a n d care gi ver ga ve c o nse nt c eases partici pati o n i n t he st u d y, 
re gar dless of circ u msta nces, bef ore t he c o m pleti o n of t he st u d y visits a n d pr oce d ures. 
Patie nts will be pre mat urel y  disc o nti n ue d fr o m t he st u d y f or reas o ns of safet y i ncl u di n g 
t h ose w h o e x perie nce a n S A E c o nsi dere d by t he I n vesti gat or or t he S p o ns or t o be relate d 
t o i n vesti gati o nal pr o d uct. Patie nts will als o be pre mat urel y disc o nti n ue d fr o m t he st u d y 
f or e vi de nce of si g nifica nt v ol u me de pleti o n a n d/ or si g nifica nt electr ol y te a n d/or E C G 
a b n or malities t hat are c o nsi dere d b y t he I n vesti gat or or S p o ns or t o be relate d t o diarr hea 
relate d t o t he i n vesti gati o nal pr o d uct
 
. T he In vesti gat or s h o ul d c o ntact t he St u d y Ph y sicia n if 
t here is a ny q uesti o n w he t her t he criteria f or a n A E 
 ha ve bee n met a n d 
t he patie nt s h o ul d be disc o nti n ue d fr o m t he st u d y.
Patie nts ca n als o be pre mat urel y disc o nti n ue d fr o m t he st u d y after caref ul c o nsi derati o n 
f or o ne of t he f oll o wi n g reas o ns:

Scree n fail ure (fail ure t o meet i ncl usi o n/e xcl usi o n criteria) 

Wit h dra wal of c o nse nt

A E

Lac k of efficac y

Pr ot oc ol vi olati o n 

N o nc o m plia nce wit h i n vesti gati o nal pr o d uct

L ost t o f oll o w - u p

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
3 1

St u d y  ter mi nate d b y S p o ns or 

Site ter mi nate d b y  S p o ns or

Ot her
All ra n d o mize d patie nts w h o pre mat urel y  disc o nti n ue fr o m t he st u d y, re gar dless of ca use, 
s h o ul d be see n f or t he assess me nts t o be c o m plete d at t he E n d - of-Treat me nt Visit 
( Wee k 4/ Visit 5). T he e n d - of-treat me nt assess me nts are defi ne d as c o m pleti o n of t he 
e val uati o ns sc he d ule d f or all patie nts at Wee k 4 ( Visit 5 ). In a d diti o n t o t he 
e n d-of- treat me nt assess me nts, all patie nts disc o nti n ui n g t he st u d y pre mat urel y s h o ul d 
e nter t he P ost-treat me nt Peri o d a n d c o m plete a P ost-treat me nt Visit ( Visit 6). 
Patie nts w h o disc o nti n ue fr o m t he st u d y  a n d d o n ot ret ur n t o t he st u d y site f or Visit 5 
a n d/ or Visit 6 m ust be re q ueste d i n writi n g t o ret ur n t o t he st u d y  site f or pr oce d ures i n 
Visit 5 or Visit 6 a n d ret ur n a n y u n use d i n vesti gati o nal pr o d uct a n d t he ha n d hel d e Diar y. 
A c o p y of t he le tter, t o get her wit h t he s o urce d oc u me ntati o n, will be ke pt i n t he 
I n vesti gat or’s files. T he reas o n f or pre mat ure disc o nti n uati o n fr o m t he st u d y will be 
rec or de d o n t he St u d y Ter mi nati o n Pa ge of t he e C R F. St u d y site staff will be c o ntacte d 
b y  t he S p o ns or after eac h pre mat ure disc o nti n uati o n t o e ns ure pr o per c haracterizati o n of 
t he reas o n f or disc o nti n uati o n is ca pt ure d.
9. 3. 4
P atie nt Re pl ace me nt Pr oce d ures
Patie nts i n t his st u d y  w h o pre mat urely disc o nti n ue treat me nt will n ot be re place d.
9. 4
T R E A T M E N T S
Patie nts meeti n g t he eli gi bilit y  criteria d uri n g Visit 3 ( Da y 1) will be ra n d o mize d i n a 
d o u ble - bli n d fas hi o n t o li nacl oti de or place b o (Ta ble 9. 4. 5 – 1 ). 
Ra n d o mizati o n will be strati fie d by a ge gr o u p:

Patie nts 7 t o 1 1 y ears of a ge will be ra n d o mize d t o li nacl oti de d oses ( A, B, or C) or 
place b o i n a 1: 1: 1: 1 all ocati o n 

Patie nts 1 2 t o 1 7 y ears of a ge will be ra n d o mize d t o li nacl oti de d oses ( A, B, or C, or 
t he a p pr o ve d a d ult d ose, 2 9 0 u g ) or place b o i n a 1: 1: 1: 1: 1 all ocati o n 

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
3 3

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
3 4
T a ble 9. 4. 2 – 1.
I n vesti g ati o n al Pr o d uct F or m ul ati o n

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
3 9
B o wel M ove me nt Fre q ue ncy

M or ni n g e Diar y
Fr o m be dti me last ni g ht u ntil n o w, h o w ma n y  ti mes di d yo u p o o p (a n d p o o p ca me 
o ut) ?
○
E nter n u m ber of ti mes

E ve ni n g e Diar y
Fr o m w he n y o u g ot u p t his m or ni n g u ntil n o w, h o w ma n y ti mes di d y o u p o o p (a n d 
p o o p ca me o ut)? 
○
E nter n u m ber of ti mes 
If res p o nse is > 0 B Ms, t he n t he patie nt a ns wers t he f oll o wi n g q uesti o n f or eac h B M 
re p orte d:
W he n di d y o u p o o p t o da y ?
○
I n t he m or ni n g (fr om w he n y o u w o ke u p u ntil l u nc h)
○
I n t he after n o o n (fr o m l u nc h u ntil di n ner)
○
I n t he e ve ni n g (fr o m di n ner u ntil be dti me)
○
I d o n't k n o w
Resc ue M e dic ati o n U se 

M or ni n g e Diar y
Fr o m be dti me last ni g ht u ntil n o w, di d y o u ta ke a n y  me dici ne t o hel p yo u p o o p, ot her 
t ha n t he st u d y me dici ne?
○
Yes
○
N o

E ve ni n g e Diar y
Fr o m w he n y o u g ot u p t his m or ni n g u ntil n o w, di d y o u ta ke a n y  me dici ne t o hel p yo u 
p o o p, ot her t ha n t he st u d y  me dici ne? 
○
Yes 
○
N o
If t he res p o nse is ‘ yes”, t he n t he patie nt a ns wers t he f oll o wi n g q uesti o n:
W he n di d y o u ta ke t he me dici ne ( N O T y o ur st u d y me dici ne) t o hel p y o u p o o p? 

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
4 0
○
I n t he m or ni n g (fr o m w he n yo u w o ke u p u ntil l u nc h)
○
I n t he after n o o n (fr o m l u nc h u ntil di n ner)
○
I n t he e ve ni n g (fr o m di n ner u ntil be dti me)
○
I d o n't k n o w
9. 5. 1. 2
Key Sec o n d ary Effic acy Assess m e nts
I n a d diti o n t o t he pri mar y efficac y assess me nt, t he k e y  sec o n dar y efficac y para meter (t he
c ha n ge fr o m b aseli ne i n 4 -wee k a b d o mi nal pai n d a y ti me sy m pt o ms ) will be deter mi ne d 
b y  t he e ve ni n g assess me nt of a b d o mi nal pai n as rec or de d i n t he e Diar y. F or t his 
para meter, patie nts will rate t heir a b d o mi nal pai n b y  res p o n di n g t o t he f oll o wi n g:
A b d o mi n al P ai n - D ayti me

Fr o m w he n y o u g ot u p t his m or ni n g u ntil n o w, di d y o ur t u m m y h urt at all?
○
Yes
○
N o
If “ yes ”, t he n patie nt a ns wers t he f oll o wi n g q uesti o n:

H o w m uc h di d y o ur t u m m y  h urt? 
1 = a ti n y bit
2 = a little 
3 = s o me 
4 = a l ot
9. 5. 1. 3
Ot her Sec o n d ary Effic acy Assess me nts
Ot her sec o n dar y  efficac y assess me nts are i ncl u de d i n t he st u d y re gar di n g B M 
c haracteristics a n d a b d o mi nal s y m pt o ms t hat will be deter mi ne d b y  t he t wice daily 
assess me nts rec or de d i n t he e Diar y .
T he f oll o wi n g B M c haracteristics will be assesse d f or eac h B M re p orte d i n t he m or ni n g 
a n d e ve ni n g e Diaries: 

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
4 1
St o ol C o nsiste ncy ( Pe di atric Brist ol St o ol F or m Sc ale )
St o ol c o nsiste nc y  of eac h B M will be base d on t he p -B S F S ( A p pe n di x V ). T he B S F S is a 
well -acce pte d a n d wi del y use d meas ure me nt of st o ol c o nsiste nc y ( Le wis a n d Heat o n, 
1 9 9 7 ). T he p-B S F S was de vel o pe d b y t he S p o ns or a n d Ir o n w o o d P har mace uticals base d 
o n t he ori gi nal B S F S a n d was refi ne d base d o n q ualitati ve researc h wit h pe diatric patie nts 
wit h F C a n d I B S -C. Patie nts will use t he p -B S F S 7 - p oi nt or di nal scale t o rate t heir st o ol 
c o nsiste nc y:
" Use t he car d pr o vi de d t o c h o ose t he p o op t hat is m ost li ke t he p o o p y o u ha d."
T y pe 1 = l o o ks li ke s mall har d l u m ps or balls, li ke pe b bles
T y pe 2 = l o o ks li ke fat sa usa ge s ha pe b ut l u m p y  a n d har d
T y pe 3 = l o o ks li ke a sa usa ge b ut wit h crac ks o n it
T y pe 4 = l o o ks li ke a sa usa ge or s na ke, s m o ot h a n d s oft
T y pe 5 = l o o ks li ke c hic ke n n u g gets, s oft s m o ot h bl o bs 
T y pe 6 = l o o ks li ke oat meal, fl uff y  m us h y pieces 
T y pe 7 = l o o ks li ke a mil ks ha ke, water y
9 9 - I d o n’t k n o w 
Str ai ni n g Wit h B o wel M ove me nt
Patie nts will assess t he de gree of strai ni n g b y res p o n di n g t o t he f oll o wi n g:

W he n y o u p o o pe d, h o w har d di d y o u p us h?
0 = n ot har d at all
1 = I p us he d a ti n y bit har d
2 = I p us he d a little har d
3 = I p us he d har d
4 = I p us he d ver y  har d
C o m plete S p o nt a ne o us B o wel M ove me nt/I nc o m plete Ev ac u ati o n 
A c o m plete s p o nta ne o us b o wel m o ve me nt ( C S B M) is a n S B M t hat is ass ociate d wit h a 
se nse of c o m plete e vac uati o n. Patie nts will rec or d t heir assess me nt of t he se nsati o n of 
i nc o m plete e vac uati o n b y res p o n di n g t o t he f oll o wi n g: 

W he n y o u p o o pe d, di d it feel li k e t here was m ore p o o p left i nsi de t hat di d n’t c o me 
o ut?
o
Yes
o
N o

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
4 2
T he f oll o wi n g a b d o mi n al sy m pt o ms will be assesse d:
A b d o mi n al Bl o ati n g - D ayti me
Patie nts will rec or d t heir assess me nt of a b d o mi nal bl oati n g b y res p o n di n g t o t he 
f oll o wi n g i n t he e ve ni n g e Diar y:

Fr o m w he n y o u g ot u p t his m or ni n g u ntil n o w, di d y o ur t u m m y F E E L bi g a n d f ull?  
1 = y es
0 = n o 
9 8 = I d o n’t k n o w w hat y o u mea n
9 9 = I d o n’t re me m ber
If “ yes” t he n patie nt a ns wers t he f oll o wi n g q uesti o n :

H o w bi g a n d f ull di d y o ur t u m m y  F E EL?
1 = a ti n y  bit
2 = a little 
3 = me di u m 
4 = ver y
9. 5. 1. 4
A d diti o n al Effic acy Assess me nt s

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○
T he e ve nt is li kel y t o be attri b ute d t o u n derl yi n g/c o nc urre nt disease, ot her 
i n vesti gati o nal pr o d ucts, or ot her fact ors, or
○
T he e ve nt is c o m m o nl y occ urri n g i n t he (st u d y) p o p ulati o n i n de pe n de nt of 
i n vesti gati o nal pr o d uct e x p os ure
9. 5. 2. 3
Severity Asses s me nt
T he In vesti gat or will pr o vi de a n assess me nt of t he se verit y of eac h A E b y rec or di n g a 
se verity rati n g o n t he a p pr o priate A E re p orti n g pa ge of t he patie nt’s e C R F. Severity,
w hic h is a descri pti o n of t he i nte nsit y  of ma nifestati o n of t he A E, is disti nct fr o m 
seri o us ness, w hic h i m plies a patie nt o utc o me or A E -re q uire d treat me nt meas ure 
ass ociate d wit h a t hreat t o life or f u ncti o nalit y ( Secti o n 9. 5. 2. 4 ). Se verity will be assesse d 
acc or di n g t o t he f oll o wi n g scale:
Mil d:
T he A E was a n a n n o ya nce t o t he patie nt b ut di d n ot f urt her hi n der 
baseli ne f u ncti o ni n g; t he A E ma y  ha ve bee n i nter mitte nt or c o nti n u o us.
M o der ate:
T he A E ca use d t he patie nt t o e x perie nce s o me disc o mf ort or s o me 
i nterfere nce wit h n or mal acti vities b ut was n ot hazar d o us t o healt h; 
prescri pti o n dr u g t hera p y ma y ha ve bee n e m pl o ye d t o treat t he A E.
Se vere:
T he A E ca use d t he patie nt t o e x perie nce se vere disc o mf ort or se verel y 
li mite d or pre ve nte d n or mal acti vities a n d re prese nte d a defi nite hazar d t o 
healt h; prescri pti o n dr u g t hera p y a n d/ or h os pitalizati o n ma y ha ve bee n 
e m pl o ye d t o treat t he A E .
9. 5. 2. 4
Seri o us A dverse Eve nts
A n S A E is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life t hreate ni n g

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

Res ults i n a persiste nt or si g nifica nt i nca pacit y  or s u bsta ntial disr u pti o n of t he a bilit y 
t o c o n d uct n or mal life f u ncti o ns, or  

Is a c o n ge nital a n o maly/ birt h defect

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
5 0
I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life t hreate ni n g, or re q uire 
h os pitalizati o n ma y  be c o nsi dere d seri o us w he n, base d o n a p pr o priate me dical j u d g me nt, 
t he y ma y je o par dize t he patie nt or s u bject a n d ma y re q uire me dical or s ur gical 
i nter venti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h 
me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n patie nt 
h os pi talizati o n, or t he de vel o p me nt of i n vesti gati o nal pr o d uct de pe n de nc y or dr u g a b use.
E mer ge nc y  r o o m visits t hat d o n ot res ult i n h os pitalizati o n s h o ul d be e val uate d f or o ne of 
t he ot her seri o us o utc o mes t o deter mi ne w het her t he y q ualif y as S A Es.
Pre pla n ne d h os pitalizati o ns (e g, electi ve pr oce d ures f or pree xisti n g c o n diti o ns t hat di d 
n ot w orse n, s uc h as c os metic s ur ger y  a n d h ysterect o m y) are e xcl u de d fr o m S A E 
re p orti n g.
9. 5. 2. 5
Re p orti n g A dverse Eve nts a n d Seri o us A dverse Eve nts
At eac h visit, patie nts are t o be q uer ie d re gar di n g a n y A Es or S A Es t hat ha ve occ urre d 
si nce t he pre vi o us visit. Patie nts will be as ke d t o v ol u nteer i nf or mati o n wit h a n o nlea di n g 
q uesti o n s uc h as, “ H o w d o y o u feel si nce y o ur last visit?” St u d y  site pers o n nel will 
rec or d all perti ne nt i nf or matio n i n t he patie nt’s e C R F. A n y A Es re p orte d i n diaries will 
als o be re p orte d o n t he rele va nt e C R F pa ge.
All A Es m ust be rec or de d o n t he a p pr o priate A E re p orti n g pa ge of t he patie nt’s e C R F 
w het her or n ot t he y  are c o nsi dere d ca usall y relate d t o t he i n vesti gati o nal pr o d uct.
F or e ver y  A E, t he In vesti gat or m ust:

Pr o vi de a n assess me nt of t he seri o us ness of t he e ve nt (ie, is it a n S A E?), as well as 
t he se verity a n d ca usal relati o ns hi p

D oc u me nt all acti o ns ta ke n wit h re gar d t o t he i n vesti gati o nal pr o d uct

D etail a n y ot her treat me nt meas ures ta ke n f or t he A E

D oc u me nt t he o utc o me of t he A E
I n a d diti o n, patie nts are t o be re mi n de d, as descri be d i n t he IC F a n d i n acc or da nce wit h 
Secti o n 9. 5. 2. 1 , t o n otif y site pers o n nel of a ny A Es occ urri n g d uri n g t he 3 0 -d a y  
p ost -st u d y peri o d. A ny A Es re p orte d b y t he patie nt ( or patie nt re prese ntati ve) d uri n g t his 
peri o d are t o be rec or de d i n t he e C R F.

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
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A n y  A Es t hat are o n g oi n g at t he ti me of t he fi nal pr ot oc ol -defi ne d st u d y visit will be 
f oll o we d u ntil t he c o n diti o n ret ur ns t o prest u dy stat us, has res ol ve d , or h as sta bilize d. If a 
f oll o w-u p visit is dee me d necessar y  f or a p pr o priate safety s ur veilla nce, it will ta ke place 
wit hi n 3 0 da y s of t he fi nal pr ot oc ol-defi ne d st u d y visit.

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9. 7. 5
Effic ac y A n al yses
Efficac y  a nalys es will be base d o n t he I T T P o p ulati o n. 

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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7 1
9. 7. 5. 2
Sec o n d ary Effic ac y P ar a meter s
Key Sec o n d ary Effic acy P ar a me ter
T he ke y  sec o n dar y efficac y para meter is c ha n ge fr o m baseli ne i n 4-wee k a b d o mi nal pai n 
da y ti me sy m pt o ms base d o n e ve ni n g assess me nt of a b d o mi nal pai n s y m pt o ms. 
A b d o mi nal pai n sc ores will be c ollecte d t wice dail y i n t he e Diar y: i n t he m or ni n g w he n a 
patie nt wa kes u p a n d i n t he e ve ni n g at be dti me. Patie nts are as ke d t o rate t heir a b d o mi nal 
pai n fr o m t he ti me t he patie nt wa kes u p u n til be dti me as part of t he e ve ni n g assess me nt ,
a n d a 5-p oi nt rati n g scale is deri ve d fr o m t he patie nt’s res p o nses. T he patie nt’s 4 -wee k 
a b d o mi nal pai n d a y ti me s ym pt o ms d uri n g t he T reat me nt Peri o d are defi ne d as t he 
a vera ge of t he n o n missi n g dail y a b d o mi nal pai n da y ti me sy m pt o ms re p orte d i n e ve ni n g 
assess me nts i n t he e Diar y d uri n g t he 4- wee k Treat me nt P eri o d.
Ot her Sec o n d ary Effic acy P ar a meters
F o ur c ha n ge fr o m baseli ne para meters are a d diti o nal sec o n dar y efficac y para meters i n 
t his st u d y. T heir descri pti o n a n d a nalys es are pr o vi de d bel o w.
C h a n ge Fr o m B aseli ne i n 4 -Wee k
St o ol C o nsiste nc y
St o ol c o nsiste nc y  will be c ollecte d t wice dail y i n t he e Diar y, i n t he m or ni n g w he n a 
patie nt wa kes u p a n d i n t he e ve ni n g at be dti me, a n d meas ure d usi n g t he 7 -p oi nt p -B S F S . 
T he patie nt’s p -B S F S sc ore i n t he 4 -wee k Treat me nt Peri o d will be t he o bser ve d 
wei g hte d a vera ge of t he dail y  p- B S F S sc ores ( usi n g wei g ht of 1 f or f ull da y a n d 0. 5 f or 
half da y ) a n d t he de n o mi nat or i n t he o bser ve d wei g hte d a vera ge will be t he s u m of t he 
wei g hts d uri n g t his peri o d . T he dail y p-B S F S sc ore will be t he a vera ge of n o n missi n g 
m or ni n g a n d/ or e ve ni n g assess me nts of t he p -B S F S sc ore fr o m t he S B Ms re p orte d b y t he 
patie nt o n t hat s pecific da y  d uri n g t he Treat me nt Peri o d.
C h a n ge Fr o m B aseli ne i n 4 - Wee k of Se verit y of Str ai ni n g
Strai ni n g wit h eac h B M will be c ollecte d t wice dail y i n t he e Diar y, i n t he m or ni n g w he n 
a patie nt wa kes u p a n d i n t he e ve ni n g at be dti me, a n d meas ure d usi n g a 5 -p oi nt scale. 
T he patie nt’s strai ni n g sc ore i n t he 4 - wee k Treat me nt Peri o d will be t he o bser ve d 
wei g hte d a vera ge of dail y  strai ni n g sc ore ( usi n g wei g ht of 1 f or f ull da y  a n d 0. 5 f or half 
da y ) a n d t he de n o mi nat or i n t he o bser ve d wei g hte d a vera ge will be t he s u m of t he 
wei g hts d uri n g t his peri o d . T he dail y sc ore f or t he Treat me nt Peri o d will be t he a vera ge 
of t he n o n missi n g m or ni n g a n d/ or e v e ni n g assess me nts of t he strai ni n g sc ore fr o m t he 
S B Ms re p orte d b y t he patie nt o n t hat s pecific da y  d uri n g t he Treat me nt Peri o d.

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1 0. 0
S T U D Y S P O N S O R S HI P
T his st u d y  is s p o nsore d b y  F orest Researc h I nstit ute, In c . i n part ners hi p wit h Ir o n w o o d 
P har mace uticals, I nc.
1 0. 1
S T U D Y T E R MI N A TI O N
T he S p o ns or reser ves t he ri g ht t o ter mi nate t he st u d y i n its e ntirety or at a s pecific st u d y 
site bef ore st u dy c o m pleti o n. 
1 0. 2
R E P O R TI N G A N D P U B LI C A TI O N
All data ge nerate d i n t his st u d y  are t he pr o perty of t he S p o ns or.
 
P u blicati o n of t he res ults b y  t he I n vesti gat or will be s u bject t o m ut ual a gree me nt bet wee n 
the In vesti gat or a n d t he S p o ns or a n d will f oll o w t he S p o ns or’s sta n dar d o perati n g 
pr oce d ures o n p u blicati o ns.

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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1 1. 0
I N V E S TI G A T O R O B LI G A TI O N S
1 1. 1  
D O C U M E N T A TI O N
T he I n vesti gat or m ust pr o vi de t he f oll o wi n g t o t he S p o ns or bef ore t he start of t he st u d y :

A c o m plete d a n d si g ne d F or m F D A 1 5 7 2. If, d uri n g t he c o urse of t he st u d y, a n y 
c ha n ges are ma de t hat are n ot reflecte d o n F or m F D A 1 5 7 2, a ne w F or m F D A 1 5 7 2 
m ust be c o m plete d a n d ret ur ne d t o t he S p o ns or f or s u b missi o n t o t he F D A

A f ull y  e xec ute d c o ntract

T h e c urric ula vitae f or t he In vesti gat or a n d all S u b in vesti gat ors liste d o n F or m F D A 
1 5 7 2, i ncl u di n g a c o p y of eac h p h ys icia n’s lice nse

A c o p y of t he ori gi nal I R B/ IE C a p pr o val f or c o n d ucti n g t he st u d y. If t he st u d y is 
o n g oi n g, re ne wals m ust be s u b mitte d at ye arl y i nter vals. All s u bse q ue nt 
m o dificati o ns m ust be s u b mitte d a n d a p pr o ve d b y t he IR B/ IE C, as state d i n 
Secti o n 5. 1

A c o p y of t he I R B/ IE C -a p pr o ve d I C F

A c o p y of t he HIP A A a ut h orizati o n f or m, or ot her l ocal pri vac y a p plica ble f or ms

A list of t he I RB/ IE C me m bers or t he U S De part me nt of Healt h a n d H u ma n Ser vices
ge neral ass ura nce n u m ber

A c o p y of t he la b orat or y certificati o ns a n d refere nce ra n ges

T he I n vesti gat or’s S tate me nt pa ge i n t his pr ot oc ol si g ne d a n d date d b y t he 
In vesti gat or

Fi na ncial discl os ure a gree me nt c o m plete d a n d si g ne d b y  t he In vesti gat or a n d all 
S u b in vesti gat ors liste d o n F or m F D A 1 5 7 2. T he In vesti gat or a n d all S u bi n vesti gat ors 
will pr o vi de a n u p date d fi na ncial discl os ure a gree me nt t o t he S p o ns or 1 year after t he 
c o m pleti o n of t he st u d y
1 1. 2
P E R F O R M A N C E
T he I n vesti gat or m ust de m o nstrate reas o na ble eff orts t o o btai n q ualifie d patie nts f or t he 
st u d y.

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
8 5
T he In vesti gat or m ust per mit access t o a n y d oc u me ntati o n relati n g t o t he st u d y u p o n 
re q uest of t he S p o ns or or a p plica ble re g ulat or y  a ut h orities. If t he I n vesti gat or f or t he 
st u d y retires, rel ocates, or f or ot her reas o ns wit h dra ws fr o m t he res p o nsi bilit y of kee pi n g 
t he st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a s uita ble alter nate c ust o dia n e m pl o yee 
of t he i nstit uti o n or t o a s uita bl y  q ualifie d a n d res p o nsi ble t hir d part y. T he S p o ns or m ust 
be n otifie d i n writi n g of t he na me a n d a d dress of t he ne w c ust o dia n i n a d va nce of t he 
tra nsfer.
F or c o u ntries falli n g wit hi n t he sc o pe of t he I C H g ui deli nes, t he s p o ns or -s pecific 
esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 y ears after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d 
mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 2 y ears ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct.  T hese d oc u me nt s 
s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d by t he a p plica ble re g ulat or y 
re q uire me nt(s) or if nee de d b y t he s p o ns or.
I n a d diti o n, f or c o u ntries n ot falli n g wit hi n t he sc o pe of t he I C H g ui deli nes, l ocal 
re g ulat or y re q uire me nts s h o ul d be f oll o we d re gar di n g t he rete nti o n of cli nical st u d y 
d oc u me ntati o n.
F or Ca na dia n st u d y  sites o nl y: All rec or ds a n d d oc u me nts pertai ni n g t o t he c o n d uct of t he 
st u d y m ust be retai ne d f or a 2 5-ye ar peri o d i n acc or da nce wit h t he Ca na dia n F o o d a n d 
Dr u gs Act a n d Re g ulati o ns. 
1 1. 6
P A TI E N T C O N FI D E N TI A L I T Y

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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1 2. 0 
I N V E S TI G A T O R’ S S T A T E M E N T
I a gree t o c o n d uct t he st u d y i n acc or da nce wit h t his pr ot oc ol ( LI N-M D - 6 3, 
A me n d me nt # 3, date d 1 6 Ma y
2 0 1 7) a n d wit h all a p plica ble g o ver n me nt re g ulati o ns a n d 
g o o d cli nical practice g ui da nce.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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1 3. 0
A P P E N DI C E S
A P P E N DI X I 
E L E M E N T S O F I N F O R M E D C O N S E N T
Pr oce d u res will c o m pl y wit h 2 1 C F R, Parts 5 0 a n d 3 1 2. Si g ne d i nf or me d c o nse nt will be 
o btai ne d fr o m eac h patie nt partici pati n g i n a cli nical researc h st u d y  or fr o m t he patie nt’s 
pare nt/ g uar dia n/ L A R. T his c o nse nt m ust i ncl u de t he f oll o wi n g ite ms:

A state me nt t hat t he st u d y i n v ol ves researc h a n d a n e x pla nati o n of t he p ur p oses of t he 
researc h; a descri pti o n of t he pr oce d ures t o be f oll o we d a n d t he i de ntificati o n of a ny 
pr oce d ures t hat are e x peri me ntal; a n d t he e x pecte d d urati o n of t he patie nt’s 
partici pati o n

A descri pti o n of a n y reas o na bl y f oreseea ble ris ks or disc o mf orts t o t he patie nt

A descri pti o n of a n y be nefits t o t he patie nt or t o ot hers t hat ma y  reas o na bl y be 
e x pecte d fr o m t he researc h. If t he patie nt is t o be pai d f or partici pati n g i n t he st u d y , 
t he c o nse nt f or m m ust state t he a m o u nt t hat he/s he will recei ve a n d t he sc he d ule of 
pa y me nt (t o e ns ure neit her c oerci o n n or u n d ue i nfl ue nce)

A discl os ure of a p pr o priate alter nati ve pr oce d ures or c o urses of treat me nt, if a n y, t hat 
mi g ht be a d va nta ge o us t o t he patie nt

A s tate me nt descri bi n g t he e xte nt, if a n y, t o w hic h c o nfi de ntialit y of rec or ds 
i de ntif yi n g t he patie nt will be mai ntai ne d a n d n oti n g t he p ossi bilit y t hat t he F D A; t he 
S p o ns or ; t he IR B /IE C ; or a n a ut h orize d c o ntract researc h or ga nizati o n ma y i ns pect 
t he rec or ds

F or researc h i n v ol vi n g m ore t ha n mi ni mal ris k, a n e x pla nati o n of w het her a n y  
me dical treat me nt is a vaila ble if i nj ur y  occ urs a n d, if s o, w hat it c o nsists of or w here 
f urt her i nf or mati o n ma y be o btai ne d

A n e x pla nati o n of w h o m t o c o ntact, i ncl u di n g t he rel e va nt tele p h o ne n u m ber, f or 
a ns wers t o perti ne nt q uesti o ns a b o ut t he researc h a n d t he researc h patie nt’s ri g hts a n d 
w h o m t o c o ntact i n t he e ve nt of a researc h -relate d i nj ur y t o t he patie nt. ( N ote: In 
s o me cases, it ma y be necessar y  t o i de ntif y a pers o n ot her t ha n t he In vesti gat or as t he 
c o ntact. T he g ui da nce of t he I R B/ IE C m a y  be re q uire d)

A state me nt t hat partici pati o n is v ol u ntar y , t hat ref usal t o partici pate will i n v ol ve n o 
pe nalt y  or l oss of be nefits t o w hic h t he patie nt is ot her wise e ntitle d, a n d t hat t he 
patie nt ma y  disc o nti n ue partici pati o n at a n y ti me wit h o ut pe nalt y or l oss of be nefits t o 
w hic h t he patie nt is ot her wise e ntitle d

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
8 8

A state me nt t hat t he partic ular treat me nt or pr oce d ures ma y  i n v ol ve ris ks t o t he 
patie nt ( or t o t he e m br y o or fet us if t he patie nt is, or ma y  bec o me, pre g na nt) t hat are 
at prese nt u nf oreseea ble

T he e x pecte d circ u msta nces f or w hic h t he patie nt’s partici pati o n ma y  be ter mi nate d 
b y  t he In vesti gat or wit h o ut re gar d t o t he patie nt’s c o nse nt

A n y  a d diti o nal c osts t o t he patie nt t hat ma y res ult fr o m partici pati o n i n t he researc h

T he c o nse q ue nces of a patie nt’s decisi o n t o wit h dra w fr o m t he researc h a n d 
pr oce d ures f or a n or derl y ter mi nati o n of t he patie nt’s partici pati o n

A state me nt t hat si g nifica nt ne w fi n di n gs de vel o pe d d uri n g t he c o ur se of t he researc h 
t hat ma y relate t o t he patie nt’s willi n g ness t o c o nti n ue partici pati o n will be pr o vi de d 
t o t he patie nt

T he a p pr o xi mate n u m ber of patie nts i n v ol ve d i n t he st u d y

A state me nt of c o nse nt (e g, “I a gree t o all o w ( m y c hil d) t o partici pate . . .”)

A place f or t he patie nt’s pare nt/ g uar dia n/ L A R si g nat ure a n d date of si g ni n g

A state me nt i n dicati n g t hat i nf or mati o n a b o ut t his st u d y  has bee n, or will be, e ntere d 
i nt o a data ba n k t hat is p u blicl y accessi ble at w w w. Cli nical Trials. g o v.
A c o p y of t he si g ne d c o nse nt f or m m ust be gi ve n t o t he patie nt’s pare nt/ g uar dia n/ L A R.
I n a d diti o n, t he patie nt will be as ke d t o pr o vi de asse nt t hat will i ncl u de a state me nt 
a greei n g t o partici pate i n t he st u d y .

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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A P P E N DI X II
C O N T A C T I N F O R M A TI O N 

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Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
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1 4. 0
LI T E R A T U R E CI T E D
Bra n dt L J, C he y W D, F o x x-Ore nstei n A E, et al . A n e vi de nce -b ase d sys te matic re vie w o n 
t he m a na ge me nt of irrita ble b o wel sy n dr o me . A m J Gastr oe nter ol 
2 0 0 9; 1 0 4 S u p pl 1: S 8 -S 3 5.
Br ya nt A P, B us b y R W, Bart oli ni W P, et al. Li nacl oti de is a p ote nt a n d selecti ve 
g ua n yl ate c yclase C a g o nist t hat elicits p har mac ol o gical effects l ocall y i n t he 
gastr oi ntesti nal tract. Life Sci 2 0 1 0; 8 6: 7 6 0 - 5. 
E uta me ne H, Bra desi S, Lara uc he M, et al. G ua n ylate c y clase C -me diate d a nti n ocice pti ve 
effects of li nacl oti de i n r o de nt m o dels of visceral pai n. Ne ur o gastr oe nter ol M otil 
2 0 1 0; 2 2: 3 1 2 -e 8 4.
H y a ms J S. F u ncti o nal gastr oi ntesti nal dis or ders. C urr O pi n Pe diatr 1 9 9 9; 1 1: 3 7 5 - 3 7 8.
Le wis SJ a n d Heat o n K W. St o ol f or m scale as a usef ul g ui de t o i ntesti nal tra nsit ti me.
Sca n d J Gastr oe nter ol 1 9 9 7; 3 2: 9 2 0 - 4.
Li nacl oti de: I n vesti gat or’s br oc h ure. E diti o n 1 1 . Ca m bri d ge, M A: Ir o n w o o d 
P har mace uticals, I nc; 2 0 1 6 N ov 2 2 .
Li nzess [ pac ka ge i nsert]. 2 0 1 5 N o v. A vaila ble fr o m 
htt p:// pi.acta vis.c o m/ data _strea m.as p? pr o d uct _ gr o u p = 1 9 0 4 & p = pi &la n g ua ge = E . 
Accesse d 2 0 1 6 J ul 1 1.
L o n gstret h G F , T h o m ps o n W G, C he y W D, et al. F u ncti o nal b o wel dis or ders. 
Gastr oe nter ol o g y  2 0 0 6; 1 3 0: 1 4 8 0- 9 1. 
Sa n d h u B K a n d Pa ul S P. Irrita ble b o wel s y n dr o me i n c hil dre n: pat h o ge nesis, dia g n osis 
a n d e vi de nce-base d treat me nt. W orl d J of Gastr oe nter ol 2 0 1 4 Ma y ; 2 0( 2 0): 6 0 1 3- 6 0 2 3.
St u d y  LI N-M D - 0 1: a p hase III, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 
parallel -gr o u p trial of li nacl oti de a d mi nistere d orall y  f or 1 2 wee ks i n patie nts wit h 
c hr o nic c o nsti pati o n. Jerse y City, NJ: F orest Researc h I nstit ute, I nc; 2 0 1 0 J u n 2. 
St u d y  LI N-M D - 0 2: a n o pe n -la bel, l o ng- ter m safet y st u d y of oral li nacl oti de a d mi nistere d 
t o patie nts wit h c hr o nic c o nsti pati o n or irrita ble b o wel s yn dr o me wit h c o nsti pati o n. 
Jerse y Cit y, NJ: F orest Researc h I nstit ute, I nc; 2 0 1 2 N o v 5 .
St u d y  LI N -M D - 0 4: a p hase 3 b , ra n d o mize d, d o u ble-bli n d, pl ace b o -c o ntr olle d, 
parallel -gr o u p trial of li nacl oti de a d mi nistere d orall y  f or 1 2 wee ks t o patie nts wit h 
c hr o nic c o nsti pati o n a n d pr o mi ne nt a b d o mi nal bl oati n g at baseli ne . Jerse y Cit y, NJ: 
F orest Researc h I nstit ute, I nc; 2 0 1 4 Marc h 1 4.

Pr ot oc ol A me n d me nt # 3 LI N -M D -6 3
F orest Researc h I nstit ute, I nc.
9 7
St u d y  LI N -M D - 3 1: a p hase III, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
parallel -gr o u p trial of li nacl oti de a d mi nistere d orall y  f or 1 2 wee ks f oll o we d b y a 4- wee k 
ra n d o mize d wit h dra wal peri o d i n patie nts wit h irrita ble b o wel sy n dr o me wit h 
c o nsti pati o n . Jerse y Cit y, NJ: F orest Researc h I nstit ute, Inc; 2 0 1 1 Ma y  1 0.
St u d y  M C P-1 0 3- 3 0 2: a p hase 3, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d,
parallel -gr o u p trial of li nacl oti de a d mi nistere d orall y  f or 2 6 wee ks i n patie nts wit h 
irrita ble b o wel sy n dr o me wit h c o nsti pati o n . Ca m bri dge, M A: Ir o n w o o d P har mace uticals, 
I nc; 2 0 1 1 M a y
2 4.
St u d y  M C P- 1 0 3- 3 0 3: a p hase 3, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d,
parallel -gr o u p, trial of li nacl oti de a d mi nistere d orall y  f or 1 2 wee ks f oll o we d b y  a 4-wee k 
ra n d o mize d wit h dra wal peri o d i n patie nts wit h c hr o nic c o nsti pati o n. Ca m bri d ge, 
M A : Ir o n w o o d P har mace uticals, Inc; 2 0 1 0 Ma y  7.
St u d y  M C P- 1 0 3- 3 0 5: a n o pe n -la bel, l o n g-ter m safet y st u d y of oral li nacl oti de
a d mi nistere d t o patie nts wit h c hr o nic c o nsti pati o n or irrita ble b o wel s y n dr o me wit h 
c o nstipati o n . Ca m bri d ge, M A: Ir o n w o o d P har mace uticals, I nc; 2 0 1 2 Oct 1 8 .
Var ni J W, B ur wi n kle T M, Berri n SJ, et al. T he Pe ds Q L i n pe diatric cere bral pals y: 
relia bilit y, vali dit y, a n d se nsiti vit y of t he Ge neric C ore Scales a n d Cere bral Pals y 
M o d ule. De v M e d C hil d N e ur ol J u n 2 0 0 6; 4 8( 6): 4 4 2 - 4 9.
Var ni J W, B ur wi n kle T M, Jac o bs J R, et al. T he Pe ds Q L i n ty pe 1 a n d t y pe 2 dia betes: 
relia bilit y a n d vali dit y of t he Pe diatric Q uality of Life I n ve nt or y Ge neric C ore Scales a n d 
t ype 1 Dia betes M o d ule. Dia betes Care Mar 2 0 0 3; 2 6( 3): 6 3 1 - 7.
Var ni J W, B ur wi n kle T M, Katz E R, et al. T he Pe ds Q L i n pe diatric ca ncer: relia bilit y  a n d 
vali dit y  of t he Pe diatric Q ualit y of Life I n ve nt or y Ge neric C ore Scales, M ulti di me nsi o nal 
Fati g ue Scale, a n d Ca ncer M o d ule. Ca ncer A pr 1 2 0 0 2; 9 4( 7): 2 0 9 0- 1 0 6.
Var ni J W, B ur wi n kle T M, Ra p off M A, et al. T he Pe ds Q L i n pe diatric ast h ma: relia bilit y 
a n d vali dit y of t he Pe diatric Q ualit y of Life I n ve nt or y ge neric c ore scales a n d ast h ma 
m o d ule. J B e ha v M e d J u n 2 0 0 4; 2 7( 3): 2 9 7 - 3 1 8.
Var ni J W, B ur wi n kle T M, Sei d M. T he Pe ds Q L  4. 0 as a sc h o ol p o p ulati o n healt h 
meas ure: feasi bilit y , relia bilit y, a n d vali dit y. Q ual Life Res. Mar 2 0 0 6; 1 5( 2): 2 0 3 -1 5.
Var ni J W, Sei d M, K urti n P S. Pe ds Q L  4. 0: relia bilit y a n d vali dit y of t he Pe diatric Q ualit y 
of Life I n ve nt or y  versi o n 4. 0 generic c ore scales i n healt h y  a n d patie nt p o p ulati o ns. 
Me d
Care A u g 2 0 0 1; 3 9( 8): 8 0 0- 1 2.
Var ni J W, Sei d M, S mit h K ni g ht T, et al. T he Pe ds Q L  i n pe diatric r he u mat ol o g y: 
relia bilit y, vali dit y, a n d res p o nsi ve ness of t he Pe diatric Q ualit y of Life I n ve nt or y Ge neric 
C ore Scales a n d R he u mat ol o g y  M o d ule. Art hritis R he u m Mar 2 0 0 2; 4 6( 3): 7 1 4- 2 5.