Clinical trial NCT02559817
Conditions: Irritable Bowel Syndrome With Constipation
Keywords: Irritable Bowel Syndrome with Constipation in children Linzess
Sponsor: Forest Laboratories
Start date: 2015-11-01; Completion date: 2019-08-30
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of linaclotide for the treatment of Irritable Bowel syndrome with Constipation (IBS-C), in children age 7-17 years.

This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients age 7-11 will receive oral liquid or oral solid capsule and patients 12-17 will receive solid oral capsule formulation. Children ages 7-11 years meeting the entry criteria will be randomized to 1 of 3 doses of linaclotide or placebo for 4 weeks. Children ages 12-17 years meeting the entry criteria will be randomized to 1 of 4 doses of linaclotide or placebo for 4 weeks.

This 4-week study will assess the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of IBS-C.

Detailed description:

Arms: arm 1: Taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast.

Dose A: 18 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg

Dose A: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg

Dose A: 36 micrograms solid oral capsule in children 12-17 years of age arm 2: Taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast.

Dose B: 36 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg

Dose B: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg

Dose B: 72 micrograms solid oral capsule in children 12-17 years of age arm 3: Taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast.

Dose C: 72 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight 18 to \<35 kg

Dose C: 145 micrograms liquid oral solution or solid oral capsule in children 7-11 years of age with weight ≥ 35 kg

Dose C: 145 micrograms solid oral capsule in children 12-17 years of age arm 4: Taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast.

Approved Adult Dose: 290 micrograms solid oral capsule in children 12-17 years of age arm 5: Taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center, after at least a 2-hour fast

Placebo liquid oral solution or placebo solid oral capsule in children 7-11 years of age

Placebo solid oral capsule in children 12-17 years of age
Interventions: intervention 1: Linaclotide Dose A intervention 2: Linaclotide Dose B intervention 3: Linaclotide Dose C intervention 4: Linaclotide Approved Adult Dose intervention 5: Matching Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 






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E T HI C A L C O N SI D E R A TI O N S ....................................................................................................1 2
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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
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Et hical C o n d uct of t he St u d y ............................................................................................1 2
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Patie nt I nf or mati o n a n d I nf or me d C o nse nt .......................................................................1 3
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Patie nt Asse nt F or m ...........................................................................................1 3
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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
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I N T R O D U C TI O N ..........................................................................................................................1 6
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S u m mar y of Li nacl oti de Pr o perties ..................................................................................1 7
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Cli nical E x perie nce ...........................................................................................................1 7
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I N V E S TI G A TI O N A L P L A N .........................................................................................................2 2
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O verall St u d y Desi g n a n d Pla n: Descri pti o n ....................................................................2 2
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Scree ni n g Peri o d .................................................................................................2 2
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Pretreat me nt Peri o d ............................................................................................2 3
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D o u ble -bli n d Treat me nt Peri o d ..........................................................................2 3
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P ost -treat me nt Peri o d .........................................................................................2 4
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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
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Selecti o n of St u d y P o p ulati o n ...........................................................................................2 5
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I ncl usi o n Criteria ................................................................................................2 5
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E xcl usi o n Criteria ...............................................................................................2 7
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Re m o val of Patie nts fr o m T hera p y or Assess me nt .............................................3 0
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Patie nt Re place me nt Pr oce d ures ........................................................................3 1
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Treat me nts ........................................................................................................................3 1
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Treat me nts A d mi nistere d ...................................................................................3 2
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Resc ue Me dicati o n ...........................................................................3 2
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I de ntit y of I n vesti gati o nal Pr o d ucts....................................................................3 2
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Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps
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Selecti o n of D osa ges i n t he St u d y ......................................................................3 5
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Selecti o n a n d Ti mi n g of D ose f or Eac h Patie nt ..................................................3 6
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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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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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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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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
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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
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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
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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 )




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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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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.
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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 




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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










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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? 


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○
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: 


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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


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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


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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.


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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. 






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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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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
F orest Researc h I nstit ute, I nc.
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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
F orest Researc h I nstit ute, I nc.
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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
F orest Researc h I nstit ute, I nc.
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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
F orest Researc h I nstit ute, I nc.
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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.
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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.

SAP_001.pdf: 
1
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N - M D-6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1. 0
TI T L E P A G E
A M ultice nter, R a n d o mize d, D o u ble -bli n d, Pl ace b o -c o ntr olle d, P ar allel -gr o u p,
S afet y a n d Effic ac y St u d y of a R a n ge of Li n acl oti de D oses A d mi nistere d Or all y t o
C hil dre n, A ges 7 t o 1 7 Ye ars, Wit h Irrit a ble B o wel S y n dr o me Wit h C o nsti p ati o n
(I B S-C) (ie, F ulfill R o me III Criteri a f or C hil d/ A d olesce nt I B S a n d F ulfill M o difie d
R o me III Criteri a f or C hil d/ A d olesce nt F u ncti o n al C o nsti p ati o n)
LI N -M D -6 3
S T A TI S TI C A L A N A L Y SI S P L A N 
Fi n al : 1 2 Dece m ber 2 0 1 6
A m e n d me nt # 1: 1 6 A u g 2 0 1 9
C o nfi de nti ality St ate me nt
T his d oc u me nt is t he pr o perty of Aller g a n plc a n d m ay n ot i n f ull or p artbe p asse d o n, 
re pr o d uce d, p u blis he d, distri b ute d t o a ny pers o n, or s u b mitte d t o a ny re g ul at ory a ut h ority 
wit h o ut t he ex press writte n per missi o n of Aller g a n plc .












7
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
T a ble 4 – 2
S C H E D U L E O F E V A L U A TI O N S: St u d y LI N -M D -6 3


8
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


9
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
5. 0
O B J E C TI V E S
T he o bjecti ve of t his st u d y  is t o 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 years of a ge w h o f ulfill t he R o me III criteria f or c hil d/a d 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.


1 0
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
6. 0
P A TI E N T P O P U L A TI O N S
6. 1
S C R E E N E D P O P U L A TI O N
T he Scree ne d P o p ulati o n will c o nsist of all patie nts w h o u n der g o t he S cree ni n g Visit ( Visit 1) 
a n d recei ve a patie nt i de ntificati o n (PI D) n u m ber.
6. 2
R A N D O MI Z E D P O P U L A TI O N
T he Ra n d o mize d P o p ulati o n will c o nsist of all patie nts i n t he Scree ne d P o p ulati o n w h o are 
ra n d o mize d t o a treat me nt gr o u p i n t he st u dy.
6. 3
S A F E T Y P O P U L A TI O N
T he Safet y P o p ulati o n will c o nsist of all patie nts i n t he Ra n d o mize d P o p ulati o n w h o t o o k at least 
1 d ose of d o u ble -bli n d i n vesti gati o nal pr o d uct (I P).
All s u m maries i n t his p o p ulati o n will be pr o vi de d base d o n t he treat me nt eac h patie nt was 
ra n d o mize d t o recei ve. Act ual treat me nt recei ve d will be deter mi ne d base d o n t he st u d y  
treat me nt recei ve d f or maj orit y of t he D B treat me nt peri o d. If t here is a tie, hi g her d ose will be 
c o nsi dere d f or act ual treat me nt f or t hat patie nt. Act ual treat me nt will be liste d f or t he patie nts i n 
t he listi n g relate d t o treat me nt d osi n g i nf or mati o n.
6. 4
I N T E N T-T O -T R E A T P O P U L A TI O N
T he I nte nt -t o-Treat (I T T) P o p ulati o n will c o nsist of all patie nts i n t he Safet y  P o p ulati o n w h o ha d 
at least 1 p ost baseli ne e ntr y o n b o wel m o ve me nt ( B M ) c haracteristic assess me nts t hat deter mi ne 
occ urre nces of s p o nta ne o us b o wel m o ve me nts ( S B Ms) (ie, B M fre q ue nc y a n d resc ue me dicati o n 
use).














1 7
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


1 8
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 1. 0
S A F E T Y A N A L Y S E S
T he sa fety a nal ys is will be perf or me d usi n g t he Safet y P o p ulati o n. T he safet y para meters will 
i ncl u de a d verse e ve nts ( A Es) a n d cli nical la b orat or y para meters, vital si g n (i ncl u di n g p ost ural), 
a n d electr ocar di o gra p hic ( E C G) para meters. F or eac h safet y para meter o f t he cli nical la b orat or y, 
vital si g n s, a n d E C G para meters, t he last n o n-missi n g safet y assess me nt bef ore t he first d ose of 
I P will be use d as t he baseli ne f or all a nal yses of t hat safety para meter. C o nti n u o us varia bles will 
be s u m marize d b y  n u m ber of patie nts a n d mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m val ues. 
Cate g orical varia bles will be s u m marize d b y  n u m ber a n d perce nta ge of patie nts. T he safet y 
s u m maries will be pr o vi de d b y treat me nt gr o u p. T he s u m maries of t he li nacl oti de a p pr o ve d 
a d ult d ose (2 9 0 u g ), will be i ncl u de d i n t he o verall a n d wit hi n a ge gr o u p 1 2 t o 1 7 years.
1 1. 1
A D V E R S E E V E N T S
A d verse e ve nts will be c o de d b y  sys te m or ga n class a n d preferre d ter m usi n g t he Me dic al 
Dicti o n ary f or Re g ul at ory Activities, versi o n 1 8. 0 or ne wer.
A n A E will be c o nsi dere d a treat me nt -e mer ge nt a d verse e ve nt ( T E A E) if it was prese nt after t he 
first d ose of I P or was prese nt bef ore t he date of t he first d ose of I P a n d i ncrease d i n se verit y  
after t he first d ose of I P. If m ore t ha n 1 A E was re p orte d bef ore t he first d ose of I P a n d c o de d t o 
t he sa me preferre d ter m, t he A E wit h t he greatest se verity will be use d f or c o m paris o n wit h t he 
A Es occ urri n g d uri n g t he Treat me nt Peri o d . A n A E t hat occ urs m ore t ha n 1 da y  after t he date of 
t he last d ose of I P will n ot be c o nsi dere d as a T EA E.
T he n u m ber a n d perce nta ge of patie nts re p orti n g T E A Es i n eac h treat me nt gr o u p will be 
ta b ulate d by desce n di n g perce nta ge i n a n y gr o u p, b y  sys te m or ga n class a n d preferre d ter m, a n d 
f urt her cate g orize d by se verit y . T he i nci de nce of treat me nt relate d T E A Es will be s u m marize d 
b y  treat me nt gr o u p, preferre d ter m. If m ore t ha n 1 A E is c o de d t o t he sa me preferre d ter m f or t he 
sa me patie nt, t he patie nt will be c o u nte d o nl y o nce f or t hat preferre d ter m usi n g t he greatest 
se verity a n d strictest ca usalit y  f or the s u m marizati o n b y  se verit y a n d ca usal relati o ns hi p. T he 
i nci de nce of c o m m o n (≥5 % of patie nts i n a n y treat me nt gr o u p) T E A Es will be s u m marize d b y 
preferre d ter m, a n d treat me nt gr o u p. 
T he o verall s u m mar y  of A Es will als o be pr o vi de d b y treat me nt gr o u p. The o verall s u m mar y  of 
A Es a n d i nci de nces of patie nts re p orti n g T E A Es i n eac h treat me nt gr o u p will als o be pr o vi de d 
wit hi n eac h a ge gr o u p. 
A seri o us a d verse e ve nt ( S A E) t hat occ urre d bet wee n t he date of t he first d ose of I P a n d 3 0 da y s 
after t he date of t he last d ose of I P, i ncl usi ve, will be c o nsi dere d a n o n- t hera p y S A E. T he n u m ber 
a n d perce nta ge of patie nts w h o ha ve o n -t hera p y S A Es will be s u m marize d b y preferre d ter m a n d 
treat me nt gr o u p. 
T he n u m ber a n d perce nta ge of patie nts i n t he Safet y P o p ulati o n w h o ha ve A Es lea di n g t o 
pre mat ure disc o nti n u ati o n of t he I P will be s u m marize d b y  preferre d ter m a n d treat me nt.




LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 1. 3
VI T A L SI G N S
Vital si g n val ues will be c o nsi dere d P C S if t he y  meet b ot h t he o bser ve d-val ue criteria a n d t he 
c ha n ge-fr o m-baseli ne criteria liste d i n Ta ble 1 1. 3 – 1 . T he n u m ber a n d perce nta ge of patie nts wit h 
P C S p ost baseli ne val ues will be ta b ulate d b y treat me nt gr o u p. T he perce nta ges will be calc ulate d 
relati ve t o t he n u m ber of patie nts wit h a vaila ble n o n-P C S baseli ne val ues a n d at least 1 
p ost baseli ne assess me nt. T he n u merat or will be t he t otal n u m ber of patie nts wit h a vaila ble n o n -
P C S baseli ne val ues a n d at least 1 P C S p ost baseli ne val ue. A s u p p orti ve ta b ular dis p la y of 
patie nts wit h P C S p ost baseli ne val ues will be pr o vi de d, i ncl u di n g t he PI D n u m ber, baseli ne a n d 
all p ost baseli ne (i ncl u di n g n o n-P C S) val ues.
A ta b ular dis pla y s h o wi n g all A Es t hat occ urre d i n patie nts w h o ha d P C S p ost baseli ne vital si g n 
val ues will als o be i ncl u de d i n t his listi n g.


2 1
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
T a ble 1 1. 3 – 1
Criteri a f or P ote nti all y Cli nic all y Si g nific a nt Vit al Si g ns


2 2
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


2 3
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


2 4
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 3. 0
I N T E RI M A N A L Y SI S
N o i nteri m a nal ys is is pla n ne d f or t his st u d y.




2 6
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 5. 0
S T A TI S TI C A L S O F T W A R E
Statistical a nal y ses will be perf or me d usi n g 
 












3 2
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
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 usi n g 4- p oi nt scale:
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
T he patie nt’s a b d o mi nal bl oati n g da y ti me s ym pt o ms d uri n g t he a nal ys is 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 bl o ati n g da yti 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 a nal ys is peri o d base d o n t he sc ores of 0, 1, 2, 3, a n d 4. F or 
t he da yti me baseli ne sy m pt o ms, 1 4 da y s pri or t o t he ra n d o mizati o n will be c o nsi dere d.
1 6. 3. 8
A b d o mi n al P ai n
A b d o mi nal pa i n sc ores will be c ollecte d 
 
ia patie nt’s res p o nses t o t he f oll o wi n g q uesti o ns. 
Patie nt will rec or d t heir assess me nt of 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  
 
:
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?
o  Yes
o  N o
If “ yes”, t he n patie nt a ns wers t he f oll o wi n g q uesti o n usi n g a 4- p oi nt scale:


3 3
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9

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
T o calc ulate patie nt’s 4 - wee k a b d o mi nal pai n sc ore, res p o nses “ n o” will be c o de d as ‘ 0’. T he 
patie nt’s 4 -wee k a b d o mi nal pai n da y ti me s ym pt o ms d uri n g t he s pecif ic 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 yti me s y 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 s pecific peri o d base d o n sc ores of 0, 1, 2, 3, a n d 4. F or t he 
da y ti me baseli ne sy m pt o ms, 1 4 da y s pri or t o t he ra n d o mizati o n will be c o nsi dere d.




3 5
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


3 6
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 6. 9
MI S SI N G D A T E I N F O R M A TI O N F O R P RI O R O R C O N C O MI T A N T 
M E DI C A TI O N S
1 6. 9. 1
I nc o m plete St art D ate


3 7
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 6. 9. 2
I nc o m plete St o p D ate


3 8
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


3 9
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9


4 0
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 7. 0
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N P R O T O C O L
Base d o n  
 fee d bac k
t o 
st o p t his p hase 2 st u d y, it was deci de d t o ter mi nate t he st u d y st o p pi n g t he e nr oll me nt i n 
t he st u d y LI N-M D - 6 3 earl y t ha n pla n ne d, bef ore t he tar get n u m ber of patie nts ha ve bee n 
e nr olle d a n d a n a b bre viate d C S R will be pla n ne d. T o li mit t he a nal y ses i n t he a b bre viate d 
C S R, n ot all a nal y ses pla n ne d i n ori gi nal S A P ( date d 1 2 Dece m ber, 2 0 1 6) a n d t he latest 
a me n de d pr ot oc ol ( versi o n 3 date d 1 6 Ma y , 2 0 1 7) will be perf or me d. 
N o statistical testi n g will be perf or me d f or efficac y para meters a n d o nly descri pti v e 
statistics will be pr o vi de d f or pri mar y, sec o n dar y, a n d a d diti o nal efficac y para meters of 
gl o bal ite ms. N o se nsiti vit y  a n d e x pl orat or y a nalys es will be c o n d ucte d f or efficac y  
para meters.  T h o u g h t he s u m mar y  of li nacl oti de a p pr o ve d a d ult d ose 2 9 0 u g will be 
pr o vi de d t o s u p p ort e x pl orat or y  o bjecti ve.  O nl y  ke y safety s u m maries will be pr o vi de d
as disc usse d i n Secti o n 1 1. 0 . S u m mar y statistics b y a ge gr o u p will be pr o vide d o nl y f or
ke y  efficac y a n d safety para meters.
F oll o wi n g c ha n ges ha ve bee n ma de i n t his S A P a me n d me nt.

Secti o n 6. 3 a n d Secti o n 1 1. 1 : A d diti o nal s u m mar y of T E A Es will n ot be pr o vi de d 
base d o n act ual treat me nt i n prese nce of differe nce bet wee n pla n ne d treat me nt 
a n d act ual treat me nt f or m ore t ha n o ne patie nt.

Secti o n 8. 0 : S u m maries f or pri or a n d c o nc o mita nt me dicati o n, me dical hist ories, 
a n d f or m ulati o n of I P will n ot be pr o vi de d. De m o gra p hics a n d baseli ne 
c haracteristics will n ot be s u m mar ize d b y a ge gr o u p wit hi n IT T P o p ulati o n. 

 
 
 

Secti o n 1 0. 0 : T he ke y c ha n ges i n efficac y anal ys es are liste d bel o w.
o
N o e x pl orat or y  a nalys is
 
n d se nsiti vit y  a nalys is will be c o n d ucte d f or 
pri mar y  a n d sec o n dar y efficac y para meters. 
 
 
 
 
 
o
N o testi n g will be perf or me d f or efficac y  para meters. N o m o del-base d 
esti mates, 9 5 % c o nfi de nce i nter vals will be pr o vi de d. O nl y descri pti ve 
s u m mar y statistics will be pr o vi de d.




4 2
Aller g a n plc
Li n acl oti de ( Li nzess)
LI N -M D -6 3 St atistic al A n alysis Pl a n ( A me n d me nt # 1)                                                           1 6 A u g 2 0 1 9
1 8. 0
R E F E R E N C E S
N o ne